Haseltine, William A. (Washington, DC, US)
What is claimed:
1. An albumin fusion protein comprising a member selected from the group consisting of: (a) a Therapeutic protein:X and albumin comprising the amino acid sequence of SEQ ID NO:18; (b) a Therapeutic protein:X and a fragment or a variant of the amino acid sequence of SEQ ID NO:18, wherein said fragment or variant has albumin activity; (c) a Therapeutic protein:X and a fragment or a variant of the amino acid sequence of SEQ ID NO:18, wherein said fragment or variant has albumin activity, and further wherein said albumin activity is the ability to prolong the shelf life of the Therapeutic protein:X compared to the shelf-life of the Therapeutic protein:X in an unfused state; (d) a Therapeutic protein:X and a fragment or a variant of the amino acid sequence of SEQ ID NO:18, wherein said fragment or variant has albumin activity, and further wherein the fragment or variant comprises the amino acid sequence of amino acids 1-387 of SEQ ID NO:18; (e) a fragment or variant of a Therapeutic protein:X and albumin comprising the amino acid sequence of SEQ ID NO:18, wherein said fragment or variant has a biological activity of the Therapeutic protein:X; (f) a Therapeutic protein:X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (e), wherein the Therapeutic protein:X, or fragment or variant thereof, is fused to the N-terminus of albumin, or the N-terminus of the fragment or variant of albumin; (g) a Therapeutic protein:X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (e), wherein the Therapeutic protein:X, or fragment or variant thereof, is fused to the C-terminus of albumin, or the C-terminus of the fragment or variant of albumin; (h) a Therapeutic protein:X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (e), wherein the Therapeutic protein:X, or fragment or variant thereof, is fused to the N-terminus and C-terminus of albumin, or the N-terminus and the C-terminus of the fragment or variant of albumin; (i) a Therapeutic protein:X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (e), which comprises a first Therapeutic protein:X, or fragment or variant thereof, and a second Therapeutic protein:X, or fragment or variant thereof, wherein said first Therapeutic protein:X, or fragment or variant thereof, is different from said second Therapeutic protein:X, or fragment or variant thereof, (j) a Therapeutic protein:X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (i), wherein the Therapeutic protein:X, or fragment or variant thereof, is separated from the albumin or the fragment or variant of albumin by a linker; and (k) a Therapeutic protein:X, or fragment or variant thereof, and albumin, or fragment or variant thereof, of (a) to (j), wherein the albumin fusion protein has the following formula:
2. The albumin fusion protein of claim 1, wherein the shelf-life of the albumin fusion protein is greater than the shelf-life of the Therapeutic protein:X, or fragment or variant thereof, in an unfused state.
3. The albumin fusion protein of claim 1, wherein the in vitro biological activity of the Therapeutic protein:X, or fragment or variant thereof, fused to albumin, or fragment or variant thereof, is greater than the in vitro biological activity of the Therapeutic protein:X, or fragment or variant thereof, in an unfused state.
4. The albumin fusion protein of claim 1, wherein the in vivo biological activity of the Therapeutic protein:X, or fragment or variant thereof, fused to albumin, or fragment or variant thereof, is greater than the in vivo biological activity of the Therapeutic protein:X, or fragment or variant thereof, in an unfused state.
5. An albumin fusion protein comprising a Therapeutic protein:X, or fragment or variant thereof, inserted into an albumin, or fragment or variant thereof, comprising the amino acid sequence of SEQ ID NO:18 or fragment or variant thereof.
6. An albumin fusion protein comprising a Therapeutic protein:X, or fragment or variant thereof, inserted into an albumin, or fragment or variant thereof, comprising an amino acid sequence selected from the group consisting of: (a) amino acids 54 to 61 of SEQ ID NO: 18; (b) amino acids 76 to 89 of SEQ ID NO: 18; (c) amino acids 92 to 100 of SEQ ID NO: 18; (d) amino acids 170 to 176 of SEQ ID NO: 18; (e) amino acids 247 to 252 of SEQ ID NO: 18; (f) amino acids 266 to 277 of SEQ ID NO: 18; (g) amino acids 280 to 288 of SEQ ID NO:18; (h) amino acids 362 to 368 of SEQ ID NO: 18; (i) amino acids 439 to 447 of SEQ ID NO: 18; (j) amino acids 462 to 475 of SEQ ID NO: 18; (k) amino acids 478 to 486 of SEQ ID NO: 18; and (l) amino acids 560 to 566 of SEQ ID NO:18.
7. The albumin fusion protein of claim 5, wherein said albumin fusion protein comprises a portion of albumin sufficient to prolong the shelf-life of the Therapeutic protein:X, or fragment or variant thereof, as compared to the shelf-life of the Therapeutic protein:X, or fragment or variant thereof, in an unfused state.
8. The albumin fusion protein of claim 6, wherein said albumin fusion protein comprises a portion of albumin sufficient to prolong the shelf-life of the Therapeutic protein:X, or fragment or variant thereof, as compared to the shelf-life of the Therapeutic protein:X, or fragment or variant thereof, in an unfused state.
9. The albumin fusion protein of claim 5, wherein said albumin fusion protein comprises a portion of albumin sufficient to prolong the in vitro biological activity of the Therapeutic protein:X, or fragment or variant thereof, fused to albumin as compared to the in vitro biological activity of the Therapeutic protein:X, or fragment or variant thereof, in an unfused state.
10. The albumin fusion protein of claim 6, wherein said albumin fusion protein comprises a portion of albumin sufficient to prolong the in vitro biological activity of the Therapeutic protein:X, or fragment or variant thereof, fused to albumin as compared to the in vitro biological activity of the Therapeutic protein:X, or fragment or variant thereof, in an unfused state.
11. The albumin fusion protein of claim 5 wherein said albumin fusion protein comprises a portion of albumin sufficient to prolong the in vivo biological activity of the Therapeutic protein:X, or fragment or variant thereof, fused to albumin compared to the in vivo biological activity of the Therapeutic protein:X, or fragment or variant thereof, in an unfused state.
12. The albumin fusion protein of claim 6 wherein said albumin fusion protein comprises a portion of albumin sufficient to prolong the in vivo biological activity of the Therapeutic protein:X, or fragment or variant thereof, fused to albumin compared to the in vivo biological activity of the Therapeutic protein:X, or fragment or variant thereof, in an unfused state.
13. The albumin fusion protein of any one of claims
14. The albumin fusion protein of any one of claims
15. The albumin fusion protein of claim 14, wherein the yeast is glycosylation deficient.
16. The albumin fusion protein of claim 14 wherein the yeast is glycosylation and protease deficient.
17. The albumin fusion protein of any one of claims
18. The albumin fusion protein of any one of claims
19. The albumin fusion protein of any one of claims
20. A composition comprising the albumin fusion protein of any one of claims
21. A kit comprising the composition of claim 20.
22. A method of treating a disease or disorder in a patient, comprising the step of administering the albumin fusion protein of any one of claims
23. The method of claim 22, wherein the disease or disorder comprises indication:Y.
24. A method of treating a patient with a disease or disorder that is modulated by Therapeutic protein:X, or fragment or variant thereof, comprising the step of administering an effective amount of the albumin fusion protein of any one of claims
25. The method of claim 24, wherein the disease or disorder is indication:Y.
26. A method of extending the shelf life of Therapeutic protein:X, or fragment or variant thereof, comprising the step of fusing the Therapeutic protein:X, or fragment or variant thereof, to albumin, or fragment or variant thereof, sufficient to extend the shelf-life of the Therapeutic protein:X, or fragment or variant thereof, compared to the shelf-life of the Therapeutic protein:X, or fragment or variant thereof, in an unfused state.
27. A nucleic acid molecule comprising a polynucleotide sequence encoding the albumin fusion protein of any one of claims
28. A vector comprising the nucleic acid molecule of claim 27.
29. A host cell comprising the nucleic acid molecule of claim 28.
[0001] This application claims the benefit of priority under 35 U.S.C. §119(e) based on the following U.S. provisional applications No. 60/229,358 filed on Apr. 12, 2000; No. 60/199,384 filed on Apr. 25, 2000; and No. 60/256,931 filed on Dec. 21, 2000. Each of the provisional applications is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] The invention relates generally to Therapeutic proteins (including, but not limited to, a polypeptide, antibody, or peptide, or fragments and variants thereof) fused to albumin or fragments or variants of albumin. The invention further relates to Therapeutic proteins (including, but not limited to, a polypeptide, antibody, or peptide, or fragments and variants thereof) fused to albumin or fragments or variants of albumin, that exhibit extended shelf-life and/or extended or therapeutic activity in solution. These fusion proteins are herein collectively referred to as “albumin fusion proteins of the invention.” The invention encompasses therapeutic albumin fusion proteins, compositions, pharmaceutical compositions, formulations and kits. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention using these nucleic acids, vectors, and/or host cells.
[0003] The invention is also directed to methods of in vitro stabilizing a Therapeutic protein via fusion or conjugation of the Therapeutic protein to albumin or fragments or variants of albumin.
[0004] Human serum albumin (HSA, or HA), a protein of 585 amino acids in its mature form (as shown in
[0005] The role of albumin as a carrier molecule and its inert nature are desirable properties for use as a carrier and transporter of polypeptides in vivo. The use of albumin as a component of an albumin fusion protein as a carrier for various proteins has been suggested in WO 93/15199, WO 93/15200, and EP 413 622. The use of N-terminal fragments of HA for fusions to polypeptides has also been proposed (EP 399 666). Fusion of albumin to the Therapeutic protein may be achieved by genetic manipulation, such that the DNA coding for HA, or a fragment thereof, is joined to the DNA coding for the Therapeutic protein. A suitable host is then transformed or transfected with the fused nucleotide sequences, so arranged on a suitable plasmid as to express a fusion polypeptide. The expression may be effected in vitro from, for example, prokaryotic or eukaryotic cells, or in vivo e.g. from a transgenic organism.
[0006] Therapeutic proteins in their native state or when recombinantly produced, such as interferons and growth hormones, are typically labile molecules exhibiting short shelf-lives, particularly when formulated in aqueous solutions. The instability in these molecules when formulated for administration dictates that many of the molecules must be lyophilized and refrigerated at all times during storage, thereby rendering the molecules difficult to transport and/or store. Storage problems are particularly acute when pharmaceutical formulations must be stored and dispensed outside of the hospital environment. Many protein and peptide drugs also require the addition of high concentrations of other protein such as albumin to reduce or prevent loss of protein due to binding to the container. This is a major concern with respect to proteins such as IFN. For this reason, many Therapeutic proteins are formulated in combination with large proportion of albumin carrier molecule (100-1000 fold excess), though this is an undesirable and expensive feature of the formulation.
[0007] Few practical solutions to the storage problems of labile protein molecules have been proposed. Accordingly, there is a need for stabilized, long lasting formulations of proteinaceous therapeutic molecules that are easily dispensed, preferably with a simple formulation requiring minimal post-storage manipulation.
SUMMARY OF THE INVENTION
[0008] The present invention is based, in part, on the discovery that Therapeutic proteins may be stabilized to extend the shelf-life, and/or to retain the Therapeutic protein's activity for extended periods of time in solution, in vitro and/or in vivo, by genetically or chemically fusing or conjugating the Therapeutic protein to albumin or a fragment (portion) or variant of albumin, that is sufficient to stabilize the protein and/or its activity. In addition it has been determined that the use of albumin-fusion proteins or albumin conjugated proteins may reduce the need to formulate protein solutions with large excesses of carrier proteins (such as albumin, unfused) to prevent loss of Therapeutic proteins due to factors such as binding to the container.
[0009] The present invention encompasses albumin fusion proteins comprising a Therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragments and variants thereof) fused to albumin or a fragment (portion) or variant of albumin. The present invention also encompasses albumin fusion proteins comprising a Therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragments and variants thereof) fused to albumin or a fragment (portion) or variant of albumin, that is sufficient to prolong the shelf life of the Therapeutic protein, and/or stabilize the Therapeutic protein and/or its activity in solution (or in a pharmaceutical composition) in vitro and/or in vivo. Nucleic acid molecules encoding the albumin fusion proteins of the invention are also encompassed by the invention, as are vectors containing these nucleic acids, host cells transformed with these nucleic acids vectors, and methods of making the albumin fusion proteins of the invention and using these nucleic acids, vectors, and/or host cells.
[0010] The invention also encompasses pharmaceutical formulations comprising an albumin fusion protein of the invention and a pharmaceutically acceptable diluent or carrier. Such formulations may be in a kit or container. Such kit or container may be packaged with instructions pertaining to the extended shelf life of the Therapeutic protein. Such formulations may be used in methods of treating, preventing, ameliorating or diagnosing a disease or disease symptom in a patient, preferably a mammal, most preferably a human, comprising the step of administering the pharmaceutical formulation to the patient.
[0011] In other embodiments, the present invention encompasses methods of preventing treating, or ameliorating a disease or disorder. In preferred embodiments, the present invention encompasses a method of treating a disease or disorder listed in the “Preferred Indication Y” column of Table 1 comprising administering to a patient in which such treatment, prevention or amelioration is desired an albumin fusion protein of the invention that comprises a Therapeutic protein portion corresponding to a Therapeutic protein (or fragment or variant thereof) disclosed in the “Therapeutic Protein X” column of Table 1 (in the same row as the disease or disorder to be treated is listed in the “Preferred Indication Y” column of Table 1) in an amount effective to treat prevent or ameliorate the disease or disorder.
[0012] In another embodiment, the invention includes a method of extending the shelf life of a Therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragments and variants thereof) comprising the step of fusing or conjugating the Therapeutic protein to albumin or a fragment (portion) or variant of albumin, that is sufficient to extend the shelf-life of the Therapeutic protein. In a preferred embodiment, the Therapeutic protein used according to this method is fused to the albumin, or the fragment or variant of albumin. In a most preferred embodiment, the Therapeutic protein used according to this method is fused to albumin, or a fragment or variant of albumin, via recombinant DNA technology or genetic engineering.
[0013] In another embodiment, the invention includes a method of stabilizing a Therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragments and variants thereof) in solution, comprising the step of fusing or conjugating the Therapeutic protein to albumin or a fragment (portion) or variant of albumin, that is sufficient to stabilize the Therapeutic protein. In a preferred embodiment, the Therapeutic protein used according to this method is fused to the albumin, or the fragment or variant of albumin. In a most preferred embodiment, the Therapeutic protein used according to this method is fused to albumin, or a fragment or variant of albumin, via recombinant DNA technology or genetic engineering.
[0014] The present invention further includes transgenic organisms modified to contain the nucleic acid molecules of the invention, preferably modified to express the albumin fusion proteins encoded by the nucleic acid molecules.
BRIEF DESCRIPTION OF THE FIGURES
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DETAILED DESCRIPTION
[0030] As described above, the present invention is based, in part, on the discovery that a Therapeutic protein (e.g., a polypeptide, antibody, or peptide, or fragments and variants thereof) may be stabilized to extend the shelf-life and/or retain the Therapeutic protein's activity for extended periods of time in solution (or in a pharmaceutical composition) in vitro and/or in vivo, by genetically fusing or chemically conjugating the Therapeutic protein, polypeptide or peptide to all or a portion of albumin sufficient to stabilize the protein and its activity.
[0031] The present invention relates generally to albumin fusion proteins and methods of treating, preventing, or ameliorating diseases or disorders. As used herein, “albumin fusion protein” refers to a protein formed by the fusion of at least one molecule of albumin (or a fragment or variant thereof) to at least one molecule of a Therapeutic protein (or fragment or variant thereof). An albumin fusion protein of the invention comprises at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are associated with one another, preferably by genetic fusion (i.e., the albumin fusion protein is generated by translation of a nucleic acid in which a polynucleotide encoding all or a portion of a Therapeutic protein is joined in-frame with a polynucleotide encoding all or a portion of albumin) or chemical conjugation to one another. The Therapeutic protein and albumin protein, once part of the albumin fusion protein, may be referred to as a “portion”, “region” or “moiety” of the albumin fusion protein (e.g., a “Therapeutic protein portion” or an “albumin protein portion”).
[0032] In one embodiment, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein (e.g., as described in Table 1) and a serum albumin protein. In other embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active fragment of a Therapeutic protein and a serum albumin protein. In other embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active variant of a Therapeutic protein and a serum albumin protein. In preferred embodiments, the serum albumin protein component of the albumin fusion protein is the mature portion of serum albumin.
[0033] In further embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein, and a biologically active and/or therapeutically active fragment of serum albumin. In further embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein and a biologically active and/or therapeutically active variant of serum albumin. In preferred embodiments, the Therapeutic protein portion of the albumin fusion protein is the mature portion of the Therapeutic protein. In a further preferred embodiment, the Therapeutic protein portion of the albumin fusion protein is the extracellular soluble domain of the Therapeutic protein. In an alternative embodiment, the Therapeutic protein portion of the albumin fusion protein is the active form of the Therapeutic protien.
[0034] In further embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active fragment or variant of a Therapeutic protein and a biologically active and/or therapeutically active fragment or variant of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of a Therapeutic protein and the mature portion of serum albumin.
[0035] Therapeutic Proteins
[0036] As stated above, an albumin fusion protein of the invention comprises at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are associated with one another, preferably by genetic fusion or chemical conjugation.
[0037] As used herein, “Therapeutic protein” refers to proteins, polypeptides, antibodies, peptides or fragments or variants thereof, having one or more therapeutic and/or biological activities. Therapeutic proteins encompassed by the invention include but are not limited to, proteins, polypeptides, peptides, antibodies, and biologics. (The terms peptides, proteins, and polypeptides are used interchangeably herein.) It is specifically contemplated that the term “Therapeutic protein” encompasses antibodies and fragments and variants thereof. Thus an albumin fusion protein of the invention may contain at least a fragment or variant of a Therapeutic protein, and/or at least a fragment or variant of an antibody. Additionally, the term “Therapeutic protein” may refer to the endogenous or naturally occurring correlate of a Therapeutic protein.
[0038] By a polypeptide displaying a “therapeutic activity” or a protein that is “therapeutically active” is meant a polypeptide that possesses one or more known biological and/or therapeutic activities associated with a therapeutic protein such as one or more of the Therapeutic proteins described herein or otherwise known in the art. As a non-limiting example, a “Therapeutic protein” is a protein that is useful to treat, prevent or ameliorate a disease, condition or disorder. As a non-limiting example, a “Therapeutic protein” may be one that binds specifically to a particular cell type (normal (e.g., lymphocytes) or abnormal e.g., (cancer cells)) and therefore may be used to target a compound (drug, or cytotoxic agent) to that cell type specifically.
[0039] In another non-limiting example, a “Therapeutic protein” is a protein that has a biological activity, and in particular, a biological activity that is useful for treating preventing or ameliorating a disease. A non-inclusive list of biological activities that may be possessed by a Therapeutic protein includes, enhancing the immune response, promoting angiogenesis, inhibiting angiogenesis, regulating hematopoietic functions, stimulating nerve growth, enhancing an immune response, inhibiting an immune response, or any one or more of the biological activities described in the “Biological Activities” section below.
[0040] As used herein, “therapeutic activity” or “activity” may refer to an activity whose effect is consistent with a desirable therapeutic outcome in humans, or to desired effects in non-human mammals or in other species or organisms. Therapeutic activity may be measured in vivo or in vitro. For example, a desirable effect may be assayed in cell culture. As an example, when hGH is the Therapeutic protein, the effects of hGH on cell proliferation as described in Example 1 may be used as the endpoint for which therapeutic activity is measured. Such in vitro or cell culture assays are commonly available for many Therapeutic proteins as described in the art. Examples of assays include, but are not limited to those described herein in the Examples section or in the “Exemplary Activity Assay” column of Table 1.
[0041] Therapeutic proteins corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention, such as cell surface and secretory proteins, are often modified by the attachment of one or more oligosaccharide groups. The modification, referred to as glycosylation, can dramatically affect the physical properties of proteins and can be important in protein stability, secretion, and localization. Glycosylation occurs at specific locations along the polypeptide backbone. There are usually two major types of glycosylation: glycosylation characterized by O-linked oligosaccharides, which are attached to serine or threonine residues; and glycosylation characterized by N-linked oligosaccharides, which are attached to asparagine residues in an Asn-X-Ser/Thr sequence, where X can be any amino acid except proline. N-acetylneuramic acid (also known as sialic acid) is usually the terminal residue of both N-linked and O-linked oligosaccharides. Variables such as protein structure and cell type influence the number and nature of the carbohydrate units within the chains at different glycosylation sites. Glycosylation isomers are also common at the same site within a given cell type.
[0042] For example, several types of human interferon are glycosylated. Natural human interferon-α2 is O-glycosylated at threonine 106, and N-glycosylation occurs at asparagine 72 in interferon-α14 (Adolf et al., J. Biochem 276:511 (1991); Nyman T A et al., J. Biochem 329:295 (1998)). The oligosaccharides at asparagine 80 in natural interferon-β1α may play an important factor in the solubility and stability of the protein, but may not be essential for its biological activity. This permits the production of an unglycosylated analog (interferon-β1b) engineered with sequence modifications to enhance stability (Hosoi et al., J. Interferon Res. 8:375 (1988; Karpusas et al., Cell Mol Life Sci 54:1203 (1998); Knight, J. Interferon Res. 2:421 (1982); Runkel et al., Pharm Res 15:641 (1998); Lin, Dev. Biol. Stand. 96:97 (1998))1. Interferon-γ contains two N-linked oligosaccharide chains at positions 25 and 97, both important for the efficient formation of the bioactive recombinant protein, and having an influence on the pharmacokinetic properties of the protein (Sareneva et al., Eur. J. Biochem 242:191 (1996); Sareneva et al, Biochem J. 303:831 (1994); Sareneva et al., J. Interferon Res. 13:267 (1993)). Mixed O-linked and N-linked glycosylation also occurs, for example in human erythropoietin, N-linked glycosylation occurs at asparagine residues located at positions 24, 38 and 83 while O-linked glycosylation occurs at a serine residue located at position 126 (Lai et al., J. Biol. Chem. 261:3116 (1986); Broudy et al., Arch. Biochem. Biophys. 265:329 (1988)).
[0043] Therapeutic proteins corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention, as well as analogs and variants thereof, may be modified so that glycosylation at one or more sites is altered as a result of manipulation(s) of their nucleic acid sequence, by the host cell in which they are expressed, or due to other conditions of their expression. For example, glycosylation isomers may be produced by abolishing or introducing glycosylation sites, e.g., by substitution or deletion of amino acid residues, such as substitution of glutamine for asparagine, or unglycosylated recombinant proteins may be produced by expressing the proteins in host cells that will not glycosylate them, e.g. in
[0044] Therapeutic proteins (particularly those disclosed in Table 1) and their nucleic acid sequences are well known in the art and available in public databases such as Chemical Abstracts Services Databases (e.g., the CAS Registry), GenBank, and GenSeq as shown in Table 1.
[0045] Additional Therapeutic proteins corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention include, but are not limited to, one or more of the Therapeutic proteins or peptides disclosed in the “Therapeutic Protein X” column of Table 1, or fragment or variable thereof.
[0046] Table 1 provides a non-exhaustive list of Therapeutic proteins that correspond to a Therapeutic protein portion of an albumin fusion protein of the invention. The “Therapeutic Protein X” column discloses Therapeutic protein molecules followed by parentheses containing scientific and brand names that comprise, or alternatively consist of, that Therapeutic protein molecule or a fragment or variant thereof. “Therapeutic protein X” as used herein may refer either to an individual Therapeutic protein molecule (as defined by the amino acid sequence obtainable from the CAS and Genbank accession numbers), or to the entire group of Therapeutic proteins associated with a given Therapeutic protein molecule disclosed in this column. The “Exemplary Identifier” column provides Chemical Abstracts Services (CAS) Registry Numbers (published by the American Chemical Society) and/or Genbank Accession Numbers ((e.g., Locus ID, NP_XXXXX (Reference Sequence Protein), and XP_XXXXX (Model Protein) identifiers available through the national Center for Biotechnology Information (NCBI) webpage at www.ncbi.nlm.nih.gov) that correspond to entries in the CAS Registry or Genbank database which contain an amino acid sequence of the Therapeutic Protein Molecule or of a fragment or variant of the Therapeutic Protein Molecule. In addition GenSeq Accession numbers and/or journal publication citations are given to identify the exemplary amino acid sequence for some polypeptides. The summary pages associated with each of these CAS and Genbank and GenSeq Accession Numbers as well as the cited journal publications (e.g., PubMed ID number (PMID)) are each incorporated by reference in their entireties, particularly with respect to the amino acid sequences described therein. The “PCT/Patent Reference” column provides U.S. Patent numbers, or PCT International Publication Numbers corresponding to patents and/or published patent applications that describe the Therapeutic protein molecule. Each of the patents and/or published patent applications cited in the “PCT/Patent Reference” column are herein incorporated by reference in their entireties. In particular, the amino acid sequences of the specified polypeptide set forth in the sequence listing of each cited “PCT/Patent Reference”, the variants of these amino acid sequences (mutations, fragments, etc.) set forth, for example, in the detailed description of each cited “PCT/Patent Reference”, the therapeutic indications set forth, for example, in the detailed description of each cited “PCT/Patent Reference”, and the activity asssaysfor the specified polypeptide set forth in the detailed description, and more particularly, the examples of each cited “PCT/Patent Reference” are incorporated herein by reference. The “Biological activity” column describes Biological activities associated with the Therapeutic protein molecule. The “Exemplary Activity Assay” column provides references that describe assays which may be used to test the therapeutic and/or biological activity of a Therapeutic protein or an albumin fusion protein of the invention comprising a Therapeutic protein X portion. Each of the references cited in the “Exemplary Activity Assay” column are herein incorporated by reference in their entireties, particularly with respect to the description of the respective activity assay described in the reference (see Methods section, for example) for assaying the corresponding biological activity set forth in the “Biological Activity” column of Table 1. The “Preferred Indication Y” column describes disease, disorders, and/or conditions that may be treated, prevented, diagnosed, or ameliorated by Therapeutic protein X or an albumin fusion protein of the invention comprising a Therapeutic protein X portion.
[0047] The recitation of “Cancer” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., leukemias, cancers, and/or as described below under “Hyperproliferative Disorders”).
[0048] In specific embodiments, a Therapeutic protein having a “Cancer” recitation in the “Preferred Indication” column of Table 1, an albumin fusion protein that comprises a Therapeutic protein portion corresponding to this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a neoplasm located in a tissue selected from the group consisting of: colon, abdomen, bone, breast, digestive system, liver, pancreas, prostate, peritoneum, lung, blood (e.g., leukemia), endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary, thymus, thyroid), uterus, eye, head and neck, nervous (central and peripheral), lymphatic system, pelvic, skin, soft tissue, spleen, thoracic, and urogenital.
[0049] In specific embodiments, a Therapeutic protein having a “Cancer” recitation in the “Preferred Indication” column of Table 1, an albumin fusion protein that comprises a Therapeutic protein portion corresponding to this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a pre-neoplastic condition, selected from the group consisting of: hyperplasia (e.g., endometrial hyperplasia and/or as described in the section entitled “Hyperproliferative Disorders”), metaplasia (e.g., connective tissue metaplasia, a typical metaplasia, and/or as described in the section entitled “Hyperproliferative Disorders”), and/or dysplasia (e.g., cervical dysplasia, and bronchopulmonary dysplasia).
[0050] In another specific embodiment, a Therapeutic protein having a “Cancer” recitation in the “Preferred Indication” column of Table 1, an albumin fusion protein that comprises a Therapeutic protein portion corresponding to this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a benign dysproliferative disorder selected from the group consisting of: benign tumors, fibrocystic conditions, tissue hypertrophy, and/or as described in the section entitled “Hyperproliferative Disorders”.
[0051] The recitation of “Immune/Hematopoietic” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”), blood disorders (e.g., as described below under “Immune Activity” “Cardiovascular Disorders” and/or “Blood-Related Disorders”), and infections (e.g., as described below under “Infectious Disease”).
[0052] In specific embodiments, a Therapeutic protein having a “Immune/Hematopoietic” recitation in the “Preferred Indication” column of Table 1, a fusion protein containing this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: anemia, pancytopenia, leukopenia, thrombocytopenia, leukemias, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphocytic anemia (ALL), plasmacytomas, multiple myeloma, Burkitt's lymphoma, arthritis, asthma, A/DS, autoimmune disease, rheumatoid arthritis, granulomatous disease, immune deficiency, inflammatory bowel disease, sepsis, neutropenia, neutrophilia, psoriasis, immune reactions to transplanted organs and tissues, systemic lupus erythematosis, hemophilia, hypercoagulation, diabetes mellitus, endocarditis, meningitis, Lyme Disease, and allergies.
[0053] The recitation of “Reproductive” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”), and disorders of the reproductive system (e.g., as described below under “Reproductive System Disorders”).
[0054] In specific embodiments, a Therapeutic protein having a “Reproductive” recitation in the “Preferred Indication” column of Table 1, a fusion protein containing this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: cryptorchism, prostatitis, inguinal hernia, varicocele, leydig cell tumors, verrucous carcinoma, prostatitis, malacoplakia, Peyronie's disease, penile carcinoma, squamous cell hyperplasia, dysmenorrhea, ovarian adenocarcinoma, Turner's syndrome, mucopurulent cervicitis, Sertoli-leydig tumors, ovarian cancer, uterine cancer, pelvic inflammatory disease, testicular cancer, prostate cancer, Klinefelter's syndrome, Young's syndrome, premature ejaculation, diabetes mellitus, cystic fibrosis, Kartagener's syndrome, testicular atrophy, testicular feminization, anorchia, ectopic testis, epididymitis, orchitis, gonorrhea, syphilis, testicular torsion, vasitis nodosa, germ cell tumors, stromal tumors, dysmenorrhea, retroverted uterus, endometriosis, fibroids, adenomyosis, anovulatory bleeding, amenorrhea, Cushing's syndrome, hydatidiform moles, Asherman's syndrome, premature menopause, precocious puberty, uterine polyps, dysfunctional uterine bleeding, cervicitis, chronic cervicitis, mucopurulent cervicitis, cervical dysplasia, cervical polyps, Nabothian cysts, cervical erosion, cervical incompetence, cervical neoplasms, pseudohermaphroditism, and premenstrual syndrome.
[0055] The recitation of “Musculoskeletal” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”), and disorders of the immune system (e.g., as described below under “Immune Activity”).
[0056] In specific embodiments, a Therapeutic protein having a “Musculoskeletal” recitation in the “Preferred Indication” column of Table 1, a fusion protein containing this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: bone cancers (e.g., osteochondromas, benign chondromas, chondroblastoma, chondromyxoid fibromas, osteoid osteomas, giant cell tumors, multiple myeloma, osteosarcomas), Paget's Disease, rheumatoid arthritis, systemic lupus erythematosus, osteomyelitis, Lyme Disease, gout, bursitis, tendonitis, osteoporosis, osteoarthritis, muscular dystrophy, mitochondrial myopathy, cachexia, and multiple sclerosis.
[0057] The recitation of “Cardiovascular” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”), and disorders of the cardiovascular system (e.g., as described below under “Cardiovascular Disorders”).
[0058] In specific embodiments, a Therapeutic protein having a “Cardiovascular” recitation in the “Preferred Indication” column of Table 1, a fusion protein containing this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: myxomas, fibromas, rhabdomyomas, cardiovascular abnormalities (e.g., congenital heart defects, cerebral arterioyenous malformations, septal defects), heart disease (e.g., heart failure, congestive heart disease, arrhythmia, tachycardia, fibrillation, pericardial Disease, endocarditis), cardiac arrest, heart valve disease (e.g., stenosis, regurgitation, prolapse), vascular disease (e.g., hypertension, coronary artery disease, angina, aneurysm, arteriosclerosis, peripheral vascular disease), hyponatremia, hypernatremia, hypokalemia, and hyperkalemia.
[0059] The recitation of “Mixed Fetal” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”).
[0060] In specific embodiments, a Therapeutic protein having a “Mixed Fetal” recitation in the “Preferred Indication” column of Table 1, an albumin fusion protein that comprises a Therapeutic protein portion corresponding to this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: spina bifida, hydranencephaly, neurofibromatosis, fetal alcohol syndrome, diabetes mellitus, PKU, Down's syndrome, Patau syndrome, Edwards syndrome, Turner syndrome, Apert syndrome, Carpenter syndrome, Conradi syndrome, Crouzon syndrome, cutis laxa, Cornelia de Lange syndrome, Ellis-van Creveld syndrome, Holt-Oram syndrome, Kartagener syndrome, Meckel-Gruber syndrome, Noonan syndrome, Pallister-Hall syndrome, Rubinstein-Taybi syndrome, Scimitar syndrome, Smith-Lemli-Opitz syndrome, thromocytopenia-absent radius (TAR) syndrome, Treacher Collins syndrome, Williams syndrome, Hirschsprung's disease, Meckel's diverticulum, polycystic kidney disease, Turner's syndrome, and gonadal dysgenesis, Klippel-Feil syndrome, Ostogenesis imperfecta, muscular dystrophy, Tay-Sachs disease, Wilm's tumor, neuroblastoma, and retinoblastoma.
[0061] The recitation of “Excretory” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”) and renal disorders (e.g., as described below under “Renal Disorders”).
[0062] In specific embodiments, a Therapeutic protein having a “Excretory” recitation in the “Preferred Indication” column of Table 1, an albumin fusion protein that comprises a Therapeutic protein portion corresponding to this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: bladder cancer, prostate cancer, benign prostatic hyperplasia, bladder disorders (e.g., urinary incontinence, urinary retention, urinary obstruction, urinary tract Infections, interstitial cystitis, prostatitis, neurogenic bladder, hematuria), renal disorders (e.g., hydronephrosis, proteinuria, renal failure, pyelonephritis, urolithiasis, reflux nephropathy, and unilateral obstructive uropathy).
[0063] The recitation of “Neural/Sensory” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”) and diseases or disorders of the nervous system (e.g., as described below under “Neural Activity and Neurological Diseases”).
[0064] In specific embodiments, a Therapeutic protein having a “Neural/Sensory” recitation in the “Preferred Indication” column of Table 1, an albumin fusion protein that comprises a Therapeutic protein portion corresponding to this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: brain cancer (e.g., brain stem glioma, brain tumors, central nervous system (Primary) lymphoma, central nervous system lymphoma, cerebellar astrocytoma, and cerebral astrocytoma, neurodegenerative disorders (e.g., Alzheimer's Disease, Creutzfeldt-Jakob Disease, Parkinson's Disease, and Idiopathic Presenile Dementia), encephalomyelitis, cerebral malaria, meningitis, metabolic brain diseases (e.g., phenylketonuria and pyruvate carboxylase deficiency), cerebellar ataxia, ataxia telangiectasia, and AIDS Dementia Complex, schizophrenia, attention deficit disorder, hyperactive attention deficit disorder, autism, and obsessive compulsive disorders.
[0065] The recitation of “Respiratory” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”) and diseases or disorders of the respiratory system (e.g., as described below under “Respiratory Disorders”).
[0066] In specific embodiments, a Therapeutic protein having a “Respiratory” recitation in the “Preferred Indication” column of Table 1, an albumin fusion protein that comprises a Therapeutic protein portion corresponding to this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: cancers of the respiratory system such as larynx cancer, pharynx cancer, trachea cancer, epiglottis cancer, lung cancer, squamous cell carcinomas, small cell (oat cell) carcinomas, large cell carcinomas, and adenocarcinomas. Allergic reactions, cystic fibrosis, sarcoidosis, histiocytosis X, infiltrative lung diseases (e.g., pulmonary fibrosis and lymphoid interstitial pneumonia), obstructive airway diseases (e.g., asthma, emphysema, chronic or acute bronchitis), occupational lung diseases (e.g., silicosis and asbestosis), pneumonia, and pleurisy.
[0067] The recitation of “Endocrine” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”) and diseases or disorders of the respiratory system (e.g., as described below under “Respiratory Disorders”), renal disorders (e.g., as described below under “Renal Disorders”), and disorders of the endocrine system (e.g., as described below under “Endocrine Disorders”.
[0068] In specific embodiments, a Therapeutic protein having a “Endocrine” recitation in the “Preferred Indication” column of Table 1, an albumin fusion protein that comprises a Therapeutic protein portion corresponding to this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: cancers of endocrine tissues and organs (e.g., cancers of the hypothalamus, pituitary gland, thyroid gland, parathyroid glands, pancreas, adrenal glands, ovaries, and testes), diabetes (e.g., diabetes insipidus, type I and type II diabetes mellitus), obesity, disorders related to pituitary glands (e.g., hyperpituitarism, hypopituitarism, and pituitary dwarfism), hypothyroidism, hyperthyroidism, goiter, reproductive disorders (e.g. male and female infertility), disorders related to adrenal glands (e.g., Addison's Disease, corticosteroid deficiency, and Cushing's Syndrome), kidney cancer (e.g., hypemephroma, transitional cell cancer, and Wilm's tumor), diabetic nephropathy, interstitial nephritis, polycystic kidney disease, glomenilonephritis (e.g., IgM mesangial proliferative glomerulonephritis and glomerulonephritis caused by autoimmune disorders; such as Goodpasture's syndrome), and nephrocalcinosis.
[0069] The recitation of “Digestive” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”) and diseases or disorders of the gastrointestinal system (e.g., as described below under “Gastrointestinal Disorders”.
[0070] In specific embodiments, a Therapeutic protein having a “Digestive” recitation in the “Preferred Indication” column of Table 1, an albumin fusion protein that comprises a Therapeutic protein portion corresponding to this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: ulcerative colitis, appendicitis, Crohn's disease, hepatitis, hepatic encephalopathy, portal hypertension, cholelithiasis, cancer of the digestive system (e.g., biliary tract cancer, stomach cancer, colon cancer, gastric cancer, pancreatic cancer, cancer of the bile duct, tumors of the colon (e.g., polyps or cancers), and cirrhosis), pancreatitis, ulcerative disease, pyloric stenosis, gastroenteritis, gastritis, gastric atropy, benign tumors of the duodenum, distension, irritable bowel syndrome, malabsorption, congenital disorders of the small intestine, bacterial and parasitic infection, megacolon, Hirschsprung's disease, aganglionic megacolon, acquired megacolon, colitis, anorectal disorders (e.g., anal fistulas, hemorrhoids), congenital disorders of the liver (e.g., Wilson's disease, hemochromatosis, cystic fibrosis, biliary atresia, and alpha1-antitrypsin deficiency), portal hypertension, cholelithiasis, and jaundice.
[0071] The recitation of “Connective/Epithelial” in the “Preferred Indication Y” column indicates that corresponding Therapeutic protein, fusion protein containing the Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate diseases and/or disorders relating to neoplastic diseases (e.g., as described below under “Hyperproliferative Disorders”), cellular and genetic abnormalities (e.g., as described below under “Diseases at the Cellular Level”), angiogenesis (e.g., as described below under “Anti-Angiogenesis Activity”), and or to promote or inhibit regeneration (e.g., as described below under “Regeneration”), and wound healing (e.g., as described below under “Wound Healing and Epithelial Cell Proliferation”).
[0072] In specific embodiments, a Therapeutic protein having a “Connective/Epithelial” recitation in the “Preferred Indication” column of Table 1, an albumin fusion protein that comprises a Therapeutic protein portion corresponding to this Therapeutic protein, and fragments and variants thereof, may be used for example, to diagnose, treat, prevent, and/or ameliorate a disease or disorder selected from the group consisting of: connective tissue metaplasia, mixed connective tissue disease, focal epithelial hyperplasia, epithelial metaplasia, mucoepithelial dysplasia, graft v. host disease, polymyositis, cystic hyperplasia, cerebral dysplasia, tissue hypertrophy, Alzheimer's disease, lymphoproliferative disorder, Waldenstron's macroglobulinemia, Crohn's disease, pernicious anemia, idiopathic Addison's disease, glomerulonephritis, bullous pemphigoid, Sjogren's syndrome, diabetes mellitus, cystic fibrosis, osteoblastoma, osteoclastoma, osteosarcoma, chondrosarcoma, osteoporosis, osteocarthritis, periodontal disease, wound healing, relapsing polychondritis, vasculitis, polyarteritis nodosa, Wegener's granulomatosis, cellulitis, rheumatoid arthritis, psoriatic arthritis, discoid lupus erythematosus, systemic lupus erythematosus, scleroderma, CREST syndrome, Sjogren's syndrome, polymyositis, dermatomyositis, mixed connective tissue disease, relapsing polychondritis, vasculitis, Henoch-Schonlein syndrome, erythema nodosum, polyarteritis nodosa, temporal (giant cell) arteritis, Takayasu's arteritis, Wegener's granulomatosis, Reiter's syndrome, Behcet's syndrome, ankylosing spondylitis, cellulitis, keloids, Ehler Danlos syndrome, Marfan syndrome, pseudoxantoma elasticum, osteogenese imperfecta, chondrodysplasias, epidermolysis bullosa, Alport syndrome, and cutis laxa.
Therapeutic Exemplary Protein X Identifier PCT/Patent Reference Preferred Indication Y HETFO52 B03768 US6066724-A Neural/Sensory, Reproductive HETEZ10 B03769 US6066724-A Cancer HLICR58 B08775 WO200052160-A1 Cancer HMCIS41 B08776 WO200052160-A1 Cancer HCESA34 B08891 WO200017222-A1 Cancer HCRMZ90 B08892 WO200017222-A1 Cancer HDPXQ54 B08893 WO200017222-A1 Immune/Hematopoietic HETCL11 B08894 WO200017222-A1 Cancer HFXDN34 B08895 WO200017222-A1 Neural/Sensory HKAAV24 B08896 WO200017222-A1 Cancer HMTBE31 B08897 WO200017222-A1 Cancer HRADL70 B08898 WO200017222-A1 Excretory, Immune/Hematopoietic HTXGG31 B08899 WO200017222-A1 Cancer HWHHL34 B08900 WO200017222-A1 Cancer HYAAY40 B08901 WO200017222-A1 Immune/Hematopoietic HPASA81 B08902 WO200017222-A1 Digestive, Endocrine, Reproductive HCNDA61 B08903 WO200017222-A1 Digestive, Reproductive HTHCZ41 B08904 WO200017222-A1 Cancer HKADJ17 B08905 WO200017222-A1 Connective/Epithelial, Immune/Hematopoietic, Reproductive HMSII78 B08906 WO200017222-A1 Cancer HCFBL76 B08907 WO200017222-A1 Cancer HFVHR84 B08908 WO200017222-A1 Connective/Epithelial, Digestive HIBCB67 B08909 WO200017222-A1 Cancer HCELI29 B08910 WO200017222-A1 Cancer HAHDZ77 B08911 WO200017222-A1 Cardiovascular, Mixed Fetal HDHMA45 B08912 WO200017222-A1 Cardiovascular, Neural/Sensory HELAW45 B08913 WO200017222-A1 Cardiovascular HFIAB31 B08914 WO200017222-A1 Cancer HLWBK05 B08915 WO200017222-A1 Cancer HLDBX13 B08916 WO200017222-A1 Digestive HMAGA15 B08917 WO200017222-A1 Cancer HMWFT53 B08918 WO200017222-A1 Immune/Hematopoietic HNFJD91 B08919 WO200017222-A1 Cardiovascular, Connective/Epithelial, Immune/Hematopoietic HTGCM55 B08920 WO200017222-A1 Cardiovascular, Digestive, Immune/Hematopoietic HTTEX77 B08921 WO200017222-A1 Cancer HFXDN34 B08922 WO200017222-A1 Neural/Sensory HDPMI18 B08923 WO200017222-A1 Cancer HETGL41 B08924 WO200017222-A1 Cancer HPASA81 B08925 WO200017222-A1 Digestive, Endocrine, Reproductive HCNDA61 B08926 WO200017222-A1 Digestive, Reproductive HTTEX77 B08927 WO200017222-A1 Cancer HFXDN34 B08934 WO200017222-A1 Neural/Sensory HETGL41 B08935 WO200017222-A1 Cancer HPASA81 B08936 WO200017222-A1 Digestive, Endocrine, Reproductive HCNDA61 B08940 WO200017222-A1 Digestive, Reproductive HTTEX77 B08982 WO200017222-A1 Cancer HAOAB14 B12301 WO200029422-A1 Digestive, Musculoskeletal HHFBY53 B12302 WO200029422-A1 Cancer HE2FE69 B12303 WO200029422-A1 Cancer HNHFI33 B12305 WO200029422-A1 Immune/Hematopoietic HAMFE15 B12306 WO200029422-A1 Cancer HAMFE82 B12307 WO200029422-A1 Cancer HCWEM59 B12308 WO200029422-A1 Immune/Hematopoietic HDPGE10 B12309 WO200029422-A1 Immune/Hematopoietic HDPGP94 B12310 WO200029422-A1 Digestive, Immune/Hematopoietic HFPBY77 B12311 WO200029422-A1 Cancer HFXHK32 B12312 WO200029422-A1 Neural/Sensory HMTAK05 B12313 WO200029422-A1 Cancer HMWDC93 B12314 WO200029422-A1 Immune/Hematopoietic HSPBY40 B12315 WO200029422-A1 Cancer HODDO08 B12316 WO200029422-A1 Cancer HCFNK47 B12317 WO200029422-A1 Cancer HE2FL70 B12318 WO200029422-A1 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory H2MBY03 B12319 WO200029422-A1 Cancer HACBS38 B12320 WO200029422-A1 Cancer HAGFG51 B12321 WO200029422-A1 Neural/Sensory HBQAB44 B12322 WO200029422-A1 Neural/Sensory, Reproductive, Respiratory HHEMA59 B12323 WO200029422-A1 Cancer HJBAV55 B12324 WO200029422-A1 Cancer HLHEY02 B12325 WO200029422-A1 Endocrine, Respiratory HSAAO94 B12326 WO200029422-A1 Cancer HTXKP61 B12327 WO200029422-A1 Cancer HWABC21 B12328 WO200029422-A1 Cancer HWBDI30 B12329 WO200029422-A1 Cancer HYBAR26 B12330 WO200029422-A1 Musculoskeletal HAJAF57 B12331 WO200029422-A1 Cancer HAMFE15 B12332 WO200029422-A1 Cancer HAMFE82 B12333 WO200029422-A1 Cancer HAMFE15 B12338 WO200029422-A1 Cancer HAMFE82 B12339 WO200029422-A1 Cancer HLDOK36 B15551 WO200056752-A2 Cancer HDPBW68 B15552 WO200056752-A2 Cancer HHEFO24 B15553 WO200056752-A2 Cardiovascular, Immune/Hematopoietic, Neural/Sensory HEGAL46 B15554 WO200056752-A2 Cancer HFOYC02 B15555 WO200056752-A2 Cancer HDABV82 B15556 WO200056752-A2 Cancer HCEMU42 B15557 WO200056752-A2 Cancer HSIFO61 B15558 WO200056752-A2 Cancer HDPBW68 B15559 WO200056752-A2 Cancer HDPBW68 B15562 WO200056752-A2 Cancer HSIFO61 B15566 WO200056752-A2 Cancer HOEAL47 B18715 WO200054651-A2 Cancer HE9SF68 B18755 WO200055204-A1 Cancer HLICQ90 B24437 WO200035937-A1 Cancer HNTSM04 B24438 WO200035937-A1 Cancer HMCAL59 B24439 WO200035937-A1 Cancer HMACO04 B24440 WO200035937-A1 Cancer HMAHY59 B24441 WO200035937-A1 Cancer HFXLL52 B24442 WO200035937-A1 Neural/Sensory HKABY55 B24443 WO200035937-A1 Cancer HCQCF36 B24444 WO200035937-A1 Digestive, Immune/Hematopoietic HTADO22 B24445 WO200035937-A1 Immune/Hematopoietic HHFHD92 B24446 WO200035937-A1 Cancer HNGFW58 B24447 WO200035937-A1 Cancer HOEFV61 B24448 WO200035937-A1 Cancer HPIAQ68 B24449 WO200035937-A1 Immune/Hematopoietic, Reproductive HNFFY60 B24450 WO200035937-A1 Cancer HCE3H20 B24451 WO200035937-A1 Cancer HE8EW79 B24452 WO200035937-A1 Cancer HTTDF41 B24453 WO200035937-A1 Cancer HSSGJ45 B24454 WO200035937-A1 Cancer HLWBY76 B24455 WO200035937-A1 Cancer HDPBN34 B24456 WO200035937-A1 Immune/Hematopoietic HMSHY73 B24457 WO200035937-A1 Cancer HPRBF19 B24458 WO200035937-A1 Cancer HNFJE06 B24459 WO200035937-A1 Immune/Hematopoietic, Musculoskeletal HCHCF61 B24460 WO200035937-A1 Reproductive HBJLH40 B24461 WO200035937-A1 Cancer HDPMV72 B24462 WO200035937-A1 Cancer HEMFA84 B24463 WO200035937-A1 Cancer HTOHW95 B24464 WO200035937-A1 Cancer HUNAH63 B24465 WO200035937-A1 Reproductive HISBT59 B24466 WO200035937-A1 Cancer HNTAS52 B24467 WO200035937-A1 Cancer HRACM44 B24468 WO200035937-A1 Excretory, Immune/Hematopoietic HFPES77 B24469 WO200035937-A1 Cancer HUSXU29 B24470 WO200035937-A1 Cancer HOHBB49 B24471 WO200035937-A1 Musculoskeletal HRABX31 B24472 WO200035937-A1 Excretory, Immune/Hematopoietic, Musculoskeletal HROBD68 B24473 WO200035937-A1 Cancer HMHBE18 B24474 WO200035937-A1 Cancer HNHDY21 B24475 WO200035937-A1 Immune/Hematopoietic HOEBZ89 B24476 WO200035937-A1 Cancer HYAAJ71 B24477 WO200035937-A1 Immune/Hematopoietic HTEKS16 B24478 WO200035937-A1 Connective/Epithelial, Mixed Fetal, Reproductive HCUFX40 B24479 WO200035937-A1 Immune/Hematopoietic HCWDL75 B24480 WO200035937-A1 Cardiovascular, Immune/Hematopoietic HNHKJ57 B24481 WO200035937-A1 Immune/Hematopoietic HCMSS06 B24482 WO200035937-A1 Cancer HIBCE35 B24483 WO200035937-A1 Cancer HE8EW79 B24484 WO200035937-A1 Cancer HTTDF41 B24485 WO200035937-A1 Cancer HSSGJ45 B24486 WO200035937-A1 Cancer HCMSS06 B24487 WO200035937-A1 Cancer HCMSS06 B24597 WO200035937-A1 Cancer HAOAB64 B25576 WO200029435-A1 Musculoskeletal, Reproductive HOHCH55 B25577 WO200029435-A1 Cancer HTLEW81 B25578 WO200029435-A1 Cancer HARAO44 B25579 WO200029435-A1 Neural/Sensory HDPCL05 B25580 WO200029435-A1 Immune/Hematopoietic HDPUW68 B25581 WO200029435-A1 Cancer HOHBY69 B25582 WO200029435-A1 Cancer HCDDP40 B25583 WO200029435-A1 Immune/Hematopoietic, Musculoskeletal HUSAQ05 B25585 WO200029435-A1 Cancer HOUDJ81 B25586 WO200029435-A1 Cancer HPWCM76 B25587 WO200029435-A1 Reproductive HOHCH55 B25588 WO200029435-A1 Cancer HDPCL05 B25589 WO200029435-A1 Immune/Hematopoietic HOHBY69 B25590 WO200029435-A1 Cancer HUSAQ05 B25592 WO200029435-A1 Cancer HOUDJ81 B25593 WO200029435-A1 Cancer HUSAQ05 B25618 WO200029435-A1 Cancer HE8NG02 B25665 WO200043495-A2 Mixed Fetal, Reproductive HWBDM37 B25666 WO200043495-A2 Digestive, Immune/Hematopoietic, Reproductive HODFN71 B25668 WO200043495-A2 Mixed Fetal, Reproductive HODGE68 B25669 WO200043495-A2 Reproductive HCECN54 B25670 WO200043495-A2 Excretory, Neural/Sensory HE8UB86 B25671 WO200043495-A2 Cancer HNHKY10 B25672 WO200043495-A2 Immune/Hematopoietic HNHLB93 B25673 WO200043495-A2 Immune/Hematopoietic HNHON23 B25674 WO200043495-A2 Immune/Hematopoietic, Musculoskeletal HTEPG70 B25675 WO200043495-A2 Reproductive HNHOJ75 B25676 WO200043495-A2 Immune/Hematopoietic HDTIT10 B25677 WO200043495-A2 Cancer HKAOS84 B25678 WO200043495-A2 Connective/Epithelial HAPUC89 B25679 WO200043495-A2 Cancer HWAAD63 B25680 WO200043495-A2 Endocrine, Excretory, Immune/Hematopoietic HUCPD31 B25681 WO200043495-A2 Cancer HDQHD03 B25682 WO200043495-A2 Immune/Hematopoietic, Neural/Sensory HKAKK09 B25683 WO200043495-A2 Connective/Epithelial, Digestive, Mixed Fetal HOCNF19 B25684 WO200043495-A2 Digestive HTLIT32 B25685 WO200043495-A2 Reproductive HODEJ32 B25686 WO200043495-A2 Reproductive HNHMV54 B25687 WO200043495-A2 Immune/Hematopoietic HODEE95 B25688 WO200043495-A2 Reproductive HLHAM10 B25689 WO200043495-A2 Cancer HNHOG73 B25690 WO200043495-A2 Immune/Hematopoietic HBGNM47 B25691 WO200043495-A2 Cancer HAUBA08 B25692 WO200043495-A2 Cancer HYBBE75 B25693 WO200043495-A2 Musculoskeletal HTLGY87 B25694 WO200043495-A2 Cancer HNHPD10 B25695 WO200043495-A2 Immune/Hematopoietic HODEI83 B25696 WO200043495-A2 Reproductive HMUAI20 B25697 WO200043495-A2 Cancer HE9OW20 B25698 WO200043495-A2 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HDTIT10 B25699 WO200043495-A2 Cancer HWAAD63 B25700 WO200043495-A2 Endocrine, Excretory, Immune/Hematopoietic HWAAD63 B25701 WO200043495-A2 Endocrine, Excretory, Immune/Hematopoietic HEMCV19 B25703 WO200043495-A2 Cancer HEMCV19 B25704 WO200043495-A2 Cancer HEMCV19 B25705 WO200043495-A2 Cancer HAUBA08 B25706 WO200043495-A2 Cancer HEMCV19 B25707 WO200043495-A2 Cancer HE9OW20 B25715 WO200043495-A2 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HT4SB02 B27560 WO200055175-A1 Immune/Hematopoietic HCHAC68 B27562 WO200055175-A1 Cancer HCHCA79 B27563 WO200055175-A1 Digestive, Neural/Sensory, Reproductive HCHMY57 B27564 WO200055175-A1 Cancer HCHOY52 B27566 WO200055175-A1 Cancer HCHQB93 B27567 WO200055175-A1 Cancer HCMSA37 B27568 WO200055175-A1 Cardiovascular HCMSX51 B27570 WO200055175-A1 Cancer HCNAI74 B27571 WO200055175-A1 Digestive HCPAE41 B27578 WO200055175-A1 Cancer HCQAQ47 B27580 WO200055175-A1 Cancer HCQBH72 B27581 WO200055175-A1 Digestive, Excretory, Immune/Hematopoietic HCQDD32 B27585 WO200055175-A1 Digestive, Immune/Hematopoietic, Reproductive HCQDT67 B27586 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HCUFQ22 W74734 WO9839448-A2 Immune/Hematopoietic HLDOU93 W74738 WO9839448-A2 Digestive, Musculoskeletal, Reproductive HNGJJ68 W74741 WO9839448-A2 Cancer HCFAW04 W74742 WO9839448-A2 Immune/Hematopoietic HLMAV65 W74743 WO9839448-A2 Cancer HPMFD84 W74744 WO9839448-A2 Cancer HE6DB26 W74745 WO9839448-A2 Cancer HODBD33 W74747 WO9839448-A2 Reproductive HBJAE44 W74750 WO9839448-A2 Immune/Hematopoietic HCFME41 W74751 WO9839448-A2 Cancer HOGCO71 W74752 WO9839448-A2 Cancer HOSEX08 W74753 WO9839448-A2 Cancer HSKNJ72 W74754 WO9839448-A2 Digestive, Musculoskeletal HEBEB69 W74755 WO9839448-A2 Neural/Sensory, Reproductive HE6EH18 W74756 WO9839448-A2 Mixed Fetal, Neural/Sensory HSSDM73 W74758 WO9839448-A2 Musculoskeletal, Neural/Sensory, Reproductive HMKCU94 W74761 WO9839448-A2 Cancer HRDEW41 W74762 WO9839448-A2 Cancer HBGDA21 W74764 WO9839448-A2 Cancer HFGAK75 W74765 WO9839448-A2 Cancer HFSAU96 W74766 WO9839448-A2 Cancer HOVCL83 W74767 WO9839448-A2 Cancer HBICM48 W74769 WO9839448-A2 Cancer HLTCL35 W74770 WO9839448-A2 Cancer HRSAN45 W74771 WO9839448-A2 Cancer HSNBB14 W74772 WO9839448-A2 Cancer HMABL38 W74773 WO9839448-A2 Cancer HSKDK47 W74774 WO9839448-A2 Cancer HOSFH03 W74775 WO9839448-A2 Cancer HOGAV75 W74776 WO9839448-A2 Cancer HBXDO23 W74777 WO9839448-A2 Cancer HAGBI17 W74778 WO9839448-A2 Cancer HPRCA31 W74780 WO9839448-A2 Cancer HPRCE95 W74781 WO9839448-A2 Cancer HHTLC66 W74782 WO9839448-A2 Cancer HMADJ02 W74783 WO9839448-A2 Cancer HPRCU93 W74784 WO9839448-A2 Cancer HSAXS65 W74785 WO9839448-A2 Cancer HHFHN61 W74787 WO9839448-A2 Cancer HCWEF90 W74788 WO9839448-A2 Cancer HFRAU10 W74790 WO9839448-A2 Neural/Sensory HATDT67 W74791 WO9839448-A2 Cancer HOUBG93 W74792 WO9839448-A2 Cancer HMWEX24 W74793 WO9839448-A2 Cancer HTOCD52 W74795 WO9839448-A2 Digestive, Immune/Hematopoietic, Reproductive HTGCP16 W74796 WO9839448-A2 Cancer HKIXR69 W74797 WO9839448-A2 Cancer HE6CN34 W74800 WO9839448-A2 Cancer HSQEL25 W74802 WO9839448-A2 Cancer HEBEG68 W74803 WO9839448-A2 Cancer HBIAB39 W74804 WO9839448-A2 Cancer HOEAS24 W74805 WO9839448-A2 Cancer HETDD75 W74806 WO9839448-A2 Cancer HSKNE46 W74807 WO9839448-A2 Cancer HPMFL27 W74808 WO9839448-A2 Cancer HPRAX55 W74810 WO9839448-A2 Cancer HE2PL77 W74812 WO9839448-A2 Cancer HLHAU92 W74813 WO9839448-A2 Cancer HTPEG42 W74814 WO9839448-A2 Cancer HAUAV32 W74816 WO9839448-A2 Cancer HNEBI60 W74817 WO9839448-A2 Cancer HTSEL31 W74819 WO9839448-A2 Cancer HAUBL57 W74820 WO9839448-A2 Cancer HE6CT48 W74822 WO9839448-A2 Digestive, Mixed Fetal HMDAA61 W74823 WO9839448-A2 Cancer HAQBK61 W74824 WO9839448-A2 Cancer HAQBF73 W74825 WO9839448-A2 Cancer HAQBT94 W74826 WO9839448-A2 Cancer HLQAB52 W74828 WO9839448-A2 Cancer HE2BG03 W74830 WO9839448-A2 Cancer HCUBC79 W74832 WO9839448-A2 Cancer HSVAF07 W74833 WO9839448-A2 Cancer HT3AM65 W74834 WO9839448-A2 Cancer HE6DK18 W74835 WO9839448-A2 Cancer HEBEK93 W74836 WO9839448-A2 Cancer HJPCM10 W74837 WO9839448-A2 Cancer HSXBL78 W74838 WO9839448-A2 Cancer HOEAW81 W74839 WO9839448-A2 Cancer HEAAR60 W74841 WO9839448-A2 Cancer HOVBA03 W74843 WO9839448-A2 Cancer HGBGK76 W74844 WO9839448-A2 Digestive, Neural/Sensory HBMUW78 W74845 WO9839448-A2 Cancer HATCM76 W74848 WO9839448-A2 Cancer H6EBJ64 W74849 WO9839448-A2 Cancer HDDAD77 W74850 WO9839448-A2 Cancer HSPAG15 W74853 WO9839448-A2 Cancer HUSHH48 W74855 WO9839448-A2 Cancer HHSCV65 W74857 WO9839448-A2 Cancer HHSDQ41 W74858 WO9839448-A2 Cancer HEBFU93 W74860 WO9839448-A2 Excretory, Neural/Sensory, Reproductive HSGSC60 W74861 WO9839448-A2 Cancer HPMGD24 W74862 WO9839448-A2 Cancer HPTVC60 W74863 WO9839448-A2 Cancer HSKNE18 W74864 WO9839448-A2 Cancer HMWIF35 W74865 WO9839448-A2 Cancer HMWGI25 W74866 WO9839448-A2 Cancer HSKGF03 W74867 WO9839448-A2 Cancer HMSKE75 W74868 WO9839448-A2 Cancer HCMSH30 W74869 WO9839448-A2 Cancer HTWCB92 W74870 WO9839448-A2 Cancer HBMDM46 W74871 WO9839448-A2 Cancer HFXHL79 W74873 WO9839448-A2 Cancer HBJFJ73 W74874 WO9839448-A2 Cancer HSJAP03 W74875 WO9839448-A2 Cancer H6EAD09 W74876 WO9839448-A2 Cancer HTLEF62 W74879 WO9839448-A2 Cancer HTLAD94 W74880 WO9839448-A2 Cancer HTSFQ12 W74881 WO9839448-A2 Cancer HCE2K05 W74882 WO9839448-A2 Cancer HLTED27 W74884 WO9839448-A2 Cancer HMKBA64 W74885 WO9839448-A2 Cancer HNFCO49 W74886 WO9839448-A2 Cancer HCELB21 W74887 WO9839448-A2 Cancer HSAAS44 W74889 WO9839448-A2 Cancer HAFAL73 W74890 WO9839448-A2 Cancer HSAWF26 W74891 WO9839448-A2 Digestive, Immune/Hematopoietic, Musculoskeletal HMQDN51 W74892 WO9839448-A2 Cancer H2LAO11 W74894 WO9839448-A2 Cancer HPTTU11 W74896 WO9839448-A2 Cancer HTEDJ34 W74898 WO9839448-A2 Cancer HFTAR26 W74900 WO9839448-A2 Cancer H2MBF44 W74901 WO9839448-A2 Cancer HE8BI92 W74902 WO9839448-A2 Cancer HFTBR48 W74903 WO9839448-A2 Cancer HE9CM64 W74904 WO9839448-A2 Cancer HATAV51 W74905 WO9839448-A2 Cancer HCEEK08 W74907 WO9839448-A2 Cancer HAFAU18 W74908 WO9839448-A2 Cancer HETBY74 W74909 WO9839448-A2 Cancer HTOAF35 W74910 WO9839448-A2 Cancer HCRBX32 W74911 WO9839448-A2 Cancer HEBGB80 W74912 WO9839448-A2 Cancer HFAMH74 W74913 WO9839448-A2 Cancer HLMAV65 W74920 WO9839448-A2 Cancer HMAGF23 W74922 WO9839448-A2 Cancer HE6EH18 W74929 WO9839448-A2 Mixed Fetal, Neural/Sensory HMKCU94 W74930 WO9839448-A2 Cancer HBGDA21 W74931 WO9839448-A2 Cancer HFKFN58 W74932 WO9839448-A2 Cancer HSNBB14 W74935 WO9839448-A2 Cancer HOSFH03 W74937 WO9839448-A2 Cancer HAGBI17 W74939 WO9839448-A2 Cancer HPRCA31 W74940 WO9839448-A2 Cancer HPRCU93 W74943 WO9839448-A2 Cancer HPDDK44 W74944 WO9839448-A2 Cancer HCWEF90 W74946 WO9839448-A2 Cancer HFRAU10 W74947 WO9839448-A2 Neural/Sensory HBIAB39 W74953 WO9839448-A2 Cancer HBIAB39 W74954 WO9839448-A2 Cancer HOEAS24 W74955 WO9839448-A2 Cancer HOEAS24 W74956 WO9839448-A2 Cancer HPRAX55 W74958 WO9839448-A2 Cancer HTPEG42 W74960 WO9839448-A2 Cancer HAUAV32 W74961 WO9839448-A2 Cancer HNEBI60 W74962 WO9839448-A2 Cancer HAUBL57 W74963 WO9839448-A2 Cancer HAUBL57 W74964 WO9839448-A2 Cancer HE6CT48 W74965 WO9839448-A2 Digestive, Mixed Fetal HMDAA61 W74966 WO9839448-A2 Cancer HAQBK61 W74967 WO9839448-A2 Cancer HCUHB01 W74968 WO9839448-A2 Cancer HETHE07 W74970 WO9839448-A2 Cancer HETHE07 W74971 WO9839448-A2 Cancer HLQAB52 W74972 WO9839448-A2 Cancer HEONN58 W74973 WO9839448-A2 Cancer HIBEK16 W74974 WO9839448-A2 Cancer HE2BG03 W74975 WO9839448-A2 Cancer HCUBC79 W74976 WO9839448-A2 Cancer HSVAF07 W74978 WO9839448-A2 Cancer HSVAF07 W74979 WO9839448-A2 Cancer HT3AM65 W74980 WO9839448-A2 Cancer HT3AM65 W74981 WO9839448-A2 Cancer HJPCM10 W74983 WO9839448-A2 Cancer HJPCM10 W74984 WO9839448-A2 Cancer HOVBA03 W74987 WO9839448-A2 Cancer H6EBJ64 W74990 WO9839448-A2 Cancer HUSHH48 W74991 WO9839448-A2 Cancer HEBFU93 W74992 WO9839448-A2 Excretory, Neural/Sensory, Reproductive HPTVC60 W74993 WO9839448-A2 Cancer HMWIF35 W74995 WO9839448-A2 Cancer HSKGF03 W74996 WO9839448-A2 Cancer HBJFJ73 W75000 WO9839448-A2 Cancer HCFBC03 W75001 WO9839448-A2 Cancer HSJAP03 W75002 WO9839448-A2 Cancer HE6FL83 W75005 WO9839448-A2 Cancer HPTTU11 W75013 WO9839448-A2 Cancer H2MBF44 W75015 WO9839448-A2 Cancer HE9CM64 W75018 WO9839448-A2 Cancer HAFAU18 W75021 WO9839448-A2 Cancer HSHCC16 W75050 WO9839448-A2 Cancer HGCMD20 W75057 WO9839446-A2 Cancer HLDBG33 W75058 WO9839446-A2 Cancer HLHEJ14 W75059 WO9839446-A2 Cancer HKCSR70 W75060 WO9839446-A2 Cancer HBMCY91 W75062 WO9839446-A2 Immune/Hematopoietic HSSGE07 W75063 WO9839446-A2 Cancer HBMBX59 W75064 WO9839446-A2 Immune/Hematopoietic, Reproductive HNGIT22 W75065 WO9839446-A2 Immune/Hematopoietic HERAD57 W75066 WO9839446-A2 Connective/Epithelial HCENJ40 W75067 WO9839446-A2 Cancer HCSRA90 W75068 WO9839446-A2 Cardiovascular, Musculoskeletal HBJFC03 W75069 WO9839446-A2 Immune/Hematopoietic HTEBY26 W75071 WO9839446-A2 Cancer HMABH07 W75072 WO9839446-A2 Cancer HSKNY94 W75073 WO9839446-A2 Cancer HMCDA67 W75074 WO9839446-A2 Immune/Hematopoietic HOSFF45 W75075 WO9839446-A2 Cancer HMJAA51 W75076 WO9839446-A2 Cancer HTEBF05 W75077 WO9839446-A2 Reproductive HTEAL31 W75078 WO9839446-A2 Cancer HSKXE91 W75080 WO9839446-A2 Cancer HPWTB39 W75081 WO9839446-A2 Mixed Fetal, 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W75145 WO9839446-A2 Digestive HHFGL62 W75146 WO9839446-A2 Cardiovascular HTHBA79 W75148 WO9839446-A2 Cancer HTEGA81 W75151 WO9839446-A2 Cancer HTEGA81 W75152 WO9839446-A2 Cancer HMHBN40 W75154 WO9839446-A2 Cancer HLHDL62 W75155 WO9839446-A2 Cancer HSXBI25 W75156 WO9839446-A2 Cancer HSXCK41 W75157 WO9839446-A2 Cancer HTTDS54 W75159 WO9839446-A2 Cancer HHFCW44 W75160 WO9839446-A2 Cancer HHSDZ57 W75161 WO9839446-A2 Cancer HAICS58 W75162 WO9839446-A2 Cancer HAICS58 W75163 WO9839446-A2 Cancer HSKDW02 W75165 WO9839446-A2 Cancer HETGL41 W75166 WO9839446-A2 Cancer HODAZ50 W75167 WO9839446-A2 Reproductive HE6ES13 W75168 WO9839446-A2 Cancer HSSEP68 W75169 WO9839446-A2 Cancer HRDEV41 W75171 WO9839446-A2 Cancer HHFGL41 W75172 WO9839446-A2 Cancer HBJEM49 W75173 WO9839446-A2 Cancer HFTAK35 W75174 WO9839446-A2 Cancer HTXCT40 W75175 WO9839446-A2 Cancer HRDBF52 W75176 WO9839446-A2 Cancer HKMND45 W75177 WO9839446-A2 Cancer HDTBJ30 W75178 WO9839446-A2 Cancer HLMDX11 W75179 WO9839446-A2 Cancer HCEAB46 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HOSCZ41 W78172 WO9856804-A1 Cancer HSQEA85 W78174 WO9856804-A1 Cancer HSTAG52 W78175 WO9856804-A1 Cancer HBXGP76 W78177 WO9856804-A1 Immune/Hematopoietic, Neural/Sensory HE6GL64 W78178 WO9856804-A1 Cardiovascular, Immune/Hematopoietic, Mixed Fetal HESAL35 W78179 WO9856804-A1 Connective/Epithelial, Mixed Fetal HNHAL34 W78183 WO9856804-A1 Cancer HOSFF78 W78184 WO9856804-A1 Cancer HPMCC16 W78188 WO9856804-A1 Cancer HOUCQ17 W78189 WO9856804-A1 Cancer HTOFC34 W78192 WO9856804-A1 Cancer H2CBJ08 W78193 WO9856804-A1 Cancer HAGFT48 W78194 WO9856804-A1 Cancer HCE5M29 W78195 WO9856804-A1 Cancer HCFNN01 W78197 WO9856804-A1 Digestive, Immune/Hematopoietic, Neural/Sensory HE7TF86 W78198 WO9856804-A1 Cancer HHGAU81 W78200 WO9856804-A1 Cancer HPTRF90 W78206 WO9856804-A1 Cancer HSRDH01 W78207 WO9856804-A1 Cancer HSAWD74 W78208 WO9856804-A1 Cancer HTEJO12 W78209 WO9856804-A1 Digestive, Reproductive HTLAB43 W78210 WO9856804-A1 Cancer HTWCT03 W78211 WO9856804-A1 Immune/Hematopoietic HSDES04 W78213 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WO9909155-A1 Cancer HMKCP66 Y07807 WO9909155-A1 Neural/Sensory HWTAL40 Y07808 WO9909155-A1 Cancer HNHDR03 Y07809 WO9909155-A1 Immune/Hematopoietic HNHFH41 Y07810 WO9909155-A1 Immune/Hematopoietic HNHFI81 Y07811 WO9909155-A1 Immune/Hematopoietic HOSFQ28 Y07812 WO9909155-A1 Cancer HPRAL78 Y07813 WO9909155-A1 Cancer HEAAA85 Y07814 WO9909155-A1 Cancer HDTAR09 Y07816 WO9909155-A1 Cancer HLYHA71 Y07843 WO9909155-A1 Cancer HCWCH14 Y07852 WO9918208-A1 Immune/Hematopoietic HE9MI43 Y07855 WO9918208-A1 Cancer HE2PI29 Y07859 WO9918208-A1 Cancer HLHDP83 Y07862 WO9918208-A1 Cancer HSIAS17 Y07863 WO9918208-A1 Cancer HOSDG32 Y07866 WO9918208-A1 Cancer HMUBU59 Y07867 WO9918208-A1 Cancer HWTCE21 Y07868 WO9918208-A1 Cancer HFIUM15 Y07869 WO9918208-A1 Cancer HTLAF13 Y07872 WO9918208-A1 Reproductive HTLFI93 Y07873 WO9918208-A1 Immune/Hematopoietic, Reproductive, Respiratory HBXGI20 Y07874 WO9918208-A1 Cancer HTPBH21 Y07875 WO9918208-A1 Connective/Epithelial, Digestive, Reproductive HSQAB87 Y07876 WO9918208-A1 Cancer HTEDJ94 Y07877 WO9918208-A1 Cancer HKMLM11 Y07878 WO9918208-A1 Cancer HNEAC05 Y07879 WO9918208-A1 Immune/Hematopoietic HETEW02 Y07880 WO9918208-A1 Cancer HLMCA59 Y07882 WO9918208-A1 Immune/Hematopoietic HOAAC90 Y07883 WO9918208-A1 Musculoskeletal HMEJQ68 Y07884 WO9918208-A1 Cancer HRTAE58 Y07888 WO9918208-A1 Digestive, Reproductive HSKNB54 Y07889 WO9918208-A1 Cancer HSKNT34 Y07890 WO9918208-A1 Cancer HTEDY42 Y07891 WO9918208-A1 Reproductive HTLAA40 Y07892 WO9918208-A1 Reproductive HTNBO91 Y07893 WO9918208-A1 Cancer H6BSD90 Y07894 WO9918208-A1 Cancer HBJBQ35 Y07895 WO9918208-A1 Immune/Hematopoietic HCE1Q89 Y07896 WO9918208-A1 Immune/Hematopoietic, Neural/Sensory HCNSB61 Y07897 WO9918208-A1 Digestive, Immune/Hematopoietic HCDBO20 Y07898 WO9918208-A1 Musculoskeletal, Respiratory HBNAW17 Y07899 WO9918208-A1 Reproductive HEAAH81 Y07902 WO9918208-A1 Cancer HEBAE88 Y07903 WO9918208-A1 Immune/Hematopoietic, Neural/Sensory HFXGV31 Y07904 WO9918208-A1 Neural/Sensory HEAAJ57 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WO9918208-A1 Immune/Hematopoietic HNGDP26 Y07935 WO9918208-A1 Immune/Hematopoietic HNGJH63 Y07936 WO9918208-A1 Immune/Hematopoietic HMDAL04 Y07937 WO9918208-A1 Neural/Sensory HMWHX28 Y07938 WO9918208-A1 Immune/Hematopoietic HNHGB09 Y07942 WO9918208-A1 Immune/Hematopoietic HNHHA15 Y07943 WO9918208-A1 Immune/Hematopoietic HHGDC01 Y07944 WO9918208-A1 Cancer HMWGU74 Y07945 WO9918208-A1 Immune/Hematopoietic HNGCF72 Y07946 WO9918208-A1 Immune/Hematopoietic HOACB38 Y07947 WO9918208-A1 Musculoskeletal HLMFD11 Y07950 WO9918208-A1 Immune/Hematopoietic HLYBA22 Y07952 WO9918208-A1 Immune/Hematopoietic HCWCH14 Y07953 WO9918208-A1 Immune/Hematopoietic HBMWF85 Y10797 WO9907891-A1 Immune/Hematopoietic HCDEJ37 Y10798 WO9907891-A1 Immune/Hematopoietic, Musculoskeletal HCE3L18 Y10799 WO9907891-A1 Neural/Sensory HCYBI42 Y10800 WO9907891-A1 Cancer HE6FB81 Y10801 WO9907891-A1 Mixed Fetal HFAMB72 Y10802 WO9907891-A1 Cancer HFCDW42 Y10803 WO9907891-A1 Cancer HFPAE26 Y10804 WO9907891-A1 Neural/Sensory HFXJM91 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Y10839 WO9907891-A1 Cardiovascular, Musculoskeletal, Neural/Sensory HHSDR11 Y10840 WO9907891-A1 Neural/Sensory HLJDQ62 Y10842 WO9907891-A1 Cancer HKGBS49 Y10843 WO9907891-A1 Reproductive HKISA27 Y10844 WO9907891-A1 Cancer HKIXE06 Y10845 WO9907891-A1 Cancer HKMMV77 Y10846 WO9907891-A1 Excretory, Reproductive HLYAB80 Y10850 WO9907891-A1 Cancer HLYAG19 Y10851 WO9907891-A1 Digestive, Immune/Hematopoietic HLYBY48 Y10852 WO9907891-A1 Immune/Hematopoietic HMUAW28 Y10853 WO9907891-A1 Immune/Hematopoietic, Musculoskeletal HMWHC36 Y10854 WO9907891-A1 Cancer HNFIS82 Y10856 WO9907891-A1 Digestive, Immune/Hematopoietic, Reproductive HNGBO16 Y10859 WO9907891-A1 Immune/Hematopoietic HNGBQ90 Y10860 WO9907891-A1 Cancer HNGBV72 Y10861 WO9907891-A1 Immune/Hematopoietic HNGEG08 Y10863 WO9907891-A1 Immune/Hematopoietic HNGFI02 Y10864 WO9907891-A1 Immune/Hematopoietic HNGGF85 Y10865 WO9907891-A1 Immune/Hematopoietic HNGHM75 Y10866 WO9907891-A1 Immune/Hematopoietic HNGIN84 Y10867 WO9907891-A1 Digestive, 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HCUEO60 Y12926 WO9911293-A1 Immune/Hematopoietic HDHEB60 Y12927 WO9911293-A1 Cancer HE6AJ31 Y12928 WO9911293-A1 Mixed Fetal HFCED59 Y12929 WO9911293-A1 Immune/Hematopoietic, Neural/Sensory HFXKJ03 Y12931 WO9911293-A1 Cardiovascular, Immune/Hematopoietic, Neural/Sensory HHFDG44 Y12932 WO9911293-A1 Cardiovascular, Endocrine, Immune/Hematopoietic HJACG02 Y12933 WO9911293-A1 Digestive, Immune/Hematopoietic HKGAJ54 Y12934 WO9911293-A1 Cancer HKMAB92 Y12935 WO9911293-A1 Cancer HLMFC54 Y12937 WO9911293-A1 Immune/Hematopoietic HLWBZ21 Y12939 WO9911293-A1 Immune/Hematopoietic, Reproductive HMJAX71 Y12940 WO9911293-A1 Neural/Sensory HNECU95 Y12941 WO9911293-A1 Connective/Epithelial, Immune/Hematopoietic HNFCK41 Y12942 WO9911293-A1 Cancer HNFHD08 Y12943 WO9911293-A1 Cancer HNGEW65 Y12944 WO9911293-A1 Endocrine, Immune/Hematopoietic HNHEN68 Y12946 WO9911293-A1 Immune/Hematopoietic HNHFG05 Y12947 WO9911293-A1 Immune/Hematopoietic HODBF19 Y12948 WO9911293-A1 Cancer HOEBK34 Y12949 WO9911293-A1 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HCUIO20 Y14453 WO9919339-A1 Immune/Hematopoietic HLTEF12 Y14454 WO9919339-A1 Cancer HCFBJ91 Y14455 WO9919339-A1 Immune/Hematopoietic HHFHP90 Y14456 WO9919339-A1 Cardiovascular HLYCQ48 Y14457 WO9919339-A1 Immune/Hematopoietic HHLAB07 Y14458 WO9919339-A1 Digestive, Immune/Hematopoietic HFOXE30 Y14459 WO9919339-A1 Musculoskeletal HBJEL68 Y14460 WO9919339-A1 Immune/Hematopoietic, Neural/Sensory HFIUR35 Y14462 WO9919339-A1 Musculoskeletal HFIZF58 Y16587 US5916769-A Cancer HNGDJ72 Y19443 WO9922243-A1 Immune/Hematopoietic HNGEO29 Y19444 WO9922243-A1 Immune/Hematopoietic HNHDL95 Y19445 WO9922243-A1 Immune/Hematopoietic HAGDS35 Y19446 WO9922243-A1 Cancer HNGEQ48 Y19447 WO9922243-A1 Immune/Hematopoietic HNGDG40 Y19448 WO9922243-A1 Immune/Hematopoietic HNGEN81 Y19449 WO9922243-A1 Immune/Hematopoietic H2MAC30 Y19450 WO9922243-A1 Cancer HNHFB16 Y19451 WO9922243-A1 Immune/Hematopoietic HPFCL43 Y19452 WO9922243-A1 Cancer HSATR82 Y19453 WO9922243-A1 Immune/Hematopoietic HNHIC21 Y19455 WO9922243-A1 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WO9922243-A1 Connective/Epithelial HTXJX80 Y19552 WO9922243-A1 Digestive, Immune/Hematopoietic HAFBD61 Y19553 WO9922243-A1 Cancer HBJJU28 Y19554 WO9922243-A1 Immune/Hematopoietic, Neural/Sensory HNHEI47 Y19555 WO9922243-A1 Immune/Hematopoietic HPMFY74 Y19556 WO9922243-A1 Reproductive HLYAP91 Y19559 WO9922243-A1 Digestive, Immune/Hematopoietic, Reproductive HSKNB56 Y19560 WO9922243-A1 Cancer HHGCW91 Y19561 WO9922243-A1 Digestive, Immune/Hematopoietic HKIYE96 Y19562 WO9922243-A1 Excretory HLYAN59 Y19563 WO9922243-A1 Immune/Hematopoietic HNEEE24 Y19564 WO9922243-A1 Immune/Hematopoietic HAPRK85 Y19565 WO9922243-A1 Cancer HLTEJ06 Y19566 WO9922243-A1 Immune/Hematopoietic HMEKT48 Y19567 WO9922243-A1 Cancer HNGHR74 Y19568 WO9922243-A1 Immune/Hematopoietic HNHED17 Y19569 WO9922243-A1 Immune/Hematopoietic HNHEP59 Y19570 WO9922243-A1 Immune/Hematopoietic HNHFJ25 Y19571 WO9922243-A1 Immune/Hematopoietic HCPAA69 Y19572 WO9922243-A1 Neural/Sensory HEAAR07 Y19573 WO9922243-A1 Reproductive HHGDW43 Y19574 WO9922243-A1 Cancer HHSDX28 Y19575 WO9922243-A1 Immune/Hematopoietic, Neural/Sensory HE8ER60 Y19576 WO9922243-A1 Cancer HMEJQ66 Y19577 WO9922243-A1 Cardiovascular HRDAD66 Y19578 WO9922243-A1 Cancer HCMST14 Y19579 WO9922243-A1 Cancer HCEBA03 Y19580 WO9922243-A1 Neural/Sensory HJAAM10 Y19582 WO9922243-A1 Cancer HOHCC74 Y19584 WO9922243-A1 Cancer HPMPY57 Y19585 WO9922243-A1 Immune/Hematopoietic, Neural/Sensory, Reproductive HFXDN63 Y19586 WO9922243-A1 Neural/Sensory HADCL76 Y19587 WO9922243-A1 Cancer HMMAS76 Y19588 WO9922243-A1 Endocrine, Immune/Hematopoietic HMKCG09 Y19589 WO9922243-A1 Digestive, Endocrine, Neural/Sensory HFPBA88 Y19590 WO9922243-A1 Cancer HMIAH29 Y19596 WO9922243-A1 Cancer HEMFS60 Y19757 WO9922243-A1 Cancer HDPVA94 Y25708 WO9938882-A1 Cancer HDPNE25 Y25709 WO9938882-A1 Cancer HASCG84 Y25711 WO9938881-A1 Cancer HDPCY37 Y25712 WO9938881-A1 Cancer HHEBB10 Y25713 WO9938881-A1 Cancer HNGJA38 Y25714 WO9938881-A1 Immune/Hematopoietic HHENL07 Y25715 WO9938881-A1 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HKMMD13 Y25739 WO9938881-A1 Excretory HLDNK64 Y25740 WO9938881-A1 Cancer HRDES01 Y25741 WO9938881-A1 Musculoskeletal HDTDZ50 Y25742 WO9938881-A1 Cancer HETAB45 Y25743 WO9938881-A1 Cancer HFPBD47 Y25744 WO9938881-A1 Cancer HJMBI18 Y25745 WO9938881-A1 Cancer HFXHK73 Y25746 WO9938881-A1 Neural/Sensory HJMBT65 Y25747 WO9938881-A1 Cancer HWHGZ26 Y25748 WO9938881-A1 Cancer HADFY83 Y25749 WO9938881-A1 Cancer HBMTV78 Y25750 WO9938881-A1 Digestive, Immune/Hematopoietic HTXJM03 Y25751 WO9938881-A1 Cancer HUSAT94 Y25752 WO9938881-A1 Cancer HCUEN88 Y25753 WO9938881-A1 Immune/Hematopoietic HCE3F70 Y25754 WO9938881-A1 Cancer HCE5F43 Y25755 WO9938881-A1 Cancer HL2AC08 Y25756 WO9938881-A1 Cancer HCNSM70 Y25757 WO9938881-A1 Cancer HDPTQ73 Y25758 WO9938881-A1 Cancer HTODG13 Y25759 WO9938881-A1 Digestive, Immune/Hematopoietic, Reproductive HE8DR25 Y25760 WO9938881-A1 Excretory, Mixed Fetal, Neural/Sensory HSAAO65 Y25761 WO9938881-A1 Cancer HKGDE09 Y25762 WO9938881-A1 Cancer HMVBS69 Y25763 WO9938881-A1 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Y27573 WO9924836-A1 Digestive, Immune/Hematopoietic, Reproductive HLHFR19 Y27574 WO9924836-A1 Neural/Sensory, Respiratory HMEET96 Y27575 WO9924836-A1 Cancer HTXCV12 Y27576 WO9924836-A1 Cancer HCEFB70 Y27577 WO9924836-A1 Immune/Hematopoietic, Neural/Sensory HDTAV25 Y27578 WO9924836-A1 Cancer HSATA21 Y27579 WO9924836-A1 Immune/Hematopoietic HKIXI03 Y27580 WO9924836-A1 Excretory HDTDC56 Y27581 WO9924836-A1 Cancer HLTBF35 Y27582 WO9924836-A1 Cancer HEPAB80 Y27583 WO9924836-A1 Reproductive HFOXB13 Y27584 WO9924836-A1 Musculoskeletal HTOAK16 Y27585 WO9924836-A1 Cardiovascular, Connective/Epithelial, Immune/Hematopoietic HBXDC63 Y27586 WO9924836-A1 Neural/Sensory HASAU43 Y27587 WO9924836-A1 Immune/Hematopoietic HAGEA31 Y27588 WO9924836-A1 Cancer HTXHB33 Y27590 WO9924836-A1 Immune/Hematopoietic HMWFT65 Y27591 WO9924836-A1 Immune/Hematopoietic HNGAZ68 Y27592 WO9924836-A1 Cardiovascular, Immune/Hematopoietic HTWFH07 Y27593 WO9924836-A1 Immune/Hematopoietic HMQDF12 Y27594 WO9924836-A1 Cancer HFABH95 Y27595 WO9924836-A1 Digestive, Neural/Sensory, Reproductive HNGDD48 Y27596 WO9924836-A1 Immune/Hematopoietic HPMBY46 Y27597 WO9924836-A1 Cancer HRKPA09 Y27598 WO9924836-A1 Cancer HAGAQ26 Y27599 WO9924836-A1 Cancer HCWFL55 Y27600 WO9924836-A1 Immune/Hematopoietic HKAAE44 Y27601 WO9924836-A1 Cancer HNGEU90 Y27602 WO9924836-A1 Immune/Hematopoietic HCFCC07 Y27603 WO9924836-A1 Digestive, Immune/Hematopoietic HLWBI63 Y27604 WO9924836-A1 Cancer HDUAC77 Y27605 WO9924836-A1 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HFOYV27 Y27606 WO9924836-A1 Cancer HGBHI35 Y27607 WO9924836-A1 Cancer HRDEU27 Y27608 WO9924836-A1 Musculoskeletal HNGJE50 Y27609 WO9924836-A1 Immune/Hematopoietic HNHDU48 Y27610 WO9924836-A1 Immune/Hematopoietic HFXJU68 Y27611 WO9924836-A1 Immune/Hematopoietic, Neural/Sensory HMMAH60 Y27612 WO9924836-A1 Immune/Hematopoietic HNGFR31 Y27613 WO9924836-A1 Immune/Hematopoietic HFPDB26 Y27614 WO9924836-A1 Immune/Hematopoietic, Neural/Sensory, Reproductive HFRAW86 Y27615 WO9924836-A1 Neural/Sensory HTEDX90 Y27616 WO9924836-A1 Reproductive HTXGG45 Y27617 WO9924836-A1 Immune/Hematopoietic HTXJI95 Y27618 WO9924836-A1 Immune/Hematopoietic, Reproductive HLYBD32 Y27619 WO9924836-A1 Immune/Hematopoietic HROAJ03 Y27621 WO9924836-A1 Cancer HTXAJ12 Y27622 WO9924836-A1 Immune/Hematopoietic HKAEL80 Y27623 WO9924836-A1 Connective/Epithelial, Immune/Hematopoietic HNHFL04 Y27624 WO9924836-A1 Immune/Hematopoietic HPCAM01 Y27625 WO9924836-A1 Cancer HJACA79 Y27626 WO9924836-A1 Immune/Hematopoietic HMSFI26 Y27628 WO9924836-A1 Immune/Hematopoietic HMSJR08 Y27629 WO9924836-A1 Immune/Hematopoietic HMWIO93 Y27630 WO9924836-A1 Cancer HNGAK47 Y27631 WO9924836-A1 Immune/Hematopoietic HNGAL31 Y27632 WO9924836-A1 Immune/Hematopoietic HNGIZ06 Y27633 WO9924836-A1 Immune/Hematopoietic HNHBI75 Y27634 WO9924836-A1 Immune/Hematopoietic HOFNT24 Y27635 WO9924836-A1 Reproductive HSAXI95 Y27636 WO9924836-A1 Immune/Hematopoietic HCMTB45 Y27637 WO9924836-A1 Cardiovascular, 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Cancer HLWAA17 Y30711 WO9943693-A1 Cancer HLYCQ18 Y30712 WO9943693-A1 Immune/Hematopoietic HOSFG70 Y30713 WO9943693-A1 Cancer HSSAJ29 Y30714 WO9943693-A1 Cancer HUSIF44 Y30715 WO9943693-A1 Cancer H6EDX46 Y30716 WO9943693-A1 Cancer HABAG37 Y30717 WO9943693-A1 Cancer HACBD91 Y30718 WO9943693-A1 Cancer HADEH21 Y30719 WO9943693-A1 Cancer HAGHD57 Y30720 WO9943693-A1 Cancer HAGHR69 Y30721 WO9943693-A1 Cancer HAHDB16 Y30722 WO9943693-A1 Cardiovascular HAHDR32 Y30723 WO9943693-A1 Cancer HAJAW93 Y30724 WO9943693-A1 Cancer HAJBR69 Y30725 WO9943693-A1 Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal HAMGO32 Y30726 WO9943693-A1 Reproductive HATBR65 Y30727 WO9943693-A1 Cancer HBJLD29 Y30728 WO9943693-A1 Immune/Hematopoietic HBJNB13 Y30729 WO9943693-A1 Immune/Hematopoietic HCE2F54 Y30730 WO9943693-A1 Cancer HCE3C52 Y30731 WO9943693-A1 Cancer HCEEA88 Y30732 WO9943693-A1 Cancer HCEFE96 Y30733 WO9943693-A1 Cancer HCEIF12 Y30734 WO9943693-A1 Cancer HCEOR67 Y30735 WO9943693-A1 Neural/Sensory HCEVB76 Y30736 WO9943693-A1 Cancer HNTOA17 Y30737 WO9943693-A1 Cancer HDPOW86 Y30811 WO9940100-A1 Cancer HSYAG26 Y30812 WO9940100-A1 Cancer HLHCH40 Y30813 WO9940100-A1 Cancer HPLBM85 Y30814 WO9940100-A1 Cancer HLMBO76 Y30815 WO9940100-A1 Excretory, Immune/Hematopoietic, Reproductive HLQDR48 Y30816 WO9940100-A1 Digestive HOHBY12 Y30817 WO9940100-A1 Musculoskeletal HOSEK86 Y30818 WO9940100-A1 Cancer HAJBZ75 Y30819 WO9940100-A1 Cancer HAGCH75 Y30820 WO9940100-A1 Neural/Sensory HE8MH91 Y30821 WO9940100-A1 Cancer HISCJ55 Y30822 WO9940100-A1 Digestive HKISB57 Y30823 WO9940100-A1 Cancer HTEBJ71 Y30824 WO9940100-A1 Cancer HCWGA40 Y30825 WO9940100-A1 Cancer HFCEW05 Y30826 WO9940100-A1 Cardiovascular, Neural/Sensory HCEPF19 Y30827 WO9940100-A1 Cancer HTACZ01 Y30828 WO9940100-A1 Immune/Hematopoietic HUDAM89 Y30829 WO9940100-A1 Reproductive HSAXF60 Y30830 WO9940100-A1 Immune/Hematopoietic HTOGR42 Y30831 WO9940100-A1 Immune/Hematopoietic HMVBN46 Y30832 WO9940100-A1 Immune/Hematopoietic, Neural/Sensory HUVEB53 Y30833 WO9940100-A1 Cancer HSVBU91 Y30834 WO9940100-A1 Cancer HTXFL30 Y30835 WO9940100-A1 Cancer HAGAM64 Y30836 WO9940100-A1 Neural/Sensory HE2PH36 Y30837 WO9940100-A1 Digestive, Immune/Hematopoietic, Mixed Fetal HGBDY06 Y30838 WO9940100-A1 Cancer HWBAO62 Y30839 WO9940100-A1 Connective/Epithelial, Immune/Hematopoietic HBAFJ33 Y30840 WO9940100-A1 Cancer HFXDJ75 Y30841 WO9940100-A1 Neural/Sensory HFPCY04 Y30842 WO9940100-A1 Neural/Sensory HSNBG78 Y30843 WO9940100-A1 Connective/Epithelial, Digestive, Immune/Hematopoietic HBQAB27 Y30844 WO9940100-A1 Endocrine, Neural/Sensory HTOJY21 Y30845 WO9940100-A1 Cancer HHTMM30 Y30846 WO9940100-A1 Cancer HLTAF58 Y30847 WO9940100-A1 Digestive, Immune/Hematopoietic HELFG13 Y30848 WO9940100-A1 Cancer HHFDM48 Y30849 WO9940100-A1 Cardiovascular, Neural/Sensory, Reproductive HKABI84 Y30850 WO9940100-A1 Cancer HMVAX72 Y30851 WO9940100-A1 Cancer HODDN60 Y30852 WO9940100-A1 Cancer HPMEI44 Y30853 WO9940100-A1 Cancer HNGJP69 Y30854 WO9940100-A1 Immune/Hematopoietic HPWBA10 Y30855 WO9940100-A1 Immune/Hematopoietic, Reproductive HLHCH40 Y30856 WO9940100-A1 Cancer HTACZ01 Y30857 WO9940100-A1 Immune/Hematopoietic HTOGR42 Y30858 WO9940100-A1 Immune/Hematopoietic HTAEK53 Y31811 WO9947538-A1 Cancer HFCCQ50 Y36224 WO9931117-A1 Cancer HTLAI54 Y36225 WO9931117-A1 Reproductive HLWBF94 Y36227 WO9931117-A1 Endocrine, Neural/Sensory, Reproductive HFKFF78 Y36228 WO9931117-A1 Excretory HSYBG37 Y36229 WO9931117-A1 Cancer HTHCA77 Y36230 WO9931117-A1 Immune/Hematopoietic HNHEZ51 Y36231 WO9931117-A1 Immune/Hematopoietic HFIAX46 Y36232 WO9931117-A1 Cardiovascular, Musculoskeletal HFOXO72 Y36233 WO9931117-A1 Cancer HODDW40 Y36234 WO9931117-A1 Cardiovascular, Immune/Hematopoietic, Reproductive HSAWG42 Y36235 WO9931117-A1 Immune/Hematopoietic HBMSK09 Y36236 WO9931117-A1 Digestive, Immune/Hematopoietic, Musculoskeletal HDPAU16 Y36237 WO9931117-A1 Cancer HFEBE12 Y36238 WO9931117-A1 Cancer HFLNB64 Y36239 WO9931117-A1 Cancer HSAWZ41 Y36240 WO9931117-A1 Immune/Hematopoietic HNFJF07 Y36241 WO9931117-A1 Immune/Hematopoietic, Neural/Sensory HNGJO57 Y36242 WO9931117-A1 Immune/Hematopoietic HE7TM22 Y36243 WO9931117-A1 Mixed Fetal HFRBR70 Y36244 WO9931117-A1 Cancer HTHBK35 Y36245 WO9931117-A1 Immune/Hematopoietic HWABA81 Y36246 WO9931117-A1 Immune/Hematopoietic HKGAA73 Y36247 WO9931117-A1 Cancer HKIYP40 Y36248 WO9931117-A1 Cancer HKMMW74 Y36249 WO9931117-A1 Excretory HLFBI27 Y36250 WO9931117-A1 Respiratory HLQCWS4 Y36251 WO9931117-A1 Digestive HBNAV22 Y36252 WO9931117-A1 Digestive, Reproductive HTEAM34 Y36253 WO9931117-A1 Reproductive HTHDK34 Y36254 WO9931117-A1 Digestive, Immune/Hematopoietic H6BSG32 Y36255 WO9931117-A1 Cardiovascular, Immune/Hematopoietic, Musculoskeletal HAECA01 Y36256 WO9931117-A1 Cancer HDTEL03 Y36257 WO9931117-A1 Cancer HFXDT43 Y36258 WO9931117-A1 Neural/Sensory HNGHQ09 Y36259 WO9931117-A1 Immune/Hematopoietic HHGDF16 Y36260 WO9931117-A1 Cancer HJBCG12 Y36261 WO9931117-A1 Cancer HOGAW62 Y36262 WO9931117-A1 Immune/Hematopoietic, Reproductive HSWBJ74 Y36263 WO9931117-A1 Cancer HGBHR26 Y36264 WO9931117-A1 Digestive HKDBF34 Y36265 WO9931117-A1 Cancer H6EAB28 Y36266 WO9931117-A1 Cancer HLWAO22 Y36267 WO9931117-A1 Cancer HAGFH53 Y36268 WO9931117-A1 Cancer HHENQ22 Y36269 WO9931117-A1 Immune/Hematopoietic HKMLK53 Y36270 WO9931117-A1 Excretory, Mixed Fetal HSKGQ58 Y36271 WO9931117-A1 Cancer HADXB45 Y36272 WO9931117-A1 Cancer HAIBZ39 Y36273 WO9931117-A1 Cancer HBXFP23 Y36274 WO9931117-A1 Cancer HEQBF32 Y36275 WO9931117-A1 Cancer HETHE81 Y36276 WO9931117-A1 Cancer HFPAC12 Y36277 WO9931117-A1 Cancer H6EFA77 Y36278 WO9931117-A1 Cancer HFXHD88 Y36279 WO9931117-A1 Neural/Sensory HFOXV65 Y36280 WO9931117-A1 Immune/Hematopoietic, Musculoskeletal, Reproductive HKADX21 Y36281 WO9931117-A1 Cancer HPZAB47 Y36282 WO9931117-A1 Cancer HAGFE79 Y36283 WO9931117-A1 Cancer HCE1X60 Y36284 WO9931117-A1 Neural/Sensory HFXKD36 Y36285 WO9931117-A1 Digestive, Musculoskeletal, Neural/Sensory HBMCU71 Y36286 WO9931117-A1 Immune/Hematopoietic HTEIV80 Y36287 WO9931117-A1 Reproductive HFIAP16 Y36288 WO9931117-A1 Musculoskeletal HODAV86 Y36289 WO9931117-A1 Reproductive HTEDF80 Y36290 WO9931117-A1 Reproductive HTODJ69 Y36291 WO9931117-A1 Immune/Hematopoietic HE6GR02 Y36292 WO9931117-A1 Immune/Hematopoietic, Mixed Fetal HAPNY86 Y36293 WO9931117-A1 Cancer HTLDR33 Y36294 WO9931117-A1 Immune/Hematopoietic, Reproductive HACBI61 Y36295 WO9931117-A1 Cancer HMEIK34 Y36296 WO9931117-A1 Cancer HKAAK02 Y36297 WO9931117-A1 Cancer HEPAA46 Y36298 WO9931117-A1 Reproductive HFPCX09 Y36299 WO9931117-A1 Mixed Fetal, Neural/Sensory HLWAA88 Y36300 WO9931117-A1 Cancer HOHBV89 Y36301 WO9931117-A1 Musculoskeletal, Reproductive HCEFL57 Y36302 WO9931117-A1 Cancer HMEKU83 Y36303 WO9931117-A1 Cardiovascular, Immune/Hematopoietic, Reproductive HOSBY40 Y36304 WO9931117-A1 Digestive, Immune/Hematopoietic, Musculoskeletal HKFBH93 Y36305 WO9931117-A1 Digestive, Reproductive HMTAD67 Y36306 WO9931117-A1 Cancer HTEBP77 Y36307 WO9931117-A1 Immune/Hematopoietic, Reproductive HE9CO69 Y36308 WO9931117-A1 Cancer HCACV51 Y36309 WO9931117-A1 Cancer HHPBI45 Y36310 WO9931117-A1 Cardiovascular, Neural/Sensory HLQDH79 Y36311 WO9931117-A1 Cancer HNGFJ67 Y36312 WO9931117-A1 Immune/Hematopoietic HEIAC52 Y36313 WO9931117-A1 Cancer HFXKL58 Y36314 WO9931117-A1 Cancer HMVAM60 Y36315 WO9931117-A1 Cancer HMVBR22 Y36316 WO9931117-A1 Cancer HPJCW04 Y36317 WO9931117-A1 Reproductive HSIDJ81 Y36318 WO9931117-A1 Digestive HSLFU05 Y36319 WO9931117-A1 Cancer HEQAK71 Y36320 WO9931117-A1 Cancer HOSEQ49 Y36321 WO9931117-A1 Cancer HRAAM50 Y36322 WO9931117-A1 Excretory, Immune/Hematopoietic, Mixed Fetal HSDFW45 Y36323 WO9931117-A1 Neural/Sensory HSLCQ82 Y36324 WO9931117-A1 Cancer HSSFT08 Y36325 WO9931117-A1 Musculoskeletal HTOIW31 Y36326 WO9931117-A1 Immune/Hematopoietic, Neural/Sensory, Reproductive HTXKQ85 Y36327 WO9931117-A1 Immune/Hematopoietic, Musculoskeletal, Reproductive HUFBK08 Y36328 WO9931117-A1 Digestive, Musculoskeletal HBJEE48 Y36330 WO9931117-A1 Cancer HBXGH74 Y36331 WO9931117-A1 Neural/Sensory HISBM03 Y36332 WO9931117-A1 Cancer HETCH46 Y36333 WO9931117-A1 Cancer HFPCX09 Y36335 WO9931117-A1 Mixed Fetal, Neural/Sensory HLWAA88 Y36336 WO9931117-A1 Cancer HCEFL57 Y36337 WO9931117-A1 Cancer HETHE81 Y36650 WO9931117-A1 Cancer HTGAU75 Y38386 WO9935158-A1 Immune/Hematopoietic HTTDP47 Y38387 WO9935158-A1 Cancer HTXJQ11 Y38388 WO9935158-A1 Cancer HADCO45 Y38389 WO9935158-A1 Cancer HMIAL37 Y38390 WO9935158-A1 Cancer HNGDU40 Y38391 WO9935158-A1 Immune/Hematopoietic HFXBO84 Y38392 WO9935158-A1 Neural/Sensory HLLAX19 Y38393 WO9935158-A1 Cancer HPMAG94 Y38394 WO9935158-A1 Cancer HSVAK93 Y38395 WO9935158-A1 Cancer HMQBO88 Y38396 WO9935158-A1 Cancer HMQBU45 Y38397 WO9935158-A1 Immune/Hematopoietic HMWAJ53 Y38398 WO9935158-A1 Immune/Hematopoietic HCUGO12 Y38401 WO9935158-A1 Digestive, Immune/Hematopoietic, Mixed Fetal HPFCX44 Y38402 WO9935158-A1 Cancer HCUBV79 Y38403 WO9935158-A1 Immune/Hematopoietic, Neural/Sensory HLQBV04 Y38404 WO9935158-A1 Cancer HMADW66 Y38405 WO9935158-A1 Cancer HLDBE54 Y38406 WO9935158-A1 Digestive, Reproductive HFTAB66 Y38407 WO9935158-A1 Digestive, Neural/Sensory HEOMQ63 Y38408 WO9935158-A1 Digestive, Immune/Hematopoietic HDPJM30 Y38409 WO9935158-A1 Immune/Hematopoietic, Neural/Sensory HCFMG62 Y38410 WO9935158-A1 Cancer HJMAG88 Y38411 WO9935158-A1 Cancer HKAAH36 Y38412 WO9935158-A1 Connective/Epithelial, Reproductive HMADS41 Y38413 WO9935158-A1 Cancer HMEFT85 Y38414 WO9935158-A1 Cancer HMSBX80 Y38415 WO9935158-A1 Immune/Hematopoietic, Reproductive HNGCL23 Y38416 WO9935158-A1 Immune/Hematopoietic HPIBO15 Y38418 WO9935158-A1 Cancer HCYBG92 Y38419 WO9935158-A1 Cancer HMDAQ29 Y38420 WO9935158-A1 Neural/Sensory, Reproductive HSYBI49 Y38421 WO9935158-A1 Cancer HDTAB58 Y38422 WO9935158-A1 Cancer HFTAB66 Y38423 WO9935158-A1 Digestive, Neural/Sensory HDPBX23 Y38424 WO9935158-A1 Immune/Hematopoietic, Neural/Sensory HCFMG62 Y38425 WO9935158-A1 Cancer HKAAH36 Y38426 WO9935158-A1 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HTTBI76 Y41347 WO9947540-A1 Cancer HTWKG71 Y41348 WO9947540-A1 Immune/Hematopoietic HTXDN32 Y41349 WO9947540-A1 Cancer HTSGX80 Y41350 WO9947540-A1 Cancer HTXEY51 Y41351 WO9947540-A1 Endocrine, Immune/Hematopoietic, Mixed Fetal HTXFH55 Y41352 WO9947540-A1 Cardiovascular, Immune/Hematopoietic HTXJW17 Y41353 WO9947540-A1 Digestive, Immune/Hematopoietic HUFCJ30 Y41354 WO9947540-A1 Cancer HWAAP70 Y41355 WO9947540-A1 Immune/Hematopoietic HWABW49 Y41356 WO9947540-A1 Immune/Hematopoietic HWBDP28 Y41357 WO9947540-A1 Cancer HWDAC39 Y41358 WO9947540-A1 Connective/Epithelial HWHGQ49 Y41359 WO9947540-A1 Cancer HJPAD75 Y41360 WO9947540-A1 Cancer HLDRP33 Y41361 WO9947540-A1 Digestive, Neural/Sensory HMSIE02 Y41362 WO9947540-A1 Cancer HNGFE55 Y41363 WO9947540-A1 Immune/Hematopoietic HRAAJ19 Y41365 WO9947540-A1 Cancer HSAWV96 Y41366 WO9947540-A1 Immune/Hematopoietic, Neural/Sensory HSBBT37 Y41367 WO9947540-A1 Cancer HSDZR57 Y41368 WO9947540-A1 Cancer HCECQ07 Y41369 WO9947540-A1 Cancer HWBCP79 Y41370 WO9947540-A1 Immune/Hematopoietic, Reproductive HYAAL70 Y41371 WO9947540-A1 Cancer HYAAY86 Y41372 WO9947540-A1 Immune/Hematopoietic HAPBS03 Y41373 WO9947540-A1 Cancer HBJLC01 Y41374 WO9947540-A1 Immune/Hematopoietic HBLKD56 Y41375 WO9947540-A1 Musculoskeletal HCENK38 Y41376 WO9947540-A1 Cancer HE6GA29 Y41379 WO9947540-A1 Mixed Fetal HETHO95 Y41381 WO9947540-A1 Digestive, Reproductive HFCFJ18 Y41382 WO9947540-A1 Cancer HFPBM30 Y41383 WO9947540-A1 Neural/Sensory HFXKT05 Y41384 WO9947540-A1 Cancer HKB1E57 Y41385 WO9947540-A1 Cancer HLWAD77 Y41386 WO9947540-A1 Cancer HLWAY54 Y41387 WO9947540-A1 Immune/Hematopoietic, Neural/Sensory, Reproductive HNGBU28 Y41388 WO9947540-A1 Immune/Hematopoietic HOUHH51 Y41389 WO9947540-A1 Cancer HRAAB15 Y41390 WO9947540-A1 Digestive, Excretory HSAVH65 Y41391 WO9947540-A1 Digestive, Immune/Hematopoietic, Reproductive HSDGN55 Y41392 WO9947540-A1 Cancer HSXAH81 Y41393 WO9947540-A1 Cancer HSXBX80 Y41394 WO9947540-A1 Cancer HTEHV08 Y41395 WO9947540-A1 Cancer HUFAK67 Y41396 WO9947540-A1 Digestive, Immune/Hematopoietic, Reproductive HUSXS50 Y41397 WO9947540-A1 Cancer HAPON17 Y41398 WO9947540-A1 Cancer HATAC53 Y41399 WO9947540-A1 Cancer HAMFK58 Y41400 WO9947540-A1 Cancer HLYCH68 Y41401 WO9947540-A1 Cancer HCUHK65 Y41402 WO9947540-A1 Cancer HLDCD04 Y41403 WO9947540-A1 Cancer HOUHH51 Y41404 WO9947540-A1 Cancer HSLCQ82 Y41571 WO9947540-A1 Cancer HCGMD59 Y45257 WO9946289-A1 Cancer HCNSD76 Y45258 WO9946289-A1 Digestive HCNSD93 Y45259 WO9946289-A1 Digestive HCWBE22 Y45260 WO9946289-A1 Immune/Hematopoietic, Neural/Sensory HFEAN33 Y45261 WO9946289-A1 Cancer HCWUM50 Y45262 WO9946289-A1 Cancer HDHIA94 Y45263 WO9946289-A1 Excretory, Neural/Sensory HDPAE76 Y45264 WO9946289-A1 Cancer HDPIO54 Y45265 WO9946289-A1 Immune/Hematopoietic, Reproductive HDPNC61 Y45266 WO9946289-A1 Cancer HDPND46 Y45267 WO9946289-A1 Immune/Hematopoietic HDPSU13 Y45268 WO9946289-A1 Immune/Hematopoietic HDTGC73 Y45269 WO9946289-A1 Cancer HE2PD49 Y45270 WO9946289-A1 Cancer HEEAJ02 Y45271 WO9946289-A1 Cancer HELHD64 Y45272 WO9946289-A1 Cancer HEPAD91 Y45273 WO9946289-A1 Digestive, Reproductive HEQBH65 Y45274 WO9946289-A1 Immune/Hematopoietic, Reproductive HETCO02 Y45275 WO9946289-A1 Cancer HFAUO78 Y45276 WO9946289-A1 Cancer HFKEE48 Y45277 WO9946289-A1 Cancer HFKFG02 Y45278 WO9946289-A1 Excretory, Immune/Hematopoietic, Neural/Sensory H2CBN14 Y45279 WO9946289-A1 Cancer HHFFJ48 Y45280 WO9946289-A1 Cardiovascular, Immune/Hematopoietic HILCF66 Y45281 WO9946289-A1 Cancer HKABN45 Y45282 WO9946289-A1 Cancer HKDBK22 Y45284 WO9946289-A1 Excretory HKGAZ06 Y45286 WO9946289-A1 Immune/Hematopoietic HKGCK61 Y45287 WO9946289-A1 Cancer HFEAN33 Y45288 WO9946289-A1 Cancer HDHIA94 Y45289 WO9946289-A1 Excretory, Neural/Sensory HDPJO39 Y52479 WO9940184-A1 Cancer HNTCF82 Y58185 US6004780-A Cardiovascular, Connective/Epithelial, Reproductive HETAB62 Y59285 WO200004183-A1 Cancer HSYAE36 Y59286 WO200004183-A1 Cancer HKAPI15 Y68800 WO200005371-A1 Connective/Epithelial HUJCT9C Y72090 WO200068247-A2 Cancer HMGBM65 Y72091 WO200068247-A2 Cancer HATEE38 Y72092 WO200068247-A2 Cancer HCHAK72 Y72093 WO200068247-A2 Cancer HHFBJ67 Y72094 WO200068247-A2 Cardiovascular, Neural/Sensory HTTJK5C Y72095 WO200068247-A2 Cancer HWLGJ11 Y72096 WO200068247-A2 Digestive HTLEG15 Y72097 WO200068247-A2 Cancer HAGAS16 Y72098 WO200068247-A2 Neural/Sensory HATEE38 Y72108 WO200068247-A2 Cancer HKABZ65 Y76124 WO9958660-A1 Connective/Epithelial HNGIC80 Y76125 WO9958660-A1 Immune/Hematopoietic HDPUG50 Y76126 WO9958660-A1 Cancer HAEAB66 Y76127 WO9958660-A1 Cancer HHEPF59 Y76128 WO9958660-A1 Cancer HE9BK23 Y76129 WO9958660-A1 Digestive, Mixed Fetal HCYBI36 Y76130 WO9958660-A1 Cancer HSSDX51 Y76131 WO9958660-A1 Cancer HSDAJ46 Y76132 WO9958660-A1 Cancer HRACG45 Y76133 WO9958660-A1 Cancer HAPPW30 Y76134 WO9958660-A1 Cancer HE2ES51 Y76135 WO9958660-A1 Cancer HTXDW56 Y76136 WO9958660-A1 Cancer HDPKI93 Y76138 WO9958660-A1 Cancer HDLAC10 Y76139 WO9958660-A1 Cancer HDPOH06 Y76140 WO9958660-A1 Cancer HCE4G61 Y76141 WO9958660-A1 Cancer HCWUI13 Y76142 WO9958660-A1 Immune/Hematopoietic HDPSP01 Y76143 WO9958660-A1 Cancer HHPEN62 Y76144 WO9958660-A1 Cancer HUKBT29 Y76145 WO9958660-A1 Cancer HARAP48 Y76146 WO9958660-A1 Cancer HBIMB51 Y76147 WO9958660-A1 Connective/Epithelial, Reproductive HE8DX88 Y76148 WO9958660-A1 Mixed Fetal HNGHT03 Y76149 WO9958660-A1 Immune/Hematopoietic HWABU17 Y76150 WO9958660-A1 Cancer HCE5F84 Y76151 WO9958660-A1 Cancer HBXCD55 Y76152 WO9958660-A1 Cancer HOVCB25 Y76153 WO9958660-A1 Reproductive HSYAV66 Y76154 WO9958660-A1 Digestive, Immune/Hematopoietic HFPCT29 Y76155 WO9958660-A1 Neural/Sensory HAWAT25 Y76156 WO9958660-A1 Cancer HNHFR04 Y76157 WO9958660-A1 Immune/Hematopoietic HOSFT61 Y76158 WO9958660-A1 Cancer HBJIO81 Y76159 WO9958660-A1 Immune/Hematopoietic HADCL55 Y76160 WO9958660-A1 Cancer HAGGJ80 Y76161 WO9958660-A1 Cancer HAIBO81 Y76162 WO9958660-A1 Neural/Sensory HBBBC37 Y76163 WO9958660-A1 Cancer HBJMX85 Y76164 WO9958660-A1 Cancer HCEES66 Y76165 WO9958660-A1 Digestive, Neural/Sensory HCEMP62 Y76166 WO9958660-A1 Cancer HE2FB90 Y76167 WO9958660-A1 Cancer HE9DS56 Y76168 WO9958660-A1 Cancer HTOHJ89 Y76169 WO9958660-A1 Immune/Hematopoietic HASCE69 Y76171 WO9958660-A1 Cancer HHTLH52 Y76172 WO9958660-A1 Neural/Sensory, Reproductive HOUCT90 Y76174 WO9958660-A1 Connective/Epithelial HCFLR78 Y76175 WO9958660-A1 Cancer HTOHT18 Y76176 WO9958660-A1 Cancer HKPMB11 Y76177 WO9958660-A1 Digestive, Excretory, Musculoskeletal HNFHS38 Y76178 WO9958660-A1 Cancer HAIBU10 Y76179 WO9958660-A1 Cancer HAPOK30 Y76180 WO9958660-A1 Cancer HCWUA22 Y76182 WO9958660-A1 Immune/Hematopoietic HDSAG91 Y76183 WO9958660-A1 Immune/Hematopoietic HNEDJ35 Y76184 WO9958660-A1 Immune/Hematopoietic, Reproductive HTHBH29 Y76185 WO9958660-A1 Immune/Hematopoietic, Mixed Fetal, Reproductive H7TBA62 Y76186 WO9958660-A1 Cancer HNGIO50 Y76187 WO9958660-A1 Immune/Hematopoietic HMIAW81 Y76188 WO9958660-A1 Immune/Hematopoietic, Neural/Sensory, Reproductive HMMCJ60 Y76189 WO9958660-A1 Immune/Hematopoietic, Musculoskeletal HDPIO09 Y76190 WO9958660-A1 Cancer HHFHH34 Y76191 WO9958660-A1 Cardiovascular HISCL83 Y76192 WO9958660-A1 Digestive HTOAI70 Y76193 WO9958660-A1 Immune/Hematopoietic HSDER95 Y76194 WO9958660-A1 Digestive, Neural/Sensory HNECL25 Y76195 WO9958660-A1 Immune/Hematopoietic HNFGZ45 Y76196 WO9958660-A1 Cardiovascular, Digestive, Immune/Hematopoietic HHGCU49 Y76197 WO9958660-A1 Cancer HETDT81 Y76199 WO9958660-A1 Digestive, Immune/Hematopoietic, Reproductive HHLBA14 Y76200 WO9958660-A1 Cancer HLTBU43 Y76201 WO9958660-A1 Immune/Hematopoietic HNTSJ84 Y76202 WO9958660-A1 Cancer HOHCG16 Y76203 WO9958660-A1 Digestive, Musculoskeletal HTHCB31 Y76204 WO9958660-A1 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HUKAM16 Y76205 WO9958660-A1 Cancer HLDOJ66 Y76206 WO9958660-A1 Digestive HTXKF10 Y76207 WO9958660-A1 Immune/Hematopoietic HPMAI22 Y76208 WO9958660-A1 Reproductive HL2AG57 Y76209 WO9958660-A1 Cancer HUSAM59 Y76210 WO9958660-A1 Cancer HNGGR26 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WO9966041-A1 Immune/Hematopoietic, Reproductive HCHPF68 Y86248 WO9966041-A1 Reproductive HDPJF37 Y86249 WO9966041-A1 Cancer HSDEZ20 Y86250 WO9966041-A1 Neural/Sensory HTEKU58 Y86251 WO9966041-A1 Cancer HLTBL58 Y86252 WO9966041-A1 Immune/Hematopoietic, Musculoskeletal, Neural/Sensory HPWDJ42 Y86253 WO9966041-A1 Digestive, Reproductive HRACD15 Y86254 WO9966041-A1 Cancer HSIAC80 Y86255 WO9966041-A1 Cancer HAGFD18 Y86256 WO9966041-A1 Cancer HAJAP76 Y86257 WO9966041-A1 Cancer HDTGC86 Y86258 WO9966041-A1 Digestive, Immune/Heinatopoietic, Reproductive HAGDI35 Y86259 WO9966041-A1 Cancer HELHN47 Y86260 WO9966041-A1 Cancer HPRBC80 Y86261 WO9966041-A1 Cancer HAQAR23 Y86262 WO9966041-A1 Cancer HAIFL18 Y86263 WO9966041-A1 Digestive, Immune/Hematopoietic HJPAY76 Y86264 WO9966041-A1 Cancer HUSXE77 Y86265 WO9966041-A1 Cancer HUFEF62 Y86266 WO9966041-A1 Digestive HTWJK32 Y86267 WO9966041-A1 Cancer HTWDF76 Y86268 WO9966041-A1 Immune/Hematopoietic HTPBN68 Y86269 WO9966041-A1 Digestive HTOIY21 Y86270 WO9966041-A1 Immune/Hematopoietic HTLDD53 Y86271 WO9966041-A1 Connective/Epithelial, Digestive, Reproductive HTLFG05 Y86272 WO9966041-A1 Cancer HDPXR23 Y86273 WO9966041-A1 Digestive, Immune/Hematopoietic HSIAC45 Y86274 WO9966041-A1 Digestive, Immune/Hematopoietic HSRGW16 Y86275 WO9966041-A1 Cancer HSSJC35 Y86276 WO9966041-A1 Cancer HTEAX23 Y86277 WO9966041-A1 Reproductive HTGCH22 Y86278 WO9966041-A1 Immune/Hematopoietic, Mixed Fetal, Reproductive HTJMA95 Y86279 WO9966041-A1 Cancer HHEAA08 Y86280 WO9966041-A1 Immune/Hematopoietic HBQAA49 Y86281 WO9966041-A1 Neural/Sensory HDPBI32 Y86282 WO9966041-A1 Excretory, Immune/Hematopoietic, Neural/Sensory HBIBF16 Y86283 WO9966041-A1 Neural/Sensory HBCAY05 Y86284 WO9966041-A1 Cancer HCUCK44 Y86285 WO9966041-A1 Cancer HCE2W56 Y86286 WO9966041-A1 Cancer HCWAG01 Y86287 WO9966041-A1 Immune/Hematopoietic HDRMI82 Y86289 WO9966041-A1 Cancer HEPCU48 Y86290 WO9966041-A1 Cancer HDPRK33 Y86291 WO9966041-A1 Immune/Hematopoietic, Mixed Fetal HKGAX42 Y86292 WO9966041-A1 Digestive, Immune/Hematopoietic, Reproductive HLMAZ95 Y86293 WO9966041-A1 Cancer HLMFC07 Y86294 WO9966041-A1 Digestive, Immune/Hematopoietic HL2AG87 Y86295 WO9966041-A1 Immune/Hematopoietic, Neural/Sensory, Reproductive HKGCO27 Y86296 WO9966041-A1 Cancer HLDCE79 Y86297 WO9966041-A1 Digestive HERAD40 Y86298 WO9966041-A1 Connective/Epithelial HFOXB55 Y86299 WO9966041-A1 Cancer HFVGZ42 Y86300 WO9966041-A1 Cancer HNHAF39 Y86301 WO9966041-A1 Immune/Hematopoietic HNTSW57 Y86302 WO9966041-A1 Cancer HOGCK20 Y86303 WO9966041-A1 Cancer HLYES38 Y86305 WO9966041-A1 Immune/Hematopoietic, Reproductive HMECK83 Y86306 WO9966041-A1 Cardiovascular HMQAG66 Y86308 WO9966041-A1 Immune/Hematopoietic HWBBP10 Y86309 WO9966041-A1 Immune/Hematopoietic, Neural/Sensory HAPAK52 Y86310 WO9966041-A1 Cancer HDPWU34 Y86311 WO9966041-A1 Cancer HKACU58 Y86312 WO9966041-A1 Cancer HLDBQ19 Y86314 WO9966041-A1 Cancer HNTMX29 Y86315 WO9966041-A1 Cancer HOABR60 Y86316 WO9966041-A1 Cancer HPWDJ42 Y86317 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HFSAG79 W58960 WO9814477-A1 Cancer HFSAG79 W58961 WO9814477-A1 Cancer HFSAG79 W58962 WO9814477-A1 Cancer HFSAG79 W58963 WO9814477-A1 Cancer HFSAG79 W58964 WO9814477-A1 Cancer HFSAG79 W58965 WO9814477-A1 Cancer HFSAG79 W58966 WO9814477-A1 Cancer HFSAG79 W58967 WO9814477-A1 Cancer HFSAG79 W58968 WO9814477-A1 Cancer HFSAG79 W58969 WO9814477-A1 Cancer HFSAG79 W58970 WO9814477-A1 Cancer HFSAG79 W58971 WO9814477-A1 Cancer HFSAG79 W58972 WO9814477-A1 Cancer HFSAG79 W58973 WO9814477-A1 Cancer HFSAG79 W58974 WO9814477-A1 Cancer HFSAG79 W58975 WO9814477-A1 Cancer HCEGH45 W59666 WO9824900-A1 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HHFCU19 W59753 US5786193-A Cancer HLMBP36 W59872 WO9831792-A1 Cancer HEMFI85 W59873 WO9831800-A2 Cancer HTXET53 W59874 WO9831800-A2 Cancer HBZAK03 W59876 WO9831800-A2 Cancer HLFBD44 W59877 WO9831800-A2 Cancer HEBGM49 W59878 WO9831800-A2 Cancer HNGBH54 W59879 WO9831800-A2 Cancer HSAAL25 W59880 WO9831800-A2 Cancer HSXCK41 W59882 WO9831800-A2 Cancer HFKFY79 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US5986069-A Cancer HSBBC75 Y55748 US5994103-A Cancer HLFBE10 Y55750 US5994103-A Cancer HLFBE10 Y57166 US5994301-A Cancer HIBCL22 Y57167 US5994506-A Cancer HTTER36 Y58185 US6004780-A Cardiovascular, Connective/Epithelial, Reproductive HWHGU74 Y59247 WO9962927-A1 Cancer HSDFB55 Y67239 US6008020-A Cancer HE2BG16 Y67356 US5998164-A Cancer HKAPI15 Y68800 WO200005371-A1 Connective/Epithelial HTWAF38 Y69674 US6013483-A Cancer HATCK89 Y69675 US6013477-A Cancer HAPOR40 Y70591 WO200015759-A1 Cancer HMUAN45 Y70785 WO200023572-A1 Cancer HATCK89 Y71884 WO200067775-A1 Cancer HKGDL36 Y71959 WO200066778-A1 Cancer HCUDS60 Y72022 WO200067793-A1 Cancer HCUDS60 Y72023 WO200067793-A1 Cancer HETAN67 Y78790 US6013469-A Cancer HDGNR10 Y80128 US6025154-A Digestive, Immune/Hematopoietic, Reproductive HBGBA67 Y87779 US6054289-A Cancer HE2CB95 Y87780 US6054289-A Immune/Hematopoietic, Mixed Fetal HPTTK55 Y87782 US6054289-A Cancer HARAO63 Y87783 US6054289-A Cancer HLHAR55 Y87787 US6054289-A Cancer HSRDG78 Y87788 US6054289-A Cancer HCCAA03 Y87789 US6054289-A Cancer HWLLM34 Y90351 WO200052136-A2 Cancer HA5AA37 Y90352 WO200052136-A2 Cancer HDPAK85 Y90353 WO200052136-A2 Cancer HPHAE52 Y90357 WO200052028-A1 Cancer HTPCH84 Y90358 WO200052028-A1 Cancer HMKEA94 Y93650 WO200036105-A1 Cancer HOEDH76 Y93912 WO200039166-A1 Cancer HOGCC45 Y93951 WO200039136-A2 Cancer HTSGS30 Y93973 WO200042189-A1 Digestive, Immune/Hematopoietic, Mixed Fetal HTSGS30 Y93975 WO200042189-A1 Digestive, Immune/Hematopoietic, Mixed Fetal HMWCF06 Y94802 WO200009148-A1 Cancer HE9DR66 Y95534 WO200040726-A1 Cancer HGBAN46 Y95535 WO200040726-A1 Cancer HE9DR66 Y95563 WO200040726-A1 Cancer HE9DR66 Y95565 WO200040726-A1 Cancer HE9DR66 Y95566 WO200040726-A1 Cancer HE9DR66 Y95567 WO200040726-A1 Cancer HE9DR66 Y95568 WO200040726-A1 Cancer HE9DR66 Y95569 WO200040726-A1 Cancer HE9DR66 Y95570 WO200040726-A1 Cancer HE9DR66 Y95571 WO200040726-A1 Cancer HE9DR66 Y95572 WO200040726-A1 Cancer HE9DR66 Y95573 WO200040726-A1 Cancer HE9DR66 Y95574 WO200040726-A1 Cancer HE9DR66 Y95575 WO200040726-A1 Cancer HE9DR66 Y95576 WO200040726-A1 Cancer HE9DR66 Y95577 WO200040726-A1 Cancer HE9DR66 Y95578 WO200040726-A1 Cancer HHEAC71 Y95879 WO200050459-A1 Connective/Epithelial, Immune/Hematopoietic HCFAZ22 Y95880 WO200050459-A1 Cancer HT5EA78 Y95881 WO200050459-A1 Connective/Epithelial, Immune/Hematopoietic HDPAK85 Y96099 WO200052135-A2 Cancer HWLLM34 Y96100 WO200052135-A2 Cancer HA5AA37 Y96101 WO200052135-A2 Cancer HAPAT57 Y96280 WO200028035-A1 Cancer HAPAT57 Y96282 WO200028035-A1 Cancer HKABZ65 Y96962 WO200039327-A1 Connective/Epithelial HWHGB15 Y96963 WO200039327-A1 Connective/Epithelial HCDDP40 Y96964 WO200039327-A1 Immune/Hematopoietic, Musculoskeletal HOSBD47 Y97144 WO200045835-A1 Cancer HOSBD47 Y97145 WO200045835-A1 Cancer HFITF82 SEQ ID NO: 73 Immune/Hematopoietic, Musculoskeletal HFITF82 SEQ ID NO: 74 Immune/Hematopoietic, Musculoskeletal HFITF82 SEQ ID NO: 75 Immune/Hematopoietic, Musculoskeletal HFITF82 SEQ ID NO: 76 Immune/Hematopoietic, Musculoskeletal HBZAI19 SEQ ID NO: 77 Immune/Hematopoietic, Reproductive HBZAI19 SEQ ID NO: 78 Immune/Hematopoietic, Reproductive HBZAI19 SEQ ID NO: 79 Immune/Hematopoietic, Reproductive HDPDI45 SEQ ID NO: 80 Cancer HDPDI45 SEQ ID NO: 81 Cancer HETHW90 SEQ ID NO: 82 Cancer HETHW90 SEQ ID NO: 83 Cancer HETHW90 SEQ ID NO: 84 Cancer HIBEB47 SEQ ID NO: 85 Digestive, Mixed Fetal, Neural/Sensory HIBEB47 SEQ ID NO: 86 Digestive, Mixed Fetal, Neural/Sensory HIBEB47 SEQ ID NO: 87 Digestive, Mixed Fetal, Neural/Sensory HIBEB47 SEQ ID NO: 88 Digestive, Mixed Fetal, Neural/Sensory HLHFR58 SEQ ID NO: 89 Cancer HLHFR58 SEQ ID NO: 90 Cancer HLHFR58 SEQ ID NO: 91 Cancer HLHFR58 SEQ ID NO: 92 Cancer HNGGK54 SEQ ID NO: 93 Cancer HNGGK54 SEQ ID NO: 94 Cancer HNGGK54 SEQ ID NO: 95 Cancer HNGGK54 SEQ ID NO: 96 Cancer HUSIE23 SEQ ID NO: 97 Cancer HUSIE23 SEQ ID NO: 98 Cancer HARMB79 SEQ ID NO: 99 Cancer HARMB79 SEQ ID NO: 100 Cancer HJBCY84 SEQ ID NO: 101 Cancer HJBCY84 SEQ ID NO: 102 Cancer HJBCY84 SEQ ID NO: 103 Cancer HCMSC92 SEQ ID NO: 104 Cancer HCMSC92 SEQ ID NO: 105 Cancer HE2AX96 SEQ ID NO: 106 Mixed Fetal HE2AX96 SEQ ID NO: 107 Mixed Fetal HE2AX96 SEQ ID NO: 108 Mixed Fetal HHPDV90 SEQ ID NO: 109 Cancer HHPDV90 SEQ ID NO: 110 Cancer HHPDV90 SEQ ID NO: 111 Cancer HT2SG64 SEQ ID NO: 112 Digestive, Immune/Hematopoietic HT2SG64 SEQ ID NO: 113 Digestive, Immune/Hematopoietic HT2SG64 SEQ ID NO: 114 Digestive, Immune/Hematopoietic HAGAN21 SEQ ID NO: 115 Digestive, Immune/Hematopoietic, Neural/Sensory HAGAN21 SEQ ID NO: 116 Digestive, Immune/Hematopoietic, Neural/Sensory HAGAN21 SEQ ID NO: 117 Digestive, Immune/Hematopoietic, Neural/Sensory HAGAN21 SEQ ID NO: 118 Digestive, Immune/Hematopoietic, Neural/Sensory HAGAN21 SEQ ID NO: 119 Digestive, Immune/Hematopoietic, Neural/Sensory HEBAH57 SEQ ID NO: 120 Neural/Sensory HEBAH57 SEQ ID NO: 121 Neural/Sensory HEBAH57 SEQ ID NO: 122 Neural/Sensory HETDB76 SEQ ID NO: 123 Musculoskeletal, Reproductive HETDB76 SEQ ID NO: 124 Musculoskeletal, Reproductive HETDB76 SEQ ID NO: 125 Musculoskeletal, Reproductive HETDB76 SEQ ID NO: 126 Musculoskeletal, Reproductive HE8SE91 SEQ ID NO: 127 Cancer HE8SE91 SEQ ID NO: 128 Cancer HE8SE91 SEQ ID NO: 129 Cancer HRGBL78 SEQ ID NO: 130 Cancer HRGBL78 SEQ ID NO: 131 Cancer HRGBL78 SEQ ID NO: 132 Cancer HRGBL78 SEQ ID NO: 133 Cancer HHFUC40 SEQ ID NO: 134 Cardiovascular HHFUC40 SEQ ID NO: 135 Cardiovascular HETCP58 SEQ ID NO: 136 Immune/Hematopoietic, Reproductive HETCP58 SEQ ID NO: 137 Immune/Hematopoietic, Reproductive HETCP58 SEQ ID NO: 138 Immune/Hematopoietic, Reproductive HTTBM40 SEQ ID NO: 139 Cancer HTTBM40 SEQ ID NO: 140 Cancer HTTBS64 SEQ ID NO: 141 Reproductive HTTBS64 SEQ ID NO: 142 Reproductive HTTBS64 SEQ ID NO: 143 Reproductive HCEVB32 SEQ ID NO: 144 Cancer HCEVB32 SEQ ID NO: 145 Cancer HCEVB32 SEQ ID NO: 146 Cancer HCEVB32 SEQ ID NO: 147 Cancer HHPFU18 SEQ ID NO: 148 Cancer HHPFU18 SEQ ID NO: 149 Cancer HPRCA90 SEQ ID NO: 150 Cancer HPRCA90 SEQ ID NO: 151 Cancer HPRCA90 SEQ ID NO: 152 Cancer HPRCA90 SEQ ID NO: 153 Cancer HPRCE33 SEQ ID NO: 154 Cancer HPRCE33 SEQ ID NO: 155 Cancer HHFFU55 SEQ ID NO: 156 Cardiovascular, Immune/Hematopoietic HHFFU55 SEQ ID NO: 157 Cardiovascular, Immune/Hematopoietic HUVDP63 SEQ ID NO: 158 Cancer HUVDP63 SEQ ID NO: 159 Cancer HUVDP63 SEQ ID NO: 160 Cancer HUVDP63 SEQ ID NO: 161 Cancer HUVDP63 SEQ ID NO: 162 Cancer HCEFI77 SEQ ID NO: 163 Neural/Sensory HCEFI77 SEQ ID NO: 164 Neural/Sensory HCEFI77 SEQ ID NO: 165 Neural/Sensory HHFDH56 SEQ ID NO: 166 Cancer HHFDN48 SEQ ID NO: 167 Cancer HHFDN48 SEQ ID NO: 168 Cancer HHFDN48 SEQ ID NO: 169 Cancer HHFDN48 SEQ ID NO: 170 Cancer HHFDN48 SEQ ID NO: 171 Cancer HHFDN67 SEQ ID NO: 172 Cardiovascular HHFDN67 SEQ ID NO: 173 Cardiovascular HHFDG51 SEQ ID NO: 174 Connective/Epithelial, Musculoskeletal HHFDG51 SEQ ID NO: 175 Connective/Epithelial, Musculoskeletal HHFDG51 SEQ ID NO: 176 Connective/Epithelial, Musculoskeletal HE8AO36 SEQ ID NO: 177 Cancer HE8AO36 SEQ ID NO: 178 Cancer HE8AO36 SEQ ID NO: 179 Cancer HTPAB57 SEQ ID NO: 180 Cancer HTPAB57 SEQ ID NO: 181 Cancer HTPAB57 SEQ ID NO: 182 Cancer HTPAB57 SEQ ID NO: 183 Cancer HFXAX45 SEQ ID NO: 184 Neural/Sensory HFXAX45 SEQ ID NO: 185 Neural/Sensory HFXAX45 SEQ ID NO: 186 Neural/Sensory HTLBE23 SEQ ID NO: 187 Reproductive HTLBE23 SEQ ID NO: 188 Reproductive HCQAM33 SEQ ID NO: 189 Musculoskeletal, Reproductive HCQAM33 SEQ ID NO: 190 Musculoskeletal, Reproductive HCQAM33 SEQ ID NO: 191 Musculoskeletal, Reproductive HCEWE17 SEQ ID NO: 192 Digestive, Neural/Sensory HCEWE17 SEQ ID NO: 193 Digestive, Neural/Sensory HCEWE17 SEQ ID NO: 194 Digestive, Neural/Sensory HTEGI42 SEQ ID NO: 195 Cancer HTEGI42 SEQ ID NO: 196 Cancer HTEGI42 SEQ ID NO: 197 Cancer HTEGI42 SEQ ID NO: 198 Cancer HTEGI42 SEQ ID NO: 199 Cancer HCEIE80 SEQ ID NO: 200 Cancer HCEIE80 SEQ ID NO: 201 Cancer HCEIE80 SEQ ID NO: 202 Cancer HCEIE80 SEQ ID NO: 203 Cancer HLMCA92 SEQ ID NO: 204 Digestive, Immune/Hematopoietic, Neural/Sensory HLMCA92 SEQ ID NO: 205 Digestive, Immune/Hematopoietic, Neural/Sensory HLMCA92 SEQ ID NO: 206 Digestive, Immune/Hematopoietic, Neural/Sensory HLMCA92 SEQ ID NO: 207 Digestive, Immune/Hematopoietic, Neural/Sensory HLHCF36 SEQ ID NO: 208 Respiratory HLHCF36 SEQ ID NO: 209 Respiratory HLHCF36 SEQ ID NO: 210 Respiratory HCEZR26 SEQ ID NO: 211 Cancer HCEZR26 SEQ ID NO: 212 Cancer HGBCO51 SEQ ID NO: 213 Cancer HGBCO51 SEQ ID NO: 214 Cancer HGBCO51 SEQ ID NO: 215 Cancer HGBCO51 SEQ ID NO: 216 Cancer HTABP30 SEQ ID NO: 217 Cancer HTABP30 SEQ ID NO: 218 Cancer HUKCD10 SEQ ID NO: 219 Cancer HUKCD10 SEQ ID NO: 220 Cancer HUKCD10 SEQ ID NO: 221 Cancer HOUHT39 SEQ ID NO: 222 Cancer HOUHT39 SEQ ID NO: 223 Cancer HOUHT39 SEQ ID NO: 224 Cancer HTXBN56 SEQ ID NO: 225 Cancer HTXBN56 SEQ ID NO: 226 Cancer HTXBN56 SEQ ID NO: 227 Cancer HETEU28 SEQ ID NO: 228 Cancer HETEU28 SEQ ID NO: 229 Cancer HODDD43 SEQ ID NO: 230 Cancer HODDD43 SEQ ID NO: 231 Cancer HODDD43 SEQ ID NO: 232 Cancer HPWAL61 SEQ ID NO: 233 Musculoskeletal, Reproductive HPWAL61 SEQ ID NO: 234 Musculoskeletal, Reproductive HPWAL61 SEQ ID NO: 235 Musculoskeletal, Reproductive HPWAL61 SEQ ID NO: 236 Musculoskeletal, Reproductive HTSER67 SEQ ID NO: 237 Cancer HTSER67 SEQ ID NO: 238 Cancer HMSDL37 SEQ ID NO: 239 Cancer HMSDL37 SEQ ID NO: 240 Cancer HMSDL37 SEQ ID NO: 241 Cancer HMSDL37 SEQ ID NO: 242 Cancer HSDAJ53 SEQ ID NO: 243 Cancer HSDAJ53 SEQ ID NO: 244 Cancer HSDAJ53 SEQ ID NO: 245 Cancer HSDAJ53 SEQ ID NO: 246 Cancer HEBDF05 SEQ ID NO: 247 Neural/Sensory HEBDF05 SEQ ID NO: 248 Neural/Sensory HEBDF05 SEQ ID NO: 249 Neural/Sensory HSQFT30 SEQ ID NO: 250 Cancer HSQFT30 SEQ ID NO: 251 Cancer HSIDX71 SEQ ID NO: 252 Digestive, Neural/Sensory HSIDX71 SEQ ID NO: 253 Digestive, Neural/Sensory HSAUA82 SEQ ID NO: 254 Immune/Hematopoietic, Reproductive HSAUA82 SEQ ID NO: 255 Immune/Hematopoietic, Reproductive HPWAY46 SEQ ID NO: 256 Cancer HPWAY46 SEQ ID NO: 257 Cancer HPWAY46 SEQ ID NO: 258 Cancer HSSEN70 SEQ ID NO: 259 Cancer HSSEN70 SEQ ID NO: 260 Cancer HTOHB55 SEQ ID NO: 261 Cancer HTOHB55 SEQ ID NO: 262 Cancer HTOHM15 SEQ ID NO: 263 Cancer HTOHM15 SEQ ID NO: 264 Cancer HTOHM15 SEQ ID NO: 265 Cancer HTOHM15 SEQ ID NO: 266 Cancer HHNAB56 SEQ ID NO: 267 Digestive HHNAB56 SEQ ID NO: 268 Digestive HHNAB56 SEQ ID NO: 269 Digestive HJABL02 SEQ ID NO: 270 Cancer HJABL02 SEQ ID NO: 271 Cancer HJACG30 SEQ ID NO: 272 Immune/Hematopoietic HJACG30 SEQ ID NO: 273 Immune/Hematopoietic HJACG30 SEQ ID NO: 274 Immune/Hematopoietic HTAEE28 SEQ ID NO: 275 Digestive, Immune/Hematopoietic, Mixed Fetal HTAEE28 SEQ ID NO: 276 Digestive, Immune/Hematopoietic, Mixed Fetal HTAEE28 SEQ ID NO: 277 Digestive, Immune/Hematopoietic, Mixed Fetal HTHBG43 SEQ ID NO: 278 Immune/Hematopoietic HTHBG43 SEQ ID NO: 279 Immune/Hematopoietic HJPCE80 SEQ ID NO: 280 Cancer HJPCE80 SEQ ID NO: 281 Cancer HJPCE80 SEQ ID NO: 282 Cancer HTOIZ02 SEQ ID NO: 283 Cancer HTOIZ02 SEQ ID NO: 284 Cancer HJPCR70 SEQ ID NO: 285 Cancer HJPCR70 SEQ ID NO: 286 Cancer HJPCR70 SEQ ID NO: 287 Cancer HJPCR70 SEQ ID NO: 288 Cancer HJPCP42 SEQ ID NO: 289 Digestive, Immune/Hematopoietic HJPCP42 SEQ ID NO: 290 Digestive, Immune/Hematopoietic HJPCP42 SEQ ID NO: 291 Digestive, Immune/Hematopoietic HJPCP42 SEQ ID NO: 292 Digestive, Immune/Hematopoietic HNFFD47 SEQ ID NO: 293 Immune/Hematopoietic HNFFD47 SEQ ID NO: 294 Immune/Hematopoietic HNFFD47 SEQ ID NO: 295 Immune/Hematopoietic HNFFI46 SEQ ID NO: 296 Cancer HNFFI46 SEQ ID NO: 297 Cancer HNFFI46 SEQ ID NO: 298 Cancer HNFFI46 SEQ ID NO: 299 Cancer HNFFI46 SEQ ID NO: 300 Cancer HTOIQ42 SEQ ID NO: 301 Cancer HTOIQ42 SEQ ID NO: 302 Cancer HLTDW13 SEQ ID NO: 303 Cancer HLTDW13 SEQ ID NO: 304 Cancer HLTDW13 SEQ ID NO: 305 Cancer HLTDW13 SEQ ID NO: 306 Cancer HLTDW13 SEQ ID NO: 307 Cancer HLTDY51 SEQ ID NO: 308 Cancer HLTDY51 SEQ ID NO: 309 Cancer HNFFZ56 SEQ ID NO: 310 Cancer HNFFZ56 SEQ ID NO: 311 Cancer HNGAV54 SEQ ID NO: 312 Immune/Hematopoietic HNGAV54 SEQ ID NO: 313 Immune/Hematopoietic HSLCA15 SEQ ID NO: 314 Cancer HSLCA15 SEQ ID NO: 315 Cancer HSLCA15 SEQ ID NO: 316 Cancer HSLCA15 SEQ ID NO: 317 Cancer HSLCA15 SEQ ID NO: 318 Cancer HSLCA15 SEQ ID NO: 319 Cancer HSLCP57 SEQ ID NO: 320 Cancer HSLCP57 SEQ ID NO: 321 Cancer HTOJP95 SEQ ID NO: 322 Immune/Hematopoietic HTOJP95 SEQ ID NO: 323 Immune/Hematopoietic HBMVI55 SEQ ID NO: 324 Cancer HBMVI55 SEQ ID NO: 325 Cancer HBMVI55 SEQ ID NO: 326 Cancer HBMVI55 SEQ ID NO: 327 Cancer HBMVI55 SEQ ID NO: 328 Cancer HFXBS68 SEQ ID NO: 329 Neural/Sensory HFXBS68 SEQ ID NO: 330 Neural/Sensory HFXBS68 SEQ ID NO: 331 Neural/Sensory HFXBS68 SEQ ID NO: 332 Neural/Sensory HNGBC07 SEQ ID NO: 333 Immune/Hematopoietic HNGBC07 SEQ ID NO: 334 Immune/Hematopoietic HNGBC07 SEQ ID NO: 335 Immune/Hematopoietic HMSFK67 SEQ ID NO: 336 Cancer HMSFK67 SEQ ID NO: 337 Cancer HMSFK67 SEQ ID NO: 338 Cancer HCE1P80 SEQ ID NO: 339 Cancer HCE1P80 SEQ ID NO: 340 Cancer HCE1P80 SEQ ID NO: 341 Cancer HOUDU29 SEQ ID NO: 342 Cancer HOUDU29 SEQ ID NO: 343 Cancer HOUDU29 SEQ ID NO: 344 Cancer HOUDU29 SEQ ID NO: 345 Cancer HOUDU29 SEQ ID NO: 346 Cancer HHFEC49 SEQ ID NO: 347 Cancer HCE3T57 SEQ ID NO: 348 Immune/Hematopoietic, Neural/Sensory, Reproductive HCE3T57 SEQ ID NO: 349 Immune/Hematopoietic, Neural/Sensory, Reproductive HCE3T57 SEQ ID NO: 350 Immune/Hematopoietic, Neural/Sensory, Reproductive HCE3T57 SEQ ID NO: 351 Immune/Hematopoietic, Neural/Sensory, Reproductive HCE3T57 SEQ ID NO: 352 Immune/Hematopoietic, Neural/Sensory, Reproductive HCE4Y07 SEQ ID NO: 353 Cancer HCE4Y07 SEQ ID NO: 354 Cancer HCE5G23 SEQ ID NO: 355 Cancer HCE5G23 SEQ ID NO: 356 Cancer HCE5G23 SEQ ID NO: 357 Cancer HFCEP45 SEQ ID NO: 358 Neural/Sensory HFCEP45 SEQ ID NO: 359 Neural/Sensory HFCEP45 SEQ ID NO: 360 Neural/Sensory HFCEP45 SEQ ID NO: 361 Neural/Sensory HMWEJ52 SEQ ID NO: 362 Immune/Hematopoietic HMWEJ52 SEQ ID NO: 363 Immune/Hematopoietic HMWEY26 SEQ ID NO: 364 Cancer HMWEY26 SEQ ID NO: 365 Cancer HMWEY26 SEQ ID NO: 366 Cancer HMWEY26 SEQ ID NO: 367 Cancer HMWEY26 SEQ ID NO: 368 Cancer HATDM46 SEQ ID NO: 369 Cancer HATDM46 SEQ ID NO: 370 Cancer HATDM46 SEQ ID NO: 371 Cancer HATDM46 SEQ ID NO: 372 Cancer HATDM46 SEQ ID NO: 373 Cancer HATDM46 SEQ ID NO: 374 Cancer HHFHD37 SEQ ID NO: 375 Cardiovascular, Immune/Hematopoietic, Respiratory HHFHD37 SEQ ID NO: 376 Cardiovascular, Immune/Hematopoietic, Respiratory HHFHI76 SEQ ID NO: 377 Cancer HHFHI76 SEQ ID NO: 378 Cancer HATDZ29 SEQ ID NO: 379 Endocrine, Immune/Hematopoietic HATDZ29 SEQ ID NO: 380 Endocrine, Immune/Hematopoietic HFVGE32 SEQ ID NO: 381 Digestive, Immune/Hematopoietic HFVGE32 SEQ ID NO: 382 Digestive, Immune/Hematopoietic HLHFE92 SEQ ID NO: 383 Cancer HLHFE92 SEQ ID NO: 384 Cancer HLHFE92 SEQ ID NO: 385 Cancer HMKAI25 SEQ ID NO: 386 Cancer HMKAI25 SEQ ID NO: 387 Cancer HMKAI25 SEQ ID NO: 388 Cancer HMKAI25 SEQ ID NO: 389 Cancer HMKAI25 SEQ ID NO: 390 Cancer HNHEI42 SEQ ID NO: 391 Endocrine, Immune/Hematopoietic HNHEI42 SEQ ID NO: 392 Endocrine, Immune/Hematopoietic HNHEI42 SEQ ID NO: 393 Endocrine, Immune/Hematopoietic HNHEI42 SEQ ID NO: 394 Endocrine, Immune/Hematopoietic HNHEI85 SEQ ID NO: 395 Digestive, Immune/Hematopoietic, Musculoskeletal HNHEI85 SEQ ID NO: 396 Digestive, Immune/Hematopoietic, Musculoskeletal HOEDE28 SEQ ID NO: 397 Cancer HOEDE28 SEQ ID NO: 398 Cancer H2CBH03 SEQ ID NO: 399 Cancer HTHCA18 SEQ ID NO: 400 Immune/Hematopoietic HTHCA18 SEQ ID NO: 401 Immune/Hematopoietic HTHCO79 SEQ ID NO: 402 Cancer HTHCO79 SEQ ID NO: 403 Cancer HNGFB76 SEQ ID NO: 404 Digestive, Immune/Hematopoietic, Neural/Sensory HNGFB76 SEQ ID NO: 405 Digestive, Immune/Hematopoietic, Neural/Sensory HNGFB76 SEQ ID NO: 406 Digestive, Immune/Hematopoietic, Neural/Sensory HNGFB76 SEQ ID NO: 407 Digestive, Immune/Hematopoietic, Neural/Sensory HOQBJ82 SEQ ID NO: 408 Cancer HOQBJ82 SEQ ID NO: 409 Cancer HNFHY51 SEQ ID NO: 410 Immune/Hematopoietic, Reproductive HNFHY51 SEQ ID NO: 411 Immune/Hematopoietic, Reproductive HNFHY51 SEQ ID NO: 412 Immune/Hematopoietic, Reproductive HNFHY51 SEQ ID NO: 413 Immune/Hematopoietic, Reproductive HNEEB45 SEQ ID NO: 414 Immune/Hematopoietic, Mixed Fetal HNEEB45 SEQ ID NO: 415 Immune/Hematopoietic, Mixed Fetal HSDFA44 SEQ ID NO: 416 Neural/Sensory HSDFA44 SEQ ID NO: 417 Neural/Sensory HSDFA44 SEQ ID NO: 418 Neural/Sensory HAGEB14 SEQ ID NO: 419 Cancer HAGEB14 SEQ ID NO: 420 Cancer HCGBE81 SEQ ID NO: 421 Neural/Sensory, Reproductive HCGBE81 SEQ ID NO: 422 Neural/Sensory, Reproductive HEOMX53 SEQ ID NO: 423 Digestive, Immune/Hematopoietic, Neural/Sensory HEOMX53 SEQ ID NO: 424 Digestive, Immune/Hematopoietic, Neural/Sensory HEOMX53 SEQ ID NO: 425 Digestive, Immune/Hematopoietic, Neural/Sensory HEONC95 SEQ ID NO: 426 Cancer HEONC95 SEQ ID NO: 427 Cancer HKMLP68 SEQ ID NO: 428 Excretory, Mixed Fetal, Reproductive HKMLP68 SEQ ID NO: 429 Excretory, Mixed Fetal, Reproductive HKMLP68 SEQ ID NO: 430 Excretory, Mixed Fetal, Reproductive HMWIG83 SEQ ID NO: 431 Cancer HMWIG83 SEQ ID NO: 432 Cancer HMSKH19 SEQ ID NO: 433 Cancer HMSKH19 SEQ ID NO: 434 Cancer HMSKH19 SEQ ID NO: 435 Cancer HFAME37 SEQ ID NO: 436 Neural/Sensory HFAME37 SEQ ID NO: 437 Neural/Sensory HFAME37 SEQ ID NO: 438 Neural/Sensory HFXFG45 SEQ ID NO: 439 Immune/Hematopoietic, Neural/Sensory HFXFG45 SEQ ID NO: 440 Immune/Hematopoietic, Neural/Sensory HFXFG45 SEQ ID NO: 441 Immune/Hematopoietic, Neural/Sensory HFXFG45 SEQ ID NO: 442 Immune/Hematopoietic, Neural/Sensory HFXFH04 SEQ ID NO: 443 Immune/Hematopoietic, Neural/Sensory HFXFH04 SEQ ID NO: 444 Immune/Hematopoietic, Neural/Sensory HFXFH04 SEQ ID NO: 445 Immune/Hematopoietic, Neural/Sensory HFXFH04 SEQ ID NO: 446 Immune/Hematopoietic, Neural/Sensory HGCAC66 SEQ ID NO: 447 Cancer HGCAC66 SEQ ID NO: 448 Cancer HSSJF55 SEQ ID NO: 449 Musculoskeletal HSSJF55 SEQ ID NO: 450 Musculoskeletal HFXHM17 SEQ ID NO: 451 Cancer HFXHM17 SEQ ID NO: 452 Cancer HFXHM17 SEQ ID NO: 453 Cancer HFXHM17 SEQ ID NO: 454 Cancer HOSFQ65 SEQ ID NO: 455 Cancer HOSFQ65 SEQ ID NO: 456 Cancer HOSFQ65 SEQ ID NO: 457 Cancer HOSFQ65 SEQ ID NO: 458 Cancer HOSFQ65 SEQ ID NO: 459 Cancer HKGAS32 SEQ ID NO: 460 Connective/Epithelial, Neural/Sensory HKGAS32 SEQ ID NO: 461 Connective/Epithelial, Neural/Sensory HKGAU45 SEQ ID NO: 462 Immune/Hematopoietic HKGAU45 SEQ ID NO: 463 Immune/Hematopoietic HKGAU45 SEQ ID NO: 464 Immune/Hematopoietic HKGBH24 SEQ ID NO: 465 Cancer HKGBH24 SEQ ID NO: 466 Cancer HKGBH24 SEQ ID NO: 467 Cancer HKGBS01 SEQ ID NO: 468 Cancer HKGBS01 SEQ ID NO: 469 Cancer HKGBS01 SEQ ID NO: 470 Cancer HACCL63 SEQ ID NO: 471 Cancer HACCL63 SEQ ID NO: 472 Cancer HACCL63 SEQ ID NO: 473 Cancer HACCL63 SEQ ID NO: 474 Cancer HFIIN69 SEQ ID NO: 475 Musculoskeletal, Neural/Sensory, Reproductive HFIIN69 SEQ ID NO: 476 Musculoskeletal, Neural/Sensory, Reproductive HFIIN69 SEQ ID NO: 477 Musculoskeletal, Neural/Sensory, Reproductive HFIIZ70 SEQ ID NO: 478 Cancer HFIIZ70 SEQ ID NO: 479 Cancer HMIAJ30 SEQ ID NO: 480 Cancer HMIAJ30 SEQ ID NO: 481 Cancer HMIAJ30 SEQ ID NO: 482 Cancer HMIAJ30 SEQ ID NO: 483 Cancer HMIAV73 SEQ ID NO: 484 Cancer HMIAV73 SEQ ID NO: 485 Cancer HMIAV73 SEQ ID NO: 486 Cancer HMIAV73 SEQ ID NO: 487 Cancer HAPOD80 SEQ ID NO: 488 Cancer HISBL03 SEQ ID NO: 489 Cancer HISBL03 SEQ ID NO: 490 Cancer HISBL03 SEQ ID NO: 491 Cancer HISBL03 SEQ ID NO: 492 Cancer HISBL03 SEQ ID NO: 493 Cancer HISBL03 SEQ ID NO: 494 Cancer HISBL03 SEQ ID NO: 495 Cancer HMICK94 SEQ ID NO: 496 Cancer HMICK94 SEQ ID NO: 497 Cancer HMICK94 SEQ ID NO: 498 Cancer HISBF60 SEQ ID NO: 499 Cancer HISBF60 SEQ ID NO: 500 Cancer HISBF60 SEQ ID NO: 501 Cancer HISBF60 SEQ ID NO: 502 Cancer HISBF60 SEQ ID NO: 503 Cancer HMVAV54 SEQ ID NO: 504 Immune/Hematopoietic HMVAV54 SEQ ID NO: 505 Immune/Hematopoietic HMVAV54 SEQ ID NO: 506 Immune/Hematopoietic HMVAV54 SEQ ID NO: 507 Immune/Hematopoietic HMVAV54 SEQ ID NO: 508 Immune/Hematopoietic HPICB53 SEQ ID NO: 509 Cancer HPICB53 SEQ ID NO: 510 Cancer HPICC86 SEQ ID NO: 511 Reproductive HPICC86 SEQ ID NO: 512 Reproductive HPICC86 SEQ ID NO: 513 Reproductive HPICC86 SEQ ID NO: 514 Reproductive HPICC86 SEQ ID NO: 515 Reproductive HPJAP43 SEQ ID NO: 516 Cancer HPJAP43 SEQ ID NO: 517 Cancer HPJAP43 SEQ ID NO: 518 Cancer HPJCG42 SEQ ID NO: 519 Immune/Hematopoietic, Reproductive HPJCG42 SEQ ID NO: 520 Immune/Hematopoietic, Reproductive HPJCG42 SEQ ID NO: 521 Immune/Hematopoietic, Reproductive HPJCG42 SEQ ID NO: 522 Immune/Hematopoietic, Reproductive HPJCG42 SEQ ID NO: 523 Immune/Hematopoietic, Reproductive HPJBK11 SEQ ID NO: 524 Cardiovascular, Neural/Sensory, Reproductive HPJBK11 SEQ ID NO: 525 Cardiovascular, Neural/Sensory, Reproductive HPJBK11 SEQ ID NO: 526 Cardiovascular, Neural/Sensory, Reproductive HPJBK12 SEQ ID NO: 527 Reproductive HPJBK12 SEQ ID NO: 528 Reproductive HPJBK12 SEQ ID NO: 529 Reproductive HPJBK12 SEQ ID NO: 530 Reproductive HPJCT08 SEQ ID NO: 531 Connective/Epithelial, Reproductive HPJCT08 SEQ ID NO: 532 Connective/Epithelial, Reproductive HPJCT08 SEQ ID NO: 533 Connective/Epithelial, Reproductive HT4ES80 SEQ ID NO: 534 Cancer HT4ES80 SEQ ID NO: 535 Cancer HT4ES80 SEQ ID NO: 536 Cancer HNTNB49 SEQ ID NO: 537 Cancer HNTNB49 SEQ ID NO: 538 Cancer HNTRS57 SEQ ID NO: 539 Cancer HNTRS57 SEQ ID NO: 540 Cancer HNTRS57 SEQ ID NO: 541 Cancer HNTRS57 SEQ ID NO: 542 Cancer HNTRS57 SEQ ID NO: 543 Cancer HNTSL47 SEQ ID NO: 544 Cardiovascular, Digestive HNTSL47 SEQ ID NO: 545 Cardiovascular, Digestive HNTSL47 SEQ ID NO: 546 Cardiovascular, Digestive HBJLR70 SEQ ID NO: 547 Immune/Hematopoietic, Neural/Sensory HBJLR70 SEQ ID NO: 548 Immune/Hematopoietic, Neural/Sensory HNTSY18 SEQ ID NO: 549 Cardiovascular, Reproductive HNTSY18 SEQ ID NO: 550 Cardiovascular, Reproductive HBHME51 SEQ ID NO: 551 Reproductive, Respiratory HBHME51 SEQ ID NO: 552 Reproductive, Respiratory HBHME51 SEQ ID NO: 553 Reproductive, Respiratory HMCHR48 SEQ ID NO: 554 Connective/Epithelial, Immune/Hematopoietic, Reproductive HMCHR48 SEQ ID NO: 555 Connective/Epithelial, Immune/Hematopoietic, Reproductive HMCHR48 SEQ ID NO: 556 Connective/Epithelial, Immune/Hematopoietic, Reproductive HMCIJ07 SEQ ID NO: 557 Immune/Hematopoietic HMCIJ07 SEQ ID NO: 558 Immune/Hematopoietic HSIFL06 SEQ ID NO: 559 Cancer HSIFL06 SEQ ID NO: 560 Cancer HMZME33 SEQ ID NO: 561 Connective/Epithelial, Digestive HMZME33 SEQ ID NO: 562 Connective/Epithelial, Digestive HMZMF54 SEQ ID NO: 563 Digestive HMZMF54 SEQ ID NO: 564 Digestive HMZMF54 SEQ ID NO: 565 Digestive HMVCQ82 SEQ ID NO: 566 Immune/Hematopoietic HMVCQ82 SEQ ID NO: 567 Immune/Hematopoietic HMVCQ82 SEQ ID NO: 568 Immune/Hematopoietic HMVDP35 SEQ ID NO: 569 Immune/Hematopoietic, Reproductive HMVDP35 SEQ ID NO: 570 Immune/Hematopoietic, Reproductive HMVDP35 SEQ ID NO: 571 Immune/Hematopoietic, Reproductive HMVDF54 SEQ ID NO: 572 Cancer HMVDF54 SEQ ID NO: 573 Cancer HMVDF54 SEQ ID NO: 574 Cancer HROBM46 SEQ ID NO: 575 Connective/Epithelial, Digestive HROBM46 SEQ ID NO: 576 Connective/Epithelial, Digestive HCNDR47 SEQ ID NO: 577 Cancer HCNDR47 SEQ ID NO: 578 Cancer HCNDR47 SEQ ID NO: 579 Cancer HCNDV12 SEQ ID NO: 580 Digestive, Reproductive HCNDV12 SEQ ID NO: 581 Digestive, Reproductive HCNDV12 SEQ ID NO: 582 Digestive, Reproductive HSODE04 SEQ ID NO: 583 Digestive HSODE04 SEQ ID NO: 584 Digestive HBFMC03 SEQ ID NO: 585 Digestive, Musculoskeletal, Reproductive HBFMC03 SEQ ID NO: 586 Digestive, Musculoskeletal, Reproductive HHSFB67 SEQ ID NO: 587 Neural/Sensory HHSFB67 SEQ ID NO: 588 Neural/Sensory HHSFB67 SEQ ID NO: 589 Neural/Sensory HHSFB67 SEQ ID NO: 590 Neural/Sensory HHSGW69 SEQ ID NO: 591 Cancer HHSGW69 SEQ ID NO: 592 Cancer HHSGW69 SEQ ID NO: 593 Cancer HCLCJ15 SEQ ID NO: 594 Cancer HCLCJ15 SEQ ID NO: 595 Cancer HCLCJ15 SEQ ID NO: 596 Cancer HCLCJ15 SEQ ID NO: 597 Cancer HSLJG37 SEQ ID NO: 598 Cancer HSLJG37 SEQ ID NO: 599 Cancer HSLJG37 SEQ ID NO: 600 Cancer HWLEC41 SEQ ID NO: 601 Cancer HWLEC41 SEQ ID NO: 602 Cancer HWLEC41 SEQ ID NO: 603 Cancer HSXEQ06 SEQ ID NO: 604 Cancer HSXEQ06 SEQ ID NO: 605 Cancer HSXEQ06 SEQ ID NO: 606 Cancer HEEAA16 SEQ ID NO: 607 Cancer HEEAA16 SEQ ID NO: 608 Cancer HEEAA16 SEQ ID NO: 609 Cancer HEEAM62 SEQ ID NO: 610 Reproductive HEEAM62 SEQ ID NO: 611 Reproductive HEEAM62 SEQ ID NO: 612 Reproductive HEEAM62 SEQ ID NO: 613 Reproductive HNHKL90 SEQ ID NO: 614 Immune/Hematopoietic HNHKL90 SEQ ID NO: 615 Immune/Hematopoietic HNHKL90 SEQ ID NO: 616 Immune/Hematopoietic HWLFQ64 SEQ ID NO: 617 Digestive HWLFQ64 SEQ ID NO: 618 Digestive HWLFR02 SEQ ID NO: 619 Cancer HWLFR02 SEQ ID NO: 620 Cancer HWLFR02 SEQ ID NO: 621 Cancer HBKED12 SEQ ID NO: 622 Cancer HBKED12 SEQ ID NO: 623 Cancer HBKED12 SEQ ID NO: 624 Cancer HBKED12 SEQ ID NO: 625 Cancer HBKED12 SEQ ID NO: 626 Cancer HWLFJ10 SEQ ID NO: 627 Cancer HWLFJ10 SEQ ID NO: 628 Cancer HCRNO87 SEQ ID NO: 629 Cancer HCRNO87 SEQ ID NO: 630 Cancer HCRNO87 SEQ ID NO: 631 Cancer HCRNO87 SEQ ID NO: 632 Cancer HWLJX42 SEQ ID NO: 633 Cancer HWLJX42 SEQ ID NO: 634 Cancer HWLJX42 SEQ ID NO: 635 Cancer HSPBY63 SEQ ID NO: 636 Digestive HSPBY63 SEQ ID NO: 637 Digestive HSPBY63 SEQ ID NO: 638 Digestive HAPSO15 SEQ ID NO: 639 Cancer HAPSO15 SEQ ID NO: 640 Cancer HAPSO15 SEQ ID NO: 641 Cancer HE8QG24 SEQ ID NO: 642 Mixed Fetal HE8QG24 SEQ ID NO: 643 Mixed Fetal HE8QG24 SEQ ID NO: 644 Mixed Fetal HE8QV43 SEQ ID NO: 645 Cancer HE8QV43 SEQ ID NO: 646 Cancer HE8QV43 SEQ ID NO: 647 Cancer HE8QV43 SEQ ID NO: 648 Cancer HE9QN39 SEQ ID NO: 649 Cancer HE9QN39 SEQ ID NO: 650 Cancer HE9RO44 SEQ ID NO: 651 Immune/Hematopoietic, Mixed Fetal HE9RO44 SEQ ID NO: 652 Immune/Hematopoietic, Mixed Fetal HE9RO44 SEQ ID NO: 653 Immune/Hematopoietic, Mixed Fetal HE9SE18 SEQ ID NO: 654 Digestive, Mixed Fetal HE9SE18 SEQ ID NO: 655 Digestive, Mixed Fetal HE9SE18 SEQ ID NO: 656 Digestive, Mixed Fetal HISCV60 SEQ ID NO: 657 Digestive HISCV60 SEQ ID NO: 658 Digestive HE8UT25 SEQ ID NO: 659 Mixed Fetal HE8UT25 SEQ ID NO: 660 Mixed Fetal HE8UT25 SEQ ID NO: 661 Mixed Fetal HE8UY36 SEQ ID NO: 662 Cancer HE8UY36 SEQ ID NO: 663 Cancer HNHNT13 SEQ ID NO: 664 Immune/Hematopoietic HNHNT13 SEQ ID NO: 665 Immune/Hematopoietic HNHNT13 SEQ ID NO: 666 Immune/Hematopoietic HODEB50 SEQ ID NO: 667 Reproductive HODEB50 SEQ ID NO: 668 Reproductive HODEB50 SEQ ID NO: 669 Reproductive HNGMJ91 SEQ ID NO: 670 Immune/Hematopoietic HNGMJ91 SEQ ID NO: 671 Immune/Hematopoietic HNGMJ91 SEQ ID NO: 672 Immune/Hematopoietic HNGNB69 SEQ ID NO: 673 Immune/Hematopoietic HODFW41 SEQ ID NO: 674 Reproductive HODFW41 SEQ ID NO: 675 Reproductive HNGOI12 SEQ ID NO: 676 Immune/Hematopoietic HNGOI12 SEQ ID NO: 677 Immune/Hematopoietic HNGOI12 SEQ ID NO: 678 Immune/Hematopoietic HNGPM78 SEQ ID NO: 679 Immune/Hematopoietic, Neural/Sensory HNGPM78 SEQ ID NO: 680 Immune/Hematopoietic, Neural/Sensory HYASC80 SEQ ID NO: 681 Cancer HYASC80 SEQ ID NO: 682 Cancer HWLHM66 SEQ ID NO: 683 Cancer HWLHM66 SEQ ID NO: 684 Cancer HWLHM66 SEQ ID NO: 685 Cancer HWLHM66 SEQ ID NO: 686 Cancer HBBBC71 SEQ ID NO: 687 Cancer HBBBC71 SEQ ID NO: 688 Cancer HBBBC71 SEQ ID NO: 689 Cancer HLJBF86 SEQ ID NO: 690 Cancer HLJBF86 SEQ ID NO: 691 Cancer HLJBF86 SEQ ID NO: 692 Cancer HLJBJ61 SEQ ID NO: 693 Cancer HLJBJ61 SEQ ID NO: 694 Cancer HHBCS39 SEQ ID NO: 695 Cancer HHBCS39 SEQ ID NO: 696 Cancer HHBCS39 SEQ ID NO: 697 Cancer HLJEA01 SEQ ID NO: 698 Respiratory HLJEA01 SEQ ID NO: 699 Respiratory HLEDB16 SEQ ID NO: 700 Cancer HOGCK63 SEQ ID NO: 701 Cancer HOGCK63 SEQ ID NO: 702 Cancer HOFMQ33 SEQ ID NO: 703 Reproductive HOFMQ33 SEQ ID NO: 704 Reproductive HOFMQ33 SEQ ID NO: 705 Reproductive HOFMQ33 SEQ ID NO: 706 Reproductive HOFMT75 SEQ ID NO: 707 Reproductive HOFMT75 SEQ ID NO: 708 Reproductive HOFMT75 SEQ ID NO: 709 Reproductive HOFMT75 SEQ ID NO: 710 Reproductive HOGCS52 SEQ ID NO: 711 Cancer HOGCS52 SEQ ID NO: 712 Cancer HOGCS52 SEQ ID NO: 713 Cancer HOFNM53 SEQ ID NO: 714 Reproductive HOFNM53 SEQ ID NO: 715 Reproductive HOFNM53 SEQ ID NO: 716 Reproductive HOFNM53 SEQ ID NO: 717 Reproductive HOFOB27 SEQ ID NO: 718 Cancer HOFOB27 SEQ ID NO: 719 Cancer HOFOB27 SEQ ID NO: 720 Cancer HOFOB27 SEQ ID NO: 721 Cancer HOFOC33 SEQ ID NO: 722 Reproductive HOFOC33 SEQ ID NO: 723 Reproductive HOFOC33 SEQ ID NO: 724 Reproductive HOFOC33 SEQ ID NO: 725 Reproductive HOFOC33 SEQ ID NO: 726 Reproductive HOFOC33 SEQ ID NO: 727 Reproductive HOFOC73 SEQ ID NO: 728 Cancer HOFOC73 SEQ ID NO: 729 Cancer HOFOC73 SEQ ID NO: 730 Cancer HOFOC73 SEQ ID NO: 731 Cancer HNTAC64 SEQ ID NO: 732 Cancer HNTAC64 SEQ ID NO: 733 Cancer HNTAC64 SEQ ID NO: 734 Cancer HNTAC64 SEQ ID NO: 735 Cancer HDTBD53 SEQ ID NO: 736 Cancer HDTBD53 SEQ ID NO: 737 Cancer HDTAQ57 SEQ ID NO: 738 Cancer HDTAQ57 SEQ ID NO: 739 Cancer HDTAR06 SEQ ID NO: 740 Cancer HDTAR06 SEQ ID NO: 741 Cancer HDPML23 SEQ ID NO: 742 Immune/Hematopoietic, Neural/Sensory HDPML23 SEQ ID NO: 743 Immune/Hematopoietic, Neural/Sensory HDPML23 SEQ ID NO: 744 Immune/Hematopoietic, Neural/Sensory HDPML23 SEQ ID NO: 745 Immune/Hematopoietic, Neural/Sensory HDPML23 SEQ ID NO: 746 Immune/Hematopoietic, Neural/Sensory HDPMM88 SEQ ID NO: 747 Cancer HDPMM88 SEQ ID NO: 748 Cancer HDPMM88 SEQ ID NO: 749 Cancer HDPMM88 SEQ ID NO: 750 Cancer HDPMM88 SEQ ID NO: 751 Cancer HDPMM88 SEQ ID NO: 752 Cancer HDPMM88 SEQ ID NO: 753 Cancer HDPMS12 SEQ ID NO: 754 Cancer HDPMS12 SEQ ID NO: 755 Cancer HDPMS12 SEQ ID NO: 756 Cancer HDPMS12 SEQ ID NO: 757 Cancer HDPMS12 SEQ ID NO: 758 Cancer HDPMS12 SEQ ID NO: 759 Cancer HDPAP35 SEQ ID NO: 760 Excretory, Immune/Hematopoietic, Neural/Sensory HDPAP35 SEQ ID NO: 761 Excretory, Immune/Hematopoietic, Neural/Sensory HDPAP35 SEQ ID NO: 762 Excretory, Immune/Hematopoietic, Neural/Sensory HDPAP35 SEQ ID NO: 763 Excretory, Immune/Hematopoietic, Neural/Sensory HDPAQ55 SEQ ID NO: 764 Digestive, Immune/Hematopoietic, Reproductive HDPAQ55 SEQ ID NO: 765 Digestive, Immune/Hematopoietic, Reproductive HDPAQ55 SEQ ID NO: 766 Digestive, Immune/Hematopoietic, Reproductive HDPAQ55 SEQ ID NO: 767 Digestive, Immune/Hematopoietic, Reproductive HKAAV61 SEQ ID NO: 768 Connective/Epithelial HKAAV61 SEQ ID NO: 769 Connective/Epithelial HKAAV61 SEQ ID NO: 770 Connective/Epithelial HDPCJ43 SEQ ID NO: 771 Cancer HDPCJ43 SEQ ID NO: 772 Cancer HDPCJ43 SEQ ID NO: 773 Cancer HDPCJ43 SEQ ID NO: 774 Cancer HKACM93 SEQ ID NO: 775 Cancer HKACM93 SEQ ID NO: 776 Cancer HKACM93 SEQ ID NO: 777 Cancer HKACM93 SEQ ID NO: 778 Cancer HKAFT66 SEQ ID NO: 779 Connective/Epithelial, Digestive, Immune/Hematopoietic HKAFT66 SEQ ID NO: 780 Connective/Epithelial, Digestive, Immune/Hematopoietic HKAFT66 SEQ ID NO: 781 Connective/Epithelial, Digestive, Immune/Hematopoietic HHEMM74 SEQ ID NO: 782 Cancer HHEMM74 SEQ ID NO: 783 Cancer HHEMM74 SEQ ID NO: 784 Cancer HHEMM74 SEQ ID NO: 785 Cancer HAMFC93 SEQ ID NO: 786 Cancer HAMFC93 SEQ ID NO: 787 Cancer HAMFC93 SEQ ID NO: 788 Cancer HSYAZ50 SEQ ID NO: 789 Cancer HSYAZ50 SEQ ID NO: 790 Cancer HSYAZ50 SEQ ID NO: 791 Cancer HSYAZ50 SEQ ID NO: 792 Cancer HLWAX42 SEQ ID NO: 793 Cancer HLWAX42 SEQ ID NO: 794 Cancer HLWAX42 SEQ ID NO: 795 Cancer HLWAZ70 SEQ ID NO: 796 Cancer HLWAZ70 SEQ ID NO: 797 Cancer HLWAZ70 SEQ ID NO: 798 Cancer HLWAZ70 SEQ ID NO: 799 Cancer HLWBG83 SEQ ID NO: 800 Cancer HLWBG83 SEQ ID NO: 801 Cancer HLWBG83 SEQ ID NO: 802 Cancer HLWBG83 SEQ ID NO: 803 Cancer HLWBG83 SEQ ID NO: 804 Cancer HLWBH18 SEQ ID NO: 805 Reproductive HLWBH18 SEQ ID NO: 806 Reproductive HRABS65 SEQ ID NO: 807 Cancer HRABV43 SEQ ID NO: 808 Cancer HRABV43 SEQ ID NO: 809 Cancer HRABV43 SEQ ID NO: 810 Cancer HHEPG23 SEQ ID NO: 811 Cancer HHEPG23 SEQ ID NO: 812 Cancer HHEPG23 SEQ ID NO: 813 Cancer HHEPJ23 SEQ ID NO: 814 Cancer HHEPJ23 SEQ ID NO: 815 Cancer HDPIW06 SEQ ID NO: 816 Digestive, Immune/Hematopoietic, Neural/Sensory HDPIW06 SEQ ID NO: 817 Digestive, Immune/Hematopoietic, Neural/Sensory HDPIW06 SEQ ID NO: 818 Digestive, Immune/Hematopoietic, Neural/Sensory HDPIW06 SEQ ID NO: 819 Digestive, Immune/Hematopoietic, Neural/Sensory HDPIW06 SEQ ID NO: 820 Digestive, Immune/Hematopoietic, Neural/Sensory HDPPA04 SEQ ID NO: 821 Cardiovascular, Connective/Epithelial, Immune/Hematopoietic HDPPA04 SEQ ID NO: 822 Cardiovascular, Connective/Epithelial, Immune/Hematopoietic HDPPA04 SEQ ID NO: 823 Cardiovascular, Connective/Epithelial, Immune/Hematopoietic HDPPN86 SEQ ID NO: 824 Cancer HDPPN86 SEQ ID NO: 825 Cancer HDTEK44 SEQ ID NO: 826 Connective/Epithelial, Immune/Hematopoietic, Rrproductive HDTEK44 SEQ ID NO: 827 Connective/Epithelial, Immune/Hematopoietic, Reproductive HDTEK44 SEQ ID NO: 828 Connective/Epithelial, Immune/Hematopoietic, Reproductive HDTEK44 SEQ ID NO: 829 Connective/Epithelial, Immune/Hematopoietic, Reproductive HOHBL42 SEQ ID NO: 830 Cancer HOHBL42 SEQ ID NO: 831 Cancer HOHBL42 SEQ ID NO: 832 Cancer HOHBL42 SEQ ID NO: 833 Cancer HOHBP82 SEQ ID NO: 834 Musculoskeletal HOHBP82 SEQ ID NO: 835 Musculoskeletal HOHBP82 SEQ ID NO: 836 Musculoskeletal HOHBP82 SEQ ID NO: 837 Musculoskeletal HOHBY44 SEQ ID NO: 838 Cancer HOHBY44 SEQ ID NO: 839 Cancer HOHBY44 SEQ ID NO: 840 Cancer HWBAD01 SEQ ID NO: 841 Immune/Hematopoietic HWBAD01 SEQ ID NO: 842 Immune/Hematopoietic HWBAD01 SEQ ID NO: 843 Immune/Hematopoietic HOHCJ90 SEQ ID NO: 844 Cancer HOHCJ90 SEQ ID NO: 845 Cancer HWABE12 SEQ ID NO: 846 Cancer HWABE12 SEQ ID NO: 847 Cancer HWABE12 SEQ ID NO: 848 Cancer HWBAR14 SEQ ID NO: 849 Cancer HWBAR14 SEQ ID NO: 850 Cancer HWBAR14 SEQ ID NO: 851 Cancer HWBAR14 SEQ ID NO: 852 Cancer HWBAR88 SEQ ID NO: 853 Cancer HWBCH13 SEQ ID NO: 854 Immune/Hematopoietic HWBCH13 SEQ ID NO: 855 Immune/Hematopoietic HWBCH13 SEQ ID NO: 856 Immune/Hematopoietic HWBCH13 SEQ ID NO: 857 Immune/Hematopoietic HWBCM79 SEQ ID NO: 858 Immune/Hematopoietic HWBCV72 SEQ ID NO: 859 Cancer HWBCV72 SEQ ID NO: 860 Cancer HWBCV72 SEQ ID NO: 861 Cancer HWBCV72 SEQ ID NO: 862 Cancer HWBDM62 SEQ ID NO: 863 Endocrine, Immune/Hematopoietic HWBDM62 SEQ ID NO: 864 Endocrine, Immune/Hematopoietic HWBDM62 SEQ ID NO: 865 Endocrine, Immune/Hematopoietic HWBDM62 SEQ ID NO: 866 Endocrine, Immune/Hematopoietic HMTAL77 SEQ ID NO: 867 Cancer HMTAL77 SEQ ID NO: 868 Cancer HDPRH52 SEQ ID NO: 869 Cancer HDPRH52 SEQ ID NO: 870 Cancer HDPSB18 SEQ ID NO: 871 Cancer HDPSB18 SEQ ID NO: 872 Cancer HDPSB18 SEQ ID NO: 873 Cancer HDPSB18 SEQ ID NO: 874 Cancer HDPSH53 SEQ ID NO: 875 Immune/Hematopoietic, Reproductive HDPSH53 SEQ ID NO: 876 Immune/Hematopoietic, Reproductive HDPLO25 SEQ ID NO: 877 Cancer HDPLO25 SEQ ID NO: 878 Cancer HDPLO25 SEQ ID NO: 879 Cancer HDPRN70 SEQ ID NO: 880 Immune/Hematopoietic HDPRN70 SEQ ID NO: 881 Immune/Hematopoietic HDPTW24 SEQ ID NO: 882 Immune/Hematopoietic HDPTW65 SEQ ID NO: 883 Excretory HDPTW65 SEQ ID NO: 884 Excretory HDPTW65 SEQ ID NO: 885 Excretory HDPWN93 SEQ ID NO: 886 Cancer HDPWN93 SEQ ID NO: 887 Cancer HDPWN93 SEQ ID NO: 888 Cancer HDPXY01 SEQ ID NO: 889 Cancer HDPXY01 SEQ ID NO: 890 Cancer HDPXY01 SEQ ID NO: 891 Cancer HDPXY01 SEQ ID NO: 892 Cancer HWHPM16 SEQ ID NO: 893 Cancer HWHPM16 SEQ ID NO: 894 Cancer HLDQA07 SEQ ID NO: 895 Digestive HLDQA07 SEQ ID NO: 896 Digestive HDTFE17 SEQ ID NO: 897 Cancer HDTFE17 SEQ ID NO: 898 Cancer HDTFE17 SEQ ID NO: 899 Cancer HWDAD17 SEQ ID NO: 900 Cancer HWDAD17 SEQ ID NO: 901 Cancer HWEAC77 SEQ ID NO: 902 Connective/Epithelial HWEAC77 SEQ ID NO: 903 Connective/Epithelial HWBEM18 SEQ ID NO: 904 Cancer HWBEM18 SEQ ID NO: 905 Cancer HWBEM18 SEQ ID NO: 906 Cancer HWBFE57 SEQ ID NO: 907 Cancer HWBFE57 SEQ ID NO: 908 Cancer HWBFE57 SEQ ID NO: 909 Cancer HOHDF66 SEQ ID NO: 910 Musculoskeletal HOHDF66 SEQ ID NO: 911 Musculoskeletal HOHDF66 SEQ ID NO: 912 Musculoskeletal HOHDC86 SEQ ID NO: 913 Musculoskeletal HOHDC86 SEQ ID NO: 914 Musculoskeletal HOHDC86 SEQ ID NO: 915 Musculoskeletal HRADO01 SEQ ID NO: 916 Excretory HRADO01 SEQ ID NO: 917 Excretory HRADO01 SEQ ID NO: 918 Excretory HRAEE45 SEQ ID NO: 919 Connective/Epithelial, Excretory, Immune/Hematopoietic HRAEE45 SEQ ID NO: 920 Connective/Epithelial, Excretory, Immune/Hematopoietic HRAEE45 SEQ ID NO: 921 Connective/Epithelial, Excretory, Immune/Hematopoietic HRAEH37 SEQ ID NO: 922 Cancer HRAEH37 SEQ ID NO: 923 Cancer HRAEH37 SEQ ID NO: 924 Cancer HWDAH38 SEQ ID NO: 925 Cancer HWDAH38 SEQ ID NO: 926 Cancer HLWCP78 SEQ ID NO: 927 Cancer HLWCP78 SEQ ID NO: 928 Cancer HLWCP78 SEQ ID NO: 929 Cancer HLWCP78 SEQ ID NO: 930 Cancer HTJML75 SEQ ID NO: 931 Cancer HTJML75 SEQ ID NO: 932 Cancer HTJNX29 SEQ ID NO: 933 Connective/Epithelial, Digestive, Immune/Hematopoietic HTJNX29 SEQ ID NO: 934 Connective/Epithelial, Digestive, Immune/Hematopoietic HTJNX29 SEQ ID NO: 935 Connective/Epithelial, Digestive, Immune/Hematopoietic HHESQ62 SEQ ID NO: 936 Immune/Hematopoietic HHESQ62 SEQ ID NO: 937 Immune/Hematopoietic HHESQ62 SEQ ID NO: 938 Immune/Hematopoietic HHESQ62 SEQ ID NO: 939 Immune/Hematopoietic HHESQ62 SEQ ID NO: 940 Immune/Hematopoietic HDQGO29 SEQ ID NO: 941 Immune/Hematopoietic HDQGO29 SEQ ID NO: 942 Immune/Hematopoietic HDQGO29 SEQ ID NO: 943 Immune/Hematopoietic HDQGO29 SEQ ID NO: 944 Immune/Hematopoietic HDQHY04 SEQ ID NO: 945 Cancer HDQHY04 SEQ ID NO: 946 Cancer HDQHY04 SEQ ID NO: 947 Cancer HBXAB02 SEQ ID NO: 948 Cancer HBXAB02 SEQ ID NO: 949 Cancer HBXAB02 SEQ ID NO: 950 Cancer HCWAU23 SEQ ID NO: 951 Immune/Hematopoietic HCWAU23 SEQ ID NO: 952 Immune/Hematopoietic HCWAU23 SEQ ID NO: 953 Immune/Hematopoietic HBXAM53 SEQ ID NO: 954 Cancer HBXAM53 SEQ ID NO: 955 Cancer HBXAM53 SEQ ID NO: 956 Cancer HCWBP34 SEQ ID NO: 957 Immune/Hematopoietic HCWBP34 SEQ ID NO: 958 Immune/Hematopoietic HCWBP34 SEQ ID NO: 959 Immune/Hematopoietic HBXCT44 SEQ ID NO: 960 Cancer HBXCT44 SEQ ID NO: 961 Cancer HBXCT44 SEQ ID NO: 962 Cancer HBXCT44 SEQ ID NO: 963 Cancer HCWDY64 SEQ ID NO: 964 Excretory, Immune/Hematopoietic HCWDY64 SEQ ID NO: 965 Excretory, Immune/Hematopoietic HCWDY64 SEQ ID NO: 966 Excretory, Immune/Hematopoietic HCWEB58 SEQ ID NO: 967 Cancer HCWEB58 SEQ ID NO: 968 Cancer HBXED80 SEQ ID NO: 969 Immune/Hematopoietic, Neural/Sensory HBXED80 SEQ ID NO: 970 Immune/Hematopoietic, Neural/Sensory HBXED80 SEQ ID NO: 971 Immune/Hematopoietic, Neural/Sensory HBXED80 SEQ ID NO: 972 Immune/Hematopoietic, Neural/Sensory HCWFT79 SEQ ID NO: 973 Immune/Hematopoietic HCWFT79 SEQ ID NO: 974 Immune/Hematopoietic HCWFT79 SEQ ID NO: 975 Immune/Hematopoietic HCWFU77 SEQ ID NO: 976 Cancer HCWFU77 SEQ ID NO: 977 Cancer HCWFU77 SEQ ID NO: 978 Cancer HBXFZ38 SEQ ID NO: 979 Cancer HBXFZ38 SEQ ID NO: 980 Cancer HBXFZ38 SEQ ID NO: 981 Cancer HCUGC55 SEQ ID NO: 982 Immune/Hematopoietic HCUGC55 SEQ ID NO: 983 Immune/Hematopoietic HCUGC55 SEQ ID NO: 984 Immune/Hematopoietic HCWGU37 SEQ ID NO: 985 Immune/Hematopoietic, Neural/Sensory, Reproductive HCWGU37 SEQ ID NO: 986 Immune/Hematopoietic, Neural/Sensory, Reproductive HCWHV88 SEQ ID NO: 987 Digestive, Immune/Hematopoietic, Reproductive HCWHV88 SEQ ID NO: 988 Digestive, Immune/Hematopoietic, Reproductive HCWHX82 SEQ ID NO: 989 Immune/Hematopoietic, Neural/Sensory HCWHX82 SEQ ID NO: 990 Immune/Hematopoietic, Neural/Sensory HCWHX82 SEQ ID NO: 991 Immune/Hematopoietic, Neural/Sensory HCWFZ59 SEQ ID NO: 992 Immune/Hematopoietic HCWFZ59 SEQ ID NO: 993 Immune/Hematopoietic HCWFZ59 SEQ ID NO: 994 Immune/Hematopoietic HCWFZ59 SEQ ID NO: 995 Immune/Hematopoietic HBWCB95 SEQ ID NO: 996 Neural/Sensory HBWCB95 SEQ ID NO: 997 Neural/Sensory HBWCB95 SEQ ID NO: 998 Neural/Sensory HBWBR94 SEQ ID NO: 999 Neural/Sensory HBWBR94 SEQ ID NO: 1000 Neural/Sensory HBWBR94 SEQ ID NO: 1001 Neural/Sensory HBWCF75 SEQ ID NO: 1002 Neural/Sensory HBWCF75 SEQ ID NO: 1003 Neural/Sensory HBWCF75 SEQ ID NO: 1004 Neural/Sensory HBWCM83 SEQ ID NO: 1005 Digestive, Immune/Hematopoietic, Neural/Sensory HBWCM83 SEQ ID NO: 1006 Digestive, Immune/Hematopoietic, Neural/Sensory HBWCM83 SEQ ID NO: 1007 Digestive, Immune/Hematopoietic, Neural/Sensory HBWCM83 SEQ ID NO: 1008 Digestive, Immune/Hematopoietic, Neural/Sensory HRSMQ86 SEQ ID NO: 1009 Cancer HRSMQ86 SEQ ID NO: 1010 Cancer HFCAA91 SEQ ID NO: 1011 Neural/Sensory HFCAA91 SEQ ID NO: 1012 Neural/Sensory HFCAA91 SEQ ID NO: 1013 Neural/Sensory HFCAL39 SEQ ID NO: 1014 Cancer HFCAL39 SEQ ID NO: 1015 Cancer HFCAL39 SEQ ID NO: 1016 Cancer HCEBN44 SEQ ID NO: 1017 Neural/Sensory HCEBN44 SEQ ID NO: 1018 Neural/Sensory HHFCP32 SEQ ID NO: 1019 Cancer HGBAJ60 SEQ ID NO: 1020 Cancer HGBAJ60 SEQ ID NO: 1021 Cancer HHFCW75 SEQ ID NO: 1022 Cardiovascular HHFCW75 SEQ ID NO: 1023 Cardiovascular HHFCW75 SEQ ID NO: 1024 Cardiovascular HHFCZ67 SEQ ID NO: 1025 Cancer HHFCZ67 SEQ ID NO: 1026 Cancer HHFCZ67 SEQ ID NO: 1027 Cancer HHFCZ67 SEQ ID NO: 1028 Cancer HJBAR01 SEQ ID NO: 1029 Cancer HJBAR01 SEQ ID NO: 1030 Cancer HETAR42 SEQ ID NO: 1031 Cancer HETAR42 SEQ ID NO: 1032 Cancer HETAR42 SEQ ID NO: 1033 Cancer HETAR42 SEQ ID NO: 1034 Cancer HETAM53 SEQ ID NO: 1035 Cancer HETAM53 SEQ ID NO: 1036 Cancer HETAM53 SEQ ID NO: 1037 Cancer HETAM53 SEQ ID NO: 1038 Cancer HETAM53 SEQ ID NO: 1039 Cancer HTPBG16 SEQ ID NO: 1040 Digestive, Immune/Hematopoietic HTPBG16 SEQ ID NO: 1041 Digestive, Immune/Hematopoietic HTPBG16 SEQ ID NO: 1042 Digestive, Immune/Hematopoietic HJAAJ58 SEQ ID NO: 1043 Immune/Hematopoietic HJAAJ58 SEQ ID NO: 1044 Immune/Hematopoietic HJAAJ58 SEQ ID NO: 1045 Immune/Hematopoietic HJAAJ58 SEQ ID NO: 1046 Immune/Hematopoietic HSBBT12 SEQ ID NO: 1047 Cancer HSBBT12 SEQ ID NO: 1048 Cancer HSBBTI2 SEQ ID NO: 1049 Cancer HE8MH77 SEQ ID NO: 1050 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HE8MH77 SEQ ID NO: 1051 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HE8MH77 SEQ ID NO: 1052 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HTEDJ85 SEQ ID NO: 1053 Cancer HTEDJ85 SEQ ID NO: 1054 Cancer HTEDJ85 SEQ ID NO: 1055 Cancer HTEDJ85 SEQ ID NO: 1056 Cancer HOVAF78 SEQ ID NO: 1057 Cancer HOVAF78 SEQ ID NO: 1058 Cancer HOVAF78 SEQ ID NO: 1059 Cancer HOVAF78 SEQ ID NO: 1060 Cancer HOVAF78 SEQ ID NO: 1061 Cancer HHGDE24 SEQ ID NO: 1062 Cancer HHGDE24 SEQ ID NO: 1063 Cancer HHGDE24 SEQ ID NO: 1064 Cancer HOUFU35 SEQ ID NO: 1065 Connective/Epithelial HOUFU35 SEQ ID NO: 1066 Connective/Epithelial HOUFU35 SEQ ID NO: 1067 Connective/Epithelial HOUFU35 SEQ ID NO: 1068 Connective/Epithelial HSIGD79 SEQ ID NO: 1069 Cancer HSIGD79 SEQ ID NO: 1070 Cancer HCQCT05 SEQ ID NO: 1071 Digestive, Endocrine, Reproductive HCQCT05 SEQ ID NO: 1072 Digestive, Endocrine, Reproductive HMVDL30 SEQ ID NO: 1073 Cancer HMVDL30 SEQ ID NO: 1074 Cancer HMVDL30 SEQ ID NO: 1075 Cancer HMVDL30 SEQ ID NO: 1076 Cancer HTGGO35 SEQ ID NO: 1077 Cancer HTGGO35 SEQ ID NO: 1078 Cancer HTGGO35 SEQ ID NO: 1079 Cancer HCLBW50 SEQ ID NO: 1080 Cancer HCLBW50 SEQ ID NO: 1081 Cancer HCLBW50 SEQ ID NO: 1082 Cancer HCLBW50 SEQ ID NO: 1083 Cancer HWLEV32 SEQ ID NO: 1084 Cancer HWLEV32 SEQ ID NO: 1085 Cancer HWLEV32 SEQ ID NO: 1086 Cancer HWLEV32 SEQ ID NO: 1087 Cancer HWLFE89 SEQ ID NO: 1088 Cancer HWLFE89 SEQ ID NO: 1089 Cancer HWLFE89 SEQ ID NO: 1090 Cancer HE8PW38 SEQ ID NO: 1091 Neural/Sensory HE8PW38 SEQ ID NO: 1092 Neural/Sensory HE8PW38 SEQ ID NO: 1093 Neural/Sensory HE9RO27 SEQ ID NO: 1094 Connective/Epithelial, Mixed Fetal HE9RO27 SEQ ID NO: 1095 Connective/Epithelial, Mixed Fetal HE9RO27 SEQ ID NO: 1096 Connective/Epithelial, Mixed Fetal HCRPV17 SEQ ID NO: 1097 Cancer HCRPV17 SEQ ID NO: 1098 Cancer HCRPV17 SEQ ID NO: 1099 Cancer HCRPV17 SEQ ID NO: 1100 Cancer HHBGF77 SEQ ID NO: 1101 Cancer HHBGF77 SEQ ID NO: 1102 Cancer HLUDB47 SEQ ID NO: 1103 Cancer HLUDB47 SEQ ID NO: 1104 Cancer HLUDB47 SEQ ID NO: 1105 Cancer HHENZ16 SEQ ID NO: 1106 Cancer HHENZ16 SEQ ID NO: 1107 Cancer HHENZ16 SEQ ID NO: 1108 Cancer HSYBZ44 SEQ ID NO: 1109 Cancer HARNB17 SEQ ID NO: 1110 Cancer HARNB17 SEQ ID NO: 1111 Cancer HARNB17 SEQ ID NO: 1112 Cancer HARNB92 SEQ ID NO: 1113 Cancer HARNB92 SEQ ID NO: 1114 Cancer HARNB92 SEQ ID NO: 1115 Cancer HAMGV47 SEQ ID NO: 1116 Cancer HAMGV47 SEQ ID NO: 1117 Cancer HAMGV47 SEQ ID NO: 1118 Cancer HDTMK50 SEQ ID NO: 1119 Cancer HDTMK50 SEQ ID NO: 1120 Cancer HDTMK50 SEQ ID NO: 1121 Cancer HARBA09 SEQ ID NO: 1122 Cancer HARBA09 SEQ ID NO: 1123 Cancer HARBA09 SEQ ID NO: 1124 Cancer HARBA09 SEQ ID NO: 1125 Cancer HE8OK73 SEQ ID NO: 1126 Mixed Fetal, Neural/Sensory HE8OK73 SEQ ID NO: 1127 Mixed Fetal, Neural/Sensory HE8OK73 SEQ ID NO: 1128 Mixed Fetal, Neural/Sensory HSDJL42 SEQ ID NO: 1129 Cancer HSDJL42 SEQ ID NO: 1130 Cancer HSDJL42 SEQ ID NO: 1131 Cancer HCE2P86 SEQ ID NO: 1132 Cancer HCE2P86 SEQ ID NO: 1133 Cancer HCE2P86 SEQ ID NO: 1134 Cancer HNGNN78 SEQ ID NO: 1135 Cancer HNGNN78 SEQ ID NO: 1136 Cancer HNGNN78 SEQ ID NO: 1137 Cancer HTLHC59 SEQ ID NO: 1138 Digestive, Reproductive HTLHC59 SEQ ID NO: 1139 Digestive, Reproductive HTLJF15 SEQ ID NO: 1140 Immune/Hematopoietic, Reproductive HTLJF15 SEQ ID NO: 1141 Immune/Hematopoietic, Reproductive HTLJF15 SEQ ID NO: 1142 Immune/Hematopoietic, Reproductive HPJCC05 SEQ ID NO: 1143 Reproductive HPJCC05 SEQ ID NO: 1144 Reproductive HPJCC05 SEQ ID NO: 1145 Reproductive HDPVW11 SEQ ID NO: 1146 Cancer HDPVW11 SEQ ID NO: 1147 Cancer HDPWP69 SEQ ID NO: 1148 Cancer HDPWP69 SEQ ID NO: 1149 Cancer HDPWP69 SEQ ID NO: 1150 Cancer HWHHD11 SEQ ID NO: 1151 Cancer HWHHD11 SEQ ID NO: 1152 Cancer HWHHD11 SEQ ID NO: 1153 Cancer HBIMT93 SEQ ID NO: 1154 Cancer HBIMT93 SEQ ID NO: 1155 Cancer HBIMT93 SEQ ID NO: 1156 Cancer HHATA33 SEQ ID NO: 1157 Cancer HHATA33 SEQ ID NO: 1158 Cancer HNTDL21 SEQ ID NO: 1159 Cancer HNTDL21 SEQ ID NO: 1160 Cancer HNTNK95 SEQ ID NO: 1161 Cancer HNTNK95 SEQ ID NO: 1162 Cancer HNTNK95 SEQ ID NO: 1163 Cancer HWEAD64 SEQ ID NO: 1164 Cancer HWEAD64 SEQ ID NO: 1165 Cancer HWLHZ28 SEQ ID NO: 1166 Cancer HWLHZ28 SEQ ID NO: 1167 Cancer HWLHZ28 SEQ ID NO: 1168 Cancer HWLHZ28 SEQ ID NO: 1169 Cancer HWLJE21 SEQ ID NO: 1170 Cancer HWLJE21 SEQ ID NO: 1171 Cancer HWLJE21 SEQ ID NO: 1172 Cancer HPASD51 SEQ ID NO: 1173 Digestive, Excretory, Reproductive HPASD51 SEQ ID NO: 1174 Digestive, Excretory, Reproductive HSICQ15 SEQ ID NO: 1175 Cancer HSICQ15 SEQ ID NO: 1176 Cancer HFEBP27 SEQ ID NO: 1177 Cancer HFEBP27 SEQ ID NO: 1178 Cancer HFEBP27 SEQ ID NO: 1179 Cancer HTOIZ28 SEQ ID NO: 1180 Cancer HTOIZ28 SEQ ID NO: 1181 Cancer HTOIZ28 SEQ ID NO: 1182 Cancer HTOIZ28 SEQ ID NO: 1183 Cancer HCE4L28 SEQ ID NO: 1184 Cancer HCE4L28 SEQ ID NO: 1185 Cancer HCE4L28 SEQ ID NO: 1186 Cancer HCE4L28 SEQ ID NO: 1187 Cancer HFVGM16 SEQ ID NO: 1188 Cancer HFVGM16 SEQ ID NO: 1189 Cancer HPMGR66 SEQ ID NO: 1190 Cancer HPMGR66 SEQ ID NO: 1191 Cancer HLYDU43 SEQ ID NO: 1192 Cancer HLYDU43 SEQ ID NO: 1193 Cancer HPJCK10 SEQ ID NO: 1194 Cancer HPJCK10 SEQ ID NO: 1195 Cancer HT5EK75 SEQ ID NO: 1196 Cancer HT5EK75 SEQ ID NO: 1197 Cancer HT5EK75 SEQ ID NO: 1198 Cancer HWLEZ82 SEQ ID NO: 1199 Cancer HWLEZ82 SEQ ID NO: 1200 Cancer HWLEZ82 SEQ ID NO: 1201 Cancer HWLEZ82 SEQ ID NO: 1202 Cancer HDRMB11 SEQ ID NO: 1203 Digestive HDRMB11 SEQ ID NO: 1204 Digestive HDRMB11 SEQ ID NO: 1205 Digestive HCRNC80 SEQ ID NO: 1206 Cancer HCRNC80 SEQ ID NO: 1207 Cancer HCRNC80 SEQ ID NO: 1208 Cancer HCRNF14 SEQ ID NO: 1209 Cancer HCRNF14 SEQ ID NO: 1210 Cancer HCRNF14 SEQ ID NO: 1211 Cancer HE9PF45 SEQ ID NO: 1212 Cancer HE9PF45 SEQ ID NO: 1213 Cancer HE9PF45 SEQ ID NO: 1214 Cancer HISEN93 SEQ ID NO: 1215 Cancer HISEN93 SEQ ID NO: 1216 Cancer HISEN93 SEQ ID NO: 1217 Cancer HODEA51 SEQ ID NO: 1218 Cancer HODEA51 SEQ ID NO: 1219 Cancer HODEA51 SEQ ID NO: 1220 Cancer HODEA51 SEQ ID NO: 1221 Cancer HUSJN32 SEQ ID NO: 1222 Cancer HUSJN32 SEQ ID NO: 1223 Cancer HUSJN32 SEQ ID NO: 1224 Cancer HNGNW50 SEQ ID NO: 1225 Immune/Hematopoietic, Mixed Fetal, Reproductive HNGNW50 SEQ ID NO: 1226 Immune/Hematopoietic, Mixed Fetal, Reproductive HNGNW50 SEQ ID NO: 1227 Immune/Hematopoietic, Mixed Fetal, Reproductive HUVFB80 SEQ ID NO: 1228 Cancer HUVFB80 SEQ ID NO: 1229 Cancer HFIDQ92 SEQ ID NO: 1230 Cancer HFIDQ92 SEQ ID NO: 1231 Cancer HFIDQ92 SEQ ID NO: 1232 Cancer HTLJC07 SEQ ID NO: 1233 Immune/Hematopoietic, Neural/Sensory, Reproductive HTLJC07 SEQ ID NO: 1234 Immune/Hematopoietic, Neural/Sensory, Reproductive HTLJC07 SEQ ID NO: 1235 Immune/Hematopoietic, Neural/Sensory, Reproductive HMSOW51 SEQ ID NO: 1236 Cancer HMSOW51 SEQ ID NO: 1237 Cancer HPJEZ38 SEQ ID NO: 1238 Cancer HPJEZ38 SEQ ID NO: 1239 Cancer HPJEZ38 SEQ ID NO: 1240 Cancer HTAGN51 SEQ ID NO: 1241 Immune/Hematopoietic, Neural/Sensory, Reproductive HTAGN51 SEQ ID NO: 1242 Immune/Hematopoietic, Neural/Sensory, Reproductive HHFLH45 SEQ ID NO: 1243 Cardiovascular, Reproductive HHFLH45 SEQ ID NO: 1244 Cardiovascular, Reproductive HHFLH45 SEQ ID NO: 1245 Cardiovascular, Reproductive HFKLE15 SEQ ID NO: 1246 Cancer HFKLE15 SEQ ID NO: 1247 Cancer HNSAA27 SEQ ID NO: 1248 Digestive HNSAA27 SEQ ID NO: 1249 Digestive HUVFY29 SEQ ID NO: 1250 Cancer HUVFY29 SEQ ID NO: 1251 Cancer HAVUR23 SEQ ID NO: 1252 Neural/Sensory HAVUR23 SEQ ID NO: 1253 Neural/Sensory HTPIH83 SEQ ID NO: 1254 Digestive, Reproductive HTPIH83 SEQ ID NO: 1255 Digestive, Reproductive HTPIH83 SEQ ID NO: 1256 Digestive, Reproductive HUCNC61 SEQ ID NO: 1257 Cancer HIDAF73 SEQ ID NO: 1258 Cancer HIDAF73 SEQ ID NO: 1259 Cancer HIDAF73 SEQ ID NO: 1260 Cancer HOFMA42 SEQ ID NO: 1261 Reproductive HOFMA42 SEQ ID NO: 1262 Reproductive HKABW11 SEQ ID NO: 1263 Cancer HKABW11 SEQ ID NO: 1264 Cancer HWBAO29 SEQ ID NO: 1265 Immune/Hematopoietic, Reproductive HWBAO29 SEQ ID NO: 1266 Immune/Hematopoietic, Reproductive HWBAO29 SEQ ID NO: 1267 Immune/Hematopoietic, Reproductive HDPTM61 SEQ ID NO: 1268 Digestive, Immune/Hematopoietic HDPTM61 SEQ ID NO: 1269 Digestive, Immune/Hematopoietic HKAHL26 SEQ ID NO: 1270 Cancer HKAHL26 SEQ ID NO: 1271 Cancer HDQHC29 SEQ ID NO: 1272 Cancer HDQHQ91 SEQ ID NO: 1273 Cancer HDQHQ91 SEQ ID NO: 1274 Cancer HDQHQ91 SEQ ID NO: 1275 Cancer HDTLR06 SEQ ID NO: 1276 Cancer HDTLR06 SEQ ID NO: 1277 Cancer HNTDE84 SEQ ID NO: 1278 Cancer HNTDE84 SEQ ID NO: 1279 Cancer HWAFT87 SEQ ID NO: 1280 Cardiovascular, Immune/Hematopoietic HWAFT87 SEQ ID NO: 1281 Cardiovascular, Immune/Hematopoietic HWAFT87 SEQ ID NO: 1282 Cardiovascular, Immune/Hematopoietic HOGCE48 SEQ ID NO: 1283 Cancer HOGCE48 SEQ ID NO: 1284 Cancer HBINS58 SEQ ID NO: 1285 Connective/Epithelial, Reproductive HBINS58 SEQ ID NO: 1286 Connective/Epithelial, Reproductive HHAUQ28 SEQ ID NO: 1287 Cancer HHAUQ28 SEQ ID NO: 1288 Cancer HBIOH81 SEQ ID NO: 1289 Cancer HBIOH81 SEQ ID NO: 1290 Cancer HOGDP46 SEQ ID NO: 1291 Cancer HOGDP46 SEQ ID NO: 1292 Cancer HWHIH10 SEQ ID NO: 1293 Cancer HWHIH10 SEQ ID NO: 1294 Cancer HCWCT62 SEQ ID NO: 1295 Immune/Hematopoietic HCWCT62 SEQ ID NO: 1296 Immune/Hematopoietic HCWCT62 SEQ ID NO: 1297 Immune/Hematopoietic HBXCL50 SEQ ID NO: 1298 Digestive, Excretory, Neural/Sensory HBXCL50 SEQ ID NO: 1299 Digestive, Excretory, Neural/Sensory HACAA29 SEQ ID NO: 1300 Cancer HACAA29 SEQ ID NO: 1301 Cancer HAJAR23 SEQ ID NO: 1302 Cancer HAJAR23 SEQ ID NO: 1303 Cancer HAJAR23 SEQ ID NO: 1304 Cancer HDPQN12 SEQ ID NO: 1305 Cancer HDPQN12 SEQ ID NO: 1306 Cancer HDQFN31 SEQ ID NO: 1307 Cancer HDQFN31 SEQ ID NO: 1308 Cancer HDQIH54 SEQ ID NO: 1309 Immune/Hematopoietic HDQIH54 SEQ ID NO: 1310 Immune/Hematopoietic HETKL27 SEQ ID NO: 1311 Cancer HETKL27 SEQ ID NO: 1312 Cancer HETKL27 SEQ ID NO: 1313 Cancer HETKL27 SEQ ID NO: 1314 Cancer HFIHQ89 SEQ ID NO: 1315 Cancer HFIHQ89 SEQ ID NO: 1316 Cancer HFKHW50 SEQ ID NO: 1317 Cancer HFKHW50 SEQ ID NO: 1318 Cancer HFKHW50 SEQ ID NO: 1319 Cancer HMEJL08 SEQ ID NO: 1320 Cancer HMEJL08 SEQ ID NO: 1321 Cancer HMEJL08 SEQ ID NO: 1322 Cancer HMSCT72 SEQ ID NO: 1323 Connective/Epithelial, Immune/Hematopoietic HMSCT72 SEQ ID NO: 1324 Connective/Epithelial, Immune/Hematopoietic HMSCT72 SEQ ID NO: 1325 Connective/Epithelial, Immune/Hematopoietic HPJEX20 SEQ ID NO: 1326 Immune/Hematopoietic, Reproductive HPJEX20 SEQ ID NO: 1327 Immune/Hematopoietic, Reproductive HPJEX20 SEQ ID NO: 1328 Immune/Hematopoietic, Reproductive HPJEX20 SEQ ID NO: 1329 Immune/Hematopoietic, Reproductive HSLGM21 SEQ ID NO: 1330 Cancer HSLGM21 SEQ ID NO: 1331 Cancer HSLHI86 SEQ ID NO: 1332 Cancer HSLHI86 SEQ ID NO: 1333 Cancer HSLHI86 SEQ ID NO: 1334 Cancer HSLHI86 SEQ ID NO: 1335 Cancer HUCNP80 SEQ ID NO: 1336 Cancer HUCNP80 SEQ ID NO: 1337 Cancer HBINK72 SEQ ID NO: 1338 Cancer HBINK72 SEQ ID NO: 1339 Cancer HBINK72 SEQ ID NO: 1340 Cancer HIABC55 SEQ ID NO: 1341 Cancer HIABC55 SEQ ID NO: 1342 Cancer HIABC55 SEQ ID NO: 1343 Cancer HIABC55 SEQ ID NO: 1344 Cancer HGBAR55 SEQ ID NO: 1345 Cancer HGBAR55 SEQ ID NO: 1346 Cancer HGBAR55 SEQ ID NO: 1347 Cancer HE2FE45 SEQ ID NO: 1348 Cancer HE2FE45 SEQ ID NO: 1349 Cancer HE2FE45 SEQ ID NO: 1350 Cancer HMRAD54 SEQ ID NO: 1351 Cancer HMRAD54 SEQ ID NO: 1352 Cancer HMRAD54 SEQ ID NO: 1353 Cancer HCEFB80 SEQ ID NO: 1354 Cancer HCEFB80 SEQ ID NO: 1355 Cancer HFTBN23 SEQ ID NO: 1356 Cancer HFTBN23 SEQ ID NO: 1357 Cancer HFTBN23 SEQ ID NO: 1358 Cancer HFTBQ52 SEQ ID NO: 1359 Cancer HFTBQ52 SEQ ID NO: 1360 Cancer HMEEJ79 SEQ ID NO: 1361 Cardiovascular, Neural/Sensory, Reproductive HMEEJ79 SEQ ID NO: 1362 Cardiovascular, Neural/Sensory, Reproductive HROAJ39 SEQ ID NO: 1363 Cancer HROAJ39 SEQ ID NO: 1364 Cancer HROAJ39 SEQ ID NO: 1365 Cancer HFEBV76 SEQ ID NO: 1366 Cancer HFEBV76 SEQ ID NO: 1367 Cancer HTADC09 SEQ ID NO: 1368 Cancer HTADC09 SEQ ID NO: 1369 Cancer HFXBJ12 SEQ ID NO: 1370 Neural/Sensory HFXBJ12 SEQ ID NO: 1371 Neural/Sensory HFXBJ12 SEQ ID NO: 1372 Neural/Sensory HMHBN86 SEQ ID NO: 1373 Cancer HMHBN86 SEQ ID NO: 1374 Cancer HMHBN86 SEQ ID NO: 1375 Cancer HFKFL92 SEQ ID NO: 1376 Cancer HFKFL92 SEQ ID NO: 1377 Cancer HFKFL92 SEQ ID NO: 1378 Cancer HASAW52 SEQ ID NO: 1379 Cancer HTLDT76 SEQ ID NO: 1380 Cardiovascular, Neural/Sensory, Reproductive HTLDT76 SEQ ID NO: 1381 Cardiovascular, Neural/Sensory, Reproductive HTLDT76 SEQ ID NO: 1382 Cardiovascular, Neural/Sensory, Reproductive HTLEC34 SEQ ID NO: 1383 Immune/Hematopoiefic, Neural/Sensory, Reproductive HTLEC34 SEQ ID NO: 1384 Immune/Hematopoietic, Neural/Sensory, Reproductive HNHFB60 SEQ ID NO: 1385 Immune/Hemaropoietic HNHFB60 SEQ ID NO: 1386 Immune/Hematopoietic HNHFB60 SEQ ID NO: 1387 Immune/Hematopoietic H2CBK33 SEQ ID NO: 1388 Cancer H2CBK33 SEQ ID NO: 1389 Cancer H2CBK33 SEQ ID NO: 1390 Cancer HNGEY29 SEQ ID NO: 1391 Cancer HNGEY29 SEQ ID NO: 1392 Cancer HUSFE58 SEQ ID NO: 1393 Cancer HUSFE58 SEQ ID NO: 1394 Cancer HMSHS36 SEQ ID NO: 1395 Immune/Hematopoietic HMSHS36 SEQ ID NO: 1396 Immune/Hematopoietic HMSKC10 SEQ ID NO: 1397 Immune/Hematopoietic HMSKC10 SEQ ID NO: 1398 Immune/Hematopoietic HMSKC10 SEQ ID NO: 1399 Immune/Hematopoietic HSLGU75 SEQ ID NO: 1400 Cancer HSLGU75 SEQ ID NO: 1401 Cancer HSLGU75 SEQ ID NO: 1402 Cancer HDABU01 SEQ ID NO: 1403 Cancer HDABU01 SEQ ID NO: 1404 Cancer HDABU01 SEQ ID NO: 1405 Cancer HADGD17 SEQ ID NO: 1406 Connective/Epithelial HADGD17 SEQ ID NO: 1407 Connective/Epithelial HADGD17 SEQ ID NO: 1408 Connective/Epithelial HFIUE67 SEQ ID NO: 1409 Cancer HKGAM29 SEQ ID NO: 1410 Cancer HACBD86 SEQ ID NO: 1411 Cancer HACBD86 SEQ ID NO: 1412 Cancer HACBD86 SEQ ID NO: 1413 Cancer HEGAK23 SEQ ID NO: 1414 Cancer HEGAK23 SEQ ID NO: 1415 Cancer HEGAK23 SEQ ID NO: 1416 Cancer HEGAK23 SEQ ID NO: 1417 Cancer HCHAR90 SEQ ID NO: 1418 Cancer HCHAR90 SEQ ID NO: 1419 Cancer HCHAR90 SEQ ID NO: 1420 Cancer HLYCK27 SEQ ID NO: 1421 Immune/Hematopoietic HMVBP38 SEQ ID NO: 1422 Cancer HMVBP38 SEQ ID NO: 1423 Cancer HMVBP38 SEQ ID NO: 1424 Cancer HFACI31 SEQ ID NO: 1425 Neural/Sensory HFACI31 SEQ ID NO: 1426 Neural/Sensory HFACI31 SEQ ID NO: 1427 Neural/Sensory HBJKC04 SEQ ID NO: 1428 Immune/Hematopoietic HBJKC04 SEQ ID NO: 1429 Immune/Hematopoietic HBJKC04 SEQ ID NO: 1430 Immune/Hematopoietic HBJIT60 SEQ ID NO: 1431 Immune/Hematopoietic HBJIT60 SEQ ID NO: 1432 Immune/Hematopoietic HBJIT60 SEQ ID NO: 1433 Immune/Hematopoietic HPJBK03 SEQ ID NO: 1434 Cancer HPJBK03 SEQ ID NO: 1435 Cancer HPJCL22 SEQ ID NO: 1436 Cancer HPJCL22 SEQ ID NO: 1437 Cancer HPJCL22 SEQ ID NO: 1438 Cancer HTWJB71 SEQ ID NO: 1439 Immune/Hematopoietic, Neural/Sensory HNTOE45 SEQ ID NO: 1440 Cancer HNTOE45 SEQ ID NO: 1441 Cancer HNTRW30 SEQ ID NO: 1442 Digestive, Immune/Hematopoietic, Mixed Fetal HNTRW30 SEQ ID NO: 1443 Digestive, Immune/Hematopoietic, Mixed Fetal HCHPU32 SEQ ID NO: 1444 Cancer HCHPU32 SEQ ID NO: 1445 Cancer HCHPU32 SEQ ID NO: 1446 Cancer HGCNC48 SEQ ID NO: 1447 Reproductive HGCNC48 SEQ ID NO: 1448 Reproductive HLTHO84 SEQ ID NO: 1449 Cancer HSLIA81 SEQ ID NO: 1450 Cancer HSLIA81 SEQ ID NO: 1451 Cancer HSLIA81 SEQ ID NO: 1452 Cancer HSLIA81 SEQ ID NO: 1453 Cancer HBFMA07 SEQ ID NO: 1454 Cancer HBODE48 SEQ ID NO: 1455 Digestive, Excretory, Immune/Hematopoietic HBODE48 SEQ ID NO: 1456 Digestive, Excretory, Immune/Hematopoietic HBODE48 SEQ ID NO: 1457 Digestive, Excretory, Immune/Hematopoietic HBODE48 SEQ ID NO: 1458 Digestive, Excretory, Immune/Hematopoietic HCRME12 SEQ ID NO: 1459 Cancer HCRME12 SEQ ID NO: 1460 Cancer HBODQ16 SEQ ID NO: 1461 Cancer HBODQ16 SEQ ID NO: 1462 Cancer HASMB80 SEQ ID NO: 1463 Cancer HASMB80 SEQ ID NO: 1464 Cancer HBOEG11 SEQ ID NO: 1465 Cancer HBOEG11 SEQ ID NO: 1466 Cancer HCRNU76 SEQ ID NO: 1467 Cancer HCRNU76 SEQ ID NO: 1468 Cancer HAPSQ21 SEQ ID NO: 1469 Reproductive, Respiratory HAPSQ21 SEQ ID NO: 1470 Reproductive, Respiratory HAPSQ21 SEQ ID NO: 1471 Reproductive, Respiratory HWLNF33 SEQ ID NO: 1472 Cancer HWLNF33 SEQ ID NO: 1473 Cancer HE8QO53 SEQ ID NO: 1474 Cancer HE8QO53 SEQ ID NO: 1475 Cancer HE8QV67 SEQ ID NO: 1476 Cancer HE8QV67 SEQ ID NO: 1477 Cancer HE8TB68 SEQ ID NO: 1478 Cancer HE8TY90 SEQ ID NO: 1479 Cancer HE8TY90 SEQ ID NO: 1480 Cancer HE8TY90 SEQ ID NO: 1481 Cancer HE8TY90 SEQ ID NO: 1482 Cancer HETLM70 SEQ ID NO: 1483 Digestive, Excretory, Reproductive HETLM70 SEQ ID NO: 1484 Digestive, Excretory, Reproductive HETLM70 SEQ ID NO: 1485 Digestive, Excretory, Reproductive HISES66 SEQ ID NO: 1486 Digestive, Reproductive HISES66 SEQ ID NO: 1487 Digestive, Reproductive HISES66 SEQ ID NO: 1488 Digestive, Reproductive HTXKV29 SEQ ID NO: 1489 Cancer HTXKV29 SEQ ID NO: 1490 Cancer HTXKV29 SEQ ID NO: 1491 Cancer HTXLH48 SEQ ID NO: 1492 Immune/Hematopoietic HTXLH48 SEQ ID NO: 1493 Immune/Hematopoietic HTXLH48 SEQ ID NO: 1494 Immune/Hematopoietic HTEMD27 SEQ ID NO: 1495 Cancer HTEMD27 SEQ ID NO: 1496 Cancer HTEME02 SEQ ID NO: 149T Cancer HTEME02 SEQ ID NO: 1498 Cancer HTEME02 SEQ ID NO: 1499 Cancer HNHLD23 SEQ ID NO: 1500 Immune/Hematopoietic HETLT82 SEQ ID NO: 1501 Immune/Hematopoietic, Reproductive HETLT82 SEQ ID NO: 1502 Immune/Hematopoietic, Reproductive HETLT82 SEQ ID NO: 1503 Immune/Hematopoietic, Reproductive HNGLH60 SEQ ID NO: 1504 Immune/Hematopoietic, Musculoskeletal HNGLH60 SEQ ID NO: 1505 Immune/Hematopoietic, Musculoskeletal HNOLH60 SEQ ID NO: 1506 Immune/Hematopoietic, Musculoskeletal HNHPG05 SEQ ID NO: 1507 Immune/Hematopoietic HNHPG05 SEQ ID NO: 1508 Immune/Hematopoietic HNHPG05 SEQ ID NO: 1509 Immune/Hematopoietic HUSIY89 SEQ ID NO: 1510 Cardiovascular, Immune/Hematopoietic HUSIY89 SEQ ID NO: 1511 Cardiovascular, Immune/Hematopoietic HUSJM25 SEQ ID NO: 1512 Cancer HUSJM25 SEQ ID NO: 1513 Cancer HTXNL31 SEQ ID NO: 1514 Digestive, Immune/Hematopoietic, Reproductive HTXNL31 SEQ ID NO: 1515 Digestive, Immune/Hematopoietic, Reproductive HBGNQ12 SEQ ID NO: 1516 Cancer HBGNQ12 SEQ ID NO: 1517 Cancer HNGNS74 SEQ ID NO: 1518 Cancer HNGNS74 SEQ ID NO: 1519 Cancer HNGOD80 SEQ ID NO: 1520 Cancer HNGOD80 SEQ ID NO: 1521 Cancer HODHK19 SEQ ID NO: 1522 Reproductive HODHK19 SEQ ID NO: 1523 Reproductive HODHK19 SEQ ID NO: 1524 Reproductive HTLHR26 SEQ ID NO: 1525 Immune/Hematopoieric, Reproductive HTLHR26 SEQ ID NO: 1526 Immune/Hematopoietic, Reproductive HTLHR26 SEQ ID NO: 1527 Immune/Hematopoietic, Reproductive HUSZS75 SEQ ID NO: 1528 Cancer HUSZS75 SEQ ID NO: 1529 Cancer HLQDY81 SEQ ID NO: 1530 Cardiovascular, Digestive, Musculoskeletal HBGNU56 SEQ ID NO: 1531 Cancer HBGNU56 SEQ ID NO: 1532 Cancer HODGL52 SEQ ID NO: 1533 Cancer HODGL52 SEQ ID NO: 1534 Cancer HTXNV67 SEQ ID NO: 1535 Cancer HTXNV67 SEQ ID NO: 1536 Cancer HTXNV67 SEQ ID NO: 1537 Cancer HOCNE30 SEQ ID NO: 1538 Digestive, Musculoskeletal, Neural/Sensory HOCNE30 SEQ ID NO: 1539 Digestive, Musculoskeletal, Neural/Sensory HOCNE30 SEQ ID NO: 1540 Digestive, Musculoskeletal, Neural/Sensory HMSOC30 SEQ ID NO: 1541 Cancer HMSOC30 SEQ ID NO: 1542 Cancer HWMAF61 SEQ ID NO: 1543 Digestive HWMAF61 SEQ ID NO: 1544 Digestive HWMAF61 SEQ ID NO: 1545 Digestive HWMAF61 SEQ ID NO: 1546 Digestive HWMAF61 SEQ ID NO: 1547 Digestive HWMAH36 SEQ ID NO: 1548 Immune/Hematopoietic HWMAH36 SEQ ID NO: 1549 Immune/Hematopoietic HXOAC69 SEQ ID NO: 1550 Cancer HXOAC69 SEQ ID NO: 1551 Cancer HPJDA23 SEQ ID NO: 1552 Mixed Fetal, Neural/Sensory, Reproductive HPJDA23 SEQ ID NO: 1553 Mixed Fetal, Neural/Sensory, Reproductive HPJEE14 SEQ ID NO: 1554 Reproductive HPJEE14 SEQ ID NO: 1555 Reproductive HPJEG57 SEQ ID NO: 1556 Reproductive HPJEG57 SEQ ID NO: 1557 Reproductive HPJEG57 SEQ ID NO: 1558 Reproductive HPJEV11 SEQ ID NO: 1559 Cancer HTTKT43 SEQ ID NO: 1560 Cancer HTTKT43 SEQ ID NO: 1561 Cancer HTTKT43 SEQ ID NO: 1562 Cancer HHFKM76 SEQ ID NO: 1563 Cancer HHFKM76 SEQ ID NO: 1564 Cancer HHFKM76 SEQ ID NO: 1565 Cancer HHFML08 SEQ ID NO: 1566 Cardiovascular, Immune/Hematopoietic, Mixed Fetal HHFML08 SEQ ID NO: 1567 Cardiovascular, Immune/Hematopoietic, Mixed Fetal HHFML08 SEQ ID NO: 1568 Cardiovascular, Immune/Hematopoietic, Mixed Fetal HTPFX69 SEQ ID NO: 1569 Cancer HTPFX69 SEQ ID NO: 1570 Cancer HTPFX69 SEQ ID NO: 1571 Cancer HTPFX69 SEQ ID NO: 1572 Cancer HFKLX38 SEQ ID NO: 1573 Excretory, Respiratory HFKLX38 SEQ ID NO: 1574 Excretory, Respiratory HFKLX38 SEQ ID NO: 1575 Excretory, Respiratory HFKME15 SEQ ID NO: 1576 Excretory HFKME15 SEQ ID NO: 1577 Excretory HUVFH14 SEQ ID NO: 1578 Cancer HUVFH14 SEQ ID NO: 1579 Cancer HUVFH14 SEQ ID NO: 1580 Cancer HE2KK74 SEQ ID NO: 1581 Cancer HE2KK74 SEQ ID NO: 1582 Cancer HE2KK74 SEQ ID NO: 1583 Cancer HMALI42 SEQ ID NO: 1584 Immune/Hematopoietic HE2LW65 SEQ ID NO: 1585 Cancer HE2LW65 SEQ ID NO: 1586 Cancer HE2LW65 SEQ ID NO: 1587 Cancer HTFOS57 SEQ ID NO: 1588 Cancer HTFOS57 SEQ ID NO: 1589 Cancer HTFOS57 SEQ ID NO: 1590 Cancer HUVHI35 SEQ ID NO: 1591 Cancer HUVHI35 SEQ ID NO: 1592 Cancer HUVHI35 SEQ ID NO: 1593 Cancer HUVHI35 SEQ ID NO: 1594 Cancer HTPHS66 SEQ ID NO: 1595 Cancer HTPHS66 SEQ ID NO: 1596 Cancer HTPHS66 SEQ ID NO: 1597 Cancer HHFOJ29 SEQ ID NO: 1598 Cancer HHFOJ29 SEQ ID NO: 1599 Cancer HHFOJ29 SEQ ID NO: 1600 Cancer HMAMI15 SEQ ID NO: 1601 Cancer HTXQM57 SEQ ID NO: 1602 Immune/Hematopoietic, Mixed Fetal HE2RO22 SEQ ID NO: 1603 Mixed Fetal HE2RO22 SEQ ID NO: 1604 Mixed Fetal HE2SI26 SEQ ID NO: 1605 Cancer HTXRE15 SEQ ID NO: 1606 Cancer HTXRE15 SEQ ID NO: 1607 Cancer HUCPD31 SEQ ID NO: 1608 Cancer HUCPD31 SEQ ID NO: 1609 Cancer HFPHA80 SEQ ID NO: 1610 Neural/Sensory HFPHA80 SEQ ID NO: 1611 Neural/Sensory HFPHA80 SEQ ID NO: 1612 Neural/Sensory HFPHA80 SEQ ID NO: 1613 Neural/Sensory HFPHB92 SEQ ID NO: 1614 Excretory, Neural/Sensory HFPHS77 SEQ ID NO: 1615 Cancer HFPHS77 SEQ ID NO: 1616 Cancer HFPHS77 SEQ ID NO: 1617 Cancer HIPAJ43 SEQ ID NO: 1618 Cancer HIPAJ43 SEQ ID NO: 1619 Cancer HDDMW90 SEQ ID NO: 1620 Cancer HDDMW90 SEQ ID NO: 1621 Cancer HBCPB32 SEQ ID NO: 1622 Neural/Sensory, Reproductive HFVKC95 SEQ ID NO: 1623 Cancer HFVKC95 SEQ ID NO: 1624 Cancer HFVKC95 SEQ ID NO: 1625 Cancer HCOMM91 SEQ ID NO: 1626 Cancer HCOMM91 SEQ ID NO: 1627 Cancer HVVAM64 SEQ ID NO: 1628 Cancer HVVAM64 SEQ ID NO: 1629 Cancer HVVAM64 SEQ ID NO: 1630 Cancer HNBUC50 SEQ ID NO: 1631 Cancer HNBUC50 SEQ ID NO: 1632 Cancer HNBUC50 SEQ ID NO: 1633 Cancer HNBUC50 SEQ ID NO: 1634 Cancer HUUDF48 SEQ ID NO: 1635 Immune/Hematopoietic HUUDF48 SEQ ID NO: 1636 Immune/Hematopoietic HBCQL32 SEQ ID NO: 1637 Cancer HBCQL32 SEQ ID NO: 1638 Cancer HCBND16 SEQ ID NO: 1639 Cancer HCBND16 SEQ ID NO: 1640 Cancer HNNBM45 SEQ ID NO: 1641 Immune/Hematopoietic, Reproductive HNNBM45 SEQ ID NO: 1642 Immune/Hematopoietic, Reproductive HWMGN33 SEQ ID NO: 1643 Digestive HWMGN33 SEQ ID NO: 1644 Digestive HWMLN52 SEQ ID NO: 1645 Digestive, Immune/Hematopoietic HWMLN52 SEQ ID NO: 1646 Digestive, Immune/Hematopoietic HWMLN52 SEQ ID NO: 1647 Digestive, Immune/Hematopoietic HVARW53 SEQ ID NO: 1648 Digestive HVARW53 SEQ ID NO: 1649 Digestive HAHFU44 SEQ ID NO: 1650 Cardiovascular, Digestive, Musculoskeletal HAHFU44 SEQ ID NO: 1651 Cardiovascular, Digestive, Musculoskeletal HAHFU44 SEQ ID NO: 1652 Cardiovascular, Digestive, Musculoskeletal HCOOS80 SEQ ID NO: 1653 Cancer HCOOS80 SEQ ID NO: 1654 Cancer HCOOS80 SEQ ID NO: 1655 Cancer HNKCO80 SEQ ID NO: 1656 Cancer HNKCO80 SEQ ID NO: 1657 Cancer HLTIP27 SEQ ID NO: 1658 Immune/Hematopoietic HLTIP27 SEQ ID NO: 1659 Immune/Hematopoietic HLTIP94 SEQ ID NO: 1660 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HLTIP94 SEQ ID NO: 1661 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HLTIP94 SEQ ID NO: 1662 Immune/Hematopoietic, Mixed Fetal, Neural/Sensory HOCPM23 SEQ ID NO: 1663 Reproductive HOCPM23 SEQ ID NO: 1664 Reproductive HPDWP28 SEQ ID NO: 1665 Reproductive HPDWP28 SEQ ID NO: 1666 Reproductive HLCND09 SEQ ID NO: 1667 Cancer HLCND09 SEQ ID NO: 1668 Cancer HEEBI05 SEQ ID NO: 1669 Digestive, Reproductive HEEBB55 SEQ ID NO: 1670 Cancer HEEBB55 SEQ ID NO: 1671 Cancer HEEBB55 SEQ ID NO: 1672 Cancer HEGCL11 SEQ ID NO: 1673 Cancer HEGCL11 SEQ ID NO: 1674 Cancer HNTPB82 SEQ ID NO: 1675 Cancer HNTPB82 SEQ ID NO: 1676 Cancer HOFMM69 SEQ ID NO: 1677 Reproductive HOFMM69 SEQ ID NO: 1678 Reproductive HLDAB75 SEQ ID NO: 1679 Cancer HLDAB75 SEQ ID NO: 1680 Cancer HKACC80 SEQ ID NO: 1681 Cancer HKACC80 SEQ ID NO: 1682 Cancer HKACC80 SEQ ID NO: 1683 Cancer HKAEL28 SEQ ID NO: 1684 Connective/Epithelial, Immune/Hematopoietic, Reproductive HKAEL28 SEQ ID NO: 1685 Connective/Epithelial, Immune/Hematopoietic, Reproductive HDPGT25 SEQ ID NO: 1686 Cancer HDPGT25 SEQ ID NO: 1687 Cancer HLWBT09 SEQ ID NO: 1688 Excretory, Reproductive HLWBT09 SEQ ID NO: 1689 Excretory, Reproductive HHEDN80 SEQ ID NO: 1690 Cancer HHEDN80 SEQ ID NO: 1691 Cancer HHEDN80 SEQ ID NO: 1692 Cancer HDFQB14 SEQ ID NO: 1693 Immune/Hematopoietic, Neural/Sensory, Reproductive HWAAW33 SEQ ID NO: 1694 Cardiovascular, Immune/Hematopoietic, Musculoskeletal HWAAW33 SEQ ID NO: 1695 Cardiovascular, Immune/Hematopoietic, Musculoskeletal HWABF47 SEQ ID NO: 1696 Cancer HWABF47 SEQ ID NO: 1697 Cancer HWABI12 SEQ ID NO: 1698 Immune/Hematopoietic HWABI12 SEQ ID NO: 1699 Immune/Hematopoietic HWBBT49 SEQ ID NO: 1700 Cancer HWBBT49 SEQ ID NO: 1701 Cancer HWBBT49 SEQ ID NO: 1702 Cancer HAMGG89 SEQ ID NO: 1703 Immune/Hematopoietic, Neural/Sensory, Reproductive HAMGG89 SEQ ID NO: 1704 Immune/Hematopoietic, Neural/Sensory, Reproductive HAJBW16 SEQ ID NO: 1705 Neural/Sensory HAJBW16 SEQ ID NO: 1706 Neural/Sensory HNTAI35 SEQ ID NO: 1707 Cancer HNTAI35 SEQ ID NO: 1708 Cancer HNTAI35 SEQ ID NO: 1709 Cancer HNTAI35 SEQ ID NO: 1710 Cancer HNTAI35 SEQ ID NO: 1711 Cancer HNTBN41 SEQ ID NO: 1712 Immune/Hematopoietic HNTBN41 SEQ ID NO: 1713 Immune/Hematopoietic HNTBN41 SEQ ID NO: 1714 Immune/Hematopoietic HNTBN41 SEQ ID NO: 1715 Immune/Hematopoietic HDPRJ60 SEQ ID NO: 1716 Cancer HDPRJ60 SEQ ID NO: 1717 Cancer HDPRJ60 SEQ ID NO: 1718 Cancer HDPSB01 SEQ ID NO: 1719 Cancer HDPSB01 SEQ ID NO: 1720 Cancer HDPSB01 SEQ ID NO: 1721 Cancer HDPSB01 SEQ ID NO: 1722 Cancer HDPSB01 SEQ ID NO: 1723 Cancer HDPTC31 SEQ ID NO: 1724 Immune/Hematopoietic HDPTC31 SEQ ID NO: 1725 Immune/Hematopoietic HDPTC31 SEQ ID NO: 1726 Immune/Hematopoietic HDPXL05 SEQ ID NO: 1727 Immune/Hematopoietic, Reproductive HDPXL05 SEQ ID NO: 1728 Immune/Hematopoietic, Reproductive HDPXL05 SEQ ID NO: 1729 Immune/Hematopoietic, Reproductive HDPXY88 SEQ ID NO: 1730 Cancer HDPXY88 SEQ ID NO: 1731 Cancer HDPXY88 SEQ ID NO: 1732 Cancer HLDQZ72 SEQ ID NO: 1733 Cancer HLDQZ72 SEQ ID NO: 1734 Cancer HLDQZ72 SEQ ID NO: 1735 Cancer HWBEV57 SEQ ID NO: 1736 Immune/Hematopoietic HWBEV57 SEQ ID NO: 1737 Immune/Hematopoietic HWBEV57 SEQ ID NO: 1738 Immune/Hematopoietic HAMHH20 SEQ ID NO: 1739 Cancer HAMHH20 SEQ ID NO: 1740 Cancer HDLAY18 SEQ ID NO: 1741 Cancer HDLAY18 SEQ ID NO: 1742 Cancer HKAHN23 SEQ ID NO: 1743 Connective/Epithelial, Digestive, Mixed Fetal HKAHN23 SEQ ID NO: 1744 Connective/Epithelial, Digestive, Mixed Fetal HKAJW28 SEQ ID NO: 1745 Cancer HKAJW28 SEQ ID NO: 1746 Cancer HDQFU73 SEQ ID NO: 1747 Digestive, Immune/Hematopoietic HDQFU73 SEQ ID NO: 1748 Digestive, Immune/Hematopoietic HDQFU73 SEQ ID NO: 1749 Digestive, Immune/Hematopoietic HDTKS69 SEQ ID NO: 1750 Cancer HSYDT06 SEQ ID NO: 1751 Cancer HSYDT06 SEQ ID NO: 1752 Cancer HSYDT06 SEQ ID NO: 1753 Cancer HSYDT06 SEQ ID NO: 1754 Cancer HNTEF28 SEQ ID NO: 1755 Cancer HNTEF28 SEQ ID NO: 1756 Cancer HNTEF53 SEQ ID NO: 1757 Cancer HNTEF53 SEQ ID NO: 1758 Cancer HNTEF53 SEQ ID NO: 1759 Cancer HNTEF53 SEQ ID NO: 1760 Cancer HDQFN60 SEQ ID NO: 1761 Cancer HDQFN60 SEQ ID NO: 1762 Cancer HHEXM06 SEQ ID NO: 1763 Immune/Hematopoietic HHEXM06 SEQ ID NO: 1764 Immune/Hematopoietic HBINU36 SEQ ID NO: 1765 Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal HBINU36 SEQ ID NO: 1766 Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal HBINU36 SEQ ID NO: 1767 Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal HUJCQ39 SEQ ID NO: 1768 Cancer HUJCQ39 SEQ ID NO: 1769 Cancer HUJCQ39 SEQ ID NO: 1770 Cancer HCCCG83 SEQ ID NO: 1771 Cancer HCCCG83 SEQ ID NO: 1772 Cancer HCCCG83 SEQ ID NO: 1773 Cancer HWHIM26 SEQ ID NO: 1774 Connective/Epithelial, Immune/Hematopoietic HWHIM26 SEQ ID NO: 1775 Connective/Epithelial, Immune/Hematopoietic HWHKC09 SEQ ID NO: 1776 Cancer HWHKC09 SEQ ID NO: 1777 Cancer HWHKC09 SEQ ID NO: 1778 Cancer HWHKC09 SEQ ID NO: 1779 Cancer HWHKR51 SEQ ID NO: 1780 Cancer HWHKR51 SEQ ID NO: 1781 Cancer HWHKR51 SEQ ID NO: 1782 Cancer HWHRL06 SEQ ID NO: 1783 Cancer HWHRL06 SEQ ID NO: 1784 Cancer HAZAD32 SEQ ID NO: 1785 Cancer HAZAD32 SEQ ID NO: 1786 Cancer HPAMY60 SEQ ID NO: 1787 Excretory HPAMY60 SEQ ID NO: 1788 Excretory HAOTS04 SEQ ID NO: 1789 Reproductive HAOTS04 SEQ ID NO: 1790 Reproductive HAZAP37 SEQ ID NO: 1791 Reproductive HKZAS29 SEQ ID NO: 1792 Cancer HKZAS29 SEQ ID NO: 1793 Cancer HOVJP29 SEQ ID NO: 1794 Reproductive HOVJP29 SEQ ID NO: 1795 Reproductive HWHSB53 SEQ ID NO: 1796 Cancer HWHSB53 SEQ ID NO: 1797 Cancer HKZBS01 SEQ ID NO: 1798 Cancer HKZBS01 SEQ ID NO: 1799 Cancer HWHSO13 SEQ ID NO: 1800 Connective/Epithelial HWHSO13 SEQ ID NO: 1801 Connective/Epithelial HKZCK47 SEQ ID NO: 1802 Immune/Hematopoietic, Reproductive HCUHQ40 SEQ ID NO: 1803 Cancer HCUHQ40 SEQ ID NO: 1804 Cancer HCUHQ40 SEQ ID NO: 1805 Cancer HPJCP79 SEQ ID NO: 1806 Cancer HPJCP79 SEQ ID NO: 1807 Cancer HPJCP79 SEQ ID NO: 1808 Cancer HPJCP79 SEQ ID NO: 1809 Cancer HFXDI56 SEQ ID NO: 1810 Immune/Hematopoietic, Musculoskeletal, Neural/Sensory HFXDI56 SEQ ID NO: 1811 Immune/Hematopoietic, Musculoskeletal, Neural/Sensory HFXDI56 SEQ ID NO: 1812 Immune/Hematopoietic, Musculoskeletal, Neural/Sensory HFXDI56 SEQ ID NO: 1813 Immune/Hematopoietic, Musculoskeletal, Neural/Sensory HRDEP41 SEQ ID NO: 1814 Cancer HRDEP41 SEQ ID NO: 1815 Cancer HTEGF16 SEQ ID NO: 1816 Cancer HTEGF16 SEQ ID NO: 1817 Cancer HTEGF16 SEQ ID NO: 1818 Cancer HSUMA53 SEQ ID NO: 1819 Cancer HSUMA53 SEQ ID NO: 1820 Cancer HSUMA53 SEQ ID NO: 1821 Cancer HSUMA53 SEQ ID NO: 1822 Cancer HISET33 SEQ ID NO: 1823 Digestive HISET33 SEQ ID NO: 1824 Digestive HTTIJ31 SEQ ID NO: 1825 Reproductive HTTIJ31 SEQ ID NO: 1826 Reproductive HTPFX16 SEQ ID NO: 1827 Digestive, Reproductive, Respiratory HTPFX16 SEQ ID NO: 1828 Digestive, Reproductive, Respiratory HTFMX90 SEQ ID NO: 1829 Cancer HTFMX90 SEQ ID NO: 1830 Cancer HTFMX90 SEQ ID NO: 1831 Cancer HE8FD93 SEQ ID NO: 1832 Cancer HE8FD93 SEQ ID NO: 1833 Cancer HE8FD93 SEQ ID NO: 1834 Cancer HE8FD93 SEQ ID NO: 1835 Cancer HKGBJ74 SEQ ID NO: 1836 Cancer HKGBJ74 SEQ ID NO: 1837 Cancer HKGBJ74 SEQ ID NO: 1838 Cancer HKGBJ74 SEQ ID NO: 1839 Cancer HEEAG84 SEQ ID NO: 1840 Reproductive HEEAG84 SEQ ID NO: 1841 Reproductive HEOQX60 SEQ ID NO: 1842 Cancer HEOQX60 SEQ ID NO: 1843 Cancer HNGGB09 SEQ ID NO: 1844 Immune/Hematopoietic HNGGB09 SEQ ID NO: 1845 Immune/Hematopoietic HKIYI48 SEQ ID NO: 1846 Cancer HKIYI48 SEQ ID NO: 1847 Cancer HKIYI48 SEQ ID NO: 1848 Cancer HKIYI48 SEQ ID NO: 1849 Cancer HSYAB05 SEQ ID NO: 1850 Cancer HSYAB05 SEQ ID NO: 1851 Cancer HARMJ38 SEQ ID NO: 1852 Cancer HARMJ38 SEQ ID NO: 1853 Cancer HARMJ38 SEQ ID NO: 1854 Cancer HARMJ38 SEQ ID NO: 1855 Cancer HDTJG33 SEQ ID NO: 1856 Cancer HWAGJ85 SEQ ID NO: 1857 Cardiovascular, Immune/Hematopoietic HWAGJ85 SEQ ID NO: 1858 Cardiovascular, Immune/Hematopoietic HE2OW03 SEQ ID NO: 1859 Mixed Fetal HE2OW03 SEQ ID NO: 1860 Mixed Fetal HBQAE92 SEQ ID NO: 1861 Digestive, Neural/Sensory HBQAE92 SEQ ID NO: 1862 Digestive, Neural/Sensory HBQAE92 SEQ ID NO: 1863 Digestive, Neural/Sensory HTODL92 SEQ ID NO: 1864 Cancer HTODL92 SEQ ID NO: 1865 Cancer HTODL92 SEQ ID NO: 1866 Cancer HLQBR41 SEQ ID NO: 1867 Cancer HLQBR41 SEQ ID NO: 1868 Cancer HDSAP92 SEQ ID NO: 1869 Cancer HDSAP92 SEQ ID NO: 1870 Cancer HTAEC92 SEQ ID NO: 1871 Cancer HTAEC92 SEQ ID NO: 1872 Cancer HSLCK11 SEQ ID NO: 1873 Cancer HSLCK11 SEQ ID NO: 1874 Cancer HSLCK11 SEQ ID NO: 1875 Cancer HFCDR13 SEQ ID NO: 1876 Neural/Sensory HSLDS06 SEQ ID NO: 1877 Musculoskeletal HSLEF58 SEQ ID NO: 1878 Cardiovascular, Digestive, Musculoskeletal HPCAO10 SEQ ID NO: 1879 Cancer HMEJL61 SEQ ID NO: 1880 Cancer HMEJL61 SEQ ID NO: 1881 Cancer HMEJL61 SEQ ID NO: 1882 Cancer HUSHH92 SEQ ID NO: 1883 Cancer HUSHH92 SEQ ID NO: 1884 Cancer HUSHH92 SEQ ID NO: 1885 Cancer HUSHH92 SEQ ID NO: 1886 Cancer HBZAI90 SEQ ID NO: 1887 Immune/Hematopoietic, Reproductive HBZAI90 SEQ ID NO: 1888 Immune/Hematopoietic, Reproductive HNGIQ57 SEQ ID NO: 1889 Immune/Hematopoietic HNGIQ57 SEQ ID NO: 1890 Immune/Hematopoietic HNGJF62 SEQ ID NO: 1891 Immune/Hematopoietic HNGJF62 SEQ ID NO: 1892 Immune/Hematopoietic HFXJY38 SEQ ID NO: 1893 Neural/Sensory HFXJY38 SEQ ID NO: 1894 Neural/Sensory HFXKR54 SEQ ID NO: 1895 Endocrine, Immune/Hematopoietic, Neural/Sensory HFXKR54 SEQ ID NO: 1896 Endocrine, Immune/Hematopoietic, Neural/Sensory HFXKR54 SEQ ID NO: 1897 Endocrine, Immune/Hematopoietic, Neural/Sensory HAPOB80 SEQ ID NO: 1898 Immune/Hematopoietic, Musculoskeletal HAPOB80 SEQ ID NO: 1899 Immune/Hematopoietic, Musculoskeletal HAPOB80 SEQ ID NO: 1900 Immune/Hematopoietic, Musculoskeletal HAPOB80 SEQ ID NO: 1901 Immune/Hematopoietic, Musculoskeletal HBJHJ80 SEQ ID NO: 1902 Connective/Epithelial, Immune/Hematopoietic, Reproductive HFADF37 SEQ ID NO: 1903 Cancer HFADF37 SEQ ID NO: 1904 Cancer HNTSS75 SEQ ID NO: 1905 Cancer HCQDE22 SEQ ID NO: 1906 Digestive HCQDE22 SEQ ID NO: 1907 Digestive HE8NQ42 SEQ ID NO: 1908 Mixed Fetal HE8NQ42 SEQ ID NO: 1909 Mixed Fetal HE8QD31 SEQ ID NO: 1910 Digestive, Mixed Fetal, Neural/Sensory HE8QD31 SEQ ID NO: 1911 Digestive, Mixed Fetal, Neural/Sensory HE9PR39 SEQ ID NO: 1912 Digestive, Mixed Fetal, Musculoskeletal HE9PR39 SEQ ID NO: 1913 Digestive, Mixed Fetal, Musculoskeletal HE9PR39 SEQ ID NO: 1914 Digestive, Mixed Fetal, Musculoskeletal HE9PR39 SEQ ID NO: 1915 Digestive, Mixed Fetal, Musculoskeletal HNHLA36 SEQ ID NO: 1916 Immune/Hematopoietic, Reproductive HNHLA36 SEQ ID NO: 1917 Immune/Hematopoietic, Reproductive HNHOD23 SEQ ID NO: 1918 Cancer HNHOD23 SEQ ID NO: 1919 Cancer HNHOD23 SEQ ID NO: 1920 Cancer HNGNI25 SEQ ID NO: 1921 Immune/Hematopoietic HNGNI25 SEQ ID NO: 1922 Immune/Hematopoietic HNGNI25 SEQ ID NO: 1923 Immune/Hematopoietic HNGNI25 SEQ ID NO: 1924 Immune/Hematopoietic HNGOQ44 SEQ ID NO: 1925 Immune/Hematopoietic HNGOQ44 SEQ ID NO: 1926 Immune/Hematopoietic HTLGE31 SEQ ID NO: 1927 Immune/Hematopoietic, HODHE60 SEQ ID NO: 1928 Reproductive HODHE60 SEQ ID NO: 1929 Reproductive HTLIV19 SEQ ID NO: 1930 Reproductive HOSDW58 SEQ ID NO: 1931 Cancer HOSDW58 SEQ ID NO: 1932 Cancer HOSDW58 SEQ ID NO: 1933 Cancer HPJDM47 SEQ ID NO: 1934 Reproductive HPJDM47 SEQ ID NO: 1935 Reproductive HPJEC20 SEQ ID NO: 1936 Cancer HPJEC20 SEQ ID NO: 1937 Cancer HTTJK27 SEQ ID NO: 1938 Reproductive HTTJK27 SEQ ID NO: 1939 Reproductive HTFOE85 SEQ ID NO: 1940 Immune/Hematopoietic HTFOE85 SEQ ID NO: 1941 Immune/Hematopoietic HTFOE85 SEQ ID NO: 1942 Immune/Hematopoietic HIPBA31 SEQ ID NO: 1943 Cancer HIPBA31 SEQ ID NO: 1944 Cancer HFVJY02 SEQ ID NO: 1945 Digestive, Mixed Fetal, Neural/Sensory HFVJY02 SEQ ID NO: 1946 Digestive, Mixed Fetal, Neural/Sensory HFVJY02 SEQ ID NO: 1947 Digestive, Mixed Fetal, Neural/Sensory HFVJY02 SEQ ID NO: 1948 Digestive, Mixed Fetal, Neural/Sensory HFVJY02 SEQ ID NO: 1949 Digestive, Mixed Fetal, Neural/Sensory HOCOO19 SEQ ID NO: 1950 Cancer HOCOO19 SEQ ID NO: 1951 Cancer HOCOO19 SEQ ID NO: 1952 Cancer HWMKQ25 SEQ ID NO: 1953 Digestive, Reproductive HWMKQ25 SEQ ID NO: 1954 Digestive, Reproductive HWMKQ25 SEQ ID NO: 1955 Digestive, Reproductive HCOPG62 SEQ ID NO: 1956 Cancer HCOPG62 SEQ ID NO: 1957 Cancer HNKEL47 SEQ ID NO: 1958 Cardiovascular, Connective/Epithelial, Digestive HNKEL47 SEQ ID NO: 1959 Cardiovascular, Connective/Epithelial, Digestive HTPIY88 SEQ ID NO: 1960 Digestive HTPIY88 SEQ ID NO: 1961 Digestive HTPIY88 SEQ ID NO: 1962 Digestive HTPIY88 SEQ ID NO: 1963 Digestive HEGBS69 SEQ ID NO: 1964 Neural/Sensory, Reproductive HEGBS69 SEQ ID NO: 1965 Neural/Sensory, Reproductive HOFMU07 SEQ ID NO: 1966 Reproductive HOFMU07 SEQ ID NO: 1967 Reproductive HLWBM40 SEQ ID NO: 1968 Neural/Sensory, Reproductive HLWBM40 SEQ ID NO: 1969 Neural/Sensory, Reproductive HLWBM40 SEQ ID NO: 1970 Neural/Sensory, Reproductive HAMFT10 SEQ ID NO: 1971 Cancer HAMFT10 SEQ ID NO: 1972 Cancer HNTBP17 SEQ ID NO: 1973 Cancer HNTBP17 SEQ ID NO: 1974 Cancer HWDAO40 SEQ ID NO: 1975 Cancer HWDAO40 SEQ ID NO: 1976 Cancer HWDAO40 SEQ ID NO: 1977 Cancer HAJCL25 SEQ ID NO: 1978 Immune/Hematopoietic HAJCL25 SEQ ID NO: 1979 Immune/Hematopoietic HAJCL25 SEQ ID NO: 1980 Immune/Hematopoietic HNTEO95 SEQ ID NO: 1981 Immune/Hematopoietic HNTEO95 SEQ ID NO: 1982 Immune/Hematopoietic HNTEO95 SEQ ID NO: 1983 Immune/Hematopoietic HWAFG52 SEQ ID NO: 1984 Cancer HWAFG52 SEQ ID NO: 1985 Cancer HWAFG52 SEQ ID NO: 1986 Cancer HWAFG52 SEQ ID NO: 1987 Cancer HWAHE17 SEQ ID NO: 1988 Digestive, Immune/Hematopoietic HWAHE17 SEQ ID NO: 1989 Digestive, Immune/Hematopoietic HWAHE17 SEQ ID NO: 1990 Digestive, Immune/Hematopoietic HUJBK19 SEQ ID NO: 1991 Cancer HUJBK19 SEQ ID NO: 1992 Cancer HUJBK19 SEQ ID NO: 1993 Cancer HWHJD93 SEQ ID NO: 1994 Cancer HWHJD93 SEQ ID NO: 1995 Cancer HAOST94 SEQ ID NO: 1996 Cancer HAOST94 SEQ ID NO: 1997 Cancer HKZAH22 SEQ ID NO: 1998 Reproductive HKZAH22 SEQ ID NO: 1999 Reproductive HKZAH22 SEQ ID NO: 2000 Reproductive HKZAO35 SEQ ID NO: 2001 Reproductive HKZAO35 SEQ ID NO: 2002 Reproductive HWHSK19 SEQ ID NO: 2003 Cancer HWHSK19 SEQ ID NO: 2004 Cancer HWHSK19 SEQ ID NO: 2005 Cancer HMWFG79 SEQ ID NO: 2006 Digestive, Immune/Hematopoietic, Reproductive HMWFG79 SEQ ID NO: 2007 Digestive, Immune/Hematopoietic, Reproductive HMWFG79 SEQ ID NO: 2008 Digestive, Immune/Hematopoietic, Reproductive HMWFG79 SEQ ID NO: 2009 Digestive, Immune/Hematopoietic, Reproductive HMWFG79 SEQ ID NO: 2010 Digestive, Immune/Hematopoietic, Reproductive HMTAE85 SEQ ID NO: 2011 Cancer HMTBI36 SEQ ID NO: 2012 Cancer HSUME76 SEQ ID NO: 2013 Cancer HSUME76 SEQ ID NO: 2014 Cancer HTEAF65 SEQ ID NO: 2015 Excretory, Reproductive HTEAT31 SEQ ID NO: 2016 Cancer HAJAN23 SEQ ID NO: 2017 Cancer HAPRJ16 SEQ ID NO: 2018 Cancer HDTDT55 SEQ ID NO: 2019 Cancer HSKDA27 SEQ ID NO: 2020 Cancer HSKDA27 SEQ ID NO: 2021 Cancer HWLED11 SEQ ID NO: 2022 Cancer HADGD33 SEQ ID NO: 2023 Connective/Epithelial, Neural/Sensory, Reproductive HCEBF19 SEQ ID NO: 2024 Cancer HCEBF19 SEQ ID NO: 2025 Cancer HDPHH40 SEQ ID NO: 2026 Cancer HHEPM33 SEQ ID NO: 2027 Cancer HJBAF16 SEQ ID NO: 2028 Cancer HJBCU04 SEQ ID NO: 2029 Cancer HWABY10 SEQ ID NO: 2030 Cancer HWABY10 SEQ ID NO: 2031 Cancer HWABY10 SEQ ID NO: 2032 Cancer HWABY10 SEQ ID NO: 2033 Cancer HDPQN11 SEQ ID NO: 2034 Cancer HDPQN11 SEQ ID NO: 2035 Cancer HMSAW68 SEQ ID NO: 2036 Cancer HMSGP80 SEQ ID NO: 2037 Cancer HPJBZ76 SEQ ID NO: 2038 Cancer HSIGM62 SEQ ID NO: 2039 Cancer HSLHS22 SEQ ID NO: 2040 Cancer HTXOZ19 SEQ ID NO: 2041 Cancer HTXOZ19 SEQ ID NO: 2042 Cancer HAPQQ94 SEQ ID NO: 2043 Immune/Hematopoietic, Reproductive HAPQQ94 SEQ ID NO: 2044 Immune/Hematopoietic, Reproductive HAPSA79 SEQ ID NO: 2045 Cancer HAPSA79 SEQ ID NO: 2046 Cancer HAPSA79 SEQ ID NO: 2047 Cancer HDPAJ93 SEQ ID NO: 2048 Cancer HELGF34 SEQ ID NO: 2049 Cancer HETEQ88 SEQ ID NO: 2050 Cancer HMSAC18 SEQ ID NO: 2051 Cancer HMSAC18 SEQ ID NO: 2052 Cancer HPQSH59 SEQ ID NO: 2053 Cancer HSIFV30 SEQ ID NO: 2054 Cancer HSVCB08 SEQ ID NO: 2055 Cancer HT3SF53 SEQ ID NO: 2056 Cancer HARMS04 SEQ ID NO: 2057 Connective/Epithelial, Digestive HCDBP36 SEQ ID NO: 2058 Musculoskeletal HCEPE30 SEQ ID NO: 2059 Excretory, Neural/Sensory HE9RM63 SEQ ID NO: 2060 Cancer HKAJF71 SEQ ID NO: 2061 Cancer HNBAF49 SEQ ID NO: 2062 Cancer HSLDJ89 SEQ ID NO: 2063 Cancer HSXGI47 SEQ ID NO: 2064 Cancer HTEAJ18 SEQ ID NO: 2065 Reproductive HTTEV40 SEQ ID NO: 2066 Cancer HWBCB89 SEQ ID NO: 2067 Cancer HWHGZ51 SEQ ID NO: 2068 Cancer HADDH60 SEQ ID NO: 2069 Connective/Epithelial, Immune/Hematopoietic, Neural/Sensory HBXCL93 SEQ ID NO: 2070 Neural/Sensory, Reproductive HPTRH66 SEQ ID NO: 2071 Cancer HNFHD58 SEQ ID NO: 2072 Cancer HACAB58 SEQ ID NO: 2073 Cancer HCE3Z39 SEQ ID NO: 2074 Cancer HCFCU69 SEQ ID NO: 2075 Cancer HCE3Z39 SEQ ID NO: 2076 Cancer HCELE47 SEQ ID NO: 2077 Cancer HCWHP79 SEQ ID NO: 2078 Immune/Hematopoietic HDLAG89 SEQ ID NO: 2079 Cancer HDLAO28 SEQ ID NO: 2080 Cancer HDQGY41 SEQ ID NO: 2081 Cancer HE8FK78 SEQ ID NO: 2082 Cancer HE8FK78 SEQ ID NO: 2083 Cancer HETHR73 SEQ ID NO: 2084 Cancer HFIUW36 SEQ ID NO: 2085 Cancer HFKKS66 SEQ ID NO: 2086 Cancer HFPFK57 SEQ ID NO: 2087 Neural/Sensory, Reproductive HFVJP07 SEQ ID NO: 2088 Digestive, Immune/Hematopoietic HLQEM64 SEQ ID NO: 2089 Cancer HSSDG41 SEQ ID NO: 2090 Cancer HLQGP82 SEQ ID NO: 2091 Connective/Epithelial, Digestive, Musculoskeletal HMSMD07 SEQ ID NO: 2092 Cancer HNGIR58 SEQ ID NO: 2093 Immune/Hematopoietic HMAMI21 SEQ ID NO: 2094 Cancer HNHNB29 SEQ ID NO: 2095 Immune/Hematopoietic HNTEO78 SEQ ID NO: 2096 Digestive, Immune/Hematopoietic HJPAY76 SEQ ID NO: 2097 Cancer HOEEK12 SEQ ID NO: 2098 Cancer HOFNC14 SEQ ID NO: 2099 Reproductive HOSNU69 SEQ ID NO: 2100 Cancer HPJCL28 SEQ ID NO: 2101 Neural/Sensory, Reproductive HRACI26 SEQ ID NO: 2102 Digestive, Excretory HTLIT63 SEQ ID NO: 2103 Reproductive HTEAM34 SEQ ID NO: 2104 Reproductive HTEAM34 SEQ ID NO: 2105 Reproductive HUFGH53 SEQ ID NO: 2106 Cancer HUSBA88 SEQ ID NO: 2107 Cancer HELHN47 SEQ ID NO: 2108 Cancer HELHN47 SEQ ID NO: 2109 Cancer HELHN47 SEQ ID NO: 2110 Cancer HETAY39 SEQ ID NO: 2111 Cancer HFICR14 SEQ ID NO: 2112 Cancer HFICR14 SEQ ID NO: 2113 Cancer HFKET18 SEQ ID NO: 2114 Cancer HFXDK20 SEQ ID NO: 2115 Immune/Hematopoietic, Neural/Sensory HKMLX18 SEQ ID NO: 2116 Cancer HMSCM88 SEQ ID NO: 2117 Immune/Hematopoietic HMABG70 SEQ ID NO: 2118 Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal HMADJ74 SEQ ID NO: 2119 Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal HMADJ14 SEQ ID NO: 2120 Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal HMADJ14 SEQ ID NO: 2121 Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal HMADJ14 SEQ ID NO: 2122 Connective/Epithelial, Immune/Hematopoietic, Musculoskeletal HNEBY54 SEQ ID NO: 2123 Cancer HNEDD37 SEQ ID NO: 2124 Cancer HNGOU82 SEQ ID NO: 2125 Immune/Hematopoietic, Reproductive HNGOW62 SEQ ID NO: 2126 Immune/Hematopoietic HSIC066 SEQ ID NO: 2127 Cancer HSIDQ93 SEQ ID NO: 2128 Cancer HSLGM81 SEQ ID NO: 2129 Cancer HSYBM41 SEQ ID NO: 2130 Cancer HSODB85 SEQ ID NO: 2131 Cancer HSRFZ57 SEQ ID NO: 2132 Excretory, Musculoskeletal HSXAZ05 SEQ ID NO: 2133 Neural/Sensory, Respiratory HTPCW21 SEQ ID NO: 2134 Digestive, Neural/Sensory HTPCW21 SEQ ID NO: 2135 Digestive, Neural/Sensory HTXKF95 SEQ ID NO: 2136 Cancer HTXKF95 SEQ ID NO: 2137 Cancer HUFBC44 SEQ ID NO: 2138 Digestive, Mixed Fetal, Neural/Sensory HAAAI67 SEQ ID NO: 2139 Cancer HFKIA71 SEQ ID NO: 2140 Cancer HAMFP32 SEQ ID NO: 2141 Cancer HAPQU71 SEQ ID NO: 2142 Cancer HAPQU71 SEQ ID NO: 2143 Cancer HLHDL42 SEQ ID NO: 2144 Cancer HAVVG36 SEQ ID NO: 2145 Cancer HBGNP63 SEQ ID NO: 2146 Reproductive HBJNC59 SEQ ID NO: 2147 Cancer HAPQT56 SEQ ID NO: 2148 Cancer HCABW07 SEQ ID NO: 2149 Cancer HDPFB02 SEQ ID NO: 2150 Cancer HMWDB84 SEQ ID NO: 2151 Cancer HDPFB02 SEQ ID NO: 2152 Cancer HDPFY41 SEQ ID NO: 2153 Cancer HDPIE85 SEQ ID NO: 2154 Cancer HDPOE32 SEQ ID NO: 2155 Cancer HWABL61 SEQ ID NO: 2156 Cancer HWABW88 SEQ ID NO: 2157 Cancer HWDAQ83 SEQ ID NO: 2158 Cancer HWDAQ83 SEQ ID NO: 2159 Cancer HWLHZ79 SEQ ID NO: 2160 Connective/Epithelial, Digestive, Reproductive HTXJM94 SEQ ID NO: 2161 Cancer HDPQG01 SEQ ID NO: 2162 Cancer HJPAD80 SEQ ID NO: 2163 Cancer HDPQG01 SEQ ID NO: 2164 Cancer HFXLF67 SEQ ID NO: 2165 Neural/Sensory HE2IO57 SEQ ID NO: 2166 Cancer HKGDP17 SEQ ID NO: 2167 Respiratory HLQFB12 SEQ ID NO: 2168 Digestive, Reproductive HLQFT18 SEQ ID NO: 2169 Digestive, Reproductive HOFNX30 SEQ ID NO: 2170 Reproductive HSSDM23 SEQ ID NO: 2171 Cancer HSSDM23 SEQ ID NO: 2172 Cancer HSVBD67 SEQ ID NO: 2173 Cancer HSVBD67 SEQ ID NO: 2174 Cancer HTGAT51 SEQ ID NO: 2175 Cardiovascular, Immune/Hematopoietic, Reproductive HTLGV19 SEQ ID NO: 2176 Excretory, Reproductive HTPHH74 SEQ ID NO: 2177 Cancer HTFOB75 SEQ ID NO: 2178 Cancer HTPHH74 SEQ ID NO: 2179 Cancer HWHGK36 SEQ ID NO: 2180 Cancer HLWAD77 SEQ ID NO: 2181 Cancer HDTGF15 SEQ ID NO: 2182 Cancer HWMBB68 SEQ ID NO: 2183 Cancer HWMBB68 SEQ ID NO: 2184 Cancer HAGDA35 SEQ ID NO: 2185 Cancer HAGDA35 SEQ ID NO: 2186 Cancer HAGDA35 SEQ ID NO: 2187 Cancer HRODQ04 SEQ ID NO: 2188 Cancer HTOJV86 SEQ ID NO: 2189 Cancer HCEFZ82 SEQ ID NO: 2190 Cancer HNGFW58 SEQ ID NO: 2191 Cancer HHBGE77 SEQ ID NO: 2192 Cancer HADFW77 SEQ ID NO: 2193 Cancer HSIED48 SEQ ID NO: 2194 Cancer HCEFZ82 SEQ ID NO: 2195 Cancer HTTCT46 SEQ ID NO: 2196 Cancer HSDEE58 SEQ ID NO: 2197 Cancer HEBCV31 SEQ ID NO: 2198 Cancer HDPOL27 SEQ ID NO: 2199 Cancer HDPOL27 SEQ ID NO: 2200 Cancer HE6DI14 SEQ ID NO: 2201 Cancer HLYAN43 SEQ ID NO: 2202 Cancer HDPUM13 SEQ ID NO: 2203 Cancer HPLAT62 SEQ ID NO: 2204 Cancer HAPQT56 SEQ ID NO: 2205 Cancer HACBG19 SEQ ID NO: 2206 Cancer HACBG19 SEQ ID NO: 2207 Cancer HLYAV34 SEQ ID NO: 2208 Cancer HCNSM85 SEQ ID NO: 2209 Cancer HTOCG60 SEQ ID NO: 2210 Cancer HLYAV34 SEQ ID NO: 2211 Cancer HDPWX42 SEQ ID NO: 2212 Cancer HOFNF53 SEQ ID NO: 2213 Reproductive HOFNF53 SEQ ID NO: 2214 Reproductive HMSEO15 SEQ ID NO: 2215 Cancer HBXFT65 SEQ ID NO: 2216 Cancer HFCEQ37 SEQ ID NO: 2217 Cancer HWNFG66 SEQ ID NO: 2218 Digestive HOHCA60 SEQ ID NO: 2219 Cancer HOHCA60 SEQ ID NO: 2220 Cancer HOHCA60 SEQ ID NO: 2221 Cancer HOHCA60 SEQ ID NO: 2222 Cancer HOHCA60 SEQ ID NO: 2223 Cancer HLDRR08 SEQ ID NO: 2224 Digestive HSKNP59 SEQ ID NO: 2225 Musculoskeletal HSKNP59 SEQ ID NO: 2226 Musculoskeletal HAMHE82 SEQ ID NO: 2227 Cancer HBIOO68 SEQ ID NO: 2228 Cancer HCE3C63 SEQ ID NO: 2229 Mixed Fetal, Neural/Sensory HCNDV12 SEQ ID NO: 2230 Digestive, Reproductive HMWDW68 SEQ ID NO: 2231 Cancer HE2BC57 SEQ ID NO: 2232 Cancer HSDEE58 SEQ ID NO: 2233 Cancer HE9OW91 SEQ ID NO: 2234 Cancer HFCFI20 SEQ ID NO: 2235 Cancer HELEN05 SEQ ID NO: 2236 Cancer HISEL50 SEQ ID NO: 2237 Cancer HLHDL62 SEQ ID NO: 2238 Cancer HDFQB93 SEQ ID NO: 2239 Cancer HLHDQ86 SEQ ID NO: 2240 Cancer HLNAB24 SEQ ID NO: 2241 Immune/Hematopoietic HLYBQ90 SEQ ID NO: 2242 Cancer HLYBQ90 SEQ ID NO: 2243 Cancer HNHDP39 SEQ ID NO: 2244 Endocrine, Immune/Hematopoietic, Reproductive HNTAC64 SEQ ID NO: 2245 Cancer HNTMY29 SEQ ID NO: 2246 Connective/Epithelial, Reproductive HOFOC33 SEQ ID NO: 2247 Reproductive HOFOC33 SEQ ID NO: 2248 Reproductive HTWFK18 SEQ ID NO: 2249 Connective/Epithelial, Immune/Hematopoietic HAPNJ39 SEQ ID NO: 2250 Cancer HDQFU27 SEQ ID NO: 2251 Cancer HETJZ45 SEQ ID NO: 2252 Cancer HTEMX36 SEQ ID NO: 2253 Cancer HNTCH90 SEQ ID NO: 2254 Cancer HWLBP46 SEQ ID NO: 2255 Cancer HA5BM53 SEQ ID NO: 2256 Cancer HMCEH49 SEQ ID NO: 2257 Cancer HKBAL25 SEQ ID NO: 2258 Digestive, Musculoskeletal HE8EF43 SEQ ID NO: 2259 Cancer HE2RN91 SEQ ID NO: 2260 Cancer HTLIO20 SEQ ID NO: 2261 Immune/Hematopoietic, Neural/Sensory HBIMF63 SEQ ID NO: 2262 Reproductive HE9PM90 SEQ ID NO: 2263 Cancer HNTDX22 SEQ ID NO: 2264 Reproductive HHFCE59 SEQ ID NO: 2265 Cancer HCGAD44 SEQ ID NO: 2266 Cancer HSSJJ51 SEQ ID NO: 2267 Cancer
[0073] In preferred embodiments, the albumin fusion proteins of the invention are capable of a therapeutic activity and/or biologic activity corresponding to the therapeutic activity and/or biologic activity of the Therapeutic protein corresponding to the Therapeutic protein portion of the albumin fusion protein listed in the corresponding row of Table 1. In further preferred embodiments, the therapeutically active protein portions of the albumin fusion proteins of the invention are fragments or variants of the reference sequence cited in the “Exemplary Identifier” column of Table 1, and are capable of the therapeutic activity and/or biologic activity of the corresponding Therapeutic protein.
[0074] Polypeptide and Polynucleotide Fragments and Variants
[0075] Fragments
[0076] The present invention is further directed to fragments of the Therapeutic proteins described in Table 1, albumin proteins, and/or albumin fusion proteins of the invention.
[0077] Even if deletion of one or more amino acids from the N-terminus of a protein results in modification or loss of one or more biological functions of the Therapeutic protein, albumin protein, and/or albumin fusion protein, other Therapeutic activities and/or functional activities (e.g., biological activities, ability to multimerize, ability to bind a ligand) may still be retained. For example, the ability of polypeptides with N-terminal deletions to induce and/or bind to antibodies which recognize the complete or mature forms of the polypeptides generally will be retained when less than the majority of the residues of the complete polypeptide are removed from the N-terminus. Whether a particular polypeptide lacking N-terminal residues of a complete polypeptide retains such immunologic activities can readily be determined by routine methods described herein and otherwise known in the art. It is not unlikely that a mutein with a large number of deleted N-terminal amino acid residues may retain some biological or immunogenic activities. In fact, peptides composed of as few as six amino acid residues may often evoke an immune response.
[0078] Accordingly, fragments of a Therapeutic protein corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention, include the full length protein as well as polypeptides having one or more residues deleted from the amino terminus of the amino acid sequence of the reference polypeptide (i.e., a Therapeutic protein as disclosed in Table 1). In particular, N-terminal deletions may be described by the general formula m−q, where q is a whole integer representing the total number of amino acid residues in a reference polypeptide (e.g., a Therapeutic protein referred to in Table 1), and m is defined as any integer ranging from 2 to q−6. Polynucleotides encoding these polypeptides are also encompassed by the invention.
[0079] In addition, fragments of serum albumin polypeptides corresponding to an albumin protein portion of an albumin fusion protein of the invention, include the full length protein as well as polypeptides having one or more residues deleted from the amino terminus of the amino acid sequence of the reference polypeptide (i.e., serum albumin). In particular, N-terminal deletions may be described by the general formula m
[0080] Moreover, fragments of albumin fusion proteins of the invention, include the full length albumin fusion protein as well as polypeptides having one or more residues deleted from the amino terminus of the albumin fusion protein. In particular, N-terminal deletions may be described by the general formula m−q, where q is a whole integer representing the total number of amino acid residues in the albumin fusion protein, and m is defined as any integer ranging from 2 to q−6. Polynucleotides encoding these polypeptides are also encompassed by the invention.
[0081] Also as mentioned above, even if deletion of one or more amino acids from the N-terminus or C-terminus of a reference polypeptide (e.g., a Therapeutic protein and/or serum albumin protein) results in modification or loss of one or more biological functions of the protein, other functional activities (e.g., biological activities, ability to multimerize, ability to bind a ligand) and/or Therapeutic activities may still be retained. For example the ability of polypeptides with C-terminal deletions to induce and/or bind to antibodies which recognize the complete or mature forms of the polypeptide generally will be retained when less than the majority of the residues of the complete or mature polypeptide are removed from the C-terminus. Whether a particular polypeptide lacking the N-terminal and/or C-terminal residues of a reference polypeptide retains Therapeutic activity can readily be determined by routine methods described herein and/or otherwise known in the art.
[0082] The present invention further provides polypeptides having one or more residues deleted from the carboxy terminus of the amino acid sequence of a Therapeutic protein corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention (e.g., a Therapeutic protein referred to in Table 1). In particular, C-terminal deletions may be described by the general formula 1−n, where n is any whole integer ranging from 6 to q−1, and where q is a whole integer representing the total number of amino acid residues in a reference polypeptide (e.g., a Therapeutic protein referred to in Table 1). Polynucleotides encoding these polypeptides are also encompassed by the invention.
[0083] In addition, the present invention provides polypeptides having one or more residues deleted from the carboxy terminus of the amino acid sequence of an albumin protein corresponding to an albumin protein portion of an albumin fusion protein of the invention (e.g., serum albumin). In particular, C-terminal deletions may be described by the general formula 1−n, where n is any whole integer ranging from 6 to 584, where 584 is the whole integer representing the total number of amino acid residues in serum albumin (SEQ ID NO: 18) minus 1. Polynucleotides encoding these polypeptides are also encompassed by the invention.
[0084] Moreover, the present invention provides polypeptides having one or more residues deleted from the carboxy terminus of an albumin fusion protein of the invention. In particular, C-terminal deletions may be described by the general formula 1−n, where n is any whole integer ranging from 6 to q−1, and where q is a whole integer representing the total number of amino acid residues in an albumin fusion protein of the invention. Polynucleotides encoding these polypeptides are also encompassed by the invention.
[0085] In addition, any of the above described N- or C-terminal deletions can be combined to produce a N- and C-terminal deleted reference polypeptide. The invention also provides polypeptides having one or more amino acids deleted from both the amino and the carboxyl termini, which may be described generally as having residues m-n of a reference polypeptide (e.g., a Therapeutic protein referred to in Table 1, or serum albumin (e.g., SEQ ID NO: 18), or an albumin fusion protein of the invention) where n and m are integers as described above. Polynucleotides encoding these polypeptides are also encompassed by the invention.
[0086] The present application is also directed to proteins containing polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a reference polypeptide sequence (e.g., a Therapeutic protein, serum albumin protein or an albumin fusion protein of the invention) set forth herein, or fragments thereof. In preferred embodiments, the application is directed to proteins comprising polypeptides at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to reference polypeptides having the amino acid sequence of N- and C-terminal deletions as described above. Polynucleotides encoding these polypeptides are also encompassed by the invention.
[0087] Preferred polypeptide fragments of the invention are fragments comprising, or alternatively, consisting of, an amino acid sequence that displays a Therapeutic activity and/or functional activity (e.g. biological activity) of the polypeptide sequence of the Therapeutic protein or serum albumin protein of which the amino acid sequence is a fragment.
[0088] Other preferred polypeptide fragments are biologically active fragments. Biologically active fragments are those exhibiting activity similar, but not necessarily identical, to an activity of the polypeptide of the present invention. The biological activity of the fragments may include an improved desired activity, or a decreased undesirable activity.
[0089] Variants
[0090] “Variant” refers to a polynucleotide or nucleic acid differing from a reference nucleic acid or polypeptide, but retaining essential properties thereof. Generally, variants are overall closely similar, and, in many regions, identical to the reference nucleic acid or polypeptide.
[0091] As used herein, “variant”, refers to a Therapeutic protein portion of an albumin fusion protein of the invention, albumin portion of an albumin fusion protein of the invention, or albumin fusion protein differing in sequence from a Therapeutic protein (e.g. see “therapeutic” column of Table 1), albumin protein, and/or albumin fusion protein of the invention, respectively, but retaining at least one functional and/or therapeutic property thereof as described elsewhere herein or otherwise known in the art. Generally, variants are overall very similar, and, in many regions, identical to the amino acid sequence of the Therapeutic protein corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention, albumin protein corresponding to an albumin protein portion of an albumin fusion protein of the invention, and/or albumin fusion protein of the invention. Nucleic acids encoding these variants are also encompassed by the invention.
[0092] The present invention is also directed to proteins which comprise, or alternatively consist of, an amino acid sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100%, identical to, for example, the amino acid sequence of a Therapeutic protein corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention (e.g., an amino acid sequence disclosed in the “Exemplary Identifier” column of Table 1, or fragments or variants thereof), albumin proteins (e.g., SEQ ID NO:18 or fragments or variants thereof) corresponding to an albumin protein portion of an albumin fusion protein of the invention, and/or albumin fusion proteins of the invention. Fragments of these polypeptides are also provided (e.g., those fragments described herein). Further polypeptides encompassed by the invention are polypeptides encoded by polynucleotides which hybridize to the complement of a nucleic acid molecule encoding an amino acid sequence of the invention under stringent hybridization conditions (e.g., hybridization to filter bound DNA in 6×Sodium chloride/Sodium citrate (SSC) at about 45 degrees Celsius, followed by one or more washes in 0.2×SSC, 0.1% SDS at about 50-65 degrees Celsius), under highly stringent conditions (e.g., hybridization to filter bound DNA in 6×sodium chloride/Sodium citrate (SSC) at about 45 degrees Celsius, followed by one or more washes in 0.1×SSC, 0.2% SDS at about 68 degrees Celsius), or under other stringent hybridization conditions which are known to those of skill in the art (see, for example, Ausubel, F. M. et al., eds., 1989
[0093] By a polypeptide having an amino acid sequence at least, for example, 95% “identical” to a query amino acid sequence of the present invention, it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a query amino acid sequence, up to 5% of the amino acid residues in the subject sequence may be inserted, deleted, or substituted with another amino acid. These alterations of the reference sequence may occur at the amino- or carboxy-terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.
[0094] As a practical matter, whether any particular polypeptide is at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, the amino acid sequence of an albumin fusion protein of the invention or a fragment thereof (such as the Therapeutic protein portion of the albumin fusion protein or the albumin portion of the albumin fusion protein), can be determined conventionally using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. (Comp. App. Biosci. 6:237-245 (1990)). In a sequence alignment the query and subject sequences are either both nucleotide sequences or both amino acid sequences. The result of said global sequence alignment is expressed as percent identity. Preferred parameters used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, Mismatch Penalty=1, Joining Penalty=20, Randomization Group Length=0, Cutoff Score=1, Window Size=sequence length, Gap Penalty=5, Gap Size Penalty=0.05, Window Size=500 or the length of the subject amino acid sequence, whichever is shorter.
[0095] If the subject sequence is shorter than the query sequence due to N- or C-terminal deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for N- and C-terminal truncations of the subject sequence when calculating global percent identity. For subject sequences truncated at the N- and C-termini, relative to the query sequence, the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, which are not matched/aligned with a corresponding subject residue, as a percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are considered for the purposes of manually adjusting the percent identity score. That is, only query residue positions outside the farthest N- and C-terminal residues of the subject sequence.
[0096] For example, a 90 amino acid residue subject sequence is aligned with a 100 residue query sequence to determine percent identity. The deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not show a matching/alignment of the first 10 residues at the N-terminus. The 10 unpaired residues represent 10% of the sequence (number of residues at the N- and C-termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 residues were perfectly matched the final percent identity would be 90%. In another example, a 90 residue subject sequence is compared with a 100 residue query sequence. This time the deletions are internal deletions so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query sequence are manually corrected for. No other manual corrections are to made for the purposes of the present invention.
[0097] The variant will usually have at least 75% (preferably at least about 80%, 90%, 95% or 99%) sequence identity with a length of normal HA or Therapeutic protein which is the same length as the variant. Homology or identity at the nucleotide or amino acid sequence level is determined by BLAST (Basic Local Alignment Search Tool) analysis using the algorithm employed by the programs blastp, blastn, blastx, tblastn and tblastx (Karlin et al., Proc. Natl. Acad. Sci. USA 87: 2264-2268 (1990) and Altschul, J. Mol. Evol. 36: 290-300 (1993), fully incorporated by reference) which are tailored for sequence similarity searching.
[0098] The approach used by the BLAST program is to first consider similar segments between a query sequence and a database sequence, then to evaluate the statistical significance of all matches that are identified and finally to summarize only those matches which satisfy a preselected threshold of significance. For a discussion of basic issues in similarity searching of sequence databases, see Altschul et al., (Nature Genetics 6: 119-129 (1994)) which is fully incorporated by reference. The search parameters for histogram, descriptions, alignments, expect (i.e., the statistical significance threshold for reporting matches against database sequences), cutoff, matrix and filter are at the default settings. The default scoring matrix used by blastp, blastx, tblastn, and tblastx is the BLOSUM62 matrix (Henikoff et al., Proc. Natl. Acad. Sci. USA 89: 10915-10919 (1992), fully incorporated by reference). For blastn, the scoring matrix is set by the ratios of M (i.e., the reward score for a pair of matching residues) to N (i.e., the penalty score for mismatching residues), wherein the default values for M and N are 5 and -4, respectively. Four blastn parameters may be adjusted as follows: Q=10 (gap creation penalty); R=10 (gap extension penalty); wink=1 (generates word hits at every wink
[0099] The polynucleotide variants of the invention may contain alterations in the coding regions, non-coding regions, or both. Especially preferred are polynucleotide variants containing alterations which produce silent substitutions, additions, or deletions, but do not alter the properties or activities of the encoded polypeptide. Nucleotide variants produced by silent substitutions due to the degeneracy of the genetic code are preferred. Moreover, polypeptide variants in which less than 50, less than 40, less than 30, less than 20, less than 10, or 5-50, 5-25, 5-10, 1-5, or 1-2 amino acids are substituted, deleted, or added in any combination are also preferred. Polynucleotide variants can be produced for a variety of reasons, e.g., to optimize codon expression for a particular host (change codons in the human mRNA to those preferred by a bacterial host, such as, yeast or
[0100] In a preferred embodiment, a polynucleotide encoding an albumin portion of an albumin fusion protein of the invention is optimized for expression in yeast or mammalian cells. In further preferred embodiment, a polynucleotide encoding a Therapeutic protein portion of an albumin fusion protein of the invention is optimized for expression in yeast or mammalian cells. In a still further preferred embodiment, a polynucleotide encoding an albumin fusion protein of the invention is optimized for expression in yeast or mammalian cells.
[0101] In an alternative embodiment, a codon optimized polynucleotide encoding a Therapeutic protein portion of an albumin fusion protein of the invention does not hybridize to the wild type polynucleotide encoding the Therapeutic protein under stringent hybridization conditions as described herein. In a further embodiment, a codon optimized polynucleotide encoding an albumin portion of an albumin fusion protein of the invention do not hybridize to the wild type polynucleotide encoding the albumin protein under stringent hybridization conditions as described herein. In another embodiment, a codon optimized polynucleotide encoding an albumin fusion protein of the invention do not hybridize to the wild type polynucleotide encoding the Therapeutic protein portin or the albumin protein portion under stringent hybridization conditions as described herein.
[0102] In an additional embodiment, polynucleotides encoding a Therapeutic protein portion of an albumin fusion protein of the invention do not comprise, or alternatively consist of, the naturally occurring sequence of that Therapeutic protein. In a further embodiment, polynucleotides encoding an albumin protein portion of an albumin fusion protein of the invention do not comprise, or alternatively consist of, the naturally occurring sequence of albumin protein. In an alternative embodiment, polynucleotides encoding an albumin fusion protein of the invention do not comprise, or alternatively consist of, the naturally occurring sequence of a Therapeutic protein portion or the albumin protein portion.
[0103] Naturally occurring variants are called “allelic variants,” and refer to one of several alternate forms of a gene occupying a given locus on a chromosome of an organism. (Genes II, Lewin, B., ed., John Wiley & Sons, New York (1985)). These allelic variants can vary at either the polynucleotide and/or polypeptide level and are included in the present invention. Alternatively, non-naturally occurring variants may be produced by mutagenesis techniques or by direct synthesis.
[0104] Using known methods of protein engineering and recombinant DNA technology, variants may be generated to improve or alter the characteristics of the polypeptides of the present invention. For instance, one or more amino acids can be deleted from the N-terminus or C-terminus of the polypeptide of the present invention without substantial loss of biological function. As an example, Ron et al. (J. Biol. Chem. 268: 2984-2988 (1993)) reported variant KGF proteins having heparin binding activity even after deleting 3, 8, or 27 amino-terminal amino acid residues. Similarly, Interferon gamma exhibited up to ten times higher activity after deleting 8-10 amino acid residues from the carboxy terminus of this protein. (Dobeli et al., J. Biotechnology 7:199-216 (1988).)
[0105] Moreover, ample evidence demonstrates that variants often retain a biological activity similar to that of the naturally occurring protein. For example, Gayle and coworkers (J. Biol. Chem. 268:22105-22111 (1993)) conducted extensive mutational analysis of human cytokine IL-1a. They used random mutagenesis to generate over 3,500 individual IL-1a mutants that averaged 2.5 amino acid changes per variant over the entire length of the molecule. Multiple mutations were examined at every possible amino acid position. The investigators found that “[m]ost of the molecule could be altered with little effect on either [binding or biological activity].” In fact, only 23 unique amino acid sequences, out of more than 3,500 nucleotide sequences examined, produced a protein that significantly differed in activity from wild-type.
[0106] Furthermore, even if deleting one or more amino acids from the N-terminus or C-terminus of a polypeptide results in modification or loss of one or more biological functions, other biological activities may still be retained. For example, the ability of a deletion variant to induce and/or to bind antibodies which recognize the secreted form will likely be retained when less than the majority of the residues of the secreted form are removed from the N-terminus or C-terminus. Whether a particular polypeptide lacking N- or C-terminal residues of a protein retains such immunogenic activities can readily be determined by routine methods described herein and otherwise known in the art.
[0107] Thus, the invention further includes polypeptide variants which have a functional activity (e.g., biological activity and/or therapeutic activity). In highly preferred embodiments the invention provides variants of albumin fusion proteins that have a functional activity (e.g., biological activity and/or therapeutic activity) that corresponds to one or more biological and/or therapeutic activities of the Therapeutic protein corresponding to the Therapeutic protein portion of the albumin fusion protein. Such variants include deletions, insertions, inversions, repeats, and substitutions selected according to general rules known in the art so as have little effect on activity.
[0108] In preferred embodiments, the variants of the invention have conservative substitutions. By “conservative substitutions” is intended swaps within groups such as replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and Ile; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gln, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly.
[0109] Guidance concerning how to make phenotypically silent amino acid substitutions is provided, for example, in Bowie et al., “Deciphering the Message in Protein Sequences: Tolerance to Amino Acid Substitutions,” Science 247:1306-1310 (1990), wherein the authors indicate that there are two main strategies for studying the tolerance of an amino acid sequence to change.
[0110] The first strategy exploits the tolerance of amino acid substitutions by natural selection during the process of evolution. By comparing amino acid sequences in different species, conserved amino acids can be identified. These conserved amino acids are likely important for protein function. In contrast, the amino acid positions where substitutions have been tolerated by natural selection indicates that these positions are not critical for protein function. Thus, positions tolerating amino acid substitution could be modified while still maintaining biological activity of the protein.
[0111] The second strategy uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene to identify regions critical for protein function. For example, site directed mutagenesis or alanine-scanning mutagenesis (introduction of single alanine mutations at every residue in the molecule) can be used. See Cunningham and Wells, Science 244:1081-1085 (1989). The resulting mutant molecules can then be tested for biological activity.
[0112] As the authors state, these two strategies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The authors further indicate which amino acid changes are likely to be permissive at certain amino acid positions in the protein. For example, most buried (within the tertiary structure of the protein) amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Moreover, tolerated conservative amino acid substitutions involve replacement of the aliphatic or hydrophobic amino acids Ala, Val, Leu and Ile; replacement of the hydroxyl residues Ser and Thr; replacement of the acidic residues Asp and Glu; replacement of the amide residues Asn and Gln, replacement of the basic residues Lys, Arg, and His; replacement of the aromatic residues Phe, Tyr, and Trp, and replacement of the small-sized amino acids Ala, Ser, Thr, Met, and Gly. Besides conservative amino acid substitution, variants of the present invention include (i) polypeptides containing substitutions of one or more of the non-conserved amino acid residues, where the substituted amino acid residues may or may not be one encoded by the genetic code, or (ii) polypeptides containing substitutions of one or more of the amino acid residues having a substituent group, or (iii) polypeptides which have been fused with or chemically conjugated to another compound, such as a compound to increase the stability and/or solubility of the polypeptide (for example, polyethylene glycol), (iv) polypeptide containing additional amino acids, such as, for example, an IgG Fc fusion region peptide. Such variant polypeptides are deemed to be within the scope of those skilled in the art from the teachings herein.
[0113] For example, polypeptide variants containing amino acid substitutions of charged amino acids with other charged or neutral amino acids may produce proteins with improved characteristics, such as less aggregation. Aggregation of pharmaceutical formulations both reduces activity and increases clearance due to the aggregate's immunogenic activity. See Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967); Robbins et al., Diabetes 36: 838-845 (1987); Cleland et al., Crit. Rev. Therapeutic Drug Carrier Systems 10:307-377 (1993).
[0114] In specific embodiments, the polypeptides of the invention comprise, or alternatively, consist of, fragments or variants of the amino acid sequence of a Therapeutic protein described herein and/or human serum albumin, and/or albumin fusion protein of the invention, wherein the fragments or variants have 1-5, 5-10, 5-25, 5-50, 10-50 or 50-150, amino acid residue additions, substitutions, and/or deletions when compared to the reference amino acid sequence. In preferred embodiments, the amino acid substitutions are conservative. Nucleic acids encoding these polypeptides are also encompassed by the invention.
[0115] The polypeptide of the present invention can be composed of amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids. The polypeptides may be modified by either natural processes, such as post-translational processing, or by chemical modification techniques which are well known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993); POST-TRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).
[0116] Functional Activity
[0117] “A polypeptide having functional activity” refers to a polypeptide capable of displaying one or more known functional activities associated with the full-length, pro-protein, and/or mature form of a Therapeutic protein. Such functional activities include, but are not limited to, biological activity, antigenicity [ability to bind (or compete with a polypeptide for binding) to an anti-polypeptide antibody], immunogenicity (ability to generate antibody which binds to a specific polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide.
[0118] “A polypeptide having biological activity” refers to a polypeptide exhibiting activity similar to, but not necessarily identical to, an activity of a Therapeutic protein of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 25-fold less and, preferably, not more than about tenfold less activity, and most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention).
[0119] In preferred embodiments, an albumin fusion protein of the invention has at least one biological and/or therapeutic activity associated with the Therapeutic protein (or fragment or variant thereof) when it is not fused to albumin.
[0120] The albumin fusion proteins of the invention can be assayed for functional activity (e.g., biological activity) using or routinely modifying assays known in the art, as well as assays described herein. Additionally, one of skill in the art may routinely assay fragments of a Therapeutic protein corresponding to a Therapeutic protein portion of an albumin fusion protein of the invention, for activity using assays referenced in its corresponding row of Table 1. Further, one of skill in the art may routinely assay fragments of an albumin protein corresponding to an albumin protein portion of an albumin fusion protein of the invention, for activity using assays known in the art and/or as described in the Examples section below.
[0121] For example, in one embodiment where one is assaying for the ability of an albumin fusion protein of the invention to bind or compete with a Therapeutic protein for binding to an anti-Therapeutic polypeptide antibody and/or anti-albumin antibody, various immunoassays known in the art can be used, including but not limited to, competitive and non-competitive assay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, in situ immunoassays (using colloidal gold, enzyme or radioisotope labels, for example), western blots, precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays), complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis assays, etc. In one embodiment, antibody binding is detected by detecting a label on the primary antibody. In another embodiment, the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labeled. Many means are known in the art for detecting binding in an immunoassay and are within the scope of the present invention.
[0122] In a preferred embodiment, where a binding partner (e.g., a receptor or a ligand) of a Therapeutic protein is identified, binding to that binding partner by an albumin fusion protein containing that Therapeutic protein as the Therapeutic protein portion of the fusion can be assayed, e.g., by means well-known in the art, such as, for example, reducing and non-reducing gel chromatography, protein affinity chromatography, and affinity blotting. See generally, Phizicky et al., Microbiol. Rev. 59:94-123 (1995). In another embodiment, the ability of physiological correlates of an albumin fusion protein of the present invention to bind to a substrate(s) of the Therapeutic polypeptide corresponding to the Therapeutic portion of the albumin fusion protein of the invention can be routinely assayed using techniques known in the art.
[0123] In an alternative embodiment, where the ability of an albumin fusion protein of the invention to multimerize is being evaluated, association with other components of the multimer can be assayed, e.g., by means well-known in the art, such as, for example, reducing and non-reducing gel chromatography, protein affinity chromatography, and affinity blotting. See generally, Phizicky et al., supra.
[0124] In preferred embodiments, an albumin fusion protein of the invention comprising all or a portion of an antibody that binds a Therapeutic protein, has at least one biological and/or therapeutic activity (e.g., to specifically bind a polypeptide or epitope) associated with the antibody that binds a Therapeutic protein (or fragment or variant thereof) when it is not fused to albumin. In other preferred embodiments, the biological activity and/or therapeutic activity of an albumin fusion protein of the invention comprising all or a portion of an antibody that binds a Therapeutic protein is the inhibition (i.e. antagonism) or activation (i.e., agonism) of one or more of the biological activities and/or therapeutic activities associated with the polypeptide that is specifically bound by antibody that binds a Therapeutic protein.
[0125] Albumin fusion proteins of the invention (e.g., comprising at least a fragment or variant of an antibody that binds a Therapeutic protein) may be characterized in a variety of ways. In particular, albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be assayed for the ability to specifically bind to the same antigens specifically bound by the antibody that binds a Therapeutic protein corresponding to the Therapeutic protein portion of the albumin fusion protein using techniques described herein or routinely modifying techniques known in the art.
[0126] Assays for the ability of the albumin fusion proteins of the invention (e.g., comprising at least a fragment or variant of an antibody that binds a Therapeutic protein) to (specifically) bind a specific protein or epitope may be performed in solution (e.g., Houghten, Bio/Techniques 13:412-421(1992)), on beads (e.g., Lam, Nature 354:82-84 (1991)), on chips (e.g., Fodor, Nature 364:555-556 (1993)), on bacteria (e.g., U.S. Pat. No. 5,223,409), on spores (e.g., Patent Nos. 5,571,698; 5,403,484; and 5,223,409), on plasmids (e.g., Cull et al., Proc. Natl. Acad. Sci. USA 89:1865-1869 (1992)) or on phage (e.g., Scott and Smith, Science 249:386-390 (1990); Devlin, Science 249:404-406 (1990); Cwirla et al., Proc. Natl. Acad. Sci. USA 87:6378-6382 (1990); and Felici, J. Mol. Biol. 222:301-310 (1991)) (each of these references is incorporated herein in its entirety by reference). Albumin fusion proteins of the invention comprising at least a fragment or variant of a Therapeutic antibody may also be assayed for their specificity and affinity for a specific protein or epitope using or routinely modifying techniques described herein or otherwise known in the art.
[0127] The albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be assayed for cross-reactivity with other antigens (e.g., molecules that have sequence/structure conservation with the molecule(s) specifically bound by the antibody that binds a Therapeutic protein (or fragment or variant thereof) corresponding to the Therapeutic protein portion of the albumin fusion protein of the invention) by any method known in the art.
[0128] Immunoassays which can be used to analyze (immunospecific) binding and cross-reactivity include, but are not limited to, competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays, to name but a few. Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, which is incorporated by reference herein in its entirety). Exemplary immunoassays are described briefly below (but are not intended by way of limitation).
[0129] Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer such as RIPA buffer (1% NP-40 or Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 M sodium phosphate at pH 7.2, 1% Trasylol) supplemented with protein phosphatase and/or protease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate), adding the albumin fusion protein of the invention (e.g., comprising at least a fragment or variant of an antibody that binds a Therapeutic protein) to the cell lysate, incubating for a period of time (e.g., 1 to 4 hours) at 40 degrees C., adding sepharose beads coupled to an anti-albumin antibody, for example, to the cell lysate, incubating for about an hour or more at 40 degrees C., washing the beads in lysis buffer and resuspending the beads in SDS/sample buffer. The ability of the albumin fusion protein of the invention to immunoprecipitate a particular antigen can be assessed by, e.g. western blot analysis. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the binding of the albumin fusion protein to an antigen and decrease the background (e.g., pre-clearing the cell lysate with sepharose beads). For further discussion regarding immunoprecipitation protocols see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 10. 16.1.
[0130] Western blot analysis generally comprises preparing protein samples, electrophoresis of the protein samples in a polyacrylamide gel (e.g., 8%-20% SDS-PAGE depending on the molecular weight of the antigen), transferring the protein sample from the polyacrylamide gel to a membrane such as nitrocellulose, PVDF or nylon, blocking the membrane in blocking solution (e.g., PBS with 3% BSA or non-fat milk), washing the membrane in washing buffer (e.g., PBS-Tween 20), applying the albumin fusion protein of the invention (diluted in blocking buffer) to the membrane, washing the membrane in washing buffer, applying a secondary antibody (which recognizes the albumin fusion protein, e.g., an anti-human serum albumin antibody) conjugated to an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) or radioactive molecule (e.g.,
[0131] ELISAs comprise preparing antigen, coating the well of a 96-well microtiter plate with the antigen, washing away antigen that did not bind the wells, adding the albumin fusion protein (e.g., comprising at least a fragment or variant of an antibody that binds a Therapeutic protein) of the invention conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the wells and incubating for a period of time, washing away unbound or non-specifically bound albumin fusion proteins, and detecting the presence of the albumin fusion proteins specifically bound to the antigen coating the well. In ELISAs the albumin fusion protein does not have to be conjugated to a detectable compound; instead, a second antibody (which recognizes albumin fusion protein) conjugated to a detectable compound may be added to the well. Further, instead of coating the well with the antigen, the albumin fusion protein may be coated to the well. In this case, the detectable molecule could be the antigen conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase). One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected as well as other variations of ELISAs known in the art. For further discussion regarding ELISAs see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 11.2.1.
[0132] The binding affinity of an albumin fusion protein to a protein, antigen, or epitope and the off-rate of an albumin fusion protein-protein/antigen/epitope interaction can be determined by competitive binding assays. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen (e.g.,
[0133] In a preferred embodiment, BIAcore kinetic analysis is used to determine the binding on and off rates of albumin fusion proteins of the invention to a protein, antigen or epitope. BIAcore kinetic analysis comprises analyzing the binding and dissociation of albumin fusion proteins, or specific polypeptides, antigens or epitopes from chips with immobilized specific polypeptides, antigens or epitopes or albumin fusion proteins, respectively, on their surface.
[0134] Antibodies that bind a Therapeutic protein corresponding to the Therapeutic protein portion of an albumin fusion protein of the invention may also be described or specified in terms of their binding affinity for a given protein or antigen, preferably the antigen which they specifically bind. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10
[0135] Albumin
[0136] As described above, an albumin fusion protein of the invention comprises at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are associated with one another, preferably by genetic fusion or chemical conjugation.
[0137] The terms, human serum albumin (HSA) and human albumin (HA) are used interchangeably herein. The terms, “albumin and “serum albumin” are broader, and encompass human serum albumin (and fragments and variants thereof) as well as albumin from other species (and fragments and variants thereof).
[0138] As used herein, “albumin” refers collectively to albumin protein or amino acid sequence, or an albumin fragment or variant, having one or more functional activities (e.g., biological activities) of albumin. In particular, “albumin” refers to human albumin or fragments thereof (see EP 201 239, EP 322 094 WO 97/24445, WO95/23857) especially the mature form of human albumin as shown in
[0139] In preferred embodiments, the human serum albumin protein used in the albumin fusion proteins of the invention contains one or both of the following sets of point mutations with reference to SEQ ID NO:18: Leu-407 to Ala, Leu-408 to Val, Val-409 to Ala, and Arg-410 to Ala; or Arg-410 to A, Lys-413 to Gln, and Lys-414 to Gln (see, e.g., International Publication No. WO95/23857, hereby incorporated in its entirety by reference herein). In even more preferred embodiments, albumin fusion proteins of the invention that contain one or both of above-described sets of point mutations have improved stability/resistance to yeast Yap3p proteolytic cleavage, allowing increased production of recombinant albumin fusion proteins expressed in yeast host cells.
[0140] As used herein, a portion of albumin sufficient to prolong the therapeutic activity or shelf-life of the Therapeutic protein refers to a portion of albumin sufficient in length or structure to stabilize or prolong the therapeutic activity of the protein so that the shelf life of the Therapeutic protein portion of the albumin fusion protein is prolonged or extended compared to the shelf-life in the non-fusion state. The albumin portion of the albumin fusion proteins may comprise the full length of the HA sequence as described above or as shown in
[0141] The albumin portion of the albumin fusion proteins of the invention may be a variant of normal HA. The Therapeutic protein portion of the albumin fusion proteins of the invention may also be variants of the Therapeutic proteins as described herein. The term “variants” includes insertions, deletions and substitutions, either conservative or non conservative, where such changes do not substantially alter one or more of the oncotic, useful ligand-binding and non-immunogenic properties of albumin, or the active site, or active domain which confers the therapeutic activities of the Therapeutic proteins.
[0142] In particular, the albumin fusion proteins of the invention may include naturally occurring polymorphic variants of human albumin and fragments of human albumin, for example those fragments disclosed in EP 322 094 (namely HA (Pn), where n is 369 to 419). The albumin may be derived from any vertebrate, especially any mammal, for example human, cow, sheep, or pig. Non-mammalian albumins include, but are not limited to, hen and salmon. The albumin portion of the albumin fusion protein may be from a different animal than the Therapeutic protein portion.
[0143] Generally speaking, an HA fragment or variant will be at least 100 amino acids long, preferably at least 150 amino acids long. The HA variant may consist of or alternatively comprise at least one whole domain of HA, for example domains 1 (amino acids 1-194 of SEQ ID NO:18), 2 (amino acids 195-387 of SEQ ID NO:18), 3 (amino acids 388-585 of SEQ ID NO:18), 1+2 (1-387 of SEQ ID NO:18), 2+3 (195-585 of SEQ ID NO:18) or 1+3 (amino acids 1-194 of SEQ ID NO:18+amino acids 388-585 of SEQ ID NO:18). Each domain is itself made up of two homologous subdomains namely 1-105, 120-194, 195-291, 316-387, 388-491 and 512-585, with flexible inter-subdomain linker regions comprising residues Lys106 to Glu119, Glu292 to Val315 and Glu492 to Ala511.
[0144] Preferably, the albumin portion of an albumin fusion protein of the invention comprises at least one subdomain or domain of HA or conservative modifications thereof. If the fusion is based on subdomains, some or all of the adjacent linker is preferably used to link to the Therapeutic protein moiety.
[0145] Antibodies that Specifically Bind Therapeutic Proteins are also Therapeutic Proteins
[0146] The present invention also encompasses albumin fusion proteins that comprise at least a fragment or variant of an antibody that specifically binds a Therapeutic protein disclosed in Table 1. It is specifically contemplated that the term “Therapeutic protein” encompasses antibodies that bind a Therapeutic protein (e.g., as Described in column I of Table 1) and fragments and variants thereof. Thus an albumin fusion protein of the invention may contain at least a fragment or variant of a Therapeutic protein, and/or at least a fragment or variant of an an antibody that binds a Therapeutic protein.
[0147] Antibody Structure and Background
[0148] The basic antibody structural unit is known to comprise a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, 1gG, IgA, and IgE, respectively. See generally,
[0149] Thus, an intact IgG antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are the same.
[0150] The chains all exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDR regions, in general, are the portions of the antibody which make contact with the antigen and determine its specificity. The CDRs from the heavy and the light chains of each pair are aligned by the framework regions, enabling binding to a specific epitope. From N-terminal to C-terminal, both light and heavy chains variable regions comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The variable regions are connected to the heavy or light chain constant region. The assignment of amino acids to each domain is in accordance with the definitions of Kabat
[0151] As used herein, “antibody” refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that specifically binds an antigen (e.g., a molecule containing one or more CDR regions of an antibody). Antibodies that may correspond to a Therapeutic protein portion of an albumin fusion protein include, but are not limited to, monoclonal, multispecific, human, humanized or chimeric antibodies, single chain antibodies (e.g., single chain Fvs), Fab fragments, F(ab′) fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies specific to antibodies of the invention), and epitope-binding fragments of any of the above (e.g., VH domains, VL domains, or one or more CDR regions).
[0152] Antibodies that Bind Therapeutic Proteins
[0153] The present invention encompasses albumin fusion proteins that comprise at least a fragment or variant of an antibody that binds a Therapeutic Protein (e.g., as disclosed in Table 1) or fragment or variant thereof.
[0154] Antibodies that bind a Therapeutic protein (or fragment or variant thereof) may be from any animal origin, including birds and mammals. Preferably, the antibodies are human, murine (e.g., mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken antibodies. Most preferably, the antibodies are human antibodies. As used herein, “human” antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries and xenomice or other organisms that have been genetically engineered to produce human antibodies.
[0155] The antibody molecules that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule. In preferred embodiments, the antibody molecules that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention are IgG1. In other preferred embodiments, the immunoglobulin molecules that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention are IgG2. In other preferred embodiments, the immunoglobulin molecules that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention are IgG4.
[0156] Most preferably the antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention are human antigen-binding antibody fragments of the present invention and include, but are not limited to, Fab, Fab′ and F(ab′)
[0157] The antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention may be monospecific, bispecific, trispecific or of greater multispecificity. Multispecific antibodies may be specific for different epitopes of a Therapeutic protein or may be specific for both a Therapeutic protein as well as for a heterologous epitope, such as a heterologous polypeptide or solid support material. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., J. Immunol. 147:60-69 (1991); U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; Kostelny et al., J. Immunol. 148:1547-1553 (1992).
[0158] Antibodies that bind a Therapeutic protein (or fragment or variant thereof) may be bispecific or bifunctional which means that the antibody is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or linking of Fab′ fragments. See, e.g., Songsivilai & Lachmann
[0159] The present invention also provides albumin fusion proteins that comprise, fragments or variants (including derivatives) of an antibody described herein or known elsewhere in the art. Standard techniques known to those of skill in the art can be used to introduce mutations in the nucleotide sequence encoding a molecule of the invention, including, for example, site-directed mutagenesis and PCR-mediated mutagenesis which result in amino acid substitutions. Preferably, the variants (including derivatives) encode less than 50 amino acid substitutions, less than 40 amino acid subsitutions, less than 30 amino acid substitutions, less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions relative to the reference VH domain, VHCDR1, VHCDR2, VHCDR3, VL domain, VLCDR1, VLCDR2, or VLCDR3. In specific embodiments, the variants encode substitutions of VHCDR3. In a preferred embodiment, the variants have conservative amino acid substitutions at one or more predicted non-essential amino acid residues.
[0160] Antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention may be described or specified in terms of the epitope(s) or portion(s) of a Therapeutic protein which they recognize or specifically bind. Antibodies which specifically bind a Therapeutic protein or a specific epitope of a Therapeutic protein may also be excluded. Therefore, the present invention encompasses antibodies that specifically bind Therapeutic proteins, and allows for the exclusion of the same. In preferred embodiments, albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, binds the same epitopes as the.
[0161] Antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention may also be described or specified in terms of their cross-reactivity. Antibodies that do not bind any other analog, ortholog, or homolog of a Therapeutic protein are included. Antibodies that bind polypeptides with at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, and at least 50% identity (as calculated using methods known in the art and described herein) to a Therapeutic protein are also included in the present invention. In specific embodiments, antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention cross-react with murine, rat and/or rabbit homologs of human proteins and the corresponding epitopes thereof. Antibodies that do not bind polypeptides with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% identity (as calculated using methods known in the art and described herein) to a Therapeutic protein are also included in the present invention. In a specific embodiment, the above-described cross-reactivity is with respect to any single specific antigenic or immunogenic polypeptide, or combination(s) of 2, 3, 4, 5, or more of the specific antigenic and/or immunogenic polypeptides disclosed herein. In preferred embodiments, albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, has similar or substantially identical cross reactivity characteristics compared to the.
[0162] Further included in the present invention are antibodies which bind polypeptides encoded by polynucleotides which hybridize to a polynucleotide encoding a Therapeutic protein under stringent hybridization conditions (as described herein). Antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention may also be described or specified in terms of their binding affinity to a polypeptide of the invention. Preferred binding affinities include those with a dissociation constant or Kd less than 5×10
[0163] The invention also provides antibodies that competitively inhibit binding of an antibody to an epitope of a Therapeutic protein as determined by any method known in the art for determining competitive binding, for example, the immunoassays described herein. In preferred embodiments, the antibody competitively inhibits binding to the epitope by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%. In preferred embodiments, albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, competitively inhibits binding of an antibody to an epitope of a Therapeutic protein as well as the competitively inhibits binding of an antibody to an epitope of a Therapeutic protein. In other preferred embodiments, albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, competitively inhibits binding of the to an epitope of a Therapeutic protein by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50%.
[0164] Antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention may act as agonists or antagonists of the Therapeutic protein. For example, the present invention includes antibodies which disrupt the receptor/ligand interactions with the polypeptides of the invention either partially or fully. The invention features both receptor-specific antibodies and ligand-specific antibodies. The invention also features receptor-specific antibodies which do not prevent ligand binding but prevent receptor activation. Receptor activation (i.e., signaling) may be determined by techniques described herein or otherwise known in the art. For example, receptor activation can be determined by detecting the phosphorylation (e.g., tyrosine or serine/threonine) of the receptor or its substrate by immunoprecipitation followed by western blot analysis (for example, as described supra). In specific embodiments, antibodies are provided that inhibit ligand activity or receptor activity by at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 60%, or at least 50% of the activity in absence of the antibody. In preferred embodiments, albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, has similar or substantially similar characteristics with regard to preventing ligand binding and/or preventing receptor activation compared to the.
[0165] The invention also features receptor-specific antibodies which both prevent ligand binding and receptor activation as well as antibodies that recognize the receptor-ligand complex, and, preferably, do not specifically recognize the unbound receptor or the unbound ligand. Likewise, included in the invention are neutralizing antibodies which bind the ligand and prevent binding of the ligand to the receptor, as well as antibodies which bind the ligand, thereby preventing receptor activation, but do not prevent the ligand from binding the receptor. Further included in the invention are antibodies which activate the receptor. These antibodies may act as receptor agonists, i.e., potentiate or activate either all or a subset of the biological activities of the ligand-mediated receptor activation, for example, by inducing dimerization of the receptor. The antibodies may be specified as agonists, antagonists or inverse agonists for biological activities comprising the specific biological activities of the Therapeutic protreins (e.g. as disclosed in Table 1). The above antibody agonists can be made using methods known in the art. See, e.g., PCT publication WO 96/40281; U.S. Pat. No. 5,811,097; Deng et al., Blood 92(6):1981-1988 (1998); Chen et al., Cancer Res. 58(16):3668-3678 (1998); Harrop et al., J. Immunol. 161(4):1786-1794 (1998); Zhu et al., Cancer Res. 58(15):3209-3214 (1998); Yoon et al., J. Immunol. 160(7):3170-3179 (1998); Prat et al., J. Cell. Sci. 111(Pt2):237-247 (1998); Pitard et al., J. Immunol. Methods 205(2):177-190 (1997); Liautard et al., Cytokine 9(4):233-241 (1997); Carlson et al., J. Biol. Chem. 272(17):11295-11301 (1997); Taryrnan et al., Neuron 14(4):755-762 (1995); Muller et al., Structure 6(9):1153-1167 (1998); Bartunek et al., Cytokine 8(1):14-20 (1996) (which are all incorporated by reference herein in their entireties). In preferred embodiments, albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, have similar or substantially identical agonist or antagonist properties as the.
[0166] Antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention may be used, for example, to purify, detect, and target Therapeutic proteins, including both in in vitro and in vivo diagnostic and therapeutic methods. For example, the antibodies have utility in immunoassays for qualitatively and quantitatively measuring levels of the Therapeutic protein in biological samples. See, e.g., Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); incorporated by reference herein in its entirety. Likewise, albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, may be used, for example, to purify, detect, and target Therapeutic proteins, including both in in vitro and in vivo diagnostic and therapeutic methods.
[0167] Antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein include derivatives that are modified, i.e, by the covalent attachment of any type of molecule to the antibody. For example, but not by way of limitation, the antibody derivatives include antibodies that have been modified, e.g., by glycosylation, acetylation, pegylation, phosphylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative may contain one or more non-classical amino acids. Albumin fusion proteins of the invention may also be modified as described above.
[0168] Methods of Producing Antibodies that Bind Therapeutic Proteins
[0169] The antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention may be generated by any suitable method known in the art. Polyclonal antibodies to an antigen-of-interest can be produced by various procedures well known in the art. For example, a Therapeutic protein may be administered to various host animals including, but not limited to, rabbits, mice, rats, etc. to induce the production of sera containing polyclonal antibodies specific for the antigen. Various adjuvants may be used to increase the immunological response, depending on the host species, and include but are not limited to, Freund's (complete and incomplete), mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and corynebacterium parvum. Such adjuvants are also well known in the art.
[0170] Monoclonal antibodies can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma techniques including those known in the art and taught, for example, in Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling, et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981) (said references incorporated by reference in their entireties). The term “monoclonal antibody” as used herein is not limited to antibodies produced through hybridoma technology. The term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.
[0171] Methods for producing and screening for specific antibodies using hybridoma technology are routine and well known in the art. In a non-limiting example, mice can be immunized with a Therapeutic protein or fragment or variant thereof or a cell expressing such a Therapeutic protein or fragment or variant thereof. Once an immune response is detected, e.g., antibodies specific for the antigen are detected in the mouse serum, the mouse spleen is harvested and splenocytes isolated. The splenocytes are then fused by well known techniques to any suitable myeloma cells, for example cells from cell line SP20 available from the ATCC. Hybridomas are selected and cloned by limited dilution. The hybridoma clones are then assayed by methods known in the art for cells that secrete antibodies capable of binding a polypeptide of the invention. Ascites fluid, which generally contains high levels of antibodies, can be generated by immunizing mice with positive hybridoma clones.
[0172] Accordingly, the present invention provides methods of generating monoclonal antibodies as well as antibodies produced by the method comprising culturing a hybridoma cell secreting an antibody wherein, preferably, the hybridoma is generated by fusing splenocytes isolated from a mouse immunized with an antigen of the invention with myeloma cells and then screening the hybridomas resulting from the fusion for hybridoma clones that secrete an antibody able to bind a polypeptide of the invention.
[0173] Another well known method for producing both polyclonal and monoclonal human B cell lines is transformation using Epstein Barr Virus (EBV). Protocols for generating EBV-transformed B cell lines are commonly known in the art, such as, for example, the protocol outlined in Chapter 7.22 of Current Protocols in Immunology, Coligan et al., Eds., 1994, John Wiley & Sons, NY, which is hereby incorporated in its entirety by reference. The source of B cells for transformation is commonly human peripheral blood, but B cells for transformation may also be derived from other sources including, but not limited to, lymph nodes, tonsil, spleen, tumor tissue, and infected tissues. Tissues are generally made into single cell suspensions prior to EBV transformation. Additionally, steps may be taken to either physically remove or inactivate T cells (e.g., by treatment with cyclosporin A) in B cell-containing samples, because T cells from individuals seropositive for anti-EBV antibodies can suppress B cell immortalization by EBV.
[0174] In general, the sample containing human B cells is innoculated with EBV, and cultured for 3-4 weeks. A typical source of EBV is the culture supernatant of the B95-8 cell line (ATCC #VR-1492). Physical signs of EBV transformation can generally be seen towards the end of the 3-4 week culture period. By phase-contrast microscopy, transformed cells may appear large, clear, hairy and tend to aggregate in tight clusters of cells. Initially, EBV lines are generally polyclonal. However, over prolonged periods of cell cultures, EBV lines may become monoclonal or polyclonal as a result of the selective outgrowth of particular B cell clones. Alternatively, polyclonal EBV transformed lines may be subcloned (e.g., by limiting dilution culture) or fused with a suitable fusion partner and plated at limiting dilution to obtain monoclonal B cell lines. Suitable fusion partners for EBV transformed cell lines include mouse myeloma cell lines (e.g., SP2/0, X63-Ag8.653), heteromyeloma cell lines (human×mouse; e.g, SPAM-8, SBC-H
[0175] Antibody fragments which recognize specific epitopes may be generated by known techniques. For example, Fab and F(ab′)
[0176] For example, antibodies that bind to a Therapeutic protein can also be generated using various phage display methods known in the art. In phage display methods, functional antibody domains are displayed on the surface of phage particles which carry the polynucleotide sequences encoding them. In a particular embodiment, such phage can be utilized to display antigen binding domains expressed from a repertoire or combinatorial antibody library (e.g., human or murine). Phage expressing an antigen binding domain that binds the antigen of interest can be selected or identified with antigen, e.g., using labeled antigen or antigen bound or captured to a solid surface or bead. Phage used in these methods are typically filamentous phage including fd and M13 binding domains expressed from phage with Fab, Fv or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene III or gene VIII protein. Examples of phage display methods that can be used to make antibodies that bind to a Therapeutic protein include those disclosed in Brinkman et al., J. Immunol. Methods 182:41-50 (1995); Ames et al., J. Immunol. Methods 184:177-186 (1995); Kettleborough et al., Eur. J. Immunol. 24:952-958 (1994); Persic et al., Gene 1879-18 (1997); Burton et al., Advances in Immunology 57:191-280 (1994); PCT application No. PCT/GB91/01134; PCT publications WO 90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO 95/15982; WO 95/20401; and U.S. Pat. Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743 and 5,969,108; each of which is incorporated herein by reference in its entirety.
[0177] As described in the above references, after phage selection, the antibody coding regions from the phage can be isolated and used to generate whole antibodies, including human antibodies, or any other desired antigen binding fragment, and expressed in any desired host, including mammalian cells, insect cells, plant cells, yeast, and bacteria, e.g., as described in detail below. For example, techniques to recombinantly produce Fab, Fab′ and F(ab′)2 fragments can also be employed using methods known in the art such as those disclosed in PCT publication WO 92/22324; Mullinax et al., BioTechniques 12(6):864-869 (1992); and Sawai et al., AJRI 34:26-34 (1995); and Better et al., Science 240:1041-1043 (1988) (said references incorporated by reference in their entireties).
[0178] Examples of techniques which can be used to produce single-chain Fvs and antibodies include those described in U.S. Pat. Nos. 4,946,778 and 5,258,498; Huston et al., Methods in Enzymology 203:46-88 (1991); Shu et al., PNAS 90:7995-7999 (1993); and Skerra et al., Science 240:1038-1040 (1988). For some uses, including in vivo use of antibodies in humans and in vitro detection assays, it may be preferable to use chimeric, humanized, or human antibodies. A chimeric antibody is a molecule in which different portions of the antibody are derived from different animal species, such as antibodies having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region. Methods for producing chimeric antibodies are known in the art. See e.g., Morrison, Science 229:1202 (1985); Oi et al., BioTechniques 4:214 (1986); Gillies et al., (1989) J. Immunol. Methods 125:191-202; U.S. Pat. Nos. 5,807,715; 4,816,567; and 4,816,397, which are incorporated herein by reference in their entirety. Humanized antibodies are antibody molecules from non-human species antibody that binds the desired antigen having one or more complementarity determining regions (CDRs) from the non-human species and a framework regions from a human immunoglobulin molecule. Often, framework residues in the human framework regions will be substituted with the corresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding. These framework substitutions are identified by methods well known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; Riechmann et al., Nature 332:323 (1988), which are incorporated herein by reference in their entireties.) Antibodies can be humanized using a variety of techniques known in the art including, for example, CDR-grafting (EP 239,400; PCT publication WO 91/09967; U.S. Pat. Nos. 5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan, Molecular Immunology 28(4/5):489-498 (1991); Studnicka et al., Protein Engineering 7(6):805-814 (1994); Roguska. et al., PNAS 91:969-973 (1994)), and chain shuffling (U.S. Pat. No. 5,565,332).
[0179] Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Human antibodies can be made by a variety of methods known in the art including phage display methods described above using antibody libraries derived from human immunoglobulin sequences. See also, U.S. Pat. Nos. 4,444,887 and 4,716,111; and PCT publications WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO 96/34096, WO 96/33735, and WO 91/10741; each of which is incorporated herein by reference in its entirety.
[0180] Human antibodies can also be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. For example, the human heavy and light chain immunoglobulin gene complexes may be introduced randomly or by homologous recombination into mouse embryonic stem cells. Alternatively, the human variable region, constant region, and diversity region may be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes. The mouse heavy and light chain immunoglobulin genes may be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination. In particular, homozygous deletion of the JH region prevents endogenous antibody production. The modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice. The chimeric mice are then bred to produce homozygous offspring which express human antibodies. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention. Monoclonal antibodies directed against the antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA, IgM and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg and Huszar, Int. Rev. Immunol. 13:65-93 (1995). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., PCT publications WO 98/24893; WO 92/01047; WO 96/34096; WO 96/33735; European Patent No. 0 598 877; U.S. Pat. Nos. 5,413,923; 5,625,126; 5,633,425; 5,569,825; 5,661,016; 5,545,806; 5,814,318; 5,885,793; 5,916,771; 5,939,598; 6,075,181; and 6,114,598, which are incorporated by reference herein in their entirety. In addition, companies such as Abgenix, Inc. (Freemont, Calif.) and Genpharm (San Jose, Calif.) can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.
[0181] Completely human antibodies which recognize a selected epitope can be generated using a technique referred to as “guided selection.” In this approach a selected non-human monoclonal antibody, e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope. (Jespers et al., Bio/technology 12:899-903 (1988)).
[0182] Polynucleotides Encoding Antibodies
[0183] The invention further provides polynucleotides comprising a nucleotide sequence encoding an antibody and fragments thereof. The invention also encompasses polynucleotides that hybridize under stringent or alternatively, under lower stringency hybridization conditions, e.g., as defined supra, to polynucleotides that encode an antibody, preferably, that specifically binds to a Therapeutic protein, and more preferably, an antibody that binds to a polypeptide having the amino acid sequence of a “therapeutic protein X as discosed in the “Exemplay Identifier” column of Table 1.
[0184] The polynucleotides may be obtained, and the nucleotide sequence of the polynucleotides determined, by any method known in the art. For example, if the nucleotide sequence of the antibody is known, a polynucleotide encoding the antibody may be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al., BioTechniques 17:242 (1994)), which, briefly, involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, annealing and ligating of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.
[0185] Alternatively, a polynucleotide encoding an antibody may be generated from nucleic acid from a suitable source. If a clone containing a nucleic acid encoding a particular antibody is not available, but the sequence of the antibody molecule is known, a nucleic acid encoding the immunoglobulin may be chemically synthesized or obtained from a suitable source (e.g., an antibody cDNA library, or a cDNA library generated from, or nucleic acid, preferably poly A+ RNA, isolated from, any tissue or cells expressing the antibody, such as hybridoma cells selected to express an antibody) by PCR amplification using synthetic primers hybridizable to the 3′ and 5′ ends of the sequence or by cloning using an oligonucleotide probe specific for the particular gene sequence to identify, e.g., a cDNA clone from a cDNA library that encodes the antibody. Amplified nucleic acids generated by PCR may then be cloned into replicable cloning vectors using any method well known in the art (See Example 60).
[0186] Once the nucleotide sequence and corresponding amino acid sequence of the antibody is determined, the nucleotide sequence of the antibody may be manipulated using methods well known in the art for the manipulation of nucleotide sequences, e.g., recombinant DNA techniques, site directed mutagenesis, PCR, etc. (see, for example, the techniques described in Sambrook et al., 1990, Molecular Cloning, A Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. and Ausubel et al., eds., 1998, Current Protocols in Molecular Biology, John Wiley & Sons, NY, which are both incorporated by reference herein in their entireties), to generate antibodies having a different amino acid sequence, for example to create amino acid substitutions, deletions, and/or insertions.
[0187] In a specific embodiment, the amino acid sequence of the heavy and/or light chain variable domains may be inspected to identify the sequences of the complementarity determining regions (CDRs) by methods that are well know in the art, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability. Using routine recombinant DNA techniques, one or more of the CDRs may be inserted within framework regions, e.g., into human framework regions to humanize a non-human antibody, as described supra. The framework regions may be naturally occurring or consensus framework regions, and preferably human framework regions (see, e.g., Chothia et al., J. Mol. Biol. 278: 457-479 (1998) for a listing of human framework regions). Preferably, the polynucleotide generated by the combination of the framework regions and CDRs encodes an antibody that specifically binds a polypeptide of the invention. Preferably, as discussed supra, one or more amino acid substitutions may be made within the framework regions, and, preferably, the amino acid substitutions improve binding of the antibody to its antigen. Additionally, such methods may be used to make amino acid substitutions or deletions of one or more variable region cysteine residues participating in an intrachain disulfide bond to generate antibody molecules lacking one or more intrachain disulfide bonds. Other alterations to the polynucleotide are encompassed by the present invention and within the skill of the art.
[0188] In addition, techniques developed for the production of “chimeric antibodies” (Morrison et al., Proc. Natl. Acad. Sci. 81:851-855 (1984); Neuberger et al., Nature 312:604-608 (1984); Takeda et al., Nature 314:452-454 (1985)) by splicing genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used. As described supra, a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region, e.g., humanized antibodies.
[0189] Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778; Bird, Science 242:423-42 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Ward et al., Nature 334:544-54 (1989)) can be adapted to produce single chain antibodies. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide. Techniques for the assembly of functional Fv fragments in
[0190] Recombinant Expression of Antibodies
[0191] Recombinant expression of an antibody, or fragment, derivative or analog thereof, (e.g., a heavy or light chain of an antibody or a single chain antibody), requires construction of an expression vector containing a polynucleotide that encodes the antibody. Once a polynucleotide encoding an antibody molecule or a heavy or light chain of an antibody, or portion thereof (preferably containing the heavy or light chain variable domain), of the invention has been obtained, the vector for the production of the antibody molecule may be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing a protein by expressing a polynucleotide containing an antibody encoding nucleotide sequence are described herein. Methods which are well known to those skilled in the art can be used to construct expression vectors containing antibody coding sequences and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. The invention, thus, provides replicable vectors comprising a nucleotide sequence encoding an antibody molecule of the invention, or a heavy or light chain thereof, or a heavy or light chain variable domain, operably linked to a promoter. Such vectors may include the nucleotide sequence encoding the constant region of the antibody molecule (see, e.g., PCT Publication WO 86/05807; PCT Publication WO 89/01036; and U.S. Pat. No. 5,122,464) and the variable domain of the antibody may be cloned into such a vector for expression of the entire heavy or light chain.
[0192] The expression vector is transferred to a host cell by conventional techniques and the transfected cells are then cultured by conventional techniques to produce an antibody. Thus, the invention includes host cells containing a polynucleotide encoding an antibody of the invention, or a heavy or light chain thereof, or a single chain antibody, operably linked to a heterologous promoter. In preferred embodiments for the expression of double-chained antibodies, vectors encoding both the heavy and light chains may be co-expressed in the host cell for expression of the entire immunoglobulin molecule, as detailed below.
[0193] A variety of host-expression vector systems may be utilized to express the antibody molecules of the invention. Such host-expression systems represent vehicles by which the coding sequences of interest may be produced and subsequently purified, but also represent cells which may, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody molecule of the invention in situ. These include but are not limited to microorganisms such as bacteria (e.g.,
[0194] In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the antibody molecule being expressed. For example, when a large quantity of such a protein is to be produced, for the generation of pharmaceutical compositions of an antibody molecule, vectors which direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited, to the
[0195] In an insect system,
[0196] In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the antibody coding sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing the antibody molecule in infected hosts. (e.g., see Logan & Shenk, Proc. Natl. Acad. Sci. USA 81:355-359 (1984)). Specific initiation signals may also be required for efficient translation of inserted antibody coding sequences. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see Bittner et al., Methods in Enzymol. 153:51-544 (1987)).
[0197] In addition, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include but are not limited to CHO, VERY, BHK, Hela, COS, MDCK, 293, 3T3, WI38, and in particular, breast cancer cell lines such as, for example, BT483, Hs578T, HTB2, BT20 and T47D, and normal mammary gland cell line such as, for example, CRL7030 and Hs578Bst.
[0198] For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the antibody molecule may be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer, sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines which express the antibody molecule. Such engineered cell lines may be particularly useful in screening and evaluation of compounds that interact directly or indirectly with the antibody molecule.
[0199] A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et al., Cell 11:223 (1977)), hypoxanthine-guanine phosphoribosyltransferase (Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA 48:202 (1992)), and adenine phosphoribosyltransferase (Lowy et al., Cell 22:817 (1980)) genes can be employed in tk-, hgprt- or aprt-cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler et al., Natl. Acad. Sci. USA 77:357 (1980); O'Hare et al., Proc. Natl. Acad. Sci. USA 78:1527 (1981)); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, Proc. Natl. Acad. Sci. USA 78:2072 (1981)); neo, which confers resistance to the aminoglycoside G-418 Clinical Pharmacy 12:488-505; Wu and Wu, Biotherapy 3:87-95 (1991); Tolstoshev, Ann. Rev. Pharmacol. Toxicol. 32:573-596 (1993); Mulligan, Science 260:926-932 (1993); and Morgan and Anderson, Ann. Rev. Biochem. 62:191-217 (1993); May, 1993, TIB TECH 11(5):155-215 (1993)); and hygro, which confers resistance to hygromycin (Santerre et al., Gene 30:147 (1984)). Methods commonly known in the art of recombinant DNA technology may be routinely applied to select the desired recombinant clone, and such methods are described, for example, in Ausubel et al. (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993); Kriegler, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990); and in Chapters 12 and 13, Dracopoli et al. (eds), Current Protocols in Human Genetics, John Wiley & Sons, NY (1994); Colberre-Garapin et al., J. Mol. Biol. 150:1 (1981), which are incorporated by reference herein in their entireties.
[0200] The expression levels of an antibody molecule can be increased by vector amplification (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol.3. (Academic Press, New York, 1987)). When a marker in the vector system expressing antibody is amplifiable, increase in the level of inhibitor present in culture of host cell will increase the number of copies of the marker gene. Since the amplified region is associated with the antibody gene, production of the antibody will also increase (Crouse et al., Mol. Cell. Biol. 3:257 (1983)).
[0201] Vectors which use glutamine synthase (GS) or DHFR as the selectable markers can be amplified in the presence of the drugs methionine sulphoximine or methotrexate, respectively. An advantage of glutamine synthase based vectors are the availabilty of cell lines (e.g., the murine myeloma cell line, NS0) which are glutamine synthase negative. Glutamine synthase expression systems can also function in glutamine synthase expressing cells (e.g. Chinese Hamster Ovary (CHO) cells) by providing additional inhibitor to prevent the functioning of the endogenous gene. A glutamine synthase expression system and components thereof are detailed in PCT publications: WO87/04462; WO86/05807; WO89/01036; WO89/10404; and WO91/06657 which are incorporated in their entireties by reference herein. Additionally, glutamine synthase expression vectors that may be used according to the present invention are commercially available from suppliers, including, for example Lonza Biologics, Inc. (Portsmouth, N.H.). Expression and production of monoclonal antibodies using a GS expression system in murine myeloma cells is described in Bebbington et al,
[0202] The host cell may be co-transfected with two expression vectors of the invention, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide. The two vectors may contain identical selectable markers which enable equal expression of heavy and light chain polypeptides. Alternatively, a single vector may be used which encodes, and is capable of expressing, both heavy and light chain polypeptides. In such situations, the light chain should be placed before the heavy chain to avoid an excess of toxic free heavy chain (Proudfoot, Nature 322:52 (1986); Kohler, Proc. Natl. Acad. Sci. USA 77:2197 (1980)). The coding sequences for the heavy and light chains may comprise cDNA or genomic DNA.
[0203] Once an antibody molecule of the invention has been produced by an animal, chemically synthesized, or recombinantly expressed, it may be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins. In addition, the antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention or fragments thereof can be fused to heterologous polypeptide sequences described herein or otherwise known in the art, to facilitate purification.
[0204] Modifications of Antibodies
[0205] Antibodies that bind a Therapeutic protein or fragments or variants can be fused to marker sequences, such as a peptide to facilitate purification. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), among others, many of which are commercially available. As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, the “HA” tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984)) and the “flag” tag.
[0206] The present invention further encompasses antibodies or fragments thereof conjugated to a diagnostic or therapeutic agent. The antibodies can be used diagnostically to, for example, monitor the development or progression of a tumor as part of a clinical testing procedure to, e.g., determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, radioactive materials, positron emitting metals using various positron emission tomographies, and nonradioactive paramagnetic metal ions. The detectable substance may be coupled or conjugated either directly to the antibody (or fragment thereof) or indirectly, through an intermediate (such as, for example, a linker known in the art) using techniques known in the art. See, for example, U.S. Pat. No. 4,741,900 for metal ions which can be conjugated to antibodies for use as diagnostics according to the present invention. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include 125I, 131I, 111In or 99Tc. Other examples of detectable substances have been described elsewwhere herein.
[0207] Further, an antibody of the invention may be conjugated to a therapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213Bi. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).
[0208] The conjugates of the invention can be used for modifying a given biological response, the therapeutic agent or drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, alpha-interferon, β-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, e.g., TNF-alpha, TNF-beta, AIM I (See, International Publication No. WO 97/33899), AIM II (See, International Publication No. WO 97/34911), Fas Ligand (Takahashi et al.,
[0209] Antibodies may also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.
[0210] Techniques for conjugating such therapeutic moiety to antibodies are well known. See, for example, Arnon et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); “Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”, Immunol. Rev. 62:119-58 (1982).
[0211] Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980, which is incorporated herein by reference in its entirety.
[0212] An antibody, with or without a therapeutic moiety conjugated to it, administered alone or in combination with cytotoxic factor(s) and/or cytokine(s) can be used as a therapeutic.
[0213] Antibody-Albumin Fusion
[0214] Antibodies that bind to a Therapeutic protein and that may correspond to a Therapeutic protein portion of an albumin fusion protein of the invention include, but are not limited to, antibodies that bind a Therapeutic protein disclosed in the “Therapeutic Protein X” column of Table 1, or a fragment or variant thereof.
[0215] In specific embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VH domain. In other embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, one, two or three VH CDRs. In other embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of the VH CDR1. In other embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VH CDR2. In other embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VH CDR3.
[0216] In specific embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VL domain. In other embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, one, two or three VL CDRs. In other embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VL CDR1. In other embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VL CDR2. In other embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, the VL CDR3.
[0217] In other embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, one, two, three, four, five, or six VH and/or VL CDRs.
[0218] In preferred embodiments, the fragment or variant of an antibody that immunospecifcally binds a Therapeutic protein and that corresponds to a Therapeutic protein portion of an albumin fusion protein comprises, or alternatively consists of, an scFv comprising the VH domain of the Therapeutic antibody, linked to the VL domain of the therapeutic antibody by a peptide linker such as (Gly
[0219] Immunophenotyping
[0220] The antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein (or fragment or variant thereof) may be utilized for immunophenotyping of cell lines and biological samples. Therapeutic proteins of the present invention may be useful as cell-specific markers, or more specifically as cellular markers that are differentially expressed at various stages of differentiation and/or maturation of particular cell types. Monoclonal antibodies (or albumin fusion proteins comprsing at least a fragment or variant of an antibody that binds a Therapeutic protein) directed against a specific epitope, or combination of epitopes, will allow for the screening of cellular populations expressing the marker. Various techniques can be utilized using monoclonal antibodies (or albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein) to screen for cellular populations expressing the marker(s), and include magnetic separation using antibody-coated magnetic beads, “panning” with antibody attached to a solid matrix (i.e., plate), and flow cytometry (See, e.g., U.S. Pat. No. 5,985,660; and Morrison et al.,
[0221] These techniques allow for the screening of particular populations of cells, such as might be found with hematological malignancies (i.e. minimal residual disease (MRD) in acute leukemic patients) and “non-self” cells in transplantations to prevent Graft-versus-Host Disease (GVHD). Alternatively, these techniques allow for the screening of hematopoietic stem and progenitor cells capable of undergoing proliferation and/or differentiation, as might be found in human umbilical cord blood.
[0222] Characterizing Antibodies that Bind a Therapeutic Protein and Albumin Fusion Proteins Comprising a Fragment or Variant of an Antibody that Binds a Therapeutic Protein
[0223] The antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein (or fragment or variant thereof) may be characterized in a variety of ways. In particular, Albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be assayed for the ability to specifically bind to the same antigens specifically bound by the antibody that binds a Therapeutic protein corresponding to the antibody that binds a Therapeutic protein portion of the albumin fusion protein using techniques described herein or routinely modifying techniques known in the art.
[0224] Assays for the ability of the antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein (or fragment or variant thereof) to (specifically) bind a specific protein or epitope may be performed in solution (e.g., Houghten, Bio/Techniques 13:412-421(1992)), on beads (e.g., Lam, Nature 354:82-84 (1991)), on chips (e.g., Fodor, Nature 364:555-556 (1993)), on bacteria (e.g., U.S. Pat. No. 5,223,409), on spores (e.g., Patent Nos. 5,571,698; 5,403,484; and 5,223,409), on plasmids (e.g., Cull et al., Proc. Natl. Acad. Sci. USA 89:1865-1869 (1992)) or on phage (e.g., Scott and Smith, Science 249:386-390 (1990); Devlin, Science 249:404-406 (1990); Cwirla et al., Proc. Natl. Acad. Sci. USA 87:6378-6382 (1990); and Felici, J. Mol. Biol. 222:301-310 (1991)) (each of these references is incorporated herein in its entirety by reference). The antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein (or fragment or variant thereof) may also be assayed for their specificity and affinity for a specific protein or epitope using or routinely modifying techniques described herein or otherwise known in the art.
[0225] The albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be assayed for cross-reactivity with other antigens (e.g., molecules that have sequence/structure conservation with the molecule(s) specifically bound by the antibody that binds a Therapeutic protein (or fragment or variant thereof) corresponding to the Therapeutic protein portion of the albumin fusion protein of the invention) by any method known in the art.
[0226] Immunoassays which can be used to analyze (immunospecific) binding and cross-reactivity include, but are not limited to, competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), “sandwich” immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, and protein A immunoassays, to name but a few. Such assays are routine and well known in the art (see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York, which is incorporated by reference herein in its entirety). Exemplary immunoassays are described briefly below (but are not intended by way of limitation).
[0227] Immunoprecipitation protocols generally comprise lysing a population of cells in a lysis buffer such as RIPA buffer (1% NP-40 or Triton X-100, 1% sodium deoxycholate, 0.1% SDS, 0.15 M NaCl, 0.01 M sodium phosphate at pH 7.2, 1% Trasylol) supplemented with protein phosphatase and/or protease inhibitors (e.g., EDTA, PMSF, aprotinin, sodium vanadate), adding an antibody of the invention or albumin fusion protein of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein (or fragment or variant thereof) to the cell lysate, incubating for a period of time (e.g., 1 to 4 hours) at 40 degrees C., adding protein A and/or protein G sepharose beads (or beads coated with an appropriate anti-iditoypic antibody or anti-albumin antibody in the case when an albumin fusion protein comprising at least a fragment or variant of a Therapeutic antibody) to the cell lysate, incubating for about an hour or more at 40 degrees C., washing the beads in lysis buffer and resuspending the beads in SDS/sample buffer. The ability of the antibody or albumin fusion protein of the invention to immunoprecipitate a particular antigen can be assessed by, e.g., western blot analysis. One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the binding of the antibody or albumin fusion protein to an antigen and decrease the background (e.g., pre-clearing the cell lysate with sepharose beads). For further discussion regarding immunoprecipitation protocols see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 10.16.1.
[0228] Western blot analysis generally comprises preparing protein samples, electrophoresis of the protein samples in a polyacrylamide gel (e.g., 8%-20% SDS-PAGE depending on the molecular weight of the antigen), transferring the protein sample from the polyacrylamide gel to a membrane such as nitrocellulose, PVDF or nylon, blocking the membrane in blocking solution (e.g., PBS with 3% BSA or non-fat milk), washing the membrane in washing buffer (e.g., PBS-Tween 20), applying the antibody or albumin fusion protein of the invention (diluted in blocking buffer) to the membrane, washing the membrane in washing buffer, applying a secondary antibody (which recognizes the albumin fusion protein, e.g., an anti-human serum albumin antibody) conjugated to an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) or radioactive molecule (e.g.,
[0229] ELISAs comprise preparing antigen, coating the well of a 96-well microtiter plate with the antigen, washing away antigen that did not bind the wells, adding the antibody or albumin fusion protein (comprising at least a fragment or variant of an antibody that binds a Therapeutic protein) of the invention conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase) to the wells and incubating for a period of time, washing away unbound or non-specifically bound albumin fusion proteins, and detecting the presence of the antibody or albumin fusion proteins specifically bound to the antigen coating the well. In ELISAs the antibody or albumin fusion protein does not have to be conjugated to a detectable compound; instead, a second antibody (which recognizes the antibody or albumin fusion protein, respectively) conjugated to a detectable compound may be added to the well. Further, instead of coating the well with the antigen, antibody or the albumin fusion protein may be coated to the well. In this case, the detectable molecule could be the antigen conjugated to a detectable compound such as an enzymatic substrate (e.g., horseradish peroxidase or alkaline phosphatase). One of skill in the art would be knowledgeable as to the parameters that can be modified to increase the signal detected as well as other variations of ELISAs known in the art. For further discussion regarding ELISAs see, e.g., Ausubel et al, eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York at 11.2.1.
[0230] The binding affinity of an albumin fusion protein to a protein, antigen, or epitope and the off-rate of an antibody- or albumin fusion protein-protein/antigen/epitope interaction can be determined by competitive binding assays. One example of a competitive binding assay is a radioimmunoassay comprising the incubation of labeled antigen (e.g.,
[0231] In a preferred embodiment, BIAcore kinetic analysis is used to determine the binding on and off rates of antibody or albumin fusion proteins of the invention to a protein, antigen or epitope. BIAcore kinetic analysis comprises analyzing the binding and dissociation of antibodies, albumin fusion proteins, or specific polypeptides, antigens or epitopes from chips with immobilized specific polypeptides, antigens or epitopes, antibodies or albumin fusion proteins, respectively, on their surface.
[0232] Therapeutic Uses
[0233] The present invention is further directed to antibody-based therapies which involve administering antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein to an animal, preferably a mammal, and most preferably a human, patient for treating one or more of the disclosed diseases, disorders, or conditions. Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (including fragments, analogs and derivatives thereof as described herein), nucleic acids encoding antibodies of the invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies as described herein), albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein, and nucleic acids encoding such albumin fusion proteins. The antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein can be used to treat, inhibit or prevent diseases, disorders or conditions associated with aberrant expression and/or activity of a Therapeutic protein, including, but not limited to, any one or more of the diseases, disorders, or conditions described herein. The treatment and/or prevention of diseases, disorders, or conditions associated with aberrant expression and/or activity of a Therapeutic protein includes, but is not limited to, alleviating symptoms associated with those diseases, disorders or conditions antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.
[0234] In a specific and preferred embodiment, the present invention is directed to antibody-based therapies which involve administering antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein to an animal, preferably a mammal, and most preferably a human, patient for treating one or more diseases, disorders, or conditions, including but not limited to: neural disorders, immune system disorders, muscular disorders, reproductive disorders, gastrointestinal disorders, pulmonary disorders, cardiovascular disorders, renal disorders, proliferative disorders, and/or cancerous diseases and conditions., and/or as described elsewhere herein. Therapeutic compounds of the invention include, but are not limited to, antibodies of the invention (e.g., antibodies directed to the full length protein expressed on the cell surface of a mammalian cell; antibodies directed to an epitope of a Therapeutic protein and nucleic acids encoding antibodies of the invention (including fragments, analogs and derivatives thereof and anti-idiotypic antibodies as described herein). The antibodies of the invention can be used to treat, inhibit or prevent diseases, disorders or conditions associated with aberrant expression and/or activity of a Therapeutic protein, including, but not limited to, any one or more of the diseases, disorders, or conditions described herein. The treatment and/or prevention of diseases, disorders, or conditions associated with aberrant expression and/or activity of a Therapeutic protein includes, but is not limited to, alleviating symptoms associated with those diseases, disorders or conditions. Antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be provided in pharmaceutically acceptable compositions as known in the art or as described herein.
[0235] A summary of the ways in which the antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be used therapeutically includes binding Therapeutic proteins locally or systemically in the body or by direct cytotoxicity of the antibody, e.g. as mediated by complement (CDC) or by effector cells (ADCC). Some of these approaches are described in more detail below. Armed with the teachings provided herein, one of ordinary skill in the art will know how to use the antibodies of the invention or albumin fusion proteins of the invention comprising at-least a fragment or variant of an antibody that binds a Therapeutic protein for diagnostic, monitoring or therapeutic purposes without undue experimentation.
[0236] The antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be advantageously utilized in combination with other monoclonal or chimeric antibodies, or with lymphokines or hematopoietic growth factors (such as, e.g., IL-2, IL-3 and IL-7), for example, which serve to increase the number or activity of effector cells which interact with the antibodies.
[0237] The antibodies of the invention or albumin fusion proteins of the invention comprising at least a fragment or variant of an antibody that binds a Therapeutic protein may be administered alone or in combination with other types of treatments (e.g., radiation therapy, chemotherapy, hormonal therapy, immunotherapy and anti-tumor agents). Generally, administration of products of a species origin or species reactivity (in the case of antibodies) that is the same species as that of the patient is preferred. Thus, in a preferred embodiment, human antibodies, fragments derivatives, analogs, or nucleic acids, are administered to a human patient for therapy or prophylaxis.
[0238] It is preferred to use high affinity and/or potent in vivo inhibiting and/or neutralizing antibodies against Therapeutic proteins, fragments or regions thereof, (or the albumin fusion protein correlate of such an antibody) for both immunoassays directed to and therapy of disorders related to polynucleotides or polypeptides, including fragments thereof, of the present invention. Such antibodies, fragments, or regions, will preferably have an affinity for polynucleotides or polypeptides of the invention, including fragments thereof. Preferred binding affinities include dissociation constants or Kd's less than 5×10
[0239] Gene Therapy
[0240] In a specific embodiment, nucleic acids comprising sequences encoding antibodies that bind therapeutic proteins or albumin fusion proteins comprising at least a fragment or varaint of an antibody that binds a Therapeutic protein are administered to treat, inhibit or prevent a disease or disorder associated with aberrant expression and/or activity of a Therapeutic protein, by way of gene therapy. Gene therapy refers to therapy performed by the administration to a subject of an expressed or expressible nucleic acid. In this embodiment of the invention, the nucleic acids produce their encoded protein that mediates a therapeutic effect.
[0241] Any of the methods for gene therapy available in the art can be used according to the present invention. Exemplary methods are described in more detail elsewhere in this application.
[0242] Demonstration of Therapeutic or Prophylactic Activity
[0243] The compounds or pharmaceutical compositions of the invention are preferably tested in vitro, and then in vivo for the desired therapeutic or prophylactic activity, prior to use in humans. For example, in vitro assays to demonstrate the therapeutic or prophylactic utility of a compound or pharmaceutical composition include, the effect of a compound on a cell line or a patient tissue sample. The effect of the compound or composition on the cell line and/or tissue sample can be determined utilizing techniques known to those of skill in the art including, but not limited to, rosette formation assays and cell lysis assays. In accordance with the invention, in vitro assays which can be used to determine whether administration of a specific compound is indicated, include in vitro cell culture assays in which a patient tissue sample is grown in culture, and exposed to or otherwise administered a compound, and the effect of such compound upon the tissue sample is observed.
[0244] Therapeutic/Prophylactic Administration and Composition
[0245] The invention provides methods of treatment, inhibition and prophylaxis by administration to a subject of an effective amount of a compound or pharmaceutical composition of the invention, preferably an antibody. In a preferred embodiment, the compound is substantially purified (e.g., substantially free from substances that limit its effect or produce undesired side-effects). The subject is preferably an animal, including but not limited to animals such as cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, and most preferably human.
[0246] Formulations and methods of administration that can be employed when the compound comprises a nucleic acid or an immunoglobulin are described above; additional appropriate formulations and routes of administration can be selected from among those described herein below.
[0247] Various delivery systems are known and can be used to administer a compound of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the compound, receptor-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid as part of a retroviral or other vector, etc. Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds or compositions may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compounds or compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent.
[0248] In a specific embodiment, it may be desirable to administer the pharmaceutical compounds or compositions of the invention locally to the area in need of treatment; this may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. Preferably, when administering a protein, including an antibody, of the invention, care must be taken to use materials to which the protein does not absorb.
[0249] In another embodiment, the compound or composition can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.)
[0250] In yet another embodiment, the compound or composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J., Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, e.g., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
[0251] Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).
[0252] In a specific embodiment where the compound of the invention is a nucleic acid encoding a protein, the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see U.S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (see e.g., Joliot et al., Proc. Natl. Acad. Sci. USA 88:1864-1868 (1991)), etc. Alternatively, a nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination.
[0253] The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of a compound, and a pharmaceutically acceptable carrier. In a specific embodiment, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
[0254] In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
[0255] The compounds of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with cations such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
[0256] The amount of the compound of the invention which will be effective in the treatment, inhibition and prevention of a disease or disorder associated with aberrant expression and/or activity of a Therapeutic protein can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
[0257] For antibodies, the dosage administered to a patient is typically 0.1 mg/kg to 100 mg/kg of the patient's body weight. Preferably, the dosage administered to a patient is between 0.1 mg/kg and 20 mg/kg of the patient's body weight, more preferably 1 mg/kg to 10 mg/kg of the patient's body weight. Generally, human antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible. Further, the dosage and frequency of administration of antibodies of the invention may be reduced by enhancing uptake and tissue penetration (e.g., into the brain) of the antibodies by modifications such as, for example, lipidation.
[0258] Diagnosis and Imaging
[0259] Labeled antibodies and derivatives and analogs thereof that bind a Therapeutic protein (or fragment or variant thereof) (including albumin fusion proteins comprising at least a fragment or variant of an antibody that binds a Therapeutic protein), can be used for diagnostic purposes to detect, diagnose, or monitor diseases, disorders, and/or conditions associated with the aberrant expression and/or activity of Therapeutic protein. The invention provides for the detection of aberrant expression of a Therapeutic protein, comprising (a) assaying the expression of the Therapeutic protein in cells or body fluid of an individual using one or more antibodies specific to the polypeptide interest and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed Therapeutic protein expression level compared to the standard expression level is indicative of aberrant expression.
[0260] The invention provides a diagnostic assay for diagnosing a disorder, comprising (a) assaying the expression of the Therapeutic protein in cells or body fluid of an individual using one or more antibodies specific to the Therapeutic protein or albumin fusion proteins comprising at least a fragment of variant of an antibody specific to a Therapeutic protein, and (b) comparing the level of gene expression with a standard gene expression level, whereby an increase or decrease in the assayed Therapeutic protein gene expression level compared to the standard expression level is indicative of a particular disorder. With respect to cancer, the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.
[0261] Antibodies of the invention or albumin fusion proteins comprising at least a fragment of variant of an antibody specific to a Therapeutic protein can be used to assay protein levels in a biological sample using classical immunohistological methods known to those of skill in the art (e.g., see Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen et al., J. Cell. Biol. 105:3087-3096 (1987)). Other antibody-based methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine (125I, 121I), carbon (14C), sulfur (35S), tritium (3H), indium (112In), and technetium (99Tc); luminescent labels, such as luminol; and fluorescent labels, such as fluorescein and rhodamine, and biotin.
[0262] One facet of the invention is the detection and diagnosis of a disease or disorder associated with aberrant expression of a Therapeutic protein in an animal, preferably a mammal and most preferably a human. In one embodiment, diagnosis comprises: a) administering (for example, parenterally, subcutaneously, or intraperitoneally) to a subject an effective amount of a labeled molecule which specifically binds to the polypeptide of interest; b) waiting for a time interval following the administering for permitting the labeled molecule to preferentially concentrate at sites in the subject where the Therapeutic protein is expressed (and for unbound labeled molecule to be cleared to background level); c) determining background level; and d) detecting the labeled molecule in the subject, such that detection of labeled molecule above the background level indicates that the subject has a particular disease or disorder associated with aberrant expression of the therapeutic protein. Background level can be determined by various methods including, comparing the amount of labeled molecule detected to a standard value previously determined for a particular system.
[0263] It will be understood in the art that the size of the subject and the imaging system used will determine the quantity of imaging moiety needed to produce diagnostic images. In the case of a radioisotope moiety, for a human subject, the quantity of radioactivity injected will normally range from about 5 to 20 millicuries of 99 mTc. The labeled antibody, antibody fragment, or albumin fusion protein comprising at least a fragement or variant of an antibody that binds a Therapeutic protein will then preferentially accumulate at the location of cells which contain the specific Therapeutic protein. In vivo tumor imaging is described in S. W. Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies and Their Fragments.” (Chapter 13 in Tumor Imaging: The Radiochemical Detection of Cancer, S. W. Burchiel and B. A. Rhodes, eds., Masson Publishing Inc. (1982)).
[0264] Depending on several variables, including the type of label used and the mode of administration, the time interval following the administration for permitting the labeled molecule to preferentially concentrate at sites in the subject and for unbound labeled molecule to be cleared to background level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. In another embodiment the time interval following administration is 5 to 20 days or 5 to 10 days.
[0265] In an embodiment, monitoring of the disease or disorder is carried out by repeating the method for diagnosing the disease or disease, for example, one month after initial diagnosis, six months after initial diagnosis, one year after initial diagnosis, etc.
[0266] Presence of the labeled molecule can be detected in the patient using methods known in the art for in vivo scanning. These methods depend upon the type of label used. Skilled artisans will be able to determine the appropriate method for detecting a particular label. Methods and devices that may be used in the diagnostic methods of the invention include, but are not limited to, computed tomography (CT), whole body scan such as position emission tomography (PET), magnetic resonance imaging (MRI), and sonography.
[0267] In a specific embodiment, the molecule is labeled with a radioisotope and is detected in the patient using a radiation responsive surgical instrument (Thurston et al., U.S. Pat. No. 5,441,050). In another embodiment, the molecule is labeled with a fluorescent compound and is detected in the patient using a fluorescence responsive scanning instrument. In another embodiment, the molecule is labeled with a positron emitting metal and is detected in the patent using positron emission-tomography. In yet another embodiment, the molecule is labeled with a paramagnetic label and is detected in a patient using magnetic resonance imaging (MRI).
[0268] Kits
[0269] The present invention provides kits that can be used in the above methods. In one embodiment, a kit comprises an antibody, preferably a purified antibody, in one or more containers. In a specific embodiment, the kits of the present invention contain a substantially isolated polypeptide comprising an epitope which is specifically immunoreactive with an antibody included in the kit. Preferably, the kits of the present invention further comprise a control antibody which does not react with the polypeptide of interest. In another specific embodiment, the kits of the present invention contain a means for detecting the binding of an antibody to a polypeptide of interest (e.g., the antibody may be conjugated to a detectable substrate such as a fluorescent compound, an enzymatic substrate, a radioactive compound or a luminescent compound, or a second antibody which recognizes the first antibody may be conjugated to a detectable substrate).
[0270] In another specific embodiment of the present invention, the kit is a diagnostic kit for use in screening serum containing antibodies specific against proliferative and/or cancerous polynucleotides and polypeptides. Such a kit may include a control antibody that does not react with the polypeptide of interest. Such a kit may include a substantially isolated polypeptide antigen comprising an epitope which is specifically immunoreactive with at least one anti-polypeptide antigen antibody. Further, such a kit includes means for detecting the binding of said antibody to the antigen (e.g., the antibody may be conjugated to a fluorescent compound such as fluorescein or rhodamine which can be detected by flow cytometry). In specific embodiments, the kit may include a recombinantly produced or chemically synthesized polypeptide antigen. The polypeptide antigen of the kit may also be attached to a solid support.
[0271] In a more specific embodiment the detecting means of the above-described kit includes a solid support to which said polypeptide antigen is attached. Such a kit may also include a non-attached reporter-labeled anti-human antibody. In this embodiment, binding of the antibody to the polypeptide antigen can be detected by binding of the said reporter-labeled antibody.
[0272] In an additional embodiment, the invention includes a diagnostic kit for use in screening serum containing antigens of the polypeptide of the invention. The diagnostic kit includes a substantially isolated antibody specifically immunoreactive with polypeptide or polynucleotide antigens, and means for detecting the binding of the polynucleotide or polypeptide antigen to the antibody. In one embodiment, the antibody is attached to a solid support. In a specific embodiment, the antibody may be a monoclonal antibody. The detecting means of the kit may include a second, labeled monoclonal antibody. Alternatively, or in addition, the detecting means may include a labeled, competing antigen.
[0273] In one diagnostic configuration, test serum is reacted with a solid phase reagent having a surface-bound antigen obtained by the methods of the present invention. After binding with specific antigen antibody to the reagent and removing unbound serum components by washing, the reagent is reacted with reporter-labeled-anti-human antibody to bind reporter to the reagent in proportion to the amount of bound anti-antigen antibody on the solid support. The reagent is again washed to remove unbound labeled antibody, and the amount of reporter associated with the reagent is determined. Typically, the reporter is an enzyme which is detected by incubating the solid phase in the presence of a suitable fluorometric, luminescent or colorimetric substrate (Sigma, St. Louis, Mo.).
[0274] The solid surface reagent in the above assay is prepared by known techniques for attaching protein material to solid support material, such as polymeric beads, dip sticks, 96-well plate or filter material. These attachment methods generally include non-specific adsorption of the protein to the support or covalent attachment of the protein, typically through a free amine group, to a chemically reactive group on the solid support, such as an activated carboxyl, hydroxyl, or aldehyde group. Alternatively, streptavidin coated plates can be used in conjunction with biotinylated antigen(s).
[0275] Thus, the invention provides an assay system or kit for carrying out this diagnostic method. The kit generally includes a support with surface-bound recombinant antigens, and a reporter-labeled anti-human antibody for detecting surface-bound anti-antigen antibody.
[0276] Albumin Fusion Proteins
[0277] The present invention relates generally to albumin fusion proteins and methods of treating, preventing, or ameliorating diseases or disorders. As used herein, “albumin fusion protein” refers to a protein formed by the fusion of at least one molecule of albumin (or a fragment or variant thereof) to at least one molecule of a Therapeutic protein (or fragment or variant thereof). An albumin fusion protein of the invention comprises at least a fragment or variant of a Therapeutic protein and at least a fragment or variant of human serum albumin, which are associated with one another, preferably by genetic fusion (i.e., the albumin fusion protein is generated by translation of a nucleic acid in which a polynucleotide encoding all or a portion of a Therapeutic protein is joined in-frame with a polynucleotide encoding all or a portion of albumin) or chemical conjugation to one another. The Therapeutic protein and albumin protein, once part of the albumin fusion protein, may be referred to as a “portion”, “region” or “moiety” of the albumin fusion protein.
[0278] In one embodiment, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein (e.g., as described in Table 1) and a serum albumin protein. In other embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active fragment of a Therapeutic protein and a serum albumin protein. In other embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active variant of a Therapeutic protein and a serum albumin protein. In preferred embodiments, the serum albumin protein component of the albumin fusion protein is the mature portion of serum albumin.
[0279] In further embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein, and a biologically active and/or therapeutically active fragment of serum albumin. In further embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a Therapeutic protein and a biologically active and/or therapeutically active variant of serum albumin. In preferred embodiments, the Therapeutic protein portion of the albumin fusion protein is the mature portion of the Therapeutic protein.
[0280] In further embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, a biologically active and/or therapeutically active fragment or variant of a Therapeutic protein and a biologically active and/or therapeutically active fragment or variant of serum albumin. In preferred embodiments, the invention provides an albumin fusion protein comprising, or alternatively consisting of, the mature portion of a Therapeutic protein and the mature portion of serum albumin.
[0281] Preferably, the albumin fusion protein comprises HA as the N-terminal portion, and a Therapeutic protein as the C-terminal portion. Alternatively, an albumin fusion protein comprising HA as the C-terminal portion, and a Therapeutic protein as the N-terminal portion may also be used.
[0282] In other embodiments, the albumin fusion protein has a Therapeutic protein fused to both the N-terminus and the C-terminus of albumin. In a preferred embodiment, the Therapeutic proteins fused at the N- and C-termini are the same Therapeutic proteins. In a preferred embodiment, the Therapeutic proteins fused at the N- and C-termini are different Therapeutic proteins. In another preferred embodiment, the Therapeutic proteins fused at the N- and C-termini are different Therapeutic proteins which may be used to treat or prevent the same disease, disorder, or condition (e.g. as listed in the “Preferred Indication Y” column of Table 1). In another preferred embodiment, the Therapeutic proteins fused at the N- and C-termini are different Therapeutic proteins which may be used to treat or prevent diseases or disorders (e.g. as listed in the “Preferred Indication Y” column of Table 1) which are known in the art to commonly occur in patients simultaneously.
[0283] In addition to albumin fusion protein in which the albumin portion is fused N-terminal and/or C-terminal of the Therapeutic protein portion, albumin fusion proteins of the invention may also be produced by inserting the Therapeutic protein or peptide of interest (e.g., a Therapeutic protein X as diclosed in Table 1, or an antibody that binds a Therapeutic protein or a fragment or variant thereof) into an internal region of HA. For instance, within the protein sequence of the HA molecule a number of loops or turns exist between the end and beginning of α-helices, which are stabilized by disulphide bonds (see FIGS.
[0284] Loops in human albumin structure into which peptides or polypeptides may be inserted to generate albumin fusion proteins of the invention include: Val54-Asn61, Thr76-Asp89, Ala92-Glu100, Gln170-Ala176, His 247-Glu252, Glu 266-Glu277, Glu 280-His288, Ala362-Glu368, Lys439-Pro447,Val462-Lys475, Thr478-Pro486, and Lys560-Thr566. In more preferred embodiments, peptides or polypeptides are inserted into the Val54-Asn61, Gln170-Ala176, and/or Lys560-Thr566 loops of mature human albumin (SEQ ID NO: 18).
[0285] Peptides to be inserted may be derived from either phage display or synthetic peptide libraries screened for specific biological activity or from the active portions of a molecule with the desired function. Additionally, random peptide libraries may be generated within particular loops or by insertions of randomized peptides into particular loops of the HA molecule and in which all possible combinations of amino acids are represented.
[0286] Such library(s) could be generated on HA or domain fragments of HA by one of the following methods:
[0287] (a) randomized mutation of amino acids within one or more peptide loops of HA or HA domain fragments. Either one, more or all the residues within a loop could be mutated in this manner (for example see
[0288] (b) replacement of, or insertion into one or more loops of HA or HA domain fragments (i.e., internal fusion) of a randomized peptide(s) of length X
[0289] (c) N-, C- or N- and C-terminal peptide/protein fusions in addition to (a) and/or (b).
[0290] The HA or HA domain fragment may also be made multifunctional by grafting the peptides derived from different screens of different loops against different targets into the same HA or HA domain fragment.
[0291] In preferred embodiments, peptides inserted into a loop of human serum albumin are peptide fragments or peptide variants of the Therapeutic proteins disclosed in Table 1. More particulary, the invention encompasses albumin fusion proteins which comprise peptide fragments or peptide variants at least 7 at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 35, or at least 40 amino acids in length inserted into a loop of human serum albumin. The invention also encompasses albumin fusion proteins which comprise peptide fragments or peptide variants at least 7 at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 35, or at least 40 amino acids fused to the N-terminus of human serum albumin. The invention also encompasses albumin fusion proteins which comprise peptide fragments or peptide variants at least 7 at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 20, at least 25, at least 30, at least 35, or at least 40 amino acids fused to the C-terminus of human serum albumin.
[0292] Generally, the albumin fusion proteins of the invention may have one HA-derived region and one Therapeutic protein-derived region. Multiple regions of each protein, however, may be used to make an albumin fusion protein of the invention. Similarly, more than one Therapeutic protein may be used to make an albumin fusion protein of the invention. For instance, a Therapeutic protein may be fused to both the N- and C-terminal ends of the HA. In such a configuration, the Therapeutic protein portions may be the same or different Therapeutic protein molecules. The structure of bifunctional albumin fusion proteins may be represented as: X-HA-Y or Y-HA-X.
[0293] For example, an anti-BLyS™ scFv-HA-IFNα-2b fusion may be prepared to modulate the immune response to IFNα-2b by anti-BLyS™ scFv. An alternative is making a bi (or even multi) functional dose of HA-fusions e.g. HA-IFNα-2b fusion mixed with HA-anti-BLyS™ scFv fusion or other HA-fusions in various ratio's depending on function, half-life etc.
[0294] Bi- or multi-functional albumin fusion proteins may also be prepared to target the Therapeutic protein portion of a fusion to a target organ or cell type via protein or peptide at the opposite terminus of HA.
[0295] As an alternative to the fusion of known therapeutic molecules, the peptides could be obtained by screening libraries constructed as fusions to the N-, C- or N- and C-termini of HA, or domain fragment of HA, of typically 6, 8, 12, 20 or 25 or X
[0296] Additionally, the albumin fusion proteins of the invention may include a linker peptide between the fused portions to provide greater physical separation between the moieties and thus maximize the accessibility of the Therapeutic protein portion, for instance, for binding to its cognate receptor. The linker peptide may consist of amino acids such that it is flexible or more rigid.
[0297] The linker sequence may be cleavable by a protease or chemically to yield the growth hormone related moiety. Preferably, the protease is one which is produced naturally by the host, for example the
[0298] Therefore, as described above, the albumin fusion proteins of the invention may have the following formula R1-L-R2; R2-L-R1; or R1-L-R2-L-R1, wherein R1 is at least one Therapeutic protein, peptide or polypeptide sequence, and not necessarily the same Therapeutic protein, L is a linker and R2 is a serum albumin sequence.
[0299] In preferred embodiments, Albumin fusion proteins of the invention comprising a Therapeutic protein have extended shelf life compared to the shelf life the same Therapeutic protein when not fused to albumin. Shelf-life typically refers to the time period over which the therapeutic activity of a Therapeutic protein in solution or in some other storage formulation, is stable without undue loss of therapeutic activity. Many of the Therapeutic proteins are highly labile in their unfused state. As described below, the typical shelf-life of these Therapeutic proteins is markedly prolonged upon incorporation into the albumin fusion protein of the invention.
[0300] Albumin fusion proteins of the invention with “prolonged” or “extended” shelf-life exhibit greater therapeutic activity relative to a standard that has been subjected to the same storage and handling conditions. The standard may be the unfused full-length Therapeutic protein. When the Therapeutic protein portion of the albumin fusion protein is an analog, a variant, or is otherwise altered or does not include the complete sequence for that protein, the prolongation of therapeutic activity may alternatively be compared to the unfused equivalent of that analog, variant, altered peptide or incomplete sequence. As an example, an albumin fusion protein of the invention may retain greater than about 100% of the therapeutic activity, or greater than about 105%, 110%, 120%, 130%, 150% or 200% of the therapeutic activity of a standard when subjected to the same storage and handling conditions as the standard when compared at a given time point.
[0301] Shelf-life may also be assessed in terms of therapeutic activity remaining after storage, normalized to therapeutic activity when storage began. Albumin fusion proteins of the invention with prolonged or extended shelf-life as exhibited by prolonged or extended therapeutic activity may retain greater than about 50% of the therapeutic activity, about 60%, 70%, 80%, or 90% or more of the therapeutic activity of the equivalent unfused Therapeutic protein when subjected to the same conditions. For example, as discussed in Example 1, an albumin fusion protein of the invention comprising hGH fused to the full length HA sequence may retain about 80% or more of its original activity in solution for periods of up to 5 weeks or more under various temperature conditions.
[0302] Expression of Fusion Proteins
[0303] The albumin fusion proteins of the invention may be produced as recombinant molecules by secretion from yeast, a microorganism such as a bacterium, or a human or animal cell line. Preferably, the polypeptide is secreted from the host cells. We have found that, by fusing the hGH coding sequence to the HA coding sequence, either to the 5′ end or 3′ end, it is possible to secrete the albumin fusion protein from yeast without the requirement for a yeast-derived pro sequence. This was surprising, as other workers have found that a yeast derived pro sequence was needed for efficient secretion of hGH in yeast.
[0304] For example, Hiramatsu et al. (Appl Environ Microbiol 56:2125 (1990); Appl Environ Microbiol 57:2052 (1991)) found that the N-terminal portion of the pro sequence in the
[0305] Hence, a particular embodiment of the invention comprises a DNA construct encoding a signal sequence effective for directing secretion in yeast, particularly a yeast-derived signal sequence (especially one which is homologous to the yeast host), and the fused molecule of the first aspect of the invention, there being no yeast-derived pro sequence between the signal and the mature polypeptide.
[0306] The
[0307] Conjugates of the kind prepared by Poznansky et al, (FEBS Lett. 239:18 (1988)), in which separately-prepared polypeptides are joined by chemical cross-linking, are not contemplated.
[0308] The present invention also includes a cell, preferably a yeast cell transformed to express an albumin fusion protein of the invention. In addition to the transformed host cells themselves, the present invention also contemplates a culture of those cells, preferably a monoclonal (clonally homogeneous) culture, or a culture derived from a monoclonal culture, in a nutrient medium. If the polypeptide is secreted, the medium will contain the polypeptide, with the cells, or without the cells if they have been filtered or centrifuged away. Many expression systems are known and may be used, including bacteria (for example
[0309] Preferred yeast strains to be used in the production of albumin fusion proteins are D88, DXY1 and BXP10. D88 [leu2-3, leu2-122, canI, praI, ubc4] is a derivative of parent strain AH22his
[0310] DXY1, a derivative of D88, has the following genotype: [leu2-3, leu2-122, canI, pra1, ubc4, ura3::yap3]. In addition to the mutations isolated in D88, this strain also has a knockout of the YAP3 protease. This protease causes cleavage of mostly di-basic residues (RR, RK, KR, KK) but can also promote cleavage at single basic residues in proteins. Isolation of this yap3 mutation resulted in higher levels of full length HSA production (see, e.g., U.S. Pat. No. 5,965,386 and Kerry-Williams et al., Yeast 14:161-169 (1998), hereby incorporated in their entireties by reference herein).
[0311] BXP10 has the following genotype: leu2-3, leu2-122, can1, pra1, ubc4, ura3, yap3::URA3, lys2, hsp150::LYS2, pmt1::URA3. In addition to the mutations isolated in DXY1, this strain also has a knockout of the PMT1 gene and the HSP150 gene. The PMT1 gene is a member of the evolutionarily conserved family of dolichyl-phosphate-D-mannose protein O-mannosyltransferases (Pmts). The transmembrane topology of Pmt1p suggests that it is an integral membrane protein of the endoplasmic reticulum with a role in O-linked glycosylation. This mutation serves to reduce/eliminate O-linked glycosylation of HSA fusions (see, e.g., International Publication No. WO00/44772, hereby incorporated in its entirety by reference herein). Studies revealed that the Hsp150 protein is inefficiently separated from rHA by ion exchange chromatography. The mutation in the HSP150 gene removes a potential contaminant that has proven difficult to remove by standard purification techniques. See, e.g., U.S. Pat. No. 5,783,423, hereby incorporated in its entirety by reference herein.
[0312] The desired protein is produced in conventional ways, for example from a coding sequence inserted in the host chromosome or on a free plasmid. The yeasts are transformed with a coding sequence for the desired protein in any of the usual ways, for example electroporation. Methods for transformation of yeast by electroporation are disclosed in Becker & Guarente (1990)
[0313] Successfully transformed cells, i.e., cells that contain a DNA construct of the present invention, can be identified by well known techniques. For example, cells resulting from the introduction of an expression construct can be grown to produce the desired polypeptide. Cells can be harvested and lysed and their DNA content examined for the presence of the DNA using a method such as that described by Southern (1975)
[0314] Useful yeast plasmid vectors include pRS403-406 and pRS413-416 and are generally available from Stratagene Cloning Systems, La Jolla, Calif. 92037, USA. Plasmids pRS403, pRS404, pRS405 and pRS406 are Yeast Integrating plasmids (YIps) and incorporate the yeast selectable markers HIS3, 7RP1, LEU2 and URA3. Plasmids pRS413-416 are Yeast Centromere plasmids (Ycps).
[0315] Preferred vectors for making albumin fusion proteins for expression in yeast include pPPC0005, pScCHSA, pScNHSA, and pC4:HSA which are described in detail in Example 2.
[0316] The plasmids, pPPC0005, pScCHSA, pScNHSA, and pC4:HSA were deposited on Apr. 11, 2001 at the American Type Culture Collection, 10801 University Boulevard, Manassas, Va. 20110-2209 and given accession numbers ATCC ______, ______, ______, and ______, respectively. Another vector useful for expressing an albumin fusion protein in yeast the pSAC35 vector which is described in Sleep et al., BioTechnology 8:42 (1990) which is hereby incorporated by reference in its entirety.
[0317] A variety of methods have been developed to operably link DNA to vectors via complementary cohesive termini. For instance, complementary homopolymer tracts can be added to the DNA segment to be inserted to the vector DNA. The vector and DNA segment are then joined by hydrogen bonding between the complementary homopolymeric tails to form recombinant DNA molecules.
[0318] Synthetic linkers containing one or more restriction sites provide an alternative method of joining the DNA segment to vectors. The DNA segment, generated by endonuclease restriction digestion, is treated with bacteriophage T4 DNA polymerase or
[0319] The combination of these activities therefore generates blunt-ended DNA segments. The blunt-ended segments are then incubated with a large molar excess of linker molecules in the presence of an enzyme that is able to catalyze the ligation of blunt-ended DNA molecules, such as bacteriophage T4 DNA ligase. Thus, the products of the reaction are DNA segments carrying polymeric linker sequences at their ends. These DNA segments are then cleaved with the appropriate restriction enzyme and ligated to an expression vector that has been cleaved with an enzyme that produces termini compatible with those of the DNA segment.
[0320] Synthetic linkers containing a variety of restriction endonuclease sites are commercially available from a number of sources including International Biotechnologies Inc, New Haven, Conn., USA.
[0321] A desirable way to modify the DNA in accordance with the invention, if, for example, HA variants are to be prepared, is to use the polymerase chain reaction as disclosed by Saiki et al. (1988)
[0322] Exemplary genera of yeast contemplated to be useful in the practice of the present invention as hosts for expressing the albumin fusion proteins are Pichia (Hansenula), Saccharomyces, Kluyveromyces, Candida, Torulopsis, Torulaspora, Schizosaccharomyces, Citeromyces, Pachysolen, Debaromyces, Metschunikowia, Rhodosporidium, Leucosporidium, Botryoascus, Sporidiobolus, Endomycopsis, and the like. Preferred genera are those selected from the group consisting of Saccharomyces, Schizosaccharomyces, Kluyveromyces, Pichia and Torulaspora. Examples of Saccharomyces spp. are
[0323] Examples of Kluyveromyces spp. are
[0324] Preferred exemplary species of Saccharomyces include
[0325] Suitable promoters for
[0326] Convenient regulatable promoters for use in
[0327] Methods of transforming Pichia for expression of foreign genes are taught in, for example, Cregg et al. (1993), and various Phillips patents (e.g. U.S. Pat. No. 4,857,467, incorporated herein by reference), and Pichia expression kits are commercially available from Invitrogen BV, Leek, Netherlands, and Invitrogen Corp., San Diego, Calif. Suitable promoters include AOXI and AOX2. Gleeson et al. (1986) J. Gen. Microbiol. 132, 3459-3465 include information on Hansenula vectors and transformation, suitable promoters being MOX1 and FMD1; whilst EP 361 991, Fleer et al. (1991) and other-publications from Rhone-Poulenc Rorer teach how to express foreign proteins in Kluyveromyces spp., a suitable promoter being PGKI.
[0328] The transcription termination signal is preferably the 3′ flanking sequence of a eukaryotic gene which contains proper signals for transcription termination and polyadenylation. Suitable 3′ flanking sequences may, for example, be those of the gene naturally linked to the expression control sequence used, i.e. may correspond to the promoter. Alternatively, they may be different in which case the termination signal of the
[0329] The desired albumin fusion protein may be initially expressed with a secretion leader sequence, which may be any leader effective in the yeast chosen. Leaders useful in
[0330] Additional Methods of Recombinant and Synthetic Production of Albumin Fusion Proteins
[0331] The present invention also relates to vectors containing a polynucleotide encoding an albumin fusion protein of the present invention, host cells, and the production of albumin fusion proteins by synthetic and recombinant techniques. The vector may be, for example, a phage, plasmid, viral, or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.
[0332] The polynucleotides encoding albumin fusion proteins of the invention may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.
[0333] The polynucleotide insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the
[0334] As indicated, the expression vectors will preferably include at least one selectable marker. Such markers include dihydrofolate reductase, G418, glutamine synthase, or neomycin resistance for eukaryotic cell culture, and tetracycline, kanamycin or ampicillin resistance genes for culturing in
[0335] Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE-9, available from QIAGEN, Inc.; pBluescript vectors, Phagescript vectors, pNH8A, pNH16a, pNH18A, pNH46A, available from Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia Biotech, Inc. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXT1 and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Preferred expression vectors for use in yeast systems include, but are not limited to pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalph, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, pPIC9K, and PAO815 (all available from Invitrogen, Carlbad, Calif.). Other suitable vectors will be readily apparent to the skilled artisan.
[0336] In one embodiment, polynucleotides encoding an albumin fusion protein of the invention may be fused to signal sequences which will direct the localization of a protein of the invention to particular compartments of a prokaryotic or eukaryotic cell and/or direct the secretion of a protein of the invention from a prokaryotic or eukaryotic cell. For example, in
[0337] Examples of signal peptides that may be fused to an albumin fusion protein of the invention in order to direct its secretion in mammalian cells include, but are not limited to, the MPIF-1 signal sequence (e.g., amino acids 1-21 of GenBank Accession number AAB51134), the stanniocalcin signal sequence (MLQNSAVLLLLVISASA, SEQ ID NO:34), and a consensus signal sequence (MPTWAWWLFLVLLLALWAPARG, SEQ ID NO:35). A suitable signal sequence that may be used in conjunction with baculoviral expression systems is the gp67 signal sequence (e.g., amino acids 1-19 of GenBank Accession Number AAA72759).
[0338] Vectors which use glutamine synthase (GS) or DHFR as the selectable markers can be amplified in the presence of the drugs methionine sulphoximine or methotrexate, respectively. An advantage of glutamine synthase based vectors are the availabilty of cell lines (e.g., the murine myeloma cell line, NSO) which are glutamine synthase negative. Glutamine synthase expression systems can also function in glutamine synthase expressing cells (e.g., Chinese Hamster Ovary (CHO) cells) by providing additional inhibitor to prevent the functioning of the endogenous gene. A glutamine synthase expression system and components thereof are detailed in PCT publications: WO87/04462; WO86/05807; WO89/01036; WO89/10404; and WO91/06657, which are hereby incorporated in their entireties by reference herein. Additionally, glutamine synthase expression vectors can be obtained from Lonza Biologics, Inc. (Portsmouth, N.H.). Expression and production of monoclonal antibodies using a GS expression system in murine myeloma cells is described in Bebbington et al.,
[0339] The present invention also relates to host cells containing the above-described vector constructs described herein, and additionally encompasses host cells containing nucleotide sequences of the invention that are operably associated with one or more heterologous control regions (e.g., promoter and/or enhancer) using techniques known of in the art. The host cell can be a higher eukaryotic cell, such as a mammalian cell (e.g., a human derived cell), or a lower eukaryotic cell, such as a yeast cell, or the host cell can be a prokaryotic cell, such as a bacterial cell. A host strain may be chosen which modulates the expression of the inserted gene sequences, or modifies and processes the gene product in the specific fashion desired. Expression from certain promoters can be elevated in the presence of certain inducers; thus expression of the genetically engineered polypeptide may be controlled. Furthermore, different host cells have characteristics and specific mechanisms for the translational and post-translational processing and modification (e.g., phosphorylation, cleavage) of proteins. Appropriate cell lines can be chosen to ensure the desired modifications and processing of the foreign protein expressed.
[0340] Introduction of the nucleic acids and nucleic acid constructs of the invention into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986). It is specifically contemplated that the polypeptides of the present invention may in fact be expressed by a host cell lacking a recombinant vector.
[0341] In addition to encompassing host cells containing the vector constructs discussed herein, the invention also encompasses primary, secondary, and immortalized host cells of vertebrate origin, particularly mammalian origin, that have been engineered to delete or replace endogenous genetic material (e.g., the coding sequence corresponding to a Therapeutic protein may be replaced with an albumin fusion protein corresponding to the Therapeutic protein), and/or to include genetic material (e.g., heterologous polynucleotide sequences such as for example, an albumin fusion protein of the invention corresponding to the Therapeutic protein may be included). The genetic material operably associated with the endogenous polynucleotide may activate, alter, and/or amplify endogenous polynucleotides.
[0342] In addition, techniques known in the art may be used to operably associate heterologous polynucleotides (e.g., polynucleotides encoding an albumin protein, or a fragment or variant thereof) and/or heterologous control regions (e.g., promoter and/or enhancer) with endogenous polynucleotide sequences encoding a Therapeutic protein via homologous recombination (see, e.g., U.S. Pat. No. 5,641,670, issued Jun. 24, 1997; International Publication Number WO 96/29411; International Publication Number WO 94/12650; Koller et al.,
[0343] Albumin fusion proteins of the invention can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, hydrophobic charge interaction chromatography and lectin chromatography. Most preferably, high performance liquid chromatography (“HPLC”) is employed for purification.
[0344] In preferred embodiments the albumin fusion proteins of the invention are purified using Anion Exchange Chromatography including, but not limited to, chromatography on Q-sepharose, DEAE sepharose, poros HQ, poros DEAE, Toyopearl Q, Toyopearl QAE, Toyopearl DEAE, Resource/Source Q and DEAE, Fractogel Q and DEAE columns.
[0345] In specific embodiments the albumin fusion proteins of the invention are purified using Cation Exchange Chromatography including, but not limited to, SP-sepharose, CM sepharose, poros HS, poros CM, Toyopearl SP, Toyopearl CM, Resource/Source S and CM, Fractogel S and CM columns and their equivalents and comparables.
[0346] In specific embodiments the albumin fusion proteins of the invention are purified using Hydrophobic Interaction Chromatography including, but not limited to, Phenyl, Butyl, Methyl, Octyl, Hexyl-sepharose, poros Phenyl, Butyl, Methyl, Octyl, Hexyl Toyopearl Phenyl, Butyl, Methyl, Octyl, Hexyl Resource/Source Phenyl, Butyl, Methyl, Octyl, Hexyl, Fractogel Phenyl, Butyl, Methyl, Octyl, Hexyl columns and their equivalents and comparables.
[0347] In specific embodiments the albumin fusion proteins of the invention are purified using Size Exclusion Chromatography including, but not limited to, sepharose S100, S200, S300, superdex resin columns and their equivalents and comparables.
[0348] In specific embodiments the albumin fusion proteins of the invention are purified using Affinity Chromatography including, but not limited to, Mimetic Dye affinity, peptide affinity and antibody affinity columns that are selective for either the HSA or the “fusion target” molecules.
[0349] In preferred embodiments albumin fusion proteins of the invention are purified using one or more Chromatography methods listed above. In other preferred embodiments, albumin fusion proteins of the invention are purified using one or more of the following Chromatography columns, Q sepharose FF column, SP Sepharose FF column, Q Sepharose High Performance Column, Blue Sepharose FF column, Blue Column, Phenyl Sepharose FF column, DEAE Sepharose FF, or Methyl Column.
[0350] Additionally, albumin fusion proteins of the invention may be purified using the process described in PCT International Publication WO 00/44772 which is herein incorporated by reference in its entirety. One of skill in the art could easily modify the process described therein for use in the purification of albumin fusion proteins of the invention.
[0351] Albumin fusion proteins of the present invention may be recovered from: products of chemical synthetic procedures; and products produced by recombinant techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect, and mammalian cells. Depending upon the host employed in a recombinant production procedure, the polypeptides of the present invention may be glycosylated or may be non-glycosylated. In addition, albumin fusion proteins of the invention may also include an initial modified methionine residue, in some cases as a result of host-mediated processes. Thus, it is well known in the art that the N-terminal methionine encoded by the translation initiation codon generally is removed with high efficiency from any protein after translation in all eukaryotic cells. While the N-terminal methionine on most proteins also is efficiently removed in most prokaryotes, for some proteins, this prokaryotic removal process is inefficient, depending on the nature of the amino acid to which the N-terminal methionine is covalently linked.
[0352] In one embodiment, the yeast
[0353] In one example, the plasmid vector pPIC9K is used to express DNA encoding an albumin fusion protein of the invention, as set forth herein, in a Pichea yeast system essentially as described in “Pichia Protocols: Methods in Molecular Biology,” D. R. Higgins and J. Cregg, eds. The Humana Press, Totowa, N.J., 1998. This expression vector allows expression and secretion of a polypeptide of the invention by virtue of the strong AOX1 promoter linked to the
[0354] Many other yeast vectors could be used in place of pPIC9K, such as, pYES2, pYD1, pTEF1/Zeo, pYES2/GS, pPICZ, pGAPZ, pGAPZalpha, pPIC9, pPIC3.5, pHIL-D2, pHIL-S1, pPIC3.5K, and PAO815, as one skilled in the art would readily appreciate, as long as the proposed expression construct provides appropriately located signals for transcription, translation, secretion (if desired), and the like, including an in-frame AUG as required.
[0355] In another embodiment, high-level expression of a heterologous coding sequence, such as, for example, a polynucleotide encoding an albumin fusion protein of the present invention, may be achieved by cloning the heterologous polynucleotide of the invention into an expression vector such as, for example, pGAPZ or pGAPZalpha, and growing the yeast culture in the absence of methanol.
[0356] In addition, albumin fusion proteins of the invention can be chemically synthesized using techniques known in the art (e.g., see Creighton, 1983, Proteins: Structures and Molecular Principles, W. H. Freeman & Co., N.Y., and Hunkapiller et al.,
[0357] The invention encompasses albumin fusion proteins of the present invention which are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited, to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH
[0358] Additional post-translational modifications encompassed by the invention include, for example, e.g., N-linked or O-linked carbohydrate chains, processing of N-terminal or C-terminal ends), attachment of chemical moieties to the amino acid backbone, chemical modifications of N-linked or O-linked carbohydrate chains, and addition or deletion of an N-terminal methionine residue as a result of procaryotic host cell expression. The albumin fusion proteins may also be modified with a detectable label, such as an enzymatic, fluorescent, isotopic or affinity label to allow for detection and isolation of the protein.
[0359] Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin; and examples of suitable radioactive material include iodine (
[0360] In specific embodiments, albumin fusion proteins of the present invention or fragments or variants thereof are attached to macrocyclic chelators that associate with radiometal ions, including but not limited to,
[0361] As mentioned, the albumin fusion proteins of the invention may be modified by either natural processes, such as post-translational processing, or by chemical modification techniques which are well known in the art. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Polypeptides of the invention may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods. Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS—STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993); POST-TRANSLATIONAL COVALENT MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (1990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992)).
[0362] Albumin fusion proteins of the invention and antibodies that bind a Therapeutic protein or fragments or variants thereof can be fused to marker sequences, such as a peptide to facilitate purification. In preferred embodiments, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, Calif., 91311), among others, many of which are commercially available. As described in Gentz et al., Proc. Natl. Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, the “HA” tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., Cell 37:767 (1984)) and the “flag” tag.
[0363] Further, an albumin fusion protein of the invention may be conjugated to a therapeutic moiety such as a cytotoxin, e.g., a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example, 213Bi. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include paclitaxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).
[0364] The conjugates of the invention can be used for modifying a given biological response, the therapeutic agent or drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, alpha-interferon, β-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator, an apoptotic agent, e.g., TNF-alpha, TNF-beta, AIM I (See, International Publication No. WO 97/33899), AIM II (See, International Publication No. WO 97/34911), Fas Ligand (Takahashi et al, Int. Immunol., 6:1567-1574 (1994)), VEGI (See, International Publication No. WO 99/23105), a thrombotic agent or an anti-angiogenic agent, e.g., angiostatin or endostatin; or, biological response modifiers such as, for example, lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”), interleukin-6 (“IL-6”), granulocyte macrophage colony stimulating factor (“GM-CSF”), granulocyte colony stimulating factor (“G-CSF”), or other growth factors. Techniques for conjugating such therapeutic moiety to proteins (e.g., albumin fusion proteins) are well known in the art.
[0365] Albumin fusion proteins may also be attached to solid supports, which are particularly useful for immunoassays or purification of polypeptides that are bound by, that bind to, or associate with albumin fusion proteins of the invention. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.
[0366] Albumin fusion proteins, with or without a therapeutic moiety conjugated to it, administered alone or in combination with cytotoxic factor(s) and/or cytokine(s) can be used as a therapeutic.
[0367] In embodiments where the albumin fusion protein of the invention comprises only the VH domain of an antibody that binds a Therapeutic protein, it may be necessary and/or desirable to coexpress the fusion protein with the VL domain of the same antibody that binds a Therapeutic protein, such that the VH-albumin fusion protein and VL protein will associate (either covalently or non-covalently) post-translationally.
[0368] In embodiments where the albumin fusion protein of the invention comprises only the VL domain of an antibody that binds a Therapeutic protein, it may be necessary and/or desirable to coexpress the fusion protein with the VH domain of the same antibody that binds a Therapeutic protein, such that the VL-albumin fusion protein and VH protein will associate (either covalently or non-covalently) post-translationally.
[0369] Some Therapeutic antibodies are bispecific antibodies, meaning the antibody that binds a Therapeutic protein is an artificial hybrid antibody having two different heavy/light chain pairs and two different binding sites. In order to create an albumin fusion protein corresponding to that Therapeutic protein, it is possible to create an albumin fusion protein which has an scFv fragment fused to both the N- and C-terminus of the albumin protein moiety. More particularly, the scFv fused to the N-terminus of albumin would correspond to one of the heavy/light (VH/VL) pairs of the original antibody that binds a Therapeutic protein and the scFv fused to the C-terminus of albumin would correspond to the other heavy/light (VH/VL) pair of the original antibody that binds a Therapeutic protein.
[0370] Also provided by the invention are chemically modified derivatives of the albumin fusion proteins of the invention which may provide additional advantages such as increased solubility, stability and circulating time of the polypeptide, or decreased immunogenicity (see U.S. Pat. No. 4,179,337). The chemical moieties for derivitization may be selected from water soluble polymers such as polyethylene glycol, ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol and the like. The albumin fusion proteins may be modified at random positions within the molecule, or at predetermined positions within the molecule and may include one, two, three or more attached chemical moieties.
[0371] The polymer may be of any molecular weight, and may be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 1 kDa and about 100 kDa (the term “about” indicating that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of sustained release desired, the effects, if any on biological activity, the ease in handling, the degree or lack of antigenicity and other known effects of the polyethylene glycol to a Therapeutic protein or analog). For example, the polyethylene glycol may have an average molecular weight of about 200, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500, 12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000, 16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, 95,000, or 100,000 kDa.
[0372] As noted above, the polyethylene glycol may have a branched structure. Branched polyethylene glycols are described, for example, in U.S. Pat. No. 5,643,575; Morpurgo et al.,
[0373] The polyethylene glycol molecules (or other chemical moieties) should be attached to the protein with consideration of effects on functional or antigenic domains of the protein. There are a number of attachment methods available to those skilled in the art, such as, for example, the method disclosed in EP 0 401 384 (coupling PEG to G-CSF), herein incorporated by reference; see also Malik et al., Exp. Hematol. 20:1028-1035 (1992), reporting pegylation of GM-CSF using tresyl chloride. For example, polyethylene glycol may be covalently bound through amino acid residues via reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule may be bound. The amino acid residues having a free amino group may include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group may include aspartic acid residues glutamic acid residues and the C-terminal amino acid residue. Sulfhydryl groups may also be used as a reactive group for attaching the polyethylene glycol molecules. Preferred for therapeutic purposes is attachment at an amino group, such as attachment at the N-terminus or lysine group.
[0374] As suggested above, polyethylene glycol may be attached to proteins via linkage to any of a number of amino acid residues. For example, polyethylene glycol can be linked to proteins via covalent bonds to lysine, histidine, aspartic acid, glutamic acid, or cysteine residues. One or more reaction chemistries may be employed to attach polyethylene glycol to specific amino acid residues (e.g., lysine, histidine, aspartic acid, glutamic acid, or cysteine) of the protein or to more than one type of amino acid residue (e.g., lysine, histidine, aspartic acid, glutamic acid, cysteine and combinations thereof) of the protein.
[0375] One may specifically desire proteins chemically modified at the N-terminus. Using polyethylene glycol as an illustration of the present composition, one may select from a variety of polyethylene glycol molecules (by molecular weight, branching, etc.), the proportion of polyethylene glycol molecules to protein (polypeptide) molecules in the reaction mix, the type of pegylation reaction to be performed, and the method of obtaining the selected N-terminally pegylated protein. The method of obtaining the N-terminally pegylated preparation (i.e., separating this moiety from other monopegylated moieties if necessary) may be by purification of the N-terminally pegylated material from a population of pegylated protein molecules. Selective proteins chemically modified at the N-terminus modification may be accomplished by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminal) available for derivatization in a particular protein. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved.
[0376] As indicated above, pegylation of the albumin fusion proteins of the invention may be accomplished by any number of means. For example, polyethylene glycol may be attached to the albumin fusion protein either directly or by an intervening linker. Linkerless systems for attaching polyethylene glycol to proteins are described in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9:249-304 (1992); Francis et al., Intern. J. of Hematol. 68:1-18 (1998); U.S. Pat. No. 4,002,531; U.S. Pat. No. 5,349,052; WO 95/06058; and WO 98/32466, the disclosures of each of which are incorporated herein by reference.
[0377] One system for attaching polyethylene glycol directly to amino acid residues of proteins without an intervening linker employs tresylated MPEG, which is produced by the modification of monmethoxy polyethylene glycol (MPEG) using tresylchloride (ClSO
[0378] Polyethylene glycol can also be attached to proteins using a number of different intervening linkers. For example, U.S. Pat. No. 5,612,460, the entire disclosure of which is incorporated herein by reference, discloses urethane linkers for connecting polyethylene glycol to proteins. Protein-polyethylene glycol conjugates wherein the polyethylene glycol is attached to the protein by a linker can also be produced by reaction of proteins with compounds such as MPEG-succinimidylsuccinate, MPEG activated with 1,1′-carbonyldiimidazole, MPEG-2,4,5-trichloropenylcarbonate, MPEG-p-nitrophenolcarbonate, and various MPEG-succinate derivatives. A number of additional polyethylene glycol derivatives and reaction chemistries for attaching polyethylene glycol to proteins are described in International Publication No. WO 98/32466, the entire disclosure of which is incorporated herein by reference. Pegylated protein products produced using the reaction chemistries set out herein are included within the scope of the invention.
[0379] The number of polyethylene glycol moieties attached to each albumin fusion protein of the invention (i.e., the degree of substitution) may also vary. For example, the pegylated proteins of the invention may be linked, on average, to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, or more polyethylene glycol molecules. Similarly, the average degree of substitution within ranges such as 1-3, 2-4, 3-5, 4-6, 5-7, 6-8, 7-9, 8-10, 9-11, 10-12, 11-13, 12-14, 13-15, 14-16, 15-17, 16-18, 17-19, or 18-20 polyethylene glycol moieties per protein molecule. Methods for determining the degree of substitution are discussed, for example, in Delgado et al., Crit. Rev. Thera. Drug Carrier Sys. 9:249-304 (1992).
[0380] The polypeptides of the invention can be recovered and purified from chemical synthesis and recombinant cell cultures by standard methods which include, but are not limited to, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Most preferably, high performance liquid chromatography (“HPLC”) is employed for purification. Well known techniques for refolding protein may be employed to regenerate active conformation when the polypeptide is denatured during isolation and/or purification.
[0381] The presence and quantity of albumin fusion proteins of the invention may be determined using ELISA, a well known immunoassay known in the art. In one ELISA protocol that would be useful for detecting/quantifying albumin fusion proteins of the invention, comprises the steps of coating an ELISA plate with an anti-human serum albumin antibody, blocking the plate to prevent non-specific binding, washing the ELISA plate, adding a solution containing the albumin fusion protein of the invention (at one or more different concentrations), adding a secondary anti-Therapeutic protein specific antibody coupled to a detectable label (as described herein or otherwise known in the art), and detecting the presence of the secondary antibody. In an alternate version of this protocol, the ELISA plate might be coated with the anti-Therapeutic protein specific antibody and the labeled secondary reagent might be the anti-human albumin specific antibody.
[0382] Uses of the Polynucleotides
[0383] Each of the polynucleotides identified herein can be used in numerous ways as reagents. The following description should be considered exemplary and utilizes known techniques.
[0384] The polynucleotides of the present invention are useful to produce the albumin fusion proteins of the invention. As described in more detail below, polynucleotides of the invention (encoding albumin fusion proteins) may be used in recombinant DNA methods useful in genetic engineering to make cells, cell lines, or tissues that express the albumin fusion protein encoded by the polynucleotides encoding albumin fusion proteins of the invention.
[0385] Polynucleotides of the present invention are also useful in gene therapy. One goal of gene therapy is to insert a normal gene into an organism having a defective gene, in an effort to correct the genetic defect. The polynucleotides disclosed in the present invention offer a means of targeting such genetic defects in a highly accurate manner. Another goal is to insert a new gene that was not present in the host genome, thereby producing a new trait in the host cell. Additional non-limiting examples of gene therapy methods encompassed by the present invention are more thoroughly described elsewhere herein (see, e.g., the sections labeled “Gene Therapy”, and Examples 17 and 18).
[0386] Uses of the Polypeptides
[0387] Each of the polypeptides identified herein can be used in numerous ways. The following description should be considered exemplary and utilizes known techniques.
[0388] Albumin fusion proteins of the invention are useful to provide immunological probes for differential identification of the tissue(s) (e.g., immunohistochemistry assays such as, for example, ABC immunoperoxidase (Hsu et al., J. Histochem. Cytochem. 29:577-580 (1981)) or cell type(s) (e.g., immunocytochemistry assays).
[0389] Albumin fusion proteins can be used to assay levels of polypeptides in a biological sample using classical immunohistological methods known to those of skill in the art (e.g., see Jalkanen, et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, et al., J. Cell. Biol. 105:3087-3096 (1987)). Other methods useful for detecting protein gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable assay labels are known in the art and include enzyme labels, such as, glucose oxidase; radioisotopes, such as iodine (
[0390] Albumin fusion proteins of the invention can also be detected in vivo by imaging. Labels or markers for in vivo imaging of protein include those detectable by X-radiography, nuclear magnetic resonance (NMR) or electron spin relaxtion (ESR). For X-radiography, suitable labels include radioisotopes such as barium or cesium, which emit detectable radiation but are not overtly harmful to the subject. Suitable markers for NMR and ESR include those with a detectable characteristic spin, such as deuterium, which may be incorporated into the albumin fusion protein by labeling of nutrients given to a cell line expressing the albumin fusion protein of the invention.
[0391] An albumin fusion protein which has been labeled with an appropriate detectable imaging moiety, such as a radioisotope (for example,
[0392] In one embodiment, the invention provides a method for the specific delivery of albumin fusion proteins of the invention to cells by administering albumin fusion proteins of the invention (e.g., polypeptides encoded by polynucleotides encoding albumin fusion proteins of the invention and/or antibodies) that are associated with heterologous polypeptides or nucleic acids. In one example, the invention provides a method for delivering a Therapeutic protein into the targeted cell. In another example, the invention provides a method for delivering a single stranded nucleic acid (e.g., antisense or ribozymes) or double stranded nucleic acid (e.g., DNA that can integrate into the cell's genome or replicate episomally and that can be transcribed) into the targeted cell.
[0393] In another embodiment, the invention provides a method for the specific destruction of cells (e.g., the destruction of tumor cells) by administering albumin fusion proteins of the invention in association with toxins or cytotoxic prodrugs.
[0394] By “toxin” is meant one or more compounds that bind and activate endogenous cytotoxic effector systems, radioisotopes, holotoxins, modified toxins, catalytic subunits of toxins, or any molecules or enzymes not normally present in or on the surface of a cell that under defined conditions cause the cell's death. Toxins that may be used according to the methods of the invention include, but are not limited to, radioisotopes known in the art, compounds such as, for example, antibodies (or complement fixing containing portions thereof) that bind an inherent or induced endogenous cytotoxic effector system, thymidine kinase, endonuclease, RNAse, alpha toxin, ricin, abrin, Pseudomonas exotoxin A, diphtheria toxin, saporin, momordin, gelonin, pokeweed antiviral protein, alpha-sarcin and cholera toxin. “Toxin” also includes a cytostatic or cytocidal agent, a therapeutic agent or a radioactive metal ion, e.g., alpha-emitters such as, for example,
[0395] Techniques known in the art may be applied to label polypeptides of the invention. Such techniques include, but are not limited to, the use of bifunctional conjugating agents (see e.g., U.S. Pat. Nos. 5,756,065; 5,714,631; 5,696,239; 5,652,361; 5,505,931; 5,489,425; 5,435,990; 5,428,139; 5,342,604; 5,274,119; 4,994,560; and 5,808,003; the contents of each of which are hereby incorporated by reference in its entirety).
[0396] The albumin fusion proteins of the present invention are useful for diagnosis, treatment, prevention and/or prognosis of various disorders in mammals, preferably humans. Such disorders include, but are not limited to, those described herein under the section heading “Biological Activities,” below.
[0397] Thus, the invention provides a diagnostic method of a disorder, which involves (a) assaying the expression level of a certain polypeptide in cells or body fluid of an individual using an albumin fusion protein of the invention; and (b) comparing the assayed polypeptide expression level with a standard polypeptide expression level, whereby an increase or decrease in the assayed polypeptide expression level compared to the standard expression level is indicative of a disorder. With respect to cancer, the presence of a relatively high amount of transcript in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.
[0398] Moreover, albumin fusion proteins of the present invention can be used to treat or prevent diseases or conditions such as, for example, neural disorders, immune system disorders, muscular disorders, reproductive disorders, gastrointestinal disorders, pulmonary disorders, cardiovascular disorders, renal disorders, proliferative disorders, and/or cancerous diseases and conditions. For example, patients can be administered a polypeptide of the present invention in an effort to replace absent or decreased levels of the polypeptide (e.g., insulin), to supplement absent or decreased levels of a different polypeptide (e.g., hemoglobin S for hemoglobin B, SOD, catalase, DNA repair proteins), to inhibit the activity of a polypeptide (e.g., an oncogene or tumor supressor), to activate the activity of a polypeptide (e.g., by binding to a receptor), to reduce the activity of a membrane bound receptor by competing with it for free ligand (e.g., soluble TNF receptors used in reducing inflammation), or to bring about a desired response (e.g., blood vessel growth inhibition, enhancement of the immune response to proliferative cells or tissues).
[0399] In particular, albumin fusion proteins comprising of at least a fragment or variant of a Therapeutic antibody can also be used to treat disease (as described supra, and elsewhere herein). For example, administration of an albumin fusion protein comprising of at least a fragment or variant of a Therapeutic antibody can bind, and/or neutralize the polypeptide to which the Therapeutic antibody used to make the albumin fusion protein specifically binds, and/or reduce overproduction of the polypeptide to which the Therapeutic antibody used to make the albumin fusion protein specifically binds. Similarly, administration of an albumin fusion protein comprising of at least a fragment or variant of a Therapeutic antibody can activate the polypeptide to which the Therapeutic antibody used to make the albumin fusion protein specifically binds, by binding to the polypeptide bound to a membrane (receptor).
[0400] At the very least, the albumin fusion proteins of the invention of the present invention can be used as molecular weight markers on SDS-PAGE gels or on molecular sieve gel filtration columns using methods well known to those of skill in the art. Albumin fusion proteins of the invention can also be used to raise antibodies, which in turn may be used to measure protein expression of the Therapeutic protein, albumin protein, and/or the albumin fusion protein of the invention from a recombinant cell, as a way of assessing transformation of the host cell, or in a biological sample. Moreover, the albumin fusion proteins of the present invention can be used to test the biological activities described herein.
[0401] Diagnostic Assays
[0402] The compounds of the present invention are useful for diagnosis, treatment, prevention and/or prognosis of various disorders in mammals, preferably humans. Such disorders include, but are not limited to, those described for each Therapeutic protein in the corresponding row of Table 1 and herein under the section headings “Immune Activity,” “Blood Related Disorders,” “Hyperproliferative Disorders,” “Renal Disorders,” “Cardiovascular Disorders,” “Respiratory Disorders,” “Anti-Angiogenesis Activity,” “Diseases at the Cellular Level,” “Wound Healing and Epithelial Cell Proliferation,” “Neural Activity and Neurological Diseases,” “Endocrine Disorders,” “Reproductive System Disorders,” “Infectious Disease,” “Regeneration,” and/or “Gastrointestinal Disorders,” infra.
[0403] For a number of disorders, substantially altered (increased or decreased) levels of gene expression can be detected in tissues, cells or bodily fluids (e.g., sera, plasma, urine, semen, synovial fluid or spinal fluid) taken from an individual having such a disorder, relative to a “standard” gene expression level, that is, the expression level in tissues or bodily fluids from an individual not having the disorder. Thus, the invention provides a diagnostic method useful during diagnosis of a disorder, which involves measuring the expression level of the gene encoding a polypeptide in tissues, cells or body fluid from an individual and comparing the measured gene expression level with a standard gene expression level, whereby an increase or decrease in the gene expression level(s) compared to the standard is indicative of a disorder. These diagnostic assays may be performed in vivo or in vitro, such as, for example, on blood samples, biopsy tissue or autopsy tissue.
[0404] The present invention is also useful as a prognostic indicator, whereby patients exhibiting enhanced or depressed gene expression will experience a worse clinical outcome By “assaying the expression level of the gene encoding a polypeptide” is intended qualitatively or quantitatively measuring or estimating the level of a particular polypeptide (e.g. a polypeptide corresponding to a Therapeutic protein disclosed in Table 1) or the level of the mRNA encoding the polypeptide of the invention in a first biological sample either directly (e.g., by determining or estimating absolute protein level or mRNA level) or relatively (e.g., by comparing to the polypeptide level or mRNA level in a second biological sample). Preferably, the polypeptide expression level or mRNA level in the first biological sample is measured or estimated and compared to a standard polypeptide level or mRNA level, the standard being taken from a second biological sample obtained from an individual not having the disorder or being determined by averaging levels from a population of individuals not having the disorder. As will be appreciated in the art, once a standard polypeptide level or mRNA level is known, it can be used repeatedly as a standard for comparison.
[0405] By “biological sample” is intended any biological sample obtained from an individual, cell line, tissue culture, or other source containing polypeptides of the invention (including portions thereof) or mRNA. As indicated, biological samples include body fluids (such as sera, plasma, urine, synovial fluid and spinal fluid) and tissue sources found to express the full length or fragments thereof of a polypeptide or mRNA. Methods for obtaining tissue biopsies and body fluids from mammals are well known in the art. Where the biological sample is to include mRNA, a tissue biopsy is the preferred source.
[0406] Total cellular RNA can be isolated from a biological sample using any suitable technique such as the single-step guanidinium-thiocyanate-phenol-chloroform method described in Chomczynski and Sacchi, Anal. Biochem. 162:156-159 (1987). Levels of mRNA encoding the polypeptides of the invention are then assayed using any appropriate method. These include Northern blot analysis, S1 nuclease mapping, the polymerase chain reaction (PCR), reverse transcription in combination with the polymerase chain reaction (RT-PCR), and reverse transcription in combination with the ligase chain reaction (RT-LCR).
[0407] The present invention also relates to diagnostic assays such as quantitative and diagnostic assays for detecting levels of polypeptides that bind to, are bound by, or associate with albumin fusion proteins of the invention, in a biological sample (e.g., cells and tissues), including determination of normal and abnormal levels of polypeptides. Thus, for instance, a diagnostic assay in accordance with the invention for detecting abnormal expression of polypeptides that bind to, are bound by, or associate with albumin fusion proteins compared to normal control tissue samples may be used to detect the presence of tumors. Assay techniques that can be used to determine levels of a polypeptide that bind to, are bound by, or associate with albumin fusion proteins of the present invention in a sample derived from a host are well-known to those of skill in the art. Such assay methods include radioimmunoassays, competitive-binding assays, Western Blot analysis and ELISA assays. Assaying polypeptide levels in a biological sample can occur using any art-known method.
[0408] Assaying polypeptide levels in a biological sample can occur using a variety of techniques. For example, polypeptide expression in tissues can be studied with classical immunohistological methods (Jalkanen et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M., et al., J. Cell. Biol. 105:3087-3096 (1987)). Other methods useful for detecting polypeptide gene expression include immunoassays, such as the enzyme linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase, and radioisotopes, such as iodine (
[0409] The tissue or cell type to be analyzed will generally include those which are known, or suspected, to express the gene of interest (such as, for example, cancer). The protein isolation methods employed herein may, for example, be such as those described in Harlow and Lane (Harlow, E. and Lane, D., 1988, “Antibodies: A Laboratory Manual”, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.), which is incorporated herein by reference in its entirety. The isolated cells can be derived from cell culture or from a patient. The analysis of cells taken from culture may be a necessary step in the assessment of cells that could be used as part of a cell-based gene therapy technique or, alternatively, to test the effect of compounds on the expression of the gene.
[0410] For example, albumin fusion proteins may be used to quantitatively or qualitatively detect the presence of polypeptides that bind to, are bound by, or associate with albumin fusion proteins of the present invention. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled albumin fusion protein coupled with light microscopic, flow cytometric, or fluorimetric detection.
[0411] In a preferred embodiment, albumin fusion proteins comprising at least a fragment or variant of an antibody that specifically binds at least a Therapeutic protein disclosed herein (e.g., the Therapeutic proteins disclosed in Table 1) or otherwise known in the art may be used to quantitatively or qualitatively detect the presence of gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody coupled with light microscopic, flow cytometric, or fluorimetric detection.
[0412] The albumin fusion proteins of the present invention may, additionally, be employed histologically, as in immunofluorescence, immunoelectron microscopy or non-immunological assays, for in situ detection of polypeptides that bind to, are bound by, or associate with an albumin fusion protein of the present invention. In situ detection may be accomplished by removing a histological specimen from a patient, and applying thereto a labeled antibody or polypeptide of the present invention. The albumin fusion proteins are preferably applied by overlaying the labeled albumin fusion proteins onto a biological sample. Through the use of such a procedure, it is possible to determine not only the presence of the polypeptides that bind to, are bound by, or associate with albumin fusion proteins, but also its distribution in the examined tissue. Using the present invention, those of ordinary skill will readily perceive that any of a wide variety of histological methods (such as staining procedures) can be modified in order to achieve such in situ detection.
[0413] Immunoassays and non-immunoassays that detect polypeptides that bind to, are bound by, or associate with albumin fusion proteins will typically comprise incubating a sample, such as a biological fluid, a tissue extract, freshly harvested cells, or lysates of cells which have been incubated in cell culture, in the presence of a detectably labeled antibody capable of binding gene products or conserved variants or peptide fragments thereof, and detecting the bound antibody by any of a number of techniques well-known in the art.
[0414] The biological sample may be brought in contact with and immobilized onto a solid phase support or carrier such as nitrocellulose, or other solid support which is capable of immobilizing cells, cell particles or soluble proteins. The support may then be washed with suitable buffers followed by treatment with the detectably labeled albumin fusion protein of the invention. The solid phase support may then be washed with the buffer a second time to remove unbound antibody or polypeptide. Optionally the antibody is subsequently labeled. The amount of bound label on solid support may then be detected by conventional means.
[0415] By “solid phase support or carrier” is intended any support capable of binding a polypeptide (e.g., an albumin fusion protein, or polypeptide that binds, is boun