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 This application is a continuation-in-part of U.S. Ser. No. 09/264,516, filed Mar. 8, 1999; which is a continuation-in-part of U.S. Ser. No. 09/234,395, filed Jan. 20, 1999; which is a continuation-in-part of U.S. Ser. No. 09/187,859, filed Nov. 6, 1998; which is a continuation-in-part of U.S. Ser. No. 09/073,040, filed May 5, 1998.
 The present invention relates generally to methods for inhibiting cancer metastasis, and more particularly to the use of OB-cadherin peptides, and antibodies that bind such peptides, to inhibit adhesion and metastasis of circulating cancer cells.
 Cancer is a significant health problem throughout the world. Although advances have been made in detection and therapy of cancer, no vaccine or other universally successful method for prevention or treatment is currently available. One reason for failure of a cancer treatment is often the growth of secondary metastatic lesions in distant organs. Therapy for metastasis currently relies on a combination of early diagnosis and aggressive treatment, which may include radiotherapy, chemotherapy or hormone therapy. However, the toxicity of such treatments limits the use of presently available anticancer agents for treatment of malignant disease. The high mortality rate for many cancers indicates that improvements are needed in metastasis prevention and treatment.
 The development of less toxic antimetastatic agents would facilitate the long term treatment of latent or residual disease. Such agents could also be used prophylactically after the removal of a precancerous tumor. It has been suggested that certain agents that inhibit metastasis may function by inhibiting adhesion of cancer cells. For example, WO 97/00956 describes the use of an antibody raised against an adhesion protein on endothelial and muscle cells for inhibiting tumor metastasis. However, such techniques are not currently available, and improved antimetastatic agents are needed to reduce cancer mortality.
 Accordingly, there is a need in the art for the development of further methods for inhibiting cancer metastasis. The present invention fulfills these needs and further provides other related advantages.
 Briefly stated, this invention provides compositions and methods for inhibiting cancer metastasis. Within certain aspects, antimetastatic agents are provided. Such agents may: (a) comprise a peptide sequence that is at least 50% identical to an OB-cadherin CAR sequence; and (b) inhibit OB-cadherin mediated cell adhesion. Certain antimetastatic agents comprise an OB-cadherin CAR sequence and are peptides ranging in size from 3 to 50, preferably from 4 to 16, amino acid residues.
 Within certain embodiments, an antimetastatic agent comprises an OB-cadherin CAR sequence that is present within a cyclic peptide. Such cyclic peptides may have the formula:
 wherein W is a tripeptide selected from the group consisting of EEY, DDK and EAQ; wherein X
 Within certain specific embodiments, an antimetastatic agent as provided herein may comprise: (a) one or more OB-cadherin CAR sequences selected from the group consisting of DDK, IDDK (SEQ ID NO:37) DDKS (SEQ ID NO:38), VIDDK (SEQ ID NO:39), IDDKS (SEQ ID NO:40), VIDDKS (SEQ ID NO:41), DDKSG (SEQ ID NO:42), IDDKSG (SEQ ID NO:43), VIDDKSG (SEQ ID NO:44), FVIDDK (SEQ ID NO:45), FVIDDKS (SEQ ID NO:46), FVIDDKSG (SEQ ID NO:47), IFVIDDK (SEQ ID NO:48), IFVIDDKS (SEQ ID NO:49), IFVIDDKSG (SEQ ID NO:50), EEY, IEEY (SEQ ID NO:51), EEYT (SEQ ID NO:52), VIEEY (SEQ ID NO:53), IEEYT (SEQ ID NO:54), VIEEYT (SEQ ID NO:55), EEYTG (SEQ ID NO:56), IEEYTG (SEQ ID NO:56), VIEEYTG (SEQ ID NO:58), FVIEEY (SEQ ID NO:59), FVIEEYT (SEQ ID NO:60), FVIEEYTG (SEQ ID NO:61), FFVEEY (SEQ ID NO:62), FFVIEEYT (SEQ ID NO:63), FFVIEEYTG (SEQ ID NO:64), EAQ, VEAQ (SEQ ID NO:65), EAQT (SEQ ID NO:66), SVEAQ (SEQ ID NO:67), VEAQT (SEQ ID NO:68), SVEAQT (SEQ ID NO:69), EAQTG (SEQ ID NO:70), VEAQTG (SEQ ID NO:71), SVEAQTG (SEQ ID NO:72), FSVEAQ (SEQ ID NO:73), FSVEAQT (SEQ ID NO:74), FSVEAQTG (SEQ ID NO:75), YFSVEAQ (SEQ ID NO:76), YFSVEAQT (SEQ ID NO:77) and YFSVEAQTG (SEQ ID NO:78); or (b) an analogue of any of the foregoing sequences that differs in one or more substitutions, deletions, additions and/or insertions such that that ability of the analogue to modulate an OB-cadherin-mediated function is not substantially diminished. For example, the agent may comprise a linear peptide having the sequence N—Ac—IFVIDDKSG—NH
 The present invention further provides antimetastatic agents that comprise an antibody or antigen-binding fragment thereof that specifically binds to an OB-cadherin CAR sequence and modulates OB-cadherin-mediated cell adhesion.
 Within further aspects, the present invention provides antimetastatic agents comprising a non-peptide mimetic of an OB-cadherin CAR sequence.
 Any of the above antimetastatic agents may, within certain embodiments, be linked to one or more of a drug, detectable marker, targeting agent or support material. Alternatively, or in addition, an antimetastatic agent as described above, may further comprise one or more of: (a) a CAR sequence that is specifically recognized by an adhesion molecule other than OB-cadherin; and/or (b) an antibody or antigen-binding fragment thereof that specifically binds to a CAR sequence that is specifically recognized by an adhesion molecule other than OB-cadherin. For example, such an adhesion molecule may be cadherin-5, cadherin-6, occludin, claudin, N-CAM, PE-CAM, CEA, L1, JAM, an integrin or N-cadherin.
 Within other aspects, the present invention provides pharmaceutical compositions comprising an antimetastatic agent as described above in combination with a physiologically acceptable carrier. Within such compositions, the antimetastatic agent may, but need not, be present within a sustained-release formulation Such compositions may, within certain embodiments, further comprise a drug and/or a modulator of cell adhesion that comprises one or more of: (a) a CAR sequence that is specifically recognized by an adhesion molecule other than OB-cadherin; and/or (b) an antibody or antigen-binding fragment thereof that specifically binds to a CAR sequence that is specifically recognized by an adhesion molecule other than OB-cadherin.
 The present invention further provides, within other aspects, methods for inhibiting cancer metastasis. Such methods generally comprise administering to a patient an antimetastatic agent as described above, or a polynucleotide encoding such an agent. The patient may be afflicted with a cancer such as a carcinoma, leukemia or melanoma, and the antimetastatic agent may be administered to the tumor or systemically. Within such methods, the antimetastatic agent may, but need not, be present within a pharmaceutical composition as recited above.
 These and other aspects of the present invention will become apparent upon reference to the following detailed description and attached drawings. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.
 As noted above, the present invention provides methods for inhibiting cancer metastasis. The methods provided herein are based, in part, on the identification of OB-cadherin cell adhesion recognition (CAR) sequences, and on the discovery that OB-cadherin is expressed by certain metastatic carcinoma cells, but not by highly differentiated, poorly invasive carcinomas. Cancer metastasis may be inhibited (i.e., prevented, diminished in severity or delayed) by the administration of agents that inhibit OB-cadherin mediated cell adhesion. Such antimetastatic agents may be peptides that correspond to an OB-cadherin CAR sequence, or may be binding agents, such as antibodies and fragments thereof, that specifically recognize an OB-cadherin CAR sequence. In general, within the methods provided herein, an antimetastatic agent is administered to a patient in an amount sufficient to inhibit metastasis
 As used herein, the term “OB-cadherin” refers to certain cell adhesion molecules that are expressed by a human or non-human individual, and that are substantially homologous to a known OB-cadherin (also known as cadherin-11; and as discussed, for example, in Munro et al., In:
 An OB-cadherin also contains characteristic cadherin repeats, but does not contain the classical cadherin CAR sequence His-Ala-Val (HAV). As used herein, a “cadherin repeat” refers to an amino acid sequence that is approximately 110 amino acid residues in length (generally 100 to 120 residues, preferably 105 to 115 residues), comprises an extracellular domain, and contains three calcium binding motifs (DXD, XDXE and DXXDX; SEQ ID NOs: 4 and 5, respectively) in the same order and in approximately the same position. The presence of an extracellular domain may generally be determined using well known techniques, such as the presence of one or more of: a hydrophilic sequence, a region that is recognized by an antibody, a region that is cleaved by trypsin and/or a potential glycosylation site with the glycosylation motif Asn-X-Ser/Thr. The second calcium binding motif commonly has the sequence LDRE (SEQ ID NO:6), although variants of this sequence with conservative substitutions are also observed, including MDRE (SEQ ID NO:7), LDFE (SEQ ID NO:8), LDYE (SEQ ID NO:9), IDRE (SEQ ID NO:10), VDRE (SEQ ID NO:11) and IDFE (SEQ ID NO:12). Within most cadherin repeats, the third calcium binding motif has the sequence [L,I,V]-X-[L,I,V]-X-D-X-N-D-[N,H]-X-P (SEQ ID NO:13), wherein residues indicated in brackets may be any one of the recited residues. A preferred third calcium binding motif has the sequence DXNDN (SEQ ID NO:14), although one or both of the D residues may be replaced by an E. Homology among cadherin repeats is generally at least 20%, preferably at least 30%, as determined by the ALIGN algorithm (Myers and Miller,
 Within the context of the present invention, the term “antimetastatic agent” refers to a molecule comprising at least one of the following components:
 (a) a linear or cyclic peptide sequence that is at least 50% identical to an OB-cadherin CAR sequence (i.e., an OB-cadherin CAR sequence or an analogue thereof that retains at least 50% sequence identity);
 (b) a mimetic (e.g., peptidomimetic or small molecule mimic) of an OB-cadherin CAR sequence;
 (c) a substance, such as an antibody or antigen-binding fragment thereof, that specifically binds an OB-cadherin CAR sequence; and/or
 (d) a polynucleotide encoding a polypeptide that comprises an OB-cadherin CAR sequence or analogue thereof.
 An antimetastatic agent may consist entirely of one or more of the above elements, or may additionally comprise further peptide and/or non-peptide regions. Additional peptide regions may be derived from an OB-cadherin (preferably an extracellular domain that comprises a CAR sequence) and/or may be heterologous. Within certain preferred embodiments, an antimetastatic agent contains no more than 85 consecutive amino acid residues, and preferably no more than 50 consecutive amino acid residues, present within an OB-cadherin.
 An antimetastatic agent is further capable of inhibiting OB-cadherin mediated cell adhesion. Such activity may generally be assessed using, for example, representative assays provided herein. In general, an antimetastatic agent should inhibit OB-cadherin mediated cell adhesion with an activity that is not substantially diminished relative to the fill length OB-cadherin (i.e., the antimetastatic agent inhibits cell adhesion at least as well as soluble OB-cadherin, when contacted with cells that express OB-cadherin). Certain antimetastatic agents further inhibit cell adhesion mediated by a different adhesion molecule.
 An OB-cadherin CAR sequence, as used herein, is an amino acid sequence that is present in a naturally occurring OB-cadherin and that is capable of detectably modulating an OB-cadherin-mediated function, such as cell adhesion, as described herein. In other words, contacting an OB-cadherin-expressing cell with a peptide comprising a CAR sequence results in a detectable change in OB-cadherin-mediated cell adhesion using at least one of the representative assays provided herein. CAR sequences are generally recognized in vivo by an OB-cadherin or other adhesion molecule (i.e., a molecule that mediates cell adhesion via a receptor on the cell surface), and are necessary for maximal heterophilic and/or homophilic interaction. CAR sequences may be of any length, but generally comprise at least three amino acid residues, preferably 4-16 amino acid residues, and more preferably 5-9 amino acid residues. A peptide antimetastatic agent may comprise any number of amino acid residues, but preferred agents comprise 3-50 residues, preferably 4-16 residues.
 It has been found, within the context of the present invention, that certain OB-cadherin CAR sequences share the consensus sequence:
 Within the consensus sequence, Aaa, Baa, Caa and Daa indicate independently selected amino acid residues; “Ile/Leu/Val” indicates an amino acid that is isoleucine, leucine or valine; “Asp/Asn/Glu” indicates an amino acid that is aspartic acid, asparagine or glutamic acid; and “Ser/Thr/Asn” indicates an amino acid that is serine, threonine or asparagine. Representative OB-cadherin CAR sequences are provided within Table I. CAR sequences specifically provided herein further include portions of such representative CAR sequences, as well as longer polypeptides that comprise at least a portion of such sequences. Additional OB-cadherin CAR sequences may be identified based on sequence homology to the OB-cadherin CAR sequences provided herein, and based on the ability of a peptide comprising such a sequence to modulate OB-cadherin-mediated cell adhesion within a representative assay provided herein Within certain embodiments, an antimetastatic agent comprises at least three consecutive residues, preferably at least five consecutive residues and more preferably at least seven consecutive residues, of an OB-cadherin CAR sequence that satisfies the above consensus sequence.
TABLE I Representative OB-Cadherin CAR Sequences Cadherin CAR Sequence Human OB-cadherin EC1 FFVIEEYTG (SEQ ID NO:50) Human OB-cadherin EC1 IFVIDDKSG (SEQ ID NO:64) Human OB-cadherin EC2 YFSVEAQTG (SEQ ID NO:78)
 OB-cadherin CAR sequences are generally physically located within the cadherin molecule in or near the binding site of an adhesion molecule (i.e., within 10 amino acids, and preferably within 5 amino acids, of such a binding site). The location of a binding site may generally be determined using well known techniques, such as evaluating the ability of a portion of the OB-cadherin to bind to another. OB-cadherin molecule. Any standard binding assay may be employed for such an evaluation. Recognition of a CAR sequence by OB-cadherin results in a measurable effect on cell adhesion. Peptides comprising a CAR sequence generally inhibit such a function.
 Certain preferred OB-cadherin CAR sequences comprise 3-9 amino acid residues of a sequence provided in Table I. For example, a CAR sequence may comprise 3, 4 or 5 residues of a 9 amino acid sequence in Table I. In general, an OB-cadherin CAR sequence comprises at least the sequence EEY, DDK or EAQ. Within certain embodiments, a CAR sequence may include at least residues 5-7 of a sequence in Table I
 Representative OB-cadherin CAR sequences comprise one or more of the peptide sequences DDK, IDDK (SEQ ID NO:37) DDKS (SEQ ID NO:38), VIDDK (SEQ ID NO:39), IDDKS (SEQ ID NO:40), VIDDKS (SEQ ID NO:41), DDKSG (SEQ ID NO:42), IDDKSG (SEQ ID NO:43), VIDDKSG (SEQ ID NO:44), FVIDDK (SEQ ID NO:45), FVIDDKS (SEQ ID NO:46), FVIDDKSG (SEQ ID NO:47), IFVIDDK (SEQ ID NO:48), IFVIDDKS (SEQ ID NO:49), IFVIDDKSG (SEQ ID NO:50), EEY, IEEY (SEQ ID NO:51), EEYT (SEQ ID NO:52), VIEEY (SEQ ID NO:53), IEEYT (SEQ ID NO:54), VIEEYT (SEQ ID NO:55), EEYTG (SEQ ID NO:56), IEEYTG (SEQ ID NO:56), VIEEYTG (SEQ ID NO:58), FVIEEY (SEQ ID NO:59), FVIEEYT (SEQ ID ND:60), FVIEEYTG (SEQ ID NO:61), FFVIEEY (SEQ ID NO:62), FFVIEEYT (SEQ ID NO:63), FFVIEEYTG (SEQ ID NO:64), EAQ, VEAQ (SEQ ID NO:65), EAQT (SEQ ID NO:66), SVEAQ (SEQ ID NO:67), VEAQT (SEQ ID NO:68), SVEAQT (SEQ ID NO:69), EAQTG (SEQ ID NO:70), VEAQTG (SEQ ID NO:71), SVEAQTG (SEQ ID NO:72), FSVEAQ (SEQ ID NO:73), FSVEAQT (SEQ ID NO:74), FSVEAQTG (SEQ ID NO:75), YFSVEAQ (SEQ ID NO:76), YFSVEAQT (SEQ ID NO:77) or YFSVEAQTG (SEQ ID NO:78). Linear peptides having such sequences may be modified at the N- and/or C-termini, as in the peptides N—Ac—IFVIDDKSG—NH
 To enhance specificity for OB-cadherin, an antimetastatic agent may contain a greater number of consecutive residues derived from OB-cadherin. In addition, further flanking sequences-may be included to enhance specificity. Such flanking sequences may be identified based on the sequences provided in
 As noted above, antimetastatic agents as described herein may comprise an analogue or mimetic of an OB-cadherin CAR sequence. An analogue generally retains at least 50% identity to a native OB-cadherin CAR sequence, and inhibits OB-cadherin-mediated cell adhesion as described herein. Such analogues preferably contain at least three consecutive residues of, and more preferably at least five consecutive residues of, an OB-cadherin CAR sequence. An analogue may contain any of a variety of amino acid substitutions, additions, insertions, deletions and/or modifications (e.g., side chain modifications). Preferred amino acid substitutions are conservative. A “conservative substitution” is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the polypeptide to be substantially unchanged. Amino acid substitutions may generally be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the residues. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine and valine; glycine and alanine; asparagine and glutamine; and serine, threonine, phenylalanine and tyrosine. Other groups of amino acids that may represent conservative changes include: (1) ala, pro, gly, glu, asp, gin, asn, ser, thr; (2) cys, ser, tyr, thr; (3) val, ile, leu, met, ala, phe; (4) lys, arg, his; and (5) phe, tyr, trp, his. The critical determining feature of an OB-cadherin CAR sequence analogue is the ability to modulate an OB-cadherin-mediated function, which may be evaluated using the representative assays provided herein.
 A mimetic is a non-peptidyl compound that is conformationally similar to an OB-cadherin CAR sequence, such that it modulates OB-cadherin-mediated cell adhesion as described below. Such mimetics may be designed based on techniques that evaluate the three dimensional structure of the peptide. For example, Nuclear Magnetic Resonance spectroscopy (NMR) and computational techniques may be used to determine the conformation of an OB-cadherin CAR sequence. NMR is widely used for structural analyses of both peptidyl and non-peptidyl compounds. Nuclear Overhauser Enhancements (NOE's), coupling constants and chemical shifts depend on the conformation of a compound. NOE data provides the interproton distance between protons through space and can be used to calculate the lowest energy conformation for the OB-cadherin CAR sequence. This information can then be used to design mimetics of the preferred conformation. Linear peptides in solution exist in many conformations. By using conformational restriction techniques it is possible to fix the peptide in the active conformation. Conformational restriction can be achieved by i) introduction of an alkyl group such as a methyl which sterically restricts free bond rotation; ii) introduction of unsaturation which fixes the relative positions of the terminal and geminal substituents; and/or iii) cyclization, which fixes the relative positions of the sidechains. Mimetics may be synthesized where one or more of the amide linkages has been replaced by isosteres, substituents or groups which have the same size or volume such as —CH
 Antimetastatic agents, or peptide portions thereof, may be linear or cyclic peptides. The term “cyclic peptide,” as used herein, refers to a peptide or salt thereof that comprises (1) an intramolecular covalent bond between two non-adjacent residues and (2) at least one OB-cadherin CAR sequence or an analogue thereof. The intramolecular bond may be a backbone to backbone, side-chain to backbone or side-chain to side-chain bond (i.e., terminal functional groups of a linear peptide and/or side chain functional groups of a terminal or interior residue may be linked to achieve cyclization). Preferred intramolecular bonds include, but are not limited to, disulfide, amide and thioether bonds. One or more OB-cadherin CAR sequences, or an analogue or mimetic thereof, may be incorporated into a cyclic peptide, with or without one or more other adhesion molecule binding sites. Additional adhesion molecule binding sites are described in greater detail below.
 The size of a cyclic peptide ring generally ranges from 5 to about 15 residues, preferably from 5 to 10 residues. Additional residue(s) may be present on the N-terminal and/or C-terminal side of an OB-cadherin CAR sequence, and may be derived from sequences that flank an OB-cadherin CAR sequence, with or without amino acid substitutions and/or other modifications. Alternatively, additional residues present on one or both sides of the CAR sequence(s) may be unrelated to an endogenous sequence (e.g., residues that facilitate cyclization, purification or other manipulation and/or residues having a targeting or other function).
 Within certain embodiments, an antimetastatic agent may comprise a cyclic peptide that contains an OB-cadherin CAR sequence as provided in Table I (or a portion of such a CAR sequence). Certain cyclic peptides have the formula:
 Within this formula, W is a tripeptide selected from the group consisting of EEY, DDK and EAQ; X
 Cyclic peptides may comprise any of the above CAR sequence(s). Such cyclic peptides may be used as antimetastatic agents without modification, or may be incorporated into an antimetastatic agent. For example, cyclic peptides may comprise any of the above OB-cadherin CAR sequence(s). Representative cyclic peptides include
 As noted above, certain preferred antimetastatic agents comprise a peptide (containing an OB-cadherin CAR sequence or an analogue thereof) in which at least one terminal amino acid residue is modified (e.g., the N-terminal amino group is modified by, for example, acetylation or alkoxybenzylation and/or an amide or ester is formed at the C-terminus). It has been found, within the context of the present invention, that the addition of at least one such group to a linear or cyclic peptide antimetastatic agent may improve the ability of the agent to modulate an OB-cadherin-mediated function. Certain preferred antimetastatic agents contain modifications at the. N- and C-terminal residues, such as N—Ac—IFVIDDKSG—NH
 Within certain embodiments, cyclic peptides that contain small CAR sequences (e.g., three residues without significant flanking sequences) may be preferred. Such peptides may contain an N-acetyl group and a C-amide group (e.g. the 5-residue ring N—Ac—
 An antimetastatic agent may contain one OB-cadherin CAR sequence, or multiple CAR sequences that are adjacent to one another (i.e., without intervening sequences) or in close proximity (i.e., separated by peptide and/or non-peptide linkers to give a distance between the OB-cadherin CAR sequences that ranges from about 0.1 to 400 nm). A linker may be any molecule (including peptide and/or non-peptide sequences) that does not contain a CAR sequence and that can be covalently linked to at least two peptide sequences. Using a linker, CAR sequence-containing peptides and other peptide or protein sequences may be joined end-to-end (i.e., the linker may be covalently attached to the carboxyl or amino group of each peptide sequence), and/or via side chains. One linker that can be used for such purposes is H
 An antimetastatic agent as described herein may additionally comprise one or more CAR sequences for one or more different adhesion molecules (including, but not limited to, other CAMs) and/or one or more substances, such as antibodies or fragments thereof, that bind to such sequences. Linkers may, but need not, be used to separate such CAR sequence(s) and/or antibody sequence(s) from the CAR sequence(s) and/or each other. Such antimetastatic agents may generally be used within methods in which it is desirable to simultaneously disrupt a function mediated by multiple adhesion molecules. As used herein, an “adhesion molecule” is any molecule that mediates cell adhesion via a receptor on a cell's surface. Adhesion molecules include cell adhesion proteins (e.g., other members of the cadherin gene superfamily, such as N-cadherin and E-cadherin); occludin; claudin; integrins; extracellular matrix proteins such as laminin, fibronectin, collagens, vitronectin, entactin and tenascin; and members of the immunoglobulin supergene family, such as N-CAM, PE-CAM, CEA, L1 or junction associated molecule (JAM; see Martin-Padura et al.,
 The total number of CAR sequences (including the OB-cadherin CAR sequence, with or without other CAR sequences derived from one or more different adhesion molecules) present within an antimetastatic agent may range from 1 to a large number, such as 100, preferably from 1 to 10, and more preferably from 1 to 5. Peptide antimetastatic agents comprising multiple CAR sequences typically contain from 6 (e.g., DDK-HAV) to about 1000 amino acid residues, preferably from 6 to 50 residues. When non-peptide linkers are employed, each CAR sequence of the antimetastatic agent is present within a peptide that generally ranges in size from 3 to 50 residues in length, preferably from 4 to 25 residues, and more preferably from 5 to 15 residues.
 As noted above, antimetastatic agents may be polypeptides or salts thereof, containing only amino acid residues linked by peptide bonds, or may contain non-peptide regions, such as linkers. Peptide regions of an antimetastatic agent may comprise residues of L-amino acids, D-amino acids, or any combination thereof. Amino acids may be from natural or non-natural sources, provided that at least one amino group and at least one carboxyl group are present in the molecule; α- and β-amino acids are generally preferred. The 20 L-amino acids commonly found in proteins are identified herein by the conventional three-letter or one-letter abbreviations, and the corresponding D-amino acids are designated by a lower case one letter symbol.
 An antimetastatic agent may also contain rare amino acids (such as 4-hydroxyproline or hydroxylysine), organic acids or amides and/or derivatives of common amino acids, such as amino acids having the C-terminal carboxylate esterified (e.g., benzyl, methyl or ethyl ester) or amidated and/or having modifications of the N-terminal amino group (e.g., acetylation or alkoxycarbonylation), with or without any of a wide variety of side-chain modifications and/or substitutions (e.g. methylation, benzylation, t-butylation, tosylation, alkoxycarbonylation, and the like). Preferred derivatives include amino acids having a C-terminal amide group. Residues other than common amino acids that may be present with an antimetastatic agent include, but are not limited to, 2-mercaptoaniline, 2-mercaptoproline, ornithine, diaminobutyric acid, α-aminoadipic acid, m-aminomethylbenzoic acid and α,β-diaminopropionic acid.
 Peptide antimetastatic agents (and peptide portions of antimetastatic agents) as described herein may be synthesized by methods well known in the art, including chemical synthesis and recombinant DNA methods. For antimetastatic agents up to about 50 residues in length, chemical synthesis may be performed using solution or solid phase peptide synthesis techniques, in which a peptide linkage occurs through the direct condensation of the α-amino group of one amino acid with the α-carboxy group of the other amino acid with the elimination of a water molecule. Peptide bond synthesis by direct condensation, as formulated above, requires suppression of the reactive character of the amino group of the first and of the carboxyl group of the second amino acid. The masking substituents must permit their ready removal, without inducing breakdown of the labile peptide molecule.
 In solution phase synthesis, a wide variety of coupling methods and protecting groups may be used (see Gross and Meienhofer, eds., “The Peptides: Analysis, Synthesis, Biology,” Vol. 1-4 (Academic Press, 1979); Bodansky and Bodansky, “The Practice of Peptide Synthesis,” 2d ed. (Springer Verlag, 1994)). In addition, intermediate purification and linear scale up are possible. Those of ordinary skill in the art will appreciate that solution synthesis requires consideration of main chain and side chain protecting groups and activation method. In addition, careful segment selection is necessary to minimize racemization during segment condensation. Solubility considerations are also a factor.
 Solid phase peptide synthesis uses an insoluble polymer for support during organic synthesis. The polymer-supported peptide chain permits the use of simple washing and filtration steps instead of laborious purifications at intermediate steps. Solid-phase peptide synthesis may generally be performed according to the method of Merrifield et al.,
 In the procedures discussed above, the selectivity of the side-chain blocking groups and of the peptide-resin link depends upon the differences in the rate of acidolytic cleavage. Orthoganol systems have been introduced in which the side-chain blocking groups and the peptide-resin link are completely stable to the reagent used to remove the α-protecting group at each step of the synthesis. The most common of these methods involves the 9-fluorenylmethyloxycarbonyl (Fmoc) approach. Within this method, the side-chain protecting groups and the peptide-resin link are completely stable to the secondary amines used for cleaving the N-α-Fmoc group. The side-chain protection and the peptide-resin link are cleaved by mild acidolysis. The repeated contact with base makes the Merrifield resin unsuitable for Fmoc chemistry, and p-alkoxybenzyl esters linked to the resin are generally used. Deprotection and cleavage are generally accomplished using TFA.
 Those of ordinary skill in the art will recognize that, in solid phase synthesis, deprotection and coupling reactions must go to completion and the side-chain blocking groups must be stable throughout the entire synthesis. In addition, solid phase synthesis is generally most suitable when peptides are to be made on a small scale.
 Acetylation of the N-terminus can be accomplished by reacting the final peptide with acetic anhydride before cleavage from the resin. C-amidation is accomplished using an appropriate resin such as methylbenzhydrylamine resin using the Boc technology.
 Following synthesis of a linear peptide, with or without N-acetylation and/or C-amidation, cyclization may be achieved if desired by any of a variety of techniques well known in the art. Within one embodiment, a bond may be generated between reactive amino acid side chains. For example, a disulfide bridge may be formed from a linear peptide comprising two thiol-containing residues by oxidizing the peptide using any of a variety of methods. Within one such method, air oxidation of thiols can generate disulfide linkages over a period of several days using either basic or neutral aqueous media. The peptide is used in high dilution to minimize aggregation and intermolecular side reactions. This method suffers from the disadvantage of being slow but has the advantage of only producing H
 DMSO, unlike I
(SEQ ID NO:79) i) N-Ac- (SEQ ID NO:86) ii) N-Ac- (SEQ ID NO:80) iii) N-Ac- (SEQ ID NO:81) iv) N-Ac- (SEQ ID NO:83) v) N-Ac- (SEQ ID NO:81) vi) N-Ac- (SEQ ID NO:83) vii) H- (SEQ ID NO:23) viii) N-Ac- (SEQ ID NO:90) ix) N-Ac- (SEQ ID NO:93) x) N-Ac- (SEQ ID NO:24) xi) N-Ac-Ile- Glu-NH (SEQ ID NO:25) xii) N-Ac-IIe- (SEQ ID NO:26) xiii) (SEQ ID NO:27) xiv)
 It will be readily apparent to those of ordinary skill in the art that, within each of these representative formulas, any of the above thiol-containing residues may be employed in place of one or both of the thiol-containing residues recited.
 Within another embodiment, cyclization may be achieved by amide bond formation. For example, a peptide bond may be formed between terminal functional groups (i.e., the amino and carboxy termini of a linear peptide prior to cyclization). One such cyclic peptide is
 Methods for forming amide bonds are well known in the art and are based on well established principles of chemical reactivity. Within one such method, carbodiimide-mediated lactam formation can be accomplished by reaction of the carboxylic acid with DCC, DIC, EDAC or DCCI, resulting in the formation of an O-acylurea that can be reacted immediately with the free amino group to complete the cyclization. The formation of the inactive N-acylurea, resulting from O→N migration, can be circumvented by converting the O-acylurea to an active ester by reaction with an N-hydroxy compound such as 1-hydroxybenzotriazole, 1-hydroxysuccinimide, 1-hydroxynorbornene carboxamide or ethyl 2-hydroximino-2-cyanoacetate. In addition to minimizing O→N migration, these additives also serve as catalysts during cyclization and assist in lowering racemization. Alternatively, cyclization can be performed using the azide method, in which a reactive azide intermediate is generated from an alkyl ester via a hydrazide. Hydrazinolysis of the terminal ester necessitates the use of a t-butyl group for the protection of side chain carboxyl functions in the acylating component. This limitation can be overcome by using diphenylphosphoryl acid (DPPA), which furnishes an azide directly upon reaction with a carboxyl group. The slow reactivity of azides and the formation of isocyanates by their disproportionation restrict the usefulness of this method. The mixed anhydride method of lactam formation is widely used because of the facile removal of reaction by-products. The anhydride is formed upon reaction of the carboxylate anion with an alkyl chloroformate or pivaloyl chloride. The attack of the amino component is then guided to the carbonyl carbon of the acylating component by the electron donating effect of the alkoxy group or by the steric bulk of the pivaloyl chloride t-butyl group, which obstructs attack on the wrong carbonyl group. Mixed anhydrides with phosphoric acid derivatives have also been successfully used. Alternatively, cyclization can be accomplished using activated esters. The presence of electron withdrawing substituents on the alkoxy carbon of esters increases their susceptibility to aminolysis. The high reactivity of esters of p-nitrophenol, N-hydroxy compounds and polyhalogenated phenols has made these “active esters” useful in the synthesis of amide bonds. The last few years have witnessed the development of benzotriazolyloxytris-(dimethylamino)phosphonium hexafluorophosphonate (BOP) and its congeners as advantageous coupling reagents. Their performance is generally superior to that of the well established carbodiimide amide bond formation reactions.
 Within a further embodiment, a thioether linkage may be formed between the side chain of a thiol-containing residue and an appropriately derivatized α-amino acid. By way of example, a lysine side chain can be coupled to bromoacetic acid through the carbodiimide coupling method (ICC, EDAC) and then reacted with the side chain of any of the thiol containing residues mentioned above to form a thioether linkage. In order to form dithioethers, any two thiol containing side-chains can be reacted with dibromoethane and diisopropylamine in DMF. Examples of thiol-containing linkages are shown below:
 Cyclization may also be achieved using δ
 Representative structures of cyclic peptides comprising OB-cadherin CAR sequences are provided in FIGS.
 For longer antimetastatic agents, recombinant methods are preferred for synthesis. Within such methods, all or part of an antimetastatic agent can be synthesized in living cells, using any of a variety of expression vectors known to those of ordinary skill in the art to be appropriate for the particular host cell. Suitable host cells may include bacteria, yeast cells, mammalian cells, insect cells, plant cells, algae and other animal cells (e.g., hybridoma, CHO, myeloma) The DNA sequences expressed in this manner may encode portions of an OB-cadherin or other adhesion molecule, or may encode a peptide comprising an OB-cadherin analogue or an antibody fragment that specifically binds to an OB-cadherin CAR sequence. Such DNA sequences may be prepared based on known cDNA or genomic sequences, or from sequences isolated by screening an appropriate library with probes designed based on the sequences of known OB-cadherins. Such screens may generally be performed as described in Sambrook et al.,
 As noted above, polynucleotides may also function as antimetastatic agents. In general, such polynucleotides should be formulated to permit expression of a polypeptide antimetastatic agent following administration to a mammal. Such formulations are particularly useful for therapeutic purposes, as described below. Those of ordinary skill in the art will appreciate that there are many ways to achieve expression of a polynucleotide within a mammal, and any suitable method may be employed. For example, a polynucleotide may be incorporated into a viral vector such as, but not limited to, adenovirus, adeno-associated virus, retrovirus, or vaccinia or other pox virus (e.g., avian pox virus). Techniques for incorporating DNA into such vectors are well known to those of ordinary skill in the art. A retroviral vector may additionally transfer or incorporate a gene for a selectable marker (to aid in the identification or selection of transfected cells) and/or a targeting moiety, such as a gene that encodes a ligand for a receptor on a specific target cell, to render the vector target specific. Targeting may also be accomplished using an antibody, by methods known to those of ordinary skill in the art. Other formulations for polynucleotides for therapeutic purposes include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. A preferred colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (i.e., an artificial membrane vesicle). The preparation and use of such systems is well known in the art.
 As noted above, an antimetastatic agent may additionally, or alternatively, comprise a substance such as an antibody or antigen-binding fragment thereof, that specifically binds to an OB-cadherin CAR sequence. As used herein, a substance is said to “specifically bind” to an OB-cadherin CAR sequence (with or without flanking amino acids) if it reacts at a detectable level with a peptide containing that sequence, and does not react detectably with peptides containing a different CAR sequence or a sequence in which the order of amino acid residues in the cadherin CAR sequence and/or flanking sequence is altered. Such antibody binding properties may generally be assessed using an ELISA, which may be readily performed by those of ordinary skill in the art and is described, for example, by Newton et al.,
 Polyclonal and monoclonal antibodies may be raised against a CAR sequence using conventional techniques. See, e.g., Harlow and Lane,
 Monoclonal antibodies specific for an OB-cadherin sequence may be prepared, for example, using the technique of Kohler and Milstein,
 Monoclonal antibodies may be isolated from the supernatants of growing hybridoma colonies, with or without the use of various techniques known in the art to enhance the yield. Contaminants may be removed from the antibodies by conventional techniques, such as chromatography, gel filtration, precipitation and extraction. Antibodies having the desired activity may generally be identified using immunofluorescence analyses of tissue sections, cell or other samples where the target cadherin is localized.
 Within certain embodiments, the use of antigen-binding fragments of antibodies may be preferred. Such fragments include Fab fragments, which may be prepared using standard techniques. Briefly, immunoglobulins may be purified from rabbit serum by affinity chromatography on Protein A bead columns (Harlow and Lane,
 Antimetastatic agents as described above are capable of inhibiting OB-cadherin-mediated cell adhesion. An initial screen for such activity may be performed by evaluating the ability of an antimetastatic agent to bind to OB-cadherin using any binding assay known to those of ordinary skill in the art. For example, a Pharmacia Biosensor machine may be used, as discussed in Jonsson et al.,
 By way of example, surface plasmon resonance experiments may be carried out using a BIAcore X™ Biosensor (Pharmacia Ltd., BIAcore, Uppsala, Sweden). Parallel flow cells of CM 5 sensor chips may be derivatized, using the amine coupling method, with streptavidin (200 μg/ml) in 10 mM Sodium Acetate, pH 4.0, according to the manufacturer's protocol. Approximately 2100-2600 resonance units (RU) of ligand may be immobilized, corresponding to a concentration of about 2.1-2.6 ng/MM
 To determine binding, test analytes (e.g., peptides containing the OB-cadherin CAR sequence) may be placed in running buffer and passed simultaneously over test and control flow cells. After a period of free buffer flow, any analyte remaining bound to the surface may be removed with, for example, a pulse of 0.1% SDS bringing the signal back to baseline. Specific binding to the derivatized sensor chips may be determined automatically by the system by subtraction of test from control flow cell responses. In general, an antimetastatic agent binds to OB-cadherin at a detectable level within such as assay. The level of binding is preferably at least that observed for the full length OB-cadherin under similar conditions.
 The ability to inhibit OB-cadherin-mediated cell adhesion may be evaluated using any of a variety of in vitro assays. It has been found, within the context of the present invention, that OB-cadherin is associated with adhesion of certain cancer cells. The ability of an agent to inhibit OB-cadherin mediated cell adhesion may generally be evaluated in vitro by assaying the effect on adhesion between OB-cadherin-expressing cells (i.e., any type of cell that expresses OB-cadherin at a detectable level, using standard techniques such as immunocytochemical protocols (e.g., Blaschuk and Farookhi,
 In general, an agent is an inhibitor of cell adhesion if contact of the test cells with the antimetastatic agent results in a discernible disruption of cell adhesion, when such cells are plated under standard conditions that, in the absence of antimetastatic agent, permit cell adhesion. In the presence of antimetastatic agent (e.g., 1 mg/mL), disruption of cell adhesion may be determined visually within 24 hours, by observing retraction of the cells from one another and the substratum.
 Alternatively, cells that do not naturally express OB-cadherin may be used within such assays. Such cells may be stably transfected with a polynucleotide (e.g., a cDNA) encoding OB-cadherin, such that OB-cadherin is expressed on the surface of the cell. Expression of the cadherin may be confirmed by assessing adhesion of the transfected cells, in conjunction with immunocytochemical techniques using antibodies directed against the cadherin of interest. The stably transfected cells that aggregate, as judged by light microscopy, following transfection express sufficient levels of OB-cadherin. Preferred cells for use in such assays include L cells, which do not detectably adhere and do not express any cadherin (Nagafuchi et al.,
 Transfection of cells for use in cell adhesion assays may be performed using standard techniques and published OB-cadherin sequences. For example, a sequence of OB-cadherin may be found within references cited herein and in the GenBank database at accession number L34056 (human OB cadherin).
 By way of example, an assay for evaluating an antimetastatic agent for the ability to inhibit OB-cadherin mediated cell adhesion may employ MDA-231 human breast cancer cells. According to a representative procedure, the cells may be plated at 10-20,000 cells per 35 mm tissue culture flasks containing DMEM with 5% FCS and subcultured periodically (Sommers et al.,
 An antimetastatic agent as described herein may, but need not, be linked to one or more additional molecules and/or support materials. For certain applications, biodegradable support materials are preferred, such as cellulose and derivatives thereof, collagen, spider silk or any of a variety of polyesters (e.g., those derived from hydroxy acids and/or lactones) or sutures (see U.S. Pat. No. 5,245,012). Suitable methods for linking an antimetastatic agent to a support material will depend upon the composition of the support and the intended use, and will be readily apparent to those of ordinary skill in the art. Attachment may generally be achieved through noncovalent association, such as adsorption or affinity or via covalent attachment (which may be a direct linkage between an antimetastatic agent and functional groups on the support, or may be a linkage by way of a cross-linking agent). Attachment of an antimetastatic agent by adsorption may be achieved by contact, in a suitable buffer, with a solid support for a suitable amount of time. The contact time varies with temperature, but is generally between about 5 seconds and 1 day, and typically between about 10 seconds and 1 hour. Covalent attachment of an antimetastatic agent to a molecule or solid support may generally be achieved by first reacting the support material with a bifunctional reagent that will also react with a functional group, such as a hydroxyl or amino group, on the antimetastatic agent. A preferred method of generating a linkage is via amino groups using glutaraldehyde. An antimetastatic agent may be linked to cellulose via ester linkages. Similarly, amide linkages may be suitable for linkage to other molecules such as keyhole limpet hemocyanin or other support materials.
 Although antimetastatic agents as described herein may preferentially bind to specific tissues or cells, and thus may be sufficient to target a desired site in vivo, it may be beneficial for certain applications to include an additional targeting agent. Accordingly, a targeting agent may also, or alternatively, be linked to an antimetastatic agent to facilitate targeting to one or more specific tissues. As used herein, a “targeting agent” may be any substance (such as a compound or cell) that, when linked to an antimetastatic agent enhances the transport of the agent to a target tissue, thereby increasing the local concentration of the antimetastatic agent. Targeting agents include antibodies or fragments thereof, receptors, ligands and other molecules that bind to cells of, or in the vicinity of, the target tissue. Known targeting agents include serum hormones, antibodies against cell surface antigens, lectins, adhesion molecules, tumor cell surface binding ligands, steroids, cholesterol, lymphokines, fibrinolytic enzymes and those drugs and proteins that bind to a desired target site. Among the many monoclonal antibodies that may serve as targeting agents are anti-TAC, or other interleukin-2 receptor antibodies; 9.2.27 and NR-ML-05, reactive with the 250 kilodalton human melanoma-associated proteoglycan; and NR-LU-10, reactive with a pancarcinoma glycoprotein. An antibody targeting agent may be an intact (whole) molecule, a fragment thereof, or a functional equivalent thereof Examples of antibody fragments are F(ab′)2, -Fab′, Fab and F[v] fragments, which may be produced by conventional methods or by genetic or protein engineering. Linkage is generally covalent and may be achieved by, for example, direct condensation or other reactions, or by way of bi- or multi-functional linkers.
 For certain embodiments, it may be beneficial to also, or alternatively, link a drug to an antimetastatic agent. As used herein, the term “drug” refers to any bioactive agent intended for administration to a mammal to prevent or treat a disease or other undesirable condition. Drugs include hormones, growth factors, proteins, peptides and other compounds. Drugs include other anticancer or antimetastatic agents.
 Antimetastatic agents as described herein may be present within a pharmaceutical composition. A pharmaceutical composition comprises one or more antimetastatic agents in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. Such compositions may comprise buffers (e.g., neutral buffered saline or phosphate buffered saline), carbohydrates (e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione, adjuvants (e.g., aluminum hydroxide) and/or preservatives. Within yet other embodiments, compositions of the present invention may be formulated as a lyophilizate. One or more antimetastatic agents (alone or in combination with a targeting agent and/or drug) may, but need not, be encapsulated within liposomes using well known technology. Compositions of the present invention may be formulated for any appropriate manner of administration, including for example, topical, oral, nasal, intravenous, intracranial, intraperitoneal, subcutaneous, sublingual or intramuscular administration.
 For certain embodiments, as discussed below, a pharmaceutical composition may further comprise a modulator of cell adhesion that is mediated by one or more molecules other than OB-cadherin. Such modulators may generally be prepared as described above, using one or more CAR sequences and/or antibodies thereto. Such compositions are particularly useful for situations in which it is desirable to inhibit cell adhesion mediated by multiple cell adhesion molecules, such as other members of the cadherin gene superfamily such as the classical cadherins (e.g., N-cadherin or E-cadherin); nonclassical cadherins (e.g., cadherin-5 or cadherin-6); integrins, occludin, claudin or members of the immunoglobulin superfamily (CEA, PE-CAM, N-CAM, L1 or JAM).
 A pharmaceutical composition may also, or alternatively, contain one or more drugs, which may be linked to an antimetastatic agent or may be free within the composition. Virtually any drug may be administered in combination with an antimetastatic agent as described herein. Examples of types of drugs that may be administered with an antimetastatic agent include anticancer drugs (e.g. taxol or mitomycin C) and chemotherapeutic agents.
 The compositions described herein may be administered as part of a sustained release formulation (i.e., a formulation such as a capsule or sponge that effects a slow release of antimetastatic agent following administration). Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain an antimetastatic agent dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane (see, e.g., European Patent Application 710,491 A). Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of antimetastatic agent release. The amount of antimetastatic agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
 Pharmaceutical compositions of the present invention may be administered in a manner appropriate to the disease to be treated (or prevented). Appropriate dosages and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease and the method of administration. In general, an appropriate dosage and treatment regimen provides the antimetastatic agent(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit. Within particularly preferred embodiments of the invention, an antimetastatic agent may be administered at a dosage ranging from 0.001 to 50 mg/kg body weight, preferably from 0.1 to 20 mg/kg, on a regimen of single or multiple daily doses. For topical administration, a cream typically comprises an amount of antimetastatic agent ranging from 0.00001% to 1%, preferably 0.0001% to 0.002%. Fluid compositions typically contain about 10 ng/ml to 5 mg/ml, preferably from about 10 μg to 2 mg/mL antimetastatic agent. Appropriate dosages may generally be determined using experimental models and/or clinical trials. In general, the use of the minimum dosage that is sufficient to provide effective antimetastatic therapy is preferred.
 In general, the antimetastatic agents and compositions described herein may be used to block tumor cell adhesion, and to inhibit metastasis of OB-cadherin expressing cancer cells. Such inhibition may be may be achieved by administering an antimetastatic agent to a human or nonhuman patient, using any method that contacts the cancer cells with the antimetastatic agent. Within the methods described herein, one or more antimetastatic agents may generally be administered alone, or within a pharmaceutical composition. A targeting agent may be employed to increase the local concentration of antimetastatic agent at a target site. Alternatively, an antimetastatic agent may be used to remove metastatic cells from blood or bone marrow ex vivo (i.e., from blood or bone marrow obtained from a patient, which may then be returned to the patient following removal of metastatic cells).
 Within certain aspects, the present invention provides methods for treating cancer and inhibiting metastasis in a mammal. Metastasis of any cancer in which cancer cells express OB-cadherin may be inhibited. Such cancers include, but are not limited to, carcinoma (e.g., breast and ovarian carcinomas), leukemias (e.g., B-cell chronic lymphocyte leukemia) and melanomas.
 Antimetastatic agents may further be designed to disrupt cell adhesion mediated by an adhesion molecule such as cadherin-5, cadherin-6, E-cadherin, N-cadherin, occludin, claudin, N-CAM, PE-CAM, L1, JAM and/or an integrin. For example such an antimetastatic agent may comprise an OB-cadherin CAR sequence (or analogue or mimetic thereof), optionally in combination with a sequence such as HAV, SHAVSS (SEQ ID NO:30), AHAVDI (SEQ ID NO:31), RGD, YIGSR (SEQ ID NO: 16) or a derivative of such a sequence. Preferably, the peptide portion(s) of such antimetastatic agents comprise 6-16 amino acids. Preferred antibody antimetastatic agents include Fab fragments directed against any of the above adhesion molecule CAR sequences. The Fab fragments may be either incorporated into an antimetastatic agent or may be present within a separate modulator that is administered concurrently.
 An antimetastatic agent may be administered alone (e.g., via the skin) or within a pharmaceutical composition. For melanomas and certain other accessible tumors, injection or topical administration as described above may be preferred. For ovarian cancers, flushing the peritoneal cavity with a composition comprising one or more antimetastatic agents may prevent metastasis of ovarian tumor cells. Other tumors (e.g., bladder tumors, bronchial tumors or tracheal tumors) may be treated by injection of the antimetastatic agent into the cavity. In other instances, the composition may be administered systemically, and targeted to the tumor using any of a variety of specific targeting agents, as described above. Preferably, the tumor is a breast, ovarian, stomach, prostate or kidney tumor. In general, the amount of antimetastatic agent administered varies depending upon the method of administration and the nature of the cancer, but may vary within the ranges identified above. The effectiveness of the cancer treatment or inhibition of metastasis may be evaluated using well known clinical observations, such as monitoring the level of serum tumor markers (e.g., CEA or PSA).
 The addition of a targeting agent as described above may be beneficial, particularly when the administration is systemic. Suitable modes of administration and dosages depend upon the condition to be prevented or treated but, in general, administration by injection is appropriate. Dosages may vary as described above. The effectiveness of the inhibition may be evaluated grossly by assessing the inability of the tumors to maintain their growth and microscopically by observing an absence of nerves at the periphery of the tumor.
 Within other aspects, antimetastatic agents may be used to remove metastatic cells from a biological sample, such as blood, bone marrow or a fraction thereof Such removal may be achieved by contacting a biological sample with an antimetastatic agents under conditions and for a time sufficient to permit OB-cadherin expressing cells to bind to the antimetastatic agent. The OB-cadherin expressing cells that have bound to the antimetastatic agent are then separated from the remainder of the sample. To facilitate this removal, an antimetastatic agent may be linked to a solid support. Preferably, the contact results in the reduction of OB-cadherin expressing cells in the sample to less than 1%, preferably less than 0.1%, of the level prior to contact with the antimetastatic agent. The extent to which such cells have been removed may be readily determined by standard methods such as, for example, qualitative and quantitative PCR analysis, immunohistochemistry and FACS analysis. Following removal of metastatic cells, the biological sample may be returned to the patient using standard techniques.
 The following Examples are offered by way of illustration and not by way of limitation.
 This Example illustrates the solid phase synthesis of representative peptide antimetastatic agents.
 The peptides were synthesized on a 431A Applied Biosystems peptide synthesizer using p-Hydroxymethylphenoxymethyl polystyrene (HMP) resin and standard Fmoc chemistry. After synthesis and deprotection, the peptides were de-salted on a Sephadex G-10 column and lyophilized. The peptides were analyzed for purity by analytical HPLC, and in each case a single peak was observed. Peptides were made as stock solutions at 10 to 25 mg/mL in dimethylsulfoxide (DMSO) or water and stored at −20° C. before use.
 This Example illustrates the ability of a representative linear peptide comprising an OB-cadherin CAR sequence to disrupt human breast epithelial cell adhesion.
 MDA-MB-231 human breast cancer cells (Lombardi Cancer Research Center, Washington, DC) were used in these experiments. They express OB-cadherin, but not N-cadherin or E-cadherin. The cells were plated (˜50,000 cells) on glass coverslips and cultured for 24 hours in DMEM containing 5% serum. Peptides (N—Ac—IFVIDDKSG—NH
 This Example illustrates the association between OB-cadherin expression and metastasis in ovarian carcinoma cells.
 An RT-PCR approach was employed to assay the presence of OB-cadherin mRNA transcripts in two ovarian cancer cell lines: SKOV3 (a metastatic cell line) and OVCAR3 (a noninvasive cell line). The cDNA was synthesized from 1 μg of total RNA by M-MLV Reverse Transcriptase (Gibco/BRL, Burlington, ON) using random hexamers as primers. PCR was performed using the contents of the first-strand reaction and the OB-cadherin-specific primers and Taq polymerase (Boehringer Mannheim, Laval, Que., Canada). The OB-cadherin-specific primers used were:
 Forward 5′-ACCAGATGTCTGTATCAGA-3′ (SEQ ID NO:33); and
 Reverse 5′-GTCTCCTGGTCATCATCTGCA-3′ (SEQ ID NO:34) (Munro and Blaschuk,
Forward 5′-CCTGCTGGATTACATTAAAGCACTG-3′; and (SEQ ID NO:35) Reverse 5′-GTCAAGGGCATATCCAACAACAAAC-3′ (SEQ ID NO:36)
 (Melton et al.,
 The results are presented in
 This Example illustrates the expression of OB-cadherin in lymphocytes of leukemia patients.
 The RT-PCR approach described in Example 3 was employed to assay the presence of OB-cadherin mRNA transcripts in lymphocytes prepared from patients with B-cell chronic lymphocytic leukemia (B-CLL). RT-PCR products (shown in
 Using the same approach, RT-PCR products (shown in
 This Example illustrates the expression of OB-cadherin on primary breast tumor cells and on breast cancer cells that have metastasized to bone.
 Paraffin sections (5 microns thick) of primary tumors or bony metastases (Lombardi Cancer Center Histopathology Core) were dewaxed and rehydrated as follows: xylene—three changes for 15 minutes each; absolute ethanol—2 changes for 5 minutes each; 95% ethanol—2 changes for 5 minutes each; 70% ethanol—2 changes for 5 minutes each; three quick rinses in deionized water. The slides were placed in a microwaveable holder and immersed in a pyrex loaf dish containing 1 L 0.01 M citrate buffer. The dish was covered loosely with plastic wrap and placed in a TAPPAN SPEEDwave 1000 microwave and microwaved for 15 minutes on the highest setting. After microwaving, the slides were allowed to cool in the buffer to room temperature.
 The slides were then placed into a dish of phosphate buffered saline (PBS) and rinsed two times for 2 minutes each time. Exogenous peroxidases were blocked by placing a solution of 30% peroxide in methanol onto each section for 40 seconds and then rinsing in PBS. Slides were then placed in 150 mm dishes and 10% goat serum (blocking solution) was applied to each section. Moistened kimwipes were placed around the slides and the dish covered and incubated at 37° C. for 15 minutes. While the sections were blocking, affinity purified rabbit anti-OB-cadherin antibody (Zymed, South San Francisco, Calif.) was prepared in PBS to a concentration of 10 μg/ml. Without rinsing, just blotting the excess goat serum from sections, the primary antibody solution was applied to each section (100 micrometers/section), the dish was covered and wrapped in plastic wrap and was placed at 4° C. for 16 hours.
 The sections were brought to room temperature and then placed at 37° C. for an additional hour. The slides were then rinsed three times for 2 minutes each time with PBS. Biotinylated goat anti-rabbit secondary antibody (Zymed) was applied to each section and the slides were incubated at 37° C. for 10 minutes The slides were again rinsed with PBS as above. Streptavidin peroxidase (Zymed) was applied to each section and the slides incubated at 37° C. for 10 minutes. The slides were again rinsed with PBS as stated above.
 While in the last PBS rinse, the AEC Chromogen solution was prepared according to the Zymed instructions and 100 μl was applied to each section. The sections were left at room temperature for 10 minutes for the color reaction to develop. The slides were then immersed in deionized water to stop the reaction. Finally the sections were counterstained by placing several drops of Mayers Hematoxylin (Zymed) onto each section for 1 minute. The slides were then rinsed in tap water followed by PBS. The slides were then returned to deionized water and mounted using GVA mount (Zymed).
 Results for primary tumor and metastatic deposits are shown in
 These results indicate that breast tumor and metastatic cells express OB-cadherin, and that metastatic cells express OB-cadherin on all cell surfaces. In addition, these results confirm the detection of breast cancer and metastatic cancer based on assays for OB-cadherin expression.
 From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.