US2005048550A1PendingUtilityA1

EphA2 T-cell epitope agonists and uses therefor

54
Assignee: UNIV PITTSBURGHPriority: Jul 30, 2003Filed: Jul 22, 2004Published: Mar 3, 2005
Est. expiryJul 30, 2023(expired)· nominal 20-yr term from priority
Inventors:Walter J. StorkusMichael S. Kinch
G01N 33/5091A61P 43/00C07K 7/06C07K 14/705C07K 14/4748G01N 33/56972G01N 33/56966C07K 14/47A61P 37/04G01N 33/505A61K 38/1793G01N 2333/5409A61P 37/00G01N 2333/57C07K 7/08A61P 35/04A61K 2039/55566A61P 35/00A61P 37/02A61K 40/422A61K 40/11A61K 2239/38A61K 2239/31A61K 39/0011
54
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Claims

Abstract

EphA2 T-cell epitope agonists are provided herein. The agonists include peptides corresponding to specific fragments of human EphA2 protein containing one or more T-cell epitopes, and conservative derivatives thereof. The EphA2 T-cell epitope agonists are useful in an assay, such as an ELISPOT assay, that may be used to determine and/or quantify a patient's immune responsiveness to EphA2. The agonists also are useful in methods of modulating a patient's immune reactivity to EphA2, which has substantial utility as a treatment for cancers that overexpress EphA2, such as renal cell carcinoma (RCC). The EphA2 agonists also can be used to vaccinate a patient against EphA2, by in vivo or ex vivo methods.

Claims

exact text as granted — not AI-modified
1 . An EphA2 T-cell epitope agonist comprising an EphA2 T-cell epitope.  
     
     
         2 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , consisting essentially of an EphA2 T-cell epitope.  
     
     
         3 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , comprising a peptide comprising an EphA2 T-cell epitope.  
     
     
         4 . The EphA2 T-cell epitope agonist as claimed in  claim 3 , wherein the peptide consists of from about 9 to about 35 amino acids.  
     
     
         5 . The EphA2 T-cell epitope agonist as claimed in  claim 3 , wherein the peptide consists of from about 9 to about 25 amino acids.  
     
     
         6 . The EphA2 T-cell epitope agonist as claimed in  claim 3 , wherein the peptide is less than about 20 amino acids.  
     
     
         7 . The EphA2 T-cell epitope agonist as claimed in  claim 3 , wherein the peptide comprises at least about 9 contiguous amino acids of SEQ ID NO: 2.  
     
     
         8 . The EphA2 T-cell epitope agonist as claimed in  claim 7 , wherein the peptide comprises from about 9 to about 25 contiguous amino acids of SEQ ID NO: 2.  
     
     
         9 . The EphA2 T-cell epitope agonist as claimed in  claim 7 , comprising a conservative derivative of the peptide in which: 
 a. one or more amino acid residues are inserted into the peptide, or    b. one or more amino acid residues of the peptide is substituted with one or more different amino acid residues, wherein the binding of the conservative derivative to an MHC molecule is substantially equal to or enhanced as compared to binding of EphA2 or a fragment thereof to the MHC molecule.    
     
     
         10 . The EphA2 T-cell epitope agonist as claimed in  claim 3 , wherein the peptide fragment can be generated by proteasomal cleavage at a proteasomal cleavage site.  
     
     
         11 . The EphA2 T-cell epitope agonist as claimed in  claim 10 , wherein the proteasomal cleavage site is determined according to a proteasomal cleavage prediction algorithm.  
     
     
         12 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , in which the agonist is a modified peptide comprising one or more of N-terminal modifications, C-terminal modifications, internal modifications or non-standard residues.  
     
     
         13 . The EphA2 T-cell epitope agonist as claimed in  claim 12 , wherein the N-terminal modifications, C-terminal modifications, internal modifications or non-standard residues are selected from the group consisting of a solubilizing group; a hydrophobic group; a lipid group; a hydrophilic group; a tag; a fluorescent tag; a polypeptide tag; a transmembrane signal sequence or a portion thereof; an amino acid enantiomer and one of an acetyl, benzyloxycarbonyl, biotin, cinnamoyl, dabcyl, dabsyl, dansyl, dinitrophenyl, cyanine, fluorescein, fmoc, formyl, lissamine rhodamine, myristoyl, n-methyl, palmitoyl, steroyl, 7-methoxycoumarin acetic acid, biotin, dabcyl, dabsyl, dansyl, disulphide, acetamidomethyl, aminohexanoic acid, aminoisobutyric acid, beta alanine, cyclohexylalanine, d-cyclohexylalanine, e-acetyl lysine, gamma aminobutyric acid, hydroxyproline, nitro-arginine, nitro-phenylalanine, nitro-tyrosine, norleucine, norvaline, octahydroindole carboxylate, ornithine, penicillamine, phenylglycine, phosphoserine, phosphothreonine, phosphotyrosine, L-malonyltyrosine, pyroglutamate, tetrahydroisoquinoline, amide, N-substituted glycine; non-amino acyl and N-acetylglycine group.  
     
     
         14 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , in which the agonist is a peptiod or a peptidomimetic comprising an EphA2 T-cell epitope.  
     
     
         15 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , comprising a T-cell epitope contained in one or more of the following EphA2 epitope sequences: TLADFDPRV (SEQ ID NO: 2, residues 883-891); VLLLVLAGV (SEQ ID NO: 2, residues 546-554); VLAGVGFFI (SEQ ID NO: 2, residues 550-558); IMNDMPIYM (SEQ ID NO: 2, residues 58-66); SLLGLKDQV (SEQ ID NO: 2, residues 961-969); WLVPIGQCL (SEQ ID NO: 2, residues 253-261); LLWGCALAA (SEQ ID NO: 2, residues 12-20); GLTRTSVTV (SEQ ID NO: 2, residues 391-399); NLYYAESDL (SEQ ID NO: 2, residues 120-128); KLNVEERSV (SEQ ID NO: 2, residues 162-170); IMGQFSHHN (SEQ ID NO: 2, residues 666-674); YSVCNVMSG (SEQ ID NO: 2, residues 67-75); MQNIMNDMP (SEQ ID NO: 2, residues 55-63) and a sequence presented in one or more of  FIGS. 5-17 .  
     
     
         16 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , comprising a peptide, or a modified version thereof, comprising one or more of the following amino acid sequences: TLADFDPRV (SEQ ID NO: 2, residues 883-891); VLLLVLAGV (SEQ ID NO: 2, residues 546-554); VLAGVGFFI (SEQ ID NO: 2, residues 550-558); IMNDMPIYM (SEQ ID NO: 2, residues 58-66); SLLGLKDQV (SEQ ID NO: 2, residues 961-969); WLVPIGQCL (SEQ ID NO: 2, residues 253-261); LLWGCALAA (SEQ ID NO: 2, residues 12-20); GLTRTSVTV (SEQ ID NO: 2, residues 391-399); NLYYAESDL (SEQ ID NO: 2, residues 120-128); KLNVEERSV (SEQ ID NO: 2, residues 162-170); IMGQFSHHN (SEQ ID NO: 2, residues 666-674); YSVCNVMSG (SEQ ID NO: 2, residues 67-75); MQNIMNDMP (SEQ ID NO: 2, residues 55-63) and a sequence presented in one or more of  FIGS. 5-17 , or a conservative derivative thereof.  
     
     
         17 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , comprising a peptide, or a modified version thereof, consisting essentially of one or more of the following amino acid sequences: TLADFDPRV (SEQ ID NO: 2, residues 883-891); VLLLVLAGV (SEQ ID NO: 2, residues 546-554); VLAGVGFFI (SEQ ID NO: 2, residues 550-558); IMNDMPIYM (SEQ ID NO: 2, residues 58-66); SLLGLKDQV (SEQ ID NO: 2, residues 961-969); WLVPIGQCL (SEQ ID NO: 2, residues 253-261); LLWGCALAA (SEQ ID NO: 2, residues 12-20); GLTRTSVTV (SEQ ID NO: 2, residues 391-399); NLYYAESDL (SEQ ID NO: 2, residues 120-128); KLNVEERSV (SEQ ID NO: 2, residues 162-170); IMGQFSHHN (SEQ ID NO: 2, residues 666-674); YSVCNVMSG (SEQ ID NO: 2, residues 67-75); MQNIMNDMP (SEQ ID NO: 2, residues 55-63) and a sequence presented in one or more of  FIGS. 5-17 , or a conservative derivative thereof.  
     
     
         18 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , consisting of one of the following peptides: TLADFDPRV (SEQ ID NO: 2, residues 883-891); VLLLVLAGV (SEQ ID NO: 2, residues 546-554); VLAGVGFFI (SEQ ID NO: 2, residues 550-558); IMNDMPIYM (SEQ ID NO: 2, residues 58-66); SLLGLKDQV (SEQ ID NO: 2, residues 961-969); WLVPIGQCL (SEQ ID NO: 2, residues 253-261); LLWGCALM (SEQ ID NO: 2, residues 12-20); GLTRTSVTV (SEQ ID NO: 2, residues 391-399); NLYYAESDL (SEQ ID NO: 2, residues 120-128); KLNVEERSV (SEQ ID NO: 2, residues 162-170); IMGQFSHHN (SEQ ID NO: 2, residues 666-674); YSVCNVMSG (SEQ ID NO: 2, residues 67-75); MQNIMNDMP (SEQ ID NO: 2, residues 55-63) and a sequence presented in one or more of  FIGS. 5-17 , or a conservative derivative thereof.  
     
     
         19 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , consisting of one of the following peptides: TLADFDPRV (SEQ ID NO: 2, residues 883-891); VLLLVLAGV (SEQ ID NO: 2, residues 546-554); VLAGVGFFI (SEQ ID NO: 2, residues 550-558); IMNDMPIYM (SEQ ID NO: 2, residues 58-66); SLLGLKDQV (SEQ ID NO: 2, residues 961-969); WLVPIGQCL (SEQ ID NO: 2, residues 253-261); LLWGCALAA (SEQ ID NO: 2, residues 12-20); GLTRTSVTV (SEQ ID NO: 2, residues 391-399); NLYYAESDL (SEQ ID NO: 2, residues 120-128); KLNVEERSV (SEQ ID NO: 2, residues 162-170); IMGQFSHHN (SEQ ID NO: 2, residues 666-674); YSVCNVMSG (SEQ ID NO: 2, residues 67-75); MQNIMNDMP (SEQ ID NO: 2, residues 55-63); EAGIMGQFSHHNIIR (SEQ ID NO: 2, residues 663-677); PIYMYSVCNVMSG (SEQ ID NO: 2, residues 63-75); and DLMQNIMNDMPIYMYS (SEQ ID NO: 2, residues 53-68).  
     
     
         20 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , comprising a peptide consisting of between about 9 and about 100 contiguous amino acids of the native EphA2 protein.  
     
     
         21 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , comprising a peptide consisting of between about 9 and about 25 contiguous amino acids of an EphA2 protein.  
     
     
         22 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , wherein the EphA2 T-cell epitope is a T-cell epitope contained substantially between EphA2 amino acid residues 12-20; 53-75; 120-128; 162-170; 253-261; 391-399; 546-558; 663-677; 883-891 or 961-969 of SEQ ID NO: 2.  
     
     
         23 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , comprising two or more EphA2 T-cell epitopes separated by a spacer.  
     
     
         24 . The EphA2 T-cell epitope agonist as claimed in  claim 1 , comprising a T-cell epitope containing peptide presented by an MHC allele listed in  FIGS. 3 and 4 .  
     
     
         25 . A composition comprising one or more EphA2 T-cell epitope agonist as claimed in  claim 1  and a pharmaceutically acceptable excipient, carrier, diluent, adjuvant or vehicle.  
     
     
         26 . An EphA2 T-cell epitope agonist comprising the amino acid sequence TLADFDPRV (SEQ ID NO: 2, residues 883-891).  
     
     
         27 . An EphA2 T-cell epitope agonist comprising the amino acid sequence VLLLVLAGV (SEQ ID NO: 2, residues 546-554).  
     
     
         28 . An EphA2 T-cell epitope agonist comprising the amino acid sequence VLAGVGFFI (SEQ ID NO: 2, residues 550-558).  
     
     
         29 . An EphA2 T-cell epitope agonist comprising the amino acid sequence IMNDMPIYM (SEQ ID NO: 2, residues 58-66).  
     
     
         30 . An EphA2 T-cell epitope agonist comprising the amino acid sequence SLLGLKDQV (SEQ ID NO: 2, residues 961-969).  
     
     
         31 . An EphA2 T-cell epitope agonist comprising the amino acid sequence WLVPIGQCL (SEQ ID NO: 2, residues 253-261).  
     
     
         32 . An EphA2 T-cell epitope agonist comprising the amino acid sequence LLWGCALAA (SEQ ID NO: 2, residues 12-20).  
     
     
         33 . An EphA2 T-cell epitope agonist comprising the amino acid sequence GLTRTSVTV (SEQ ID NO: 2, residues 391-399).  
     
     
         34 . An EphA2 T-cell epitope agonist comprising the amino acid sequence NLYYAESDL (SEQ ID NO: 2, residues 120-128).  
     
     
         35 . An EphA2 T-cell epitope agonist comprising the amino acid sequence KLNVEERSV (SEQ ID NO: 2, residues 162-170).  
     
     
         36 . An EphA2 T-cell epitope agonist comprising the amino acid sequence IMGQFSHHN (SEQ ID NO: 2, residues 666-674).  
     
     
         37 . An EphA2 T-cell epitope agonist comprising the amino acid sequence YSVCNVMSG (SEQ ID NO: 2, residues 67-75).  
     
     
         38 . An EphA2 T-cell epitope agonist comprising the amino acid sequence MQNIMNDMP (SEQ ID NO: 2, residues 55-63).  
     
     
         39 . A method of monitoring the number and/or status of EphA2-reactive T-cells in a patient, comprising determining the patient's immune reactivity to a compound or composition containing an EphA2 T-cell epitope agonist containing one or more EphA2 T-cell epitopes.  
     
     
         40 . The method of  claim 39 , comprising determining the patient's immune reactivity to a compound or composition containing one or more EphA2 T-cell epitopes using an ELISPOT assay.  
     
     
         41 . The method of  claim 40 , wherein the ELISPOT assay detects a CD8 +  response to an MHC class I protein-presented EphA2 epitope or a conservative derivative thereof.  
     
     
         42 . The method of  claim 41 , wherein the MHC class I protein is an HLA-A2 protein.  
     
     
         43 . The method of  claim 41 , wherein the ELISPOT assay detects production of IFN-γ.  
     
     
         44 . The method of  claim 37 , wherein the ELISPOT assay detects a CD4 +  to an MHC class II protein-presented EphA2 epitope or a conservative derivative thereof.  
     
     
         45 . The method of  claim 41 , wherein the MHC class II protein is an HLA-DR4 protein.  
     
     
         46 . The method of  claim 41 , wherein the ELISPOT assay detects production of IL-5.  
     
     
         47 . The method of  claim 36 , comprising contacting a population of cells containing a T-cell and an antigen-presenting cell with a compound or composition containing one or more EphA2 T-cell epitope agonists.  
     
     
         48  The method of  claim 47 , wherein the EphA2 T-cell epitope agonist comprises a T-cell epitope contained in one of the following sequences: TLADFDPRV (SEQ ID NO: 2, residues 883-891); VLLLVLAGV (SEQ ID NO: 2, residues 546-554); VLAGVGFFI (SEQ ID NO: 2, residues 550-558); IMNDMPIYM (SEQ ID NO: 2, residues 58-66); SLLGLKDQV (SEQ ID NO: 2, residues 961-969); WLVPIGQCL (SEQ ID NO: 2, residues 253-261); LLWGCALAA (SEQ ID NO: 2, residues 12-20); GLTRTSVTV (SEQ ID NO: 2, residues 391-399); NLYYAESDL (SEQ ID NO: 2, residues 120-128); KLNVEERSV (SEQ ID NO: 2, residues 162-170); IMGQFSHHN (SEQ ID NO: 2, residues 666-674); YSVCNVMSG (SEQ ID NO: 2, residues 67-75); MQNIMNDMP (SEQ ID NO: 2, residues 55-63) and a sequence presented in one or more of  FIGS. 5-17 .  
     
     
         49 . The method of  claim 47 , wherein the EphA2 T-cell epitope agonist comprises one or more sequences selected from the group consisting of: TLADFDPRV (SEQ ID NO: 2, residues 883-891); VLLLVLAGV (SEQ ID NO: 2, residues 546-554); VLAGVGFFI (SEQ ID NO: 2, residues 550-558); IMNDMPIYM (SEQ ID NO: 2, residues 58-66); SLLGLKDQV (SEQ ID NO: 2, residues 961-969); WLVPIGQCL (SEQ ID NO: 2, residues 253-261); LLWGCALAA (SEQ ID NO: 2, residues 12-20); GLTRTSVTV (SEQ ID NO: 2, residues 391-399); NLYYAESDL (SEQ ID NO: 2, residues 120-128); KLNVEERSV (SEQ ID NO: 2, residues 162-170); IMGQFSHHN (SEQ ID NO: 2, residues 666-674); YSVCNVMSG (SEQ ID NO: 2, residues 67-75); MQNIMNDMP (SEQ ID NO: 2, residues 55-63); EAGIMGQFSHHNIIR (SEQ ID NO: 2, residues 663-677); PIYMYSVCNVMSG (SEQ ID NO: 2, residues 63-75); and DLMQNIMNDMPIYMYS (SEQ ID NO: 2, residues 53-68).and a sequence presented in one or more of  FIGS. 5-17 .  
     
     
         50 . A method for inhibiting growth in a patient of a cancer in which EphA2 is overexpressed, comprising administering to the patient an amount of an EphA2 T-cell epitope agonist as claimed in  claim 1  effective to elicit an immune response to EphA2 in the patient.  
     
     
         51 . The method of  claim 50 , comprising contacting an antigen-presenting cell of a patient with the EphA2 T-cell epitope agonist.  
     
     
         52 . The method of  claim 51 , wherein the contacting an antigen-presenting cell of a patient with EphA2 T-cell epitope agonist is repeated two or more times.  
     
     
         53 . The method of  claim 51 , comprising: 
 a) isolating cells comprising an antigen-presenting cell from the patient;    b) contacting the antigen-presenting cell with the EphA2 T-cell epitope agonist; and    c) reintroducing the EphA2 T-cell epitope agonist-contacted antigen-presenting cell into the patient.    
     
     
         54 . The method of  claim 50 , wherein the EphA2 T-cell epitope agonist comprises a T-cell epitope contained in one of the following EphA2 epitope sequences: TLADFDPRV (SEQ ID NO: 2, residues 883-891); VLLLVLAGV (SEQ ID NO: 2, residues 546-554); VLAGVGFFI (SEQ ID NO: 2, residues 550-558); IMNDMPIYM (SEQ ID NO: 2, residues 58-66); SLLGLKDQV (SEQ ID NO: 2, residues 961-969); WLVPIGQCL (SEQ ID NO: 2, residues 253-261); LLWGCALAA (SEQ ID NO: 2, residues 12-20); GLTRTSVTV (SEQ ID NO: 2, residues 391-399); NLYYAESDL (SEQ ID NO: 2, residues 120-128); KLNVEERSV (SEQ ID NO: 2, residues 162-170); IMGQFSHHN (SEQ ID NO: 2, residues 666-674); YSVCNVMSG (SEQ ID NO: 2, residues 67-75); MQNIMNDMP (SEQ ID NO: 2, residues 55-63) and a sequence presented in one or more of  FIGS. 5-17 .  
     
     
         55 . The method of  claim 50 , wherein the EphA2 T-cell epitope agonist comprises an amino acid sequence selected from the group consisting of: TLADFDPRV (SEQ ID NO: 2, residues 883-891); VLLLVLAGV (SEQ ID NO: 2, residues 546-554); VLAGVGFFI (SEQ ID NO: 2, residues 550-558); IMNDMPIYM (SEQ ID NO: 2, residues 58-66); SLLGLKDQV (SEQ ID NO: 2, residues 961-969); WLVPIGQCL (SEQ ID NO: 2, residues 253-261); LLWGCALAA (SEQ ID NO: 2, residues 12-20); GLTRTSVTV (SEQ ID NO: 2, residues 391-399); NLYYAESDL (SEQ ID NO: 2, residues 120-128); KLNVEERSV (SEQ ID NO: 2, residues 162-170); IMGQFSHHN (SEQ ID NO: 2, residues 666-674); YSVCNVMSG (SEQ ID NO: 2, residues 67-75); MQNIMNDMP (SEQ ID NO: 2, residues 55-63) and a sequence presented in one or more of  FIGS. 5-17 .  
     
     
         56 . The method of  claim 50 , further comprising administering to a patient an EphA2 ligand or an agonist thereof.  
     
     
         57 . The method of  claim 56 , wherein the EphA2 ligand or an agonist thereof is one of: 
 (a) a binding reagent capable of binding to EphA2; and    (b) ephrinA1 or an agonist thereof.    
     
     
         58 . The method of  claim 56 , wherein at least one of the contacting an antigen-presenting cell of a patient with EphA2 T-cell epitope agonist and the administering to a patient an EphA2 ligand or an agonist thereof is repeated two or more times.  
     
     
         59 . The method of  claim 58 , wherein the contacting an antigen-presenting cell of a patient with an EphA2 T-cell epitope agonist and the administering to a patient an EphA2 ligand or an agonist thereof are alternated.  
     
     
         60 . The method of  claim 50 , wherein the EphA2 T-cell epitope agonist is introduced directly into the patient.  
     
     
         61 . The method of  claim 60 , wherein the EphA2 T-cell epitope agonist is injected into the patient intramuscularly.  
     
     
         62 . The method of  claim 50 , wherein the EphA2 T-cell epitope agonist is administered by introducing a gene for expressing the EphA2 T-cell epitope agonist into a cell of a patient.  
     
     
         63 . An isolated nucleic acid comprising from 5′ to 3′ and operably linked, a promoter, a coding sequence, other than a full length EphA2 coding sequence, encoding a peptide comprising one or more EphA2 T-cell epitopes and a polyadenylation signal.  
     
     
         64 . The nucleic acid of  claim 63 , wherein the promoter is either constitutive, tissue-specific, tissue specific or inducible.  
     
     
         65 . The nucleic acid of  claim 63 , wherein the sequence encoding a peptide comprising an EphA2 T-cell epitope agonist comprises a sequence encoding an affinity selection tag.  
     
     
         66 . The nucleic acid of  claim 65 , wherein the tag is a poly-histidine tag.  
     
     
         67 . The nucleic acid of  claim 63 , further comprising a sequence for propagation of the nucleic acid in a cell.  
     
     
         68 . The nucleic acid of  claim 67 , in which the sequence for propagation of the nucleic acid in a cell is a plasmid backbone.  
     
     
         69 . The nucleic acid of  claim 63 , wherein the sequence encoding a peptide comprising an EphA2 T-cell epitope agonist comprises a sequence encoding a transmembrane signal sequence.  
     
     
         70 . The nucleic acid of  claim 69 , wherein the sequence encoding a peptide encodes a peptide comprising two or more sequences encoding an EphA2 T-cell epitope, wherein the EphA2 T-cell epitopes optionally are separated by a spacer, preferably of from 1 to about 10 amino acids.  
     
     
         71 . A method of modulating a patients immune response to EphA2, comprising contacting a tumor cell that expresses EphA2 on its surface with an EphA2 ligand or an agonist thereof comprising one of: 
 (a) a binding reagent capable of binding to EphA2; and    (b) ephrinA1 or an agonist thereof.    
     
     
         72 . The method of  claim 71 , wherein the binding reagent is selected from the group consisting of an Fv fragment; a single chain Fv (scFv) fragment; an Fab′ fragment; an F(ab′)2 fragment; camelized antibodies and antibody fragments; multivalent versions of the foregoing; a monospecific or bispecific antibody; a disulfide stabilized Fv fragment, an scFv tandem; a diabody; a tribody; a tetrabody; a leucine zipper or helix stabilized scFv fragment; a recombinant antibody or fragment thereof; an aptamer and phage display product.  
     
     
         73 . The method of  claim 71 , wherein the EphA2 ligand or an agonist thereof is ephrinA1 or an agonist thereof.

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