EphA2 T-cell epitopes and uses therefor
View Patent ↗EphA2 T-cell epitope are provided herein. The epitopes 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 epitopes 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 epitopes 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 epitopes also can be used to vaccinate a patient against EphA2, by in vivo or ex vivo methods.
1. A method of treating cancer in a patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of a purified EphA2 T-cell epitope, wherein said EphA2 T-cell epitope binds to an MHC Class II molecule, wherein said EphA2 T-cell epitope is a peptide that consists of 9 to 35 contiguous amino acid residues of native human EphA2 (SEQ ID NO: 2), and wherein said EphA2 T-cell epitope has a predicted binding score of greater than 39 for the MHC Class II molecule HLA-DRβ1*0402 as determined using the Southwood algorithm.
2. A method of treating cancer, said method comprising administering to a patient in need thereof a therapeutically effective amount of a purified EphA2 T-cell epitope or a purified polypeptide comprising an EphA2 T-cell epitope and a second amino acid sequence,
wherein the EphA2 T-cell epitope is a peptide that:
(i) consists of 9 to 35 contiguous amino acid residues of native human EphA2 (SEQ ID NO: 2), and
(ii) has:
(x) a predicted binding score of 98 or below for the major histocompatibility complex (“MHC”) Class I molecule HLA-A2 as determined using the NIH BIMAS “HLA Peptide Binding Predictions” software, or
(y) an amino acid sequence identified using the ProPred software as a sequence that binds to MHC Class II molecule HLA-DRβ1*0402,
wherein said EphA2 T-cell epitope and said second amino acid sequence are not contiguous to each other in the amino acid sequence of SEQ ID NO: 2.
3. A method of eliciting an immune response to EphA2 in a patient, said method comprising administering to the patient an effective amount of a purified EphA2 T-cell epitope or a purified polypeptide comprising an EphA2 T-cell epitope and a second amino acid sequence,
wherein the EphA2 T-cell epitope is a peptide that:
(i) consists of 9 to 35 contiguous amino acid residues of native human EphA2 (SEQ ID NO: 2), and
(ii) has:
(x) a predicted binding score of 98 or below for the major histocompatibility complex (“MHC”) Class I molecule HLA-A2 as determined using the NIH BIMAS “HLA Peptide Binding Predictions” software, or
(y) an amino acid sequence identified using the ProPred software as a sequence that binds to MHC Class II molecule HLA-DRβ1*0402,
wherein said EphA2 T-cell epitope and said second amino acid sequence are not contiguous to each other in the amino acid sequence of SEQ ID NO: 2.
4. The method of claim 2 or 3 , wherein the second amino acid sequence is a heterologous amino acid sequence.
5. The method of claim 2 or 3 , wherein the second amino acid sequence is a second EphA2 T-cell epitope.
6. The method of claim 5 , wherein said second EphA2 T-cell epitope:
(i) binds to an MHC Class II molecule,
(ii) consists of 9 to 35 contiguous amino acid residues of native human EphA2 (SEQ ID NO:2), and
(iii) has:
(x) a predicted binding score of greater than 39 for the MHC Class II molecule HLA-DRβ1*0401 as determined using the Southwood algorithm, or
(y) an amino acid sequence identified using the ProPred software as a sequence that binds to MHC Class II molecule HLA-DRβ1*0402.
7. The method of claim 5 , wherein said second EphA2 T-cell epitope binds to an MHC Class II molecule and has an amino acid sequence selected from the group consisting of: WLVPIGQCL (SEQ ID NO: 2, residues 253-261), LLWGCALAA (SEQ ID NO: 2, residues 12-20), NLYYAESDL (SEQ ID NO: 2, residues 120-128), MQNIMNDMP (SEQ ID NO: 2, residues 55-63), DLMQNIMNDMPIYMYS (SEQ ID NO: 2, residues 53-68), IMGQFSHHN (SEQ ID NO: 2, residues 666-674), IVMWEVMTY (SEQ ID NO: 2, residues 805-813), IVYSVTCEQ (SEQ ID NO: 2, residues 360-368), IRLPSTSGS (SEQ ID NO: 2, residues 893-901), VELRWTPPQ (SEQ ID NO: 2, residues 344-352), LRWTPPQDS (SEQ ID NO: 2, residues 346-354), VVLLLVLAG (SEQ ID NO: 2, residues 545-553), ILVNSNLVC (SEQ ID NO: 2, residues 745-753), and MNYTFTVEA (SEQ ID NO: 2, residues 406-414).
8. The method of claim 5 , wherein the second EphA2 T-cell epitope has an amino acid sequence selected from the group consisting of: IMGQFSHHN (SEQ ID NO: 2, residues 666-674); YSVCNVMSG (SEQ ID NO: 2, residues 67-75); EAGIMGQFSHHNIIR (SEQ ID NO: 2, residues 663-677); and PIYMYSVCNVMSG (SEQ ID NO: 2, residues 63-75).
9. A method of treating cancer in a patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of a purified EphA2 T-cell epitope, wherein said EphA2 T-cell epitope is a peptide that consists of 9 to 35 contiguous amino acid residues of native human EphA2 (SEQ ID NO: 2), and is 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);
DLMQNIMNDMPIYMYS (SEQ ID NO: 2, residues 53-68);
DLMQNIMNDMPIYMYSVCNVMSG (SEQ ID NO: 2, residues 53-75); and
VLLLVLAGVGFFI (SEQ ID NO: 2, residues 546-558).