p53 Peptide Vaccine

Abstract

The invention relates to a peptide derived from p53 that could be used as a vaccine against cancer.

1 . A method for designing a peptide derived from a ubiquitously expressed self-antigen known to be associated with cancer, said peptide exhibiting a low to intermediate capacity to form stable cell surface expressed class I-MHC complexes and/or being inefficiently processed by a proteasome and/or exhibiting a low to intermediate MHC binding affinity. 
     
     
         2 . The method according to  claim 1 , wherein the peptide exhibits a low to intermediate capacity to form stable cell surface expressed class I-MHC complexes and/or is inefficiently processed by a proteasome. 
     
     
         3 . A method for designing a peptide derived from a protein that is a ubiquitously expressed self-antigen associated with cancer,
 said method comprising:   (a) selecting a set of peptides comprising an MHC class I binding residue;   (b) determining the stability of binding of each peptide of the set to an MHC class I molecule; and/or   (c) analyzing the digestion of each peptide of the set by an immunoproteasome or proteasome,   wherein the affinity of the peptide for an MHC molecule is given by the concentration of an epitope of the peptide at which 50% (IC 50 ) of the binding of a reference epitope is inhibited; and wherein the IC 50  is from about 5 μM to about 50 μM; and/or   wherein the IC 50  of the peptide class I-MHC complex at 20° C. is more than two times greater than the IC 50  at 4° C., and the IC 50  at 20° C. is <15 μM; and/or   after a one hour digestion by a proteasome, less than 1% of the peptide has been digested.   
     
     
         4 . The method of  claim 3 , wherein step (a) comprises selecting a set of peptides having a binding residue for HLA-A*0101, HLA-A*0301, HLA-A*1101 and HLA-A*2401. 
     
     
         5 . A method for treating a cell proliferative disorder, comprising administering to a subject a peptide derived from a protein that is a ubiquitously expressed self-antigen associated with cancer, said peptide exhibiting a low to intermediate capacity to form stable cell surface expressed class I-MHC complexes, and/or being inefficiently processed by a proteasome and/or exhibiting a low to intermediate MHC binding affinity, thereby treating said cell proliferative disorder. 
     
     
         6 . The method according to  claim 5 , wherein the peptide exhibits a low to intermediate capacity to form stable cell surface expressed class I-MHC complexes and/or is inefficiently processed by a proteasome. 
     
     
         7 . A method for treating a cell proliferative disorder, comprising administering to a subject a peptide derived from a protein that is a ubiquitously expressed self-antigen associated with cancer, wherein:
 the affinity of the peptide for an MHC molecule is given by the concentration of an epitope of the peptide at which 50% (IC 50 ) of the binding of a reference epitope is inhibited; and wherein the IC 50  is from about 5 μM to about 50 μM; and/or   wherein the IC 50  at 20° C. is more than two times greater than the IC 50  at 4° C., and the IC 50  at 20° C. is <15 μM; and/or   after a one hour digestion by a proteasome, less than 1% of the peptide has been digested; thereby treating the cell proliferative disorder.   
     
     
         8 . The method of  claim 3  or  7 , wherein said protein is selected from the group consisting of: p53, MDM-2, HDM2, survivin, telomerase, cytochrome p450 isoform 1B1, Her-2/neu and CD19. 
     
     
         9 . The method of  claim 7 , wherein detection of IFN-γ secreting T cells specific for the administered peptide in peripheral blood mononuclear cells (PBMC) derived from the subject following administration of the peptide indicates treatment. 
     
     
         10 . The method of  claim 7 , wherein treatment is indicated when following administration of the peptide to the subject, T-cells derived from a subject proliferate after in vitro stimulation with the peptide. 
     
     
         11 . The method of  claim 7 , wherein treatment is indicated when following administration of the peptide to the subject, there is detectable antigen spreading following in vitro stimulation of T cells derived from the subject with the peptide. 
     
     
         12 . The method of  claim 7 , wherein treatment is determined by a skin biopsy and/or a T cell proliferation assay. 
     
     
         13 . The method of  claim 7 , wherein treatment is indicated by survival of the subject. 
     
     
         14 . The method of  claim 3  or  7 , wherein the cell proliferative disorder is selected from the group consisting of: lung, colon, esophagus, ovary, pancreas, skin, gastric, head and neck, bladder, sarcoma, prostate, hepatocellular, brain, adrenal, breast, endometrium, mesothelioma, renal, thyroid, hematologic, carcinoid, melanoma, parathyroid, cervix, neuroblastoma, Wilms, testes, pituitary and pheochromocytoma cancer. 
     
     
         15 . The method of  claim 3  or  7  wherein said peptide is a peptide derived from p53. 
     
     
         16 . The method of  claim 15 , wherein the peptide comprises or consists of a peptide selected from the group consisting of: SEQ ID NOS: 2-10 and 16. 
     
     
         17 . The method of  claim 16 , wherein said peptide comprises or consists of a peptide selected from the group consisting of: SEQ ID NOS: 4, 5, 6 or 7. 
     
     
         18 . The method of  claim 16 , wherein an additional peptide selected from the group consisting of: SEQ ID NOS: 14, 15, 20 or 21 is present. 
     
     
         19 . The method of  claim 7 , wherein said peptide is administered as a composition comprising a pharmaceutical excipient and/or an immune modulator and/or an immune stimulant. 
     
     
         20 . The method of  claim 7 , wherein said peptide is administered in combination with a dendritic cell (DC) activating agent. 
     
     
         21 . The method of  claim 7 , where said peptide is administered intradermally and/or subcutaneously in the presence or absence of an immune modulator and/or an immune stimulant. 
     
     
         22 . The method of  claim 19 , wherein the immune modulator is an adjuvant. 
     
     
         23 . The method of  claim 22 , wherein said peptide is administered intradermally within less than 5, 2, 1, 0.5, 0.2 or 0.1 cm from the site of the lesion. 
     
     
         24 . The method of  claim 19 , wherein the amount of peptide in the composition is between 1 and 1000 μg.