Anti-tumour response to modified self-epitopes

Abstract

Anti-tumour immune responses to modified self-epitopes. The present invention relates to the use of tumour-associated epitopes in medicine and in particular in the treatment of cancer. The epitopes stimulate an immune reaction against the tumour and have a modification selected from deimination of arginine to citrulline, nitration of tyrosine, oxidation of tryptophan and deamination of glutamine or asparagine. The invention also relates to nucleic acids comprising sequences that encode such epitopes for use in the treatment of cancer.

1 . A tumour-associated epitope which stimulates an immune reaction against the tumour for use in medicine, the epitope having a modification selected from deimination of arginine to citrulline, nitration of tyrosine, oxidation of tryptophan and deamination of glutamine or asparagine. 
     
     
         2 . A tumour-associated epitope which stimulates an immune reaction against the tumour, and/or a nucleic acid comprising a sequence that encodes such an epitope for use in a method of treating cancer, the epitope having a modification selected from deimination of arginine to citrulline, nitration of tyrosine, oxidation of tryptophan and deamination of glutamine or asparagine. 
     
     
         3 . The epitope and/or nucleic acid for use of  claim 2 , wherein the epitope is derived from NY-ESO-1, MMPI, cytokeratins, ING4, MUC1, CEA.CAM5, CD59, bcl2, β-catenin, CXCL8, CXCL10, CXCL12, α enolase, myelin basic protein, histone, nucleophosmin, B23, co-activator complex, anti-thrombin, aggregan, elongation factor 1α, adenylcyclase associated protein (CAP1), glucose regulated protein, ALDH2, cartilage intermediate layer protein (CLIP), aldolase, phosphoglycerate kinase 1 (PGK1), calreticulin, HSP60, far upstream element-binding proteins 1 and 2 (FUSE-BPs), asporin, cathepsin D, heparin binding protein, β-actin, F-actin, capping protein α-1 subunit (CapZa-1), albumin, ghistamine receptor, protein disulphide-isomerase ER60 precursor, mitochondrial aldehyde dehydrogenase (ALDH2), BiP (GRP78), HSP90 or GSK3β. 
     
     
         4 . The epitope and/or nucleic acid for use of  claim 2 , wherein the epitope is derived from vimentin. 
     
     
         5 . The epitope and/or nucleic acid for use of  claim 3 , wherein the epitope is deiminated. 
     
     
         6 . The epitope and/or nucleic acid for use of  claim 4 , wherein the epitope comprises at least one of the following sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 55) 
                 
                     
                   YVTTSTRTYSLGSALR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 57) 
                 
                     
                   VRLRSSVPG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 58) 
                 
                     
                     RLRSSVPG V, 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 60) 
                 
                     
                   FSSLNLRET, 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein one or more of the R residues is substituted for citrulline. 
       
     
     
         7 . The epitope and/or nucleic acid for use of  claim 6 , wherein the epitope comprises at least one of the following sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 98) 
                 
                     
                   RS YVTTSTRTYSLGSALR PSTS (vim28-49), 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 59) 
                 
                     
                   SA VRLRSSVPG VR (vim65-77) 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 61) 
                 
                     
                   LPN FSSLNLRET NLDSLPL (vim415-433). 
                 
             
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         8 . The epitope and/or nucleic acid for use of  claim 4 , wherein the epitope comprises at least one of the following sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 62) 
                 
                     
                     R SSVPGV R L, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 63) 
                 
                     
                   SAV R L R SSV, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 64) 
                 
                     
                   AT R SSAV R L, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 65) 
                 
                     
                   YAT R SSAV R LRSSVPGV R L (vim 61-79), 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 66) 
                 
                     
                     R SSVPGV R L, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 67) 
                 
                     
                   GV R LLQDSV, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 68) 
                 
                     
                     R L R SSVPGV R LLQDSVDFS (vim 69-87), 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 69) 
                 
                     
                   QLKGQGKS R , 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 70) 
                 
                     
                   KS R LGDLYE, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 71) 
                 
                     
                   EQLKGQGKS R LGDLYEEEM (vim 125-154), 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 72) 
                 
                     
                   EL RR QVDQL, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 73) 
                 
                     
                   EM R EL RR QV, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 74) 
                 
                     
                   DLYEEEM R EL RR QVDQLTN (vim 148-166), 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 75) 
                 
                     
                   QLTNDKA R V, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 76) 
                 
                     
                   VEVE R DNLA, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 77) 
                 
                     
                   LTNDKA R VE, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 78) 
                 
                     
                   VDQLTNDKA R VEVE R DNLA (vim 161-179), 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 79) 
                 
                     
                   EVE R DNLAE, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 80) 
                 
                     
                   NDKA R VEVE R DNLAEDIM R  (vim 166-184), 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 81) 
                 
                     
                   IM R L R EKLQ, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 82) 
                 
                     
                   DNLAEDIM R L R EKLQEEML (vim 176-194), 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 83) 
                 
                     
                   Q R EEAENTL, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 84) 
                 
                     
                   KLQEEMLQ R , 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 85) 
                 
                     
                   EKLQEEMLQ R EEAENTLQS (vim 187-205), 
                 
                     
                   and/or 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 86) 
                 
                     
                   F R QDVDNAS, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 87) 
                 
                     
                   ENTLQSF R Q, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 88) 
                 
                     
                   EAENTLQSF R QDVDNASLA (vim 198-216), 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein one or more of the R residues is substituted for citrulline. 
       
     
     
         9 . The epitope and/or nucleic acid of  claim 4 , wherein the nucleic acid encodes full length vimentin. 
     
     
         10 . The epitope and/or nucleic acid for use of  claim 2 , wherein the epitope comprises a sequence selected from: 
       
         
           
                 
               
                   (SEQ ID NO: 1) 
                 
                   IQKLYGKRS, preferably 
                 
                     
                 
                   (SEQ ID NO: 2) 
                 
                   SQDDIKG IQKLYGKRS  (MMP7-247), 
                 
                     
                 
                   (SEQ ID NO: 3) 
                 
                   NILTIRLTAA, preferably 
                 
                     
                 
                   (SEQ ID NO: 4) 
                 
                   PGVLLKEFTVSG NILTIRLTAA DHR (NYESO-1-119), 
                 
                     
                 
                   (SEQ ID NO: 5) 
                 
                   ILTIRLTAA, preferably 
                 
                     
                 
                   (SEQ ID NO: 4) 
                 
                   PGVLLKEFTVSG NILTIRLTAA DHR (NYESO-1-119), 
                 
                     
                 
                   (SEQ ID NO: 6) 
                 
                   EIRELQSQ, preferably 
                 
                     
                 
                   (SEQ ID NO: 7) 
                 
                   EE EIRELQSQI SDTSVVLS (cytokeratin 8 229-247), 
                 
                     
                 
                   (SEQ ID NO: 8) 
                 
                   AKQDMARQLREYQEL, preferably 
                 
                     
                 
                   (SEQ ID NO: 9) 
                 
                     AKQDMARQLREYQEL MNVKL (cytokeratin 8: 363-382), 
                 
                     
                 
                   (SEQ ID NO: 10) 
                 
                   AKQDMARQ, preferably 
                 
                     
                 
                   (SEQ ID NO: 11) 
                 
                   LQR AKQDMARQ LREYQELM (cytokeratin 8: 360-378), 
                 
                     
                 
                   (SEQ ID NO: 12) 
                 
                   ISSSSFSRV, preferably 
                 
                     
                 
                   (SEQ ID NO: 13) 
                 
                   PGSR ISSSSFSRV GSS (cytokeratin 8: 29-44), 
                 
                     
                 
                   (SEQ ID NO: 14) 
                 
                   PRAFSSRS, preferably 
                 
                     
                 
                   (SEQ ID NO: 15) 
                 
                   STSG PRAFSSRS YTSGPG (cytokeratin 8: 13-30), 
                 
                     
                 
                   (SEQ ID NO: 16) 
                 
                   EAALQRAKQ, preferably 
                 
                     
                 
                   (SEQ ID NO: 17) 
                 
                   EL EAALQRAKQ DMARQL (cytokeratin 8: 355-371), 
                 
                     
                 
                   (SEQ ID NO: 18) 
                 
                   LEVDPNIQAVRTQE, preferably 
                 
                     
                 
                   (SEQ ID NO: 19) 
                 
                     LEVDPNIQAVRTQE KEQI (cytokeratin 8: 78-95), 
                 
                   and 
                 
                     
                 
                   (SEQ ID NO: 20) 
                 
                   QKKLKLVRT, preferably 
                 
                     
                 
                   (SEQ ID NO: 21) 
                 
                   A QKKLKLVRT SPEYGMP (ING4 158-174)  
                 
                     
                 
                   (SEQ ID NO: 22) 
                 
                   LKLVRTSPE, preferably 
                 
                     
                 
                   (SEQ ID NO: 21) 
                 
                   AQKK LKLVRTSPE YGMP (ING4 158-174)  
                 
                     
                 
                   (SEQ ID NO: 23) 
                 
                   KKLKLVRTS, preferably 
                 
                     
                 
                   (SEQ ID NO: 21) 
                 
                     AQKKLKLVRTS PEYGMP (ING4 158-174)  
                 
                     
                 
                   (SEQ ID NO: 24) 
                 
                   YMSSARSLS, 
                 
                     
                 
                   (SEQ ID NO: 25) 
                 
                   MSSARSLSS 
                 
                   or 
                 
                     
                 
                   (SEQ ID NO: 26) 
                 
                   TEYMSSARS, preferably 
                 
                     
                 
                   (SEQ ID NO: 27) 
                 
                   KLATEYMSSARSLSSEEK (ING4 44-58) 
                 
                     
                 
                   (SEQ ID NO: 28) 
                 
                   FDLFENRKK, preferably 
                 
                     
                 
                   (SEQ ID NO: 29) 
                 
                   RAPFDLFENRKKKNN (HSP90-346-360) 
                 
                     
                 
                   (SEQ ID NO: 30) 
                 
                   YLNFIRGVV 
                 
                   or 
                 
                     
                 
                   (SEQ ID NO: 31) 
                 
                   FIRGVVDSE, preferably 
                 
                     
                 
                   (SEQ ID NO: 32) 
                 
                   IPEYLNFIRGVVDSE (HSP90-378-392), 
                 
                     
                 
                   (SEQ ID NO: 33) 
                 
                   LRYYTSASG, 
                 
                     
                 
                   (SEQ ID NO: 34) 
                 
                   LLRYYTSAS 
                 
                   or 
                 
                   (SEQ ID NO: 35) 
                 
                   LSELLRYYT, preferably 
                 
                     
                 
                   (SEQ ID NO: 36) 
                 
                   RKKLSELLRYYTSASGDEMVSL (HSP90-456-477)  
                 
                     
                 
                   (SEQ ID NO: 37) 
                 
                   RRRLSELLRYHTSQS (HSP90 beta 456-460), 
                 
                     
                 
                   (SEQ ID NO: 38) 
                 
                   VGVFKNGRV 
                 
                   or 
                 
                     
                 
                   (SEQ ID NO: 39) 
                 
                   FKNGRVEII, preferably 
                 
                     
                 
                   (SEQ ID NO: 40) 
                 
                   YSCVGVFKNGRVEII (BiP39-53), 
                 
                     
                 
                   (SEQ ID NO: 41) 
                 
                   YFNDAQRQA, preferably 
                 
                     
                 
                   (SEQ ID NO: 42) 
                 
                   VPAYFNDAQRQATKDA (BiP 172-186), 
                 
                     
                 
                   (SEQ ID NO: 43) 
                 
                   VTFEIDVNG, preferably 
                 
                     
                 
                   (SEQ ID NO: 44) 
                 
                   EVTFEIDVNGILRVT (BiP 497-511), 
                 
                     
                 
                   (SEQ ID NO: 45) 
                 
                   ITNDQNRLT, preferably 
                 
                     
                 
                   (SEQ ID NO: 46) 
                 
                   KITITNDQNRLTPEE (BiP 522-536), 
                 
                     
                 
                   (SEQ ID NO: 47) 
                 
                   LQIVARLKN 
                 
                   or 
                 
                     
                 
                   (SEQ ID NO: 48) 
                 
                   VARLKNNNR, preferably 
                 
                     
                 
                   (SEQ ID NO: 49) 
                 
                   NCALQIVARLKNNNR (CXCL12-54-68)  
                 
                     
                 
                   (SEQ ID NO: 50) 
                 
                   VEIIATMKK 
                 
                   or 
                 
                     
                 
                   (SEQ ID NO: 51) 
                 
                   RVEIIATMK, preferably 
                 
                     
                 
                   (SEQ ID NO: 52) 
                 
                   CPRVEIIATMKKKGE (CXCL 1057-71), 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein one or more of the R residues is substituted for citrulline. 
       
     
     
         11 . An epitope comprising the sequence YVTTSTRTYSLGSALR (SEQ ID NO: 55), optionally comprising the sequence RSYVTTSTRTYSLGSALRPSTS (vim28-49) (SEQ ID NO: 56), and/or a nucleic acid encoding such an epitope, for use in a method of treating cancer. 
     
     
         12 . The epitope and/or nucleic acid for use of  claim 2 , wherein the cancer is melanoma, breast, endometrial, colorectal or ovarian cancer. 
     
     
         13 . An epitope comprising the sequence FSSLNLRET (SEQ ID NO: 60), optionally comprising the sequence LPNFSSLNLRETNLDSLPL (vim415-433) (SEQ ID NO: 61), and/or a nucleic acid encoding such an epitope, for use in a method of treating autoimmune disease. 
     
     
         14 . The epitope and/or nucleic acid for use of  claim 2 , wherein the use is human or veterinary use. 
     
     
         15 . A peptide comprising, consisting essentially of or consisting of the amino acid sequence YVTTSTcitTYSLGSALcit (SEQ ID NO: 53), optionally comprising, consisting essentially of or consisting of the amino acids the sequence citSYVTTSTcitTYSLGSALcitPSTS (vim28-49) (SEQ ID NO: 54), wherein cit represents citrulline. 
     
     
         16 . A modified epitope which stimulates an IL-10 immune reaction against self-antigens for use in medicine, the epitope having a modification selected from deimination of arginine to citrulline, nitration of tyrosine, oxidation of tryptophan and deamination of glutamine or asparagine. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled)