TARGET PEPTIDES FOR IMMUNOTHERAPY AND DIAGNOSTICS

• US 20150224182A1
• Filed: 09/03/2013
• Published: 08/13/2015
• Est. Priority Date: 08/31/2012
• Status: Active Grant

• Current Assignee: University of Birmingham
• Original Assignee: UVA Licensing & Ventures Group
• Inventors: Hunt, Donald F., Shabanowitz, Jeffrey, Engelhard, Victor H., Cummings, Kara L., Cobbold, Mark, Malaker, Stacy A., Zarling, Angela, Obeng, Rebecca C.
• Granted Patent: US 9,561,266 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2039/57 characterised by the type of response, e.g. Th1, Th2
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2239/48 Blood cells, e.g. leukemia or lymphoma
• CPC Class Codes: A61K 2239/57 Skin; melanoma
• CPC Class Codes: A61K 35/15 Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/001106 Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
• CPC Class Codes: A61K 39/00111 Hepatocyte growth factor receptor [HGFR or c-met]
• CPC Class Codes: A61K 39/001113 CD22, BL-CAM, siglec-2 or sialic acid- binding Ig-related lectin 2
• CPC Class Codes: A61K 39/001132 Fibroblast growth factors [FGF]
• CPC Class Codes: A61K 39/001151 p53
• CPC Class Codes: A61K 39/001156 Tyrosinase and tyrosinase related proteinases [TRP-1 or TRP-2]
• CPC Class Codes: A61K 39/001157 Telomerase or TERT [telomerase reverse transcriptase]
• CPC Class Codes: A61K 39/001162 Kinases, e.g. Raf or Src
• CPC Class Codes: A61K 39/001164 GTPases, e.g. Ras or Rho
• CPC Class Codes: A61K 39/001166 Adhesion molecules, e.g. NRCAM, EpCAM or cadherins
• CPC Class Codes: A61K 39/001181 Alpha-feto protein
• CPC Class Codes: A61K 39/001182 Carcinoembryonic antigen [CEA]
• CPC Class Codes: A61K 39/001184 : Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
• CPC Class Codes: A61K 39/001186 : MAGE
• CPC Class Codes: A61K 39/001188 : NY-ESO
• CPC Class Codes: A61K 39/001189 : PRAME
• CPC Class Codes: A61K 39/00119 : Melanoma antigens
• CPC Class Codes: A61K 39/001192 : Glycoprotein 100 [Gp100]
• CPC Class Codes: A61K 39/001193 : Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
• CPC Class Codes: A61K 39/001194 : Prostate specific antigen [PSA]
• CPC Class Codes: A61K 39/001195 : Prostate specific membrane antigen [PSMA]
• CPC Class Codes: A61K 39/001197 : Breakpoint cluster region-abelson tyrosine kinase [BCR-ABL]
• CPC Class Codes: A61K 39/4611 : T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4615 : Dendritic cells
• CPC Class Codes: A61K 39/4622 : Antigen presenting cells
• CPC Class Codes: A61K 39/46449 : Melanoma antigens
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2833 : against MHC-molecules, e.g. HLA-molecules
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: G01N 33/57496 : involving intracellular compounds
• CPC Class Codes: G01N 33/6863 : Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors

Abstract

A set of target peptides are presented by HLA A*0101, A*0201, A*0301, B*4402, B*2705, B*1402, and B*0702 on the surface of disease cells. They are envisioned to among other things (a) stimulate an immune response to the proliferative disease, e.g., cancer, (b) to function as immunotherapeutics in adoptive T cell therapy or as a vaccine, (c) facilitate antibody recognition of tumor boundaries in surgical pathology samples, (d) act as biomarkers for early detection and/or diagnosis of the disease, and (e) act as targets in the generation antibody-like molecules which recognize the target-peptide/MHC complex.

Claims

1. A composition comprising at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more synthetic target peptides, each of which is at least or about 8, 9, 10, 11, 12, 13, 14, or 15 amino acids long, comprising:

a first peptide comprising a sequence selected from the group consisting of SEQ ID NO;

398, SEQ ID NO;

2000, SEQ ID NO;

2001, and SEQ ID NO;

2002; and

/or

a second peptide comprising a sequence selected from the group consisting of SEQ ID NO;

418, SEQ ID NO;

2062, and SEQ ID NO;

2063; and

/or

an optional third peptide comprising a sequence selected from the group consisting of SEQ ID NO;

427;

SEQ ID NO;

2078, SEQ ID NO;

2079, SEQ ID NO;

2080, SEQ ID NO;

2081, SEQ ID NO;

2082, SEQ ID NO;

2083, and SEQ ID NO;

2084; and

/or

an optional fourth peptide selected from the group consisting of GLLGpSPVRA (SEQ ID NO;

396; and

SEQ ID NO;

1996; and

/or

an optional fifth peptide from the group consisting of VMIGsPKKV (SEQ ID NO;

     426) and (SEQ ID NO;

     2077);

wherein said composition has the ability to stimulate an T cell mediated immune response to said first, second and/or third peptides; and

optionally wherein the composition is capable of eliciting a memory T cell response to said first, second and/or third peptides.

2. The composition of claim 1, wherein the first peptide is SEQ ID NO:

398.

3. The composition of claim 1, wherein the second peptide is SEQ ID NO:

2080.

4. The composition of claim 1, wherein the third peptide is SEQ ID NO:

418.

5. The composition of claim 1, wherein at least one serine residue in any of the peptides is replaced with a homo-serine.

6. The composition of claim 1, wherein the composition comprises a non-hydrolyzable phosphate.

7. The composition of claim 1, wherein at least one of the peptides binds MHC class I at least 500% more tightly than its native counterpart.

8. The composition of claim 1, wherein at least one of the peptides is capable of eliciting more activated CD8⁺ T cells specific for MHC class I molecule complexed with the phosphopeptide of SEQ ID NO:

427 than a control composition comprising the same peptides wherein SEQ ID NO;

427 is used rather than SEQ ID NO;

2080.

9. The composition of claim 1, wherein the composition is at least 100% more immunogenic than a control composition comprising the same peptides wherein SEQ ID NO:

427 is used rather than SEQ ID NO;

2080.

10. The composition of claim 1, wherein the composition is capable of reducing tumor size in a NOD/SCID/IL-2Ryc−

/−

mouse comprising transgenic T cells specific for human beta-catenin phosphopeptides such as SEQ ID NO;

427, by at least 30% compared to a control composition comprising the same peptides wherein SEQ ID NO;

427 is used rather than SEQ ID NO;

2080.

11. The composition of claim 1, wherein the composition is immunologically suitable for at least 60 to 88% of melanoma patients.

12. The composition of claim 1, wherein the composition comprises at least 5 different peptides.

13. The composition of claim 1, wherein the composition comprises at least 10 different peptides.

14. The composition of claim 1, wherein the composition comprises at least 15 different peptides.

15. The composition of claim 1, comprising a peptide capable of binding to an MHC class I molecule selected from the group consisting of HLA-A*0201, HLA-A*0101, HLA-A*0301, HLA-B*4402, HLA-B*0702, HLA-B*-2705 and HLA-B*1402.

16. The composition of claim 1, comprising a peptide capable of binding to an MHC class I molecule selected from the group consisting of HLA-A*0101, HLA-A*0301, HLA-B*4402, HLA-B*0702, HLA-B*-2705 and HLA-B*1402.

17. The composition of claim 1, comprising a peptide capable of binding to an MHC class I molecule of the HLA-A*0201, HLA-A*0101 or HLA-B*0702 alleles.

18. The composition of claim 1, wherein the composition is capable of increasing the 5-year survival rate of malignant melanoma patients treated with the composition by at least 20 percent relative to average 5-year survival rates that could have been expected without treatment with the composition.

19. The composition of claim 1, wherein the composition is capable of increasing the survival rate of malignant melanoma patients treated with the composition by at least 20 percent relative to a survival rate that could have been expected without treatment with the composition.

20. The composition of claim 1, wherein the composition is capable of increasing the treatment response rate of malignant melanoma patients treated with the composition by at least 20 percent relative to a treatment rate that could have been expected without treatment with the composition.

21. The composition of claim 1, wherein the composition is capable of increasing the overall median survival of patients of malignant melanoma patients treated with the composition by at least two months relative to an overall median survival that could have been expected without treatment with the composition.

22. The composition of claim 1, comprising at least one peptide derived from MelanA (MART-I), gp100 (Pmel 17), tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15(58), CEA, RAGE, NY-ESO (LAGE), SCP-1, Hom/Mel-40, PRAME, p53, H-Ras, HER-2/neu, BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, β

-Catenin, CDK4, Mum-1, p16, TAGE, PSMA, PSCA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, alpha-fetoprotein, β

-HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associated protein), TAAL6, TAG72, TLP and TPS.

23. The composition of claim 1, comprising an agent selected from the group consisting of anti-CTLA-4, vermurafenib, ipilimumab, dacarbazine, IL-2, temozolomide, imatinib, gefitinib, erlotinib, sunitinib, tyrphostins and telatinib.

24. The composition of claim 1, further comprising darcarbazine, carmustine and tamoxifen.

25. The composition of claim 1, wherein the composition comprises an adjuvant selected from the group consisting of montanide ISA-51 (Seppic, Inc.), QS-21 (Aquila Pharmaceuticals, Inc.), tetanus helper peptides, GM-CSF, cyclophosamide, bacillus Calmette-Guerin (BCG), corynbacterium parvum, levamisole, azimezone, isoprinisone, dinitrochlorobenezene (DNCB), keyhole limpet hemocyanins (KLH), Freunds adjuvant (complete and incomplete), mineral gels, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, diphtheria toxin (DT).

26. An in vitro population of dendritic cells comprising the compositions of any one of claims 1-25 or a composition comprising at least one target peptide.

27. An in vitro population of CD8⁺ T cells capable of being activated upon being brought into contact with a population of dendritic cells, wherein the dendritic cells comprise the compositions of any one of claims 1-25 or a composition comprising at least one target peptide.

34. A method of treating or preventing cancer comprising administering to a patient in need thereof a dose of the composition of any of claims 1-25 or a composition comprising at least one target peptide.

35. A method of treating or preventing melanoma comprising administering to a patient in need thereof a dose of the composition of any of claims 1-25 or a composition comprising at least one target peptide in combination with a pharmaceutically acceptable carrier.

36. A method of treating or preventing cancer comprising administering to a patient in need thereof a dose of the CD8⁺ T cells of claim 27 in combination with a pharmaceutically acceptable carrier.

37. A method of treating or preventing cancer comprising administering to a patient in need thereof the population of the dendritic cells of claim 26 in combination with a pharmaceutically acceptable carrier.

39. A method making a cancer vaccine comprising combining the composition of any of claims 1-25 (or any composition with at least one target peptide) with an agent of claim 23, the adjuvant of claim 25 and a pharmaceutically acceptable carrier;

and placing the composition, adjuvant and pharmaceutical carrier into a syringe into a syringe.

40. A method of screening target peptides for inclusion in an immunotherapy composition or for use in the method of claim 39 comprising:

(a) administering the target peptide to a human;

(b) determining whether the target peptide is capable of inducing a target peptide-specific memory T cell response in the human; and

(c) selecting the target peptide for inclusion in an immunotherapy composition if the target peptide elicits a memory T cell response in the human.

44. The kit of claim 42, wherein the at least one target peptide composition is a compositions of any of claims 1-25.

28. An antibody or antibody-like molecule that specifically binds to both a first complex of MHC class I molecule and a peptide represented by SEQ ID NO:

2080 and a second complex of MHC class I molecule and a peptide represented by SEQ ID NO;

427;

wherein the antibody or antibody-like molecule does not bind the same complexes containing an unphosphorylated version of SEQ ID NO;

2080 or SEQ ID NO;

427.

29. The antibody or antibody-like molecule of claim 28, wherein the antibody or antibody-like molecule is a member of the immunoglobulin superfamily.

30. The antibody or antibody-like molecule of claim 28, wherein the antibody or antibody-like molecule comprises a binding member selected from the group consisting an Fab, Fab′

, F(ab′

)₂, Fv, and a single-chain antibody.

31. The antibody or antibody-like molecule of claim 28, comprising a therapeutic agent selected from the group consisting of an alkylating agent, an antimetabolite, a mitotic inhibitor, a taxoid, a vinca alkaloid and an antibiotic.

32. The antibody or antibody-like molecule of claim 28, wherein the antibody or antibody-like molecule is a T cell receptor, optionally linked to a CD3 agonist.

33. An in vitro population of T cells transfected with mRNA encoding the T cell receptors of claim 32.

38. A method of treating or preventing cancer comprising administering to a patient in need thereof the population T cells of claim 33 in combination with a pharmaceutically acceptable carrier.

41. A method of determining the prognosis of a cancer patient comprising:

(a) administering a target peptide associated with the patient'"'"'s cancer to the cancer patient;

(b) determining whether the target peptide is capable of inducing a target peptide-specific memory T cell response in the cancer patient; and

(c) determining that the cancer patient has a better prognosis if the cancer patient mounts a memory T cell response to said target peptide than if the cancer patient did not mount a memory T cell response to said target peptide.

42. A kit comprising at least one target peptide composition comprising at least one target peptide and a cytokine and/or an adjuvant.

43. The kit of claim 42, comprising at least 2, 3, 4, or 5 target peptide compositions.

45. The kit of claim 42, wherein the cytokine is selected from the group consisting of transforming growth factors (TGFs) such as TGF-alpha and TGF-beta;

insulin-like growth factor-I and -II;

erythropoietin (EPO);

osteoinductive factors;

interferons such as interferon-alpha -beta, and -gamma;

colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF);

granulocyte-macrophage-CSF (GM-CSF); and

granulocyte-CSF (G-CSF).

46. The kit of claim 42, further comprising an agent selected from the group consisting of anti-CTLA-4, vermurafenib, ipilimumab, dacarbazine, IL-2, temozolomide, imatinib, gefitinib, erlotinib, sunitinib, tyrphostins and telatinib.

47. The kit of claim 42 wherein the adjuvant selected from the group consisting of montanide ISA-51 (Seppic, Inc.), QS-21 (Aquila Pharmaceuticals, Inc.), tetanus helper peptides, GM-CSF, cyclophosamide, bacillus Calmette-Guerin (BCG), corynbacterium parvum, levamisole, azimezone, isoprinisone, dinitrochlorobenezene (DNCB), keyhole limpet hemocyanins (KLH), Freunds adjuvant (complete and incomplete), mineral gels, aluminum hydroxide (Alum), lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, diphtheria toxin (DT).

48. The kit of claim 42, wherein the cytokine is selected from the group consisting of nerve growth factors such as NGF-beta;

platelet-growth factor;

transforming growth factors (TGFs) such as TGF-alpha and TGF-beta;

insulin-like growth factor-I and -II;

erythropoietin (EPO);

osteoinductive factors;

interferons such as interferon-alpha -beta, and -gamma;

colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF);

granulocyte-macrophage-CSF (GM-CSF); and

granulocyte-CSF (G-CSF);

interleukins (Ils) such as IL-1, IL-1alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12;

IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, LIF, G-CSF, GM-CSF, M-CSF, EPO, kit-ligand or FLT-3, angiostatin, thrombospondin, endostatin, tumor necrosis factor and LT.

49. The kit of claim 42, further comprising at least one peptide derived from MelanA (MART-I), gp100 (Pmel 17), tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, p15(58), CEA, RAGE, NY-ESO (LAGE), SCP-1, Hom/Mel-40, PRAME, p53, H-Ras, HER-2/neu, BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, β

-Catenin, CDK4, Mum-1, p16, TAGE, PSMA, PSCA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, alpha-fetoprotein, β

-HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding protein\cyclophilin C-associated protein), TAAL6, TAG72, TLP and TPS.

50. The kit of claim 42, wherein the at least one target peptide is selected from the SEQ ID Nos:

1-2167.

51. The kit of claim 42, wherein the at least one target peptide composition comprises target peptides is selected from the HLA groupings shown in Tables 14 and 15.