NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY AGAINST VARIOUS TUMORS
The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.
1 . A peptide consisting of the amino acid sequence of SEQ ID No. 155; or a pharmaceutical acceptable salt of said peptide, or an MHC complex of said peptide or pharmaceutical acceptable salt of said peptide.
2 . The peptide according to claim 1 , wherein said peptide is modified and/or includes non-peptide bonds.
3 . The peptide according to claim 1 , wherein said peptide is part of a fusion protein.
4 . The peptide according to claim 3 , wherein said fusion protein comprises the N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii).
5 . The peptide according to claim 1 , wherein the pharmaceutical acceptable salt is a chloride salt or acetate salt.
6 . A Method for identifying a TCR that specifically binds to the peptide according to claim 1 when bound to HLA, said method comprising:
a) incubating PBMCs from HLA-A*02-negative healthy donors with monomers of HLA-A2 and the peptide according to claim 1 , and incubating said PBMCs with tetramer-phycoerythrin (PE), or
immunizing a transgenic mouse comprising the entire human TCRαβ gene loci, and being deficient of mouse TCRs, whose T-cells express a diverse human TCR repertoire with the peptide according to claim 1 , isolating PBMCs obtained from said transgenic mouse with tetramer-phycoerythrin (PE),
b) isolating said T-cells by fluorescence activated cell sorting (FACS)—Calibur analysis, and
c) identifying a TCR that specifically binds to the peptide according to claim 1 when bound to HLA.
7 . The method according to claim 6 , further comprising the step of identifying the TCR as identified as a TCR with high avidity for the peptide according to claim 1 when bound to HLA.
8 . The method according to claim 6 , further comprising the step of producing the TCR as identified, comprising suitable culturing of a recombinant host cell expressing said TCR as identified, and isolating said TCR from said host cell and/or its culture medium.
9 . An antibody that specifically binds to a human major histocompatibility complex (MHC) complexed with the peptide according to claim 1 .
10 . The antibody according to claim 9 wherein the antibody is a polyclonal antibody, monoclonal antibody, bi-specific antibody and/or a chimeric antibody.
11 . A pharmaceutical composition comprising the peptide according to claim 1 .
12 . The pharmaceutical composition according to claim 11 , wherein the pharmaceutically acceptable carrier is selected from the group consisting of saline, Ringer's solution and dextrose solution.
13 . The pharmaceutical composition according to claim 11 , comprising additional pharmaceutically acceptable excipients and/or stabilizers.
14 . The pharmaceutical composition according to claim 13 , wherein said additional pharmaceutically acceptable excipients are selected from the group consisting of buffers, binding agents, blasting agents, diluents, flavors, and lubricants.
15 . The pharmaceutical composition according to claim 11 , wherein said pharmaceutical composition is a vaccine.
16 . A method of treating cancer in a patient comprising administering the pharmaceutical composition according to claim 11 to said patient.
17 . The method according to claim 16 wherein said administering is by intravenous, intraperitoneal, subcutaneous or intramuscular injection or infusion.
18 . The method according to claim 16 , wherein the cancer is selected from the group consisting of HCC, CRC, GB, GC, esophageal cancer, NSCLC, PC, RCC, BPH/PCA, OC, MCC, melanoma, breast cancer, SCLC, NHL, AML, GBC, CCC, UBC, UEC, and CLL.
19 . A kit comprising the pharmaceutical composition according to claim 11 .
20 . The kit according to claim 19 further comprising a second compound selected from the group consisting of an adjuvant, a chemotherapeutic agent, a natural product, a hormone or antagonist, an anti-angiogenesis agent or inhibitor, an apoptosis-inducing agent, a chelator, or a pharmaceutical composition thereof.