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 comprising SEQ ID No. 245, and variant sequences thereof which are at least 88% homologous to SEQ ID No. 245, and wherein said variant binds to molecule(s) of the major histocompatibility complex (MHC) and/or induces T cells cross-reacting with said variant peptide; and a pharmaceutical acceptable salt thereof, wherein said peptide is not a full-length polypeptide.
2 . The peptide according to claim 1 , wherein said peptide has the ability to bind to an MHC class-I or -II molecule, and wherein said peptide, when bound to said MHC, is capable of being recognized by CD4 and/or CD8 T cells.
4 . The peptide or variant thereof according to claim 1 , wherein said peptide or variant thereof has an overall length of from 8 to 100 amino acids.
5 . The peptide or variant thereof according to claim 1 , wherein the peptide consists or consists essentially of SEQ ID No. 245.
6 . The peptide or variant thereof according to claim 1 , wherein said peptide is modified and/or includes non-peptide bonds.
7 . The peptide or variant thereof according to claim 1 , wherein said peptide is part of a fusion protein, and wherein the fusion protein optionally comprises N-terminal amino acids of the HLA-DR antigen-associated invariant chain (Ii).
8 . A nucleic acid, encoding a peptide or variant thereof according to claim 1 , wherein the nucleic acid is optionally linked to a heterologous promoter sequence.
9 . An expression vector expressing the nucleic acid according to claim 8 .
10 . A recombinant host cell comprising the peptide according to claim 1 .
11 . A recombinant host cell comprising the nucleic acid according to claim 8 .
12 . A recombinant host cell comprising the expression vector according to claim 9 , wherein said host cell is optionally an antigen presenting cell.
13 . A method for producing a peptide comprising SEQ ID No. 245 or variant thereof, the method comprising culturing the host cell according to claim 10 , and isolating the peptide or variant thereof from the host cell or its culture medium.
14 . An in vitro method for producing activated T lymphocytes, the method comprising contacting in vitro T cells with antigen loaded human class I or II MHC molecules expressed on the surface of a suitable antigen-presenting cell or an artificial construct mimicking an antigen-presenting cell for a period of time sufficient to activate said T cells in an antigen specific manner, wherein said antigen is a peptide according to claim 1 .
15 . An antibody, that specifically recognizes the peptide or variant thereof according to claim 1 , optionally wherein the antibody is a soluble or membrane-bound antibody.
16 . The antibody of claim 15 , wherein the antibody specifically recognizes the peptide or variant thereof according to claim 1 when bound to an MHC molecule.
17 . A method of using a peptide according to claim 1 for the treatment of cancer or in the manufacture of a medicament against cancer.
18 . The method according to claim 17 , wherein said cancer is selected from the group of hepatocellular carcinoma (HCC), colorectal carcinoma (CRC), glioblastoma (GB), gastric cancer (GC), esophageal cancer, non-small cell lung cancer (NSCLC), pancreatic cancer (PC), renal cell carcinoma (RCC), benign prostate hyperplasia (BPH), prostate cancer (PCA), ovarian cancer (OC), melanoma, breast cancer, chronic lymphocytic leukemia (CLL), Merkel cell carcinoma (MCC), small cell lung cancer (SCLC), Non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), gallbladder cancer and cholangiocarcinoma (GBC, CCC), urinary bladder cancer (UBC), uterine cancer (UEC), and other tumors that show an overexpression of a protein from which a peptide of SEQ ID No. 245 is derived from.
19 . A soluble or membrane-bound T-cell receptor that is reactive with an HLA ligand, wherein said ligand has at least 75% identity to SEQ ID No. 245.
20 . The T-cell receptor according to claim 19 , wherein said amino acid sequence is at least 88% identical to SEQ ID No. 245.
21 . The T-cell receptor according to claim 19 , wherein said amino acid sequence consists of SEQ ID No. 245.
22 . A nucleic acid encoding a T-cell receptor according to claim 19 , optionally wherein the nucleic acid is linked to a heterologous promoter sequence.
23 . An expression vector expressing the nucleic acid according to claim 22 .
24 . A host cell comprising the nucleic acid according to claim 22 , wherein said host cell is optionally a T cell or NK cell.
25 . A method for producing a T cell receptor that is reactive with an HLA ligand, wherein said ligand has at least 75% identity to SEQ ID No. 245, said method comprising culturing a host cell according to claim 24 , and isolating said T cell receptor from said host cell and/or its culture medium.
26 . A pharmaceutical composition comprising at least one active ingredient selected from the group consisting of:
a) a peptide comprising SEQ ID No. 245 or variant, wherein said peptide or variant thereof has an overall length of from 8 to 100 amino acids;
b) a T-cell receptor reactive with a peptide and/or the peptide-MHC complex according to a);
c) a fusion protein comprising a peptide according to a), and the N-terminal amino acids 1 to 80 of the HLA-DR antigen-associated invariant chain (Ii);
d) a nucleic acid encoding for any of a) to c) or an expression vector comprising said nucleic acid;
e) a host cell comprising the expression vector of d;
f) an activated T-lymphocyte, obtained by a method comprising contacting in vitro T cells with a peptide according to a) expressed on the surface of a suitable antigen presenting cell for a period of time sufficient to activate said T cell in an antigen specific manner, as well as a method to transfer these activated T cells into the autologous or other patients;
g) an antibody, or soluble T-cell receptor, reactive to a peptide and/or the peptide-MHC complex according to a) and/or a cell presenting a peptide according to a), and potentially modified by fusion with for example immune-activating domains or toxins;
h) an aptamer recognizing a peptide of SEQ ID No. 245 and/or a complex of a peptide of SEQ ID No. 245 with a MHC molecule; and
i) a conjugated or labelled peptide or scaffold according to any of a) to h) and a pharmaceutically acceptable carrier, and optionally, pharmaceutically acceptable excipients and/or stabilizers.