JPWO2020002063A5

JPWO2020002063A5 -

Info

Publication number: JPWO2020002063A5
Application number: JP2020560739A
Authority: JP
Publication date: 2022-06-28

Claims

A peptide or pharmaceutically acceptable salt thereof comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 272, SEQ ID NO: 1 to SEQ ID NO: 226 and SEQ ID NO: 252 to SEQ ID NO: 27 1 . A peptide in which the peptide is less than 30 amino acids long and has the ability to bind to major histocompatibility complex (MHC) molecules and / or cross-react with T cells.

The peptide according to claim 1, or a pharmaceutical agent thereof, which has the ability to bind to an MHC class I or II molecule and becomes recognizable by CD4 and / or CD8 T cells when bound to the MHC. Acceptable salt .

The peptide according to claim 1 or 2 , wherein the peptide comprises a modified and / or non-peptide bond .

A fusion protein comprising the peptide according to any one of claims 1 to 3 , fused to 80 N -terminal amino acids of the HLA-DR antigen-related invariant chain (Ii).

Soluble antibody, membrane-bound antibody, or functional antibody fragment,
Any one of claims 1 to 3 when the peptide according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof is specifically recognized or bound to an MHC molecule. Specific recognition of the peptide described or a pharmaceutically acceptable salt thereof,
Soluble antibody, membrane-bound antibody, or fragment thereof, or
Soluble antibody, membrane-bound antibody, or functional antibody fragment,
Any one of claims 1 to 3 when the peptide according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof is specifically recognized or bound to an MHC molecule. Specific recognition of the peptide described or a pharmaceutically acceptable salt thereof
The antibody is at least one selected from monoclonal antibodies, human antibodies, humanized antibodies, bispecific antibodies, and / or chimeric antibodies.
Soluble antibody, membrane-bound antibody, or fragment thereof.

A T cell receptor or fragment thereof that reacts with an HLA ligand.
The ligand is the peptide according to any one of claims 1 to 3, which forms a complex with MHC molecule, or a pharmaceutically acceptable salt thereof.
T cell receptor or said fragment, or
A T cell receptor or fragment thereof that reacts with an HLA ligand.
The ligand is the peptide according to any one of claims 1 to 3, which forms a complex with MHC molecule, or a pharmaceutically acceptable salt thereof.
The T cell receptor is a soluble T cell receptor,
T cell receptor or said fragment.

The T cell receptor is provided as a soluble molecule and the antibody or T cell receptor further possesses an effector function, or the T cell receptor is provided as a soluble molecule and the antibody or T cell receptor is provided. In addition , it possesses an immunostimulatory domain or toxin effector function,
The antibody according to claim 5 or the T cell receptor according to claim 6 .

The peptide according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof , or the peptide according to any one of claims 1 to 3 bound to an MHC molecule. Is an aptamer that specifically recognizes its pharmaceutically acceptable salt .

The peptide according to any one of claims 1 to 3, the antibody or fragment thereof according to claim 5, the nucleic acid encoding the T cell receptor or fragment thereof according to claim 6, or the nucleic acid according to claims 1 to 3 . A nucleic acid encoding the peptide according to any one of the above, the antibody or fragment thereof according to claim 5 , and the T cell receptor or fragment thereof according to claim 6 , wherein the nucleic acid is heterologous. Nucleic acid linked to the promoter sequence.

An expression vector comprising the nucleic acid according to claim 9.

The peptide according to any one of claims 1 to 3, the antibody or fragment thereof according to claim 5, the T cell receptor or fragment thereof according to claim 6, the nucleic acid according to claim 9, or the claim. The recombinant host cell containing the expression vector according to claim 10, the peptide according to any one of claims 1 to 3 , the antibody according to claim 5 , or a fragment thereof, claim 6 . A recombinant host cell comprising the T cell receptor or fragment thereof, the nucleic acid according to claim 9 , or the expression vector according to claim 10 , wherein the host cell is an antigen-presenting cell. , T cells or NK cells , recombinant host cells.

Antigen-loaded human class I or II MHC molecules expressed on the surface of suitable antigen-presenting cells or on the surface of artificial constructs that mimic antigen-presenting cells for a time sufficient to activate the T cells in an antigen-specific manner. In vitro method for producing activated T lymphocytes, comprising the step of in vitro contacting T cells, wherein the antigen is the peptide according to any one of claims 1 to 3 .

Activated T lymphocytes that selectively recognize cells presenting the peptide according to any one of claims 1 to 3 .

The peptide according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, the fusion protein according to claim 4, the antibody according to claim 5 or 7, or a fragment thereof, claim 6 or 7. T cell receptor or fragment thereof, claim 8, nucleic acid according to claim 9, expression vector according to claim 10, recombinant host cell according to claim 11, or claim. Item 13: The active ingredient selected from the group consisting of activated T lymphocytes, or the conjugated or labeled active ingredient, and a pharmaceutically acceptable carrier, and / or pharmaceuticals. A pharmaceutical composition comprising a pharmaceutically acceptable excipient, or a peptide according to any one of claims 1 to 3 , or a pharmaceutically acceptable salt thereof , and a fusion protein according to claim 4. , The antibody or fragment thereof according to claim 5 or 7 , the T cell receptor or fragment thereof according to claim 6 or 7 , the aptamer according to claim 8 , the nucleic acid according to claim 9 . With at least one active ingredient selected from the group consisting of the expression vector of claim 10, the recombinant host cell of claim 11 or the activated T lymphocytes of claim 13. A pharmaceutical composition comprising the conjugated or labeled active ingredient, a pharmaceutically acceptable carrier, and / or a pharmaceutically acceptable excipient . A pharmaceutical composition, wherein is a vaccine or cell therapy composition.

The pharmaceutical composition further comprises an adjuvant, or
The pharmaceutical composition further comprises an adjuvant, the adjuvant being interleukin, or
The pharmaceutical composition further comprises an adjuvant, the adjuvant being interleukin, and the interleukin being IL-2 and / or IL-15.
The pharmaceutical composition according to claim 14.

The step of culturing the host cell according to claim 11 and the step of isolating the peptide , antibody or fragment thereof, or T cell receptor or fragment thereof from the host cell and / or its culture solution. The peptide according to any one of claims 1 to 3 , the antibody according to claim 5 or a fragment thereof, or the T cell receptor according to claim 6 or a fragment thereof. how to.

The peptide according to any one of claims 1 to 3 , or a pharmaceutically acceptable salt thereof , the fusion protein according to claim 4, the antibody according to claim 5 or 7, or a fragment thereof, claim. The T cell receptor or fragment thereof according to claim 6 or 7 , the aptamer according to claim 8 , the nucleic acid according to claim 9 , the expression vector according to claim 10, and the expression vector according to claim 11 . A pharmaceutical comprising the recombinant host cell of the above, or the activated T lymphocyte according to claim 13 .

A target cell killing agent comprising the activated T lymphocyte population as defined in claim 13, wherein the target cell presents the peptide according to any one of claims 1 to 3 . , Target cell killing agent .

The peptide according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof , the fusion protein according to claim 4, in the manufacture of a drug for diagnosing and / or treating cancer. 5. The antibody or fragment thereof according to claim 5 , the T cell receptor or fragment thereof according to claim 6 or 7 , the aptamer according to claim 8 , the nucleic acid according to claim 9 , claim 10. Use of the expression vector of claim 11 , the recombinant host cell of claim 11 , the activated T lymphocyte of claim 13, or the pharmaceutical composition of claim 14 or 15.

Acute myeloid leukemia, breast cancer, bile duct cells, wherein the cancer exhibits an overpresentation of a peptide comprising the amino acid sequences set forth in SEQ ID NOs: 272, SEQ ID NOs: 1-226 and SEQ ID NOs: 252 to 271. Cancer, Chronic lymphocytic leukemia, Colon-rectal cancer, Bile sac cancer, Glioblastoma, Gastric cancer, Hepatic cell cancer, Head and neck tonsillar cancer, Black tumor, Non-Hodgkin lymphoma, Lung cancer ( Non- small cell lung cancer) (Including adenocarcinoma, squamous cell non-small cell lung cancer, and small cell lung cancer), ovarian cancer, esophageal cancer, pancreatic cancer, prostate cancer, renal cell cancer, bladder cancer, uterus and endometrial 19. The use according to claim 19 , selected from the group of cancer and other tumors.

The peptide according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, the fusion protein according to claim 4, the antibody according to claim 5 or 7, or a fragment thereof, claim 6 or 7. The T cell receptor or fragment thereof, the aptamer of claim 8, the nucleic acid of claim 9, the expression vector of claim 10, the recombinant host cell of claim 11, the recombinant host cell of claim 11. A diagnostic and / or therapeutic agent for cancer comprising the activated T lymphocytes according to 13 or the pharmaceutical composition according to claim 14 or 15.

Acute myeloid leukemia, breast cancer, bile duct cells, wherein the cancer exhibits an overpresentation of a peptide comprising the amino acid sequences set forth in SEQ ID NOs: 272, SEQ ID NOs: 1-226 and SEQ ID NOs: 252 to 271. , Chronic lymphocytic leukemia, colorectal cancer, bile sac cancer, glioma, gastric cancer, hepatocellular carcinoma, head and neck tonsillar cancer, melanoma, non-hodgkin lymphoma, lung cancer (non-small cell lung cancer gland) Cancer, including squamous cell non-small cell lung cancer, and small cell lung cancer), ovarian cancer, esophageal cancer, pancreatic cancer, prostate cancer, renal cell cancer, bladder cancer, uterus and endometrial The cancer diagnostic and / or therapeutic agent of claim 21, selected from the group of cancers and other tumors.

(A) The peptide according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in a solution or a freeze-dried form, the fusion protein according to claim 4, the fusion protein according to claim 5 or 7 . The antibody or fragment thereof, the T cell receptor or fragment thereof according to claim 6 or 7 , the aptamer according to claim 8 , the nucleic acid according to claim 9 , and the expression according to claim 10. A container comprising a vector, the recombinant host cell of claim 11 or a pharmaceutical composition comprising the activated T lymphocytes of claim 13; and .
(B) A second container containing a diluent or reconstituted solution for the lyophilized formulation;
A kit that includes.

23. The kit of claim 23, further comprising one or more of the following:
(C) At least another peptide selected from the group consisting of SEQ ID NOs: 1 to 249 and SEQ ID NOs: 252 to 272, and
(D) One or more selected from the group consisting of (i) buffer, (ii) diluent, (iii) filter, (iv) needle, (v) syringe, or (vi) adjuvant.

a) With the step of identifying the tumor-related peptide (TUMAP) presented by the tumor sample from the individual patient;
b) The step of comparing the peptide identified in a) to a peptide reservoir preselected for immunogenicity and / or overpresentation in tumors in comparison to normal tissue, wherein the reservoir is SEQ ID NO: 272. With a reservoir containing peptides selected from the group consisting of SEQ ID NOs: 1 to 226 and SEQ ID NOs: 252 to 271 ;
c) With the step of selecting the peptide from the reservoir consistent with the TUMAP identified in the patient;
d) Compound-based and / or cell therapy for individual patients, comprising the steps of creating and / or prescribing personalized vaccines or compound-based and / or cell therapies based on step c). How to produce a personalized anti-cancer vaccine for.

25. The method of claim 25, comprising one or more selected from the group consisting of the following (1) to (4):
(1) The TUMAP is
a1) A step of comparing the expression data from the tumor sample with the expression data from the normal tissue sample corresponding to the histological type of the tumor sample to identify proteins that are overexpressed or abnormally expressed in the tumor sample. ;
a2) MHC derived from a protein overexpressed or abnormally expressed by the tumor by correlating the expression data with the sequence of MHC ligand bound to the MHC class I / or class II molecule in the tumor sample. Identified by the step of identifying the ligand ;
(2) The sequence of the MHC ligand is identified by eluting the binding peptide from the MHC molecule isolated from the tumor sample and sequencing the eluted ligand;
(3) The normal tissue corresponding to the histological type of the tumor sample is obtained from the same patient;
(4) The immunogenicity of the peptide contained in the reservoir is determined by a method comprising in vitro immunogenicity assay, MHC multimer staining, ELISPOT assay and / or intracellular cytokine staining.

The steps to identify at least one mutation specific to the tumor sample as compared to the normal corresponding tissue from the individual patient, and to include in the vaccine or to make a cell therapy agent . It further comprises, or includes, a step of selecting a peptide associated with the mutation.
The step of identifying at least one mutation specific to the tumor sample as compared to the normal corresponding tissue from the individual patient, and to include in the vaccine or to make a cytotherapeutic agent. It further comprises selecting a peptide associated with the mutation, and said at least one mutation is identified by whole genome sequencing.
25 or 26 .

Containing an activated T cell population that kills cancer cells presenting a peptide consisting of an amino acid sequence selected from SEQ ID NOs: 272, SEQ ID NOs: 1-226 and SEQ ID NOs: 252 to 271. , An immune response -inducing agent in patients with cancer, the cancers are acute myeloid leukemia, breast cancer, bile duct cell cancer, chronic lymphocytic leukemia, colon-rectal cancer, bile sac cancer, neuroglid. Tumors, gastric cancer, hepatocellular carcinoma, head and neck tonsillar cancer, melanoma, non-hodgkin lymphoma, lung cancer (including non-small cell lung cancer adenocarcinoma, squamous cell non-small cell lung cancer, and small cell lung cancer ) , An immune response inducer selected from ovarian cancer, esophageal cancer, pancreatic cancer, prostate cancer, renal cell cancer, bladder cancer, uterine cancer and endometrial cancer.

A peptide consisting of an amino acid sequence selected from SEQ ID NO: 272, SEQ ID NO: 1-226 and SEQ ID NO: 252 to SEQ ID NO: 271 in the manufacture of a drug for treating a patient with cancer is presented. The use of activated T cell populations that kill cells, said cancers are acute myeloid leukemia, breast cancer, bile duct cell cancer, chronic lymphocytic leukemia, colorectal cancer, bile sac cancer, nerves. Glioblastoma, gastric cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, melanoma, non-hodgkin lymphoma, lung cancer (including non-small cell lung cancer adenocarcinoma, squamous cell non-small cell lung cancer, and small cell lung cancer) , Selected from ovarian cancer, esophageal cancer, pancreatic cancer, prostate cancer, renal cell cancer, bladder cancer, uterine cancer and endometrial cancer, use.

Acute myeloid leukemia, breast cancer, bile duct cell cancer, chronic lymphocytic leukemia, colorectal cancer, bile sac cancer, glioblastoma, gastric cancer, hepatocellular carcinoma, head and neck oblate epithelial cancer, melanoma, Non-hodgkin lymphoma, lung cancer (including non-small cell lung cancer adenocarcinoma, squamous cell non-small cell lung cancer, and small cell lung cancer ) , ovarian cancer, esophageal cancer, pancreatic cancer, prostate cancer, renal cells A composition comprising a peptide in the form of a pharmaceutically acceptable salt for use in the treatment of cancer, bladder cancer, and / or uterine and endometrial cancer, wherein the peptide is sequenced . Consisting of an amino acid sequence selected from No. 272, SEQ ID NO: 1 to SEQ ID NO: 226 and SEQ ID NO: 252 to SEQ ID NO: 27 1 , the use thereof is acute myeloid leukemia, breast cancer, bile duct cell cancer, chronic lymphocytic leukemia. , Colon-rectal cancer, bile sac cancer, glioblastoma, gastric cancer, hepatocellular carcinoma, head and neck pancreatic epithelial cancer, melanoma, non-hodgkin lymphoma, lung cancer (non-small cell lung cancer adenocarcinoma, squamous epithelial cell non) T for small cell lung cancer, and small cell lung cancer ) , ovarian cancer, esophageal cancer, pancreatic cancer, prostate cancer, renal cell cancer, bladder cancer, and / or uterine and endometrial cancer Including inducing a cellular response,
Composition.