Binding protein, isolated nucleic acid molecule, vector, host cell, and pharmaceutical composition and use of the binding protein.

Abstract

Provided is a binding protein, comprising a binding domain having antigen specificity for an antigen peptide:HLA complex, wherein the binding domain comprises a T cell receptor (TCR) α-chain variable region and a TCR β-chain variable region. Further provided are uses of the binding protein and a pharmaceutical composition comprising the binding protein in the treatment of cancers associated with the antigen peptide.

Description

1 / 70 “BINDING PROTEIN, ISOLATED NUCLEIC ACID MOLECULE, VECTOR, HOST CELL AND PHARMACEUTICAL COMPOSITION AND USE OF THE BINDING PROTEIN” Cross-reference to related orders

[001] This application claims priority over Chinese patent application No. 202310507375.6, filed with the State Intellectual Property Office of China on May 6, 2023, the full content of which is incorporated herein by reference. Technical Field

[002] This document refers to TCR molecules and cells that express such TCR molecules, in particular TCR molecules targeting target cells that have the KRAS G12V mutation, as well as immune effector cells that express these TCR molecules. This document also refers to the therapeutic applications of these TCR molecules and cells. State of the Art

[003] The RAS gene family (HRAS, KRAS, NRAS) constitutes the group of proto-oncogenes most frequently associated with tumor genesis. Among them, mutations in the KRAS gene—concentrated mainly in codon 12—are the most prevalent, being present in approximately 22% to 30% of tumors. The frequency is particularly high in pancreatic adenocarcinoma (~60-90%), colorectal cancer (~40%), lung cancer (~10% in China; ~30% in Europe and the USA), cholangiocarcinoma (~17%-37%), as well as in ovarian and endometrial carcinomas (~10%-40%, depending on the histopathological subtype, with a higher incidence in the serous variant). By way of example, in the case of Petition 870250073401, dated 08 / 20 / 2025, p. 15 / 115 2 / 70 of pancreatic adenocarcinoma was diagnosed, and it was estimated that in 2021, approximately 60,430 people would be diagnosed with the disease, with approximately 48,220 deaths attributed to pancreatic cancer. Despite advances in the diagnosis and treatment of pancreatic cancer in the last decade, the five-year survival rate remains around 9% due to a scarcity of effective therapeutic options. Currently, the treatment of unresectable pancreatic cancer is mainly based on chemotherapy aimed at reducing tumor volume, but its effectiveness is limited by the development of resistance. Furthermore, the success of targeted therapies has been modest to date. In addition, pancreatic cancer also exhibits resistance to immunotherapy, which may be partly due to the low mutational load of the disease, resulting in a scarcity of tumor-infiltrating lymphocytes reactive to neoantigens.Research targeting the KRAS-G12V TCR-T may effectively improve the current situation of a lack of effective therapeutic options for tumors with KRAS mutations. Disclosure of the Invention

[004] In one aspect, the present document provides a fusion protein that includes a binding domain with antigenic specificity for the antigenic peptide:HLA complex. Said binding domain comprises the variable region of the α chain of the T cell receptor (TCR) and the variable region of the β chain of the TCR, where: The aforementioned antigenic peptide includes the amino acid sequence VVGAVGVGK (SEQ ID NO: 91); The HLA in question is HLA-A*11:01; Petition 870250073401, dated 08 / 20 / 2025, p. 16 / 115 3 / 70 - The CDR3 of the variable region of the α chain includes the amino acid sequence represented by SEQ ID NO: 5, 15, 25, 35, 45, 55, 65, 75 or 85, or an amino acid sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequences represented by SEQ ID NO: 5, 15, 25, 35, 45, 55, 65, 75 or 85; - The CDR3 of the variable region of the β chain includes the amino acid sequence represented by SEQ ID NO: 10, 20, 30, 40, 50, 60, 70, 80 or 90, or an amino acid sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequences represented by SEQ ID NO: 10, 20, 30, 40, 50, 60, 70, 80 or 90.

[005] In some embodiments, the antigenic peptide mentioned is VVGAVGVGK (SEQ ID NO: 91) or VVVGAVGVGK (SEQ ID NO: 92).

[006] In some embodiments, in the variable region of the α chain: 1) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 3, CDR2 comprises the amino acid sequence represented by SEQ ID NO: 4, CDR3 comprises the amino acid sequence represented by SEQ ID NO: 5, or an amino acid sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequence represented by SEQ ID NO: 5; 2) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 13, CDR2 by SEQ ID NO: 14, CDR3 by SEQ ID NO: 15, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% Petition 870250073401, dated 08 / 20 / 2025, p. 17 / 115 4 / 70 or 95% with SEQ ID NO: 15; 3) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 23, CDR2 by SEQ ID NO: 24, CDR3 by SEQ ID NO: 25, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 25; 4) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 33, CDR2 by SEQ ID NO: 34, CDR3 by SEQ ID NO: 35, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 35; 5) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 43, CDR2 by SEQ ID NO: 44, CDR3 by SEQ ID NO: 45, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 45;6) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 53, CDR2 by SEQ ID NO: 54, CDR3 by SEQ ID NO: 55, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 55; 7) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 63, CDR2 by SEQ ID NO: 64, CDR3 by SEQ ID NO: 65, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 65; 8) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 73, CDR2 by SEQ ID NO: 74, CDR3 by SEQ ID NO: 75, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 75; or 9) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 83, a; Petition 870250073401, dated 08 / 20 / 2025, p. 18 / 115 5 / 70 CDR2 by SEQ ID NO: 84, CDR3 by SEQ ID NO: 85, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 85.

[007] In the variable region of the β chain: 1) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 8, CDR2 by SEQ ID NO: 9, CDR3 by SEQ ID NO: 10, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequence represented by SEQ ID NO: 10; 2) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 18, CDR2 by SEQ ID NO: 19, CDR3 by SEQ ID NO: 20, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequence represented by SEQ ID NO: 20; 3) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 28, CDR2 by SEQ ID NO: 29, CDR3 by SEQ ID NO: 30, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequence represented by SEQ ID NO: 30;4) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 38, CDR2 by SEQ ID NO: 39, CDR3 by SEQ ID NO: 40, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequence represented by SEQ ID NO: 40; 5) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 48, CDR2 by SEQ ID NO: 49, CDR3 by SEQ ID NO: 50, or a sequence with at least 80% identity, preferably; Petition 870250073401, dated 08 / 20 / 2025, p. 19 / 115 6 / 70 at least 85%, more preferably 90% or 95% identity with the sequence represented by SEQ ID NO: 50; 6) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 58, CDR2 by SEQ ID NO: 59, CDR3 by SEQ ID NO: 60, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequence represented by SEQ ID NO: 60; 7) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 68, CDR2 by SEQ ID NO: 69, CDR3 by SEQ ID NO: 70, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequence represented by SEQ ID NO: 70;8) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 78, CDR2 by SEQ ID NO: 79, CDR3 by SEQ ID NO: 80, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequence represented by SEQ ID NO: 80; or 9) CDR1 comprises the amino acid sequence represented by SEQ ID NO: 88, CDR2 by SEQ ID NO: 89, CDR3 by SEQ ID NO: 90, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with the sequence represented by SEQ ID NO: 90.

[008] In some embodiments, 1) in the variable region of the α chain, CDR1 comprises the amino acid sequence represented by SEQ ID NO: 3, CDR2 by SEQ ID NO: 4, CDR3 by SEQ ID NO: 5, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 5; Petition 870250073401, dated 08 / 20 / 2025, p. 20 / 115 7 / 70 and in the variable region of the β chain, CDR1 comprises SEQ ID NO: 8, CDR2 SEQ ID NO: 9, CDR3 SEQ ID NO: 10, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 10; 2) in the α chain, CDR1 comprises SEQ ID NO: 13, CDR2 SEQ ID NO: 14, CDR3 SEQ ID NO: 15, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 15; and in the β chain, CDR1 comprises SEQ ID NO: 18, CDR2 SEQ ID NO: 19, CDR3 SEQ ID NO: 20, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 20; 3) in the α chain, CDR1 comprises SEQ ID NO: 23, CDR2 SEQ ID NO: 24, CDR3 SEQ ID NO: 25, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 25;and in the β chain, CDR1 comprises SEQ ID NO: 28, CDR2 SEQ ID NO: 29, CDR3 SEQ ID NO: 30, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 30; 4) in the α chain, CDR1 comprises SEQ ID NO: 33, CDR2 SEQ ID NO: 34, CDR3 SEQ ID NO: 35, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 35; and in the β chain, CDR1 comprises SEQ ID NO: 38, CDR2 SEQ ID NO: 39, CDR3 SEQ ID NO: 40, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 40; 5) in the α chain, CDR1 comprises SEQ ID NO: 43, CDR2 SEQ ID NO: 44, CDR3 SEQ ID NO: 45, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO:; Petition 870250073401, dated 08 / 20 / 2025, p. 21 / 115 8 / 70 45; and in the β chain, CDR1 comprises SEQ ID NO: 48, CDR2 SEQ ID NO: 49, CDR3 SEQ ID NO: 50, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 50; 6) in the α chain, CDR1 comprises SEQ ID NO: 53, CDR2 SEQ ID NO: 54, CDR3 SEQ ID NO: 55, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 55; and in the β chain, CDR1 comprises SEQ ID NO: 58, CDR2 SEQ ID NO: 59, CDR3 SEQ ID NO: 60, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 60; 7) in the α chain, CDR1 comprises SEQ ID NO: 63, CDR2 SEQ ID NO: 64, CDR3 SEQ ID NO: 65, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 65;and in the β chain, CDR1 comprises SEQ ID NO: 68, CDR2 SEQ ID NO: 69, CDR3 SEQ ID NO: 70, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 70; 8) in the α chain, CDR1 comprises SEQ ID NO: 73, CDR2 SEQ ID NO: 74, CDR3 SEQ ID NO: 75, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 75; and in chain β, CDR1 comprises SEQ ID NO: 78, CDR2 SEQ ID NO: 79, CDR3 SEQ ID NO: 80, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 80; or 9) in chain α, CDR1 comprises SEQ ID NO: 83, CDR2 SEQ ID NO: 84, CDR3 SEQ ID NO: 85, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 85; and in chain; Petition 870250073401, dated 08 / 20 / 2025, p. 22 / 115 9 / 70 β, CDR1 comprises SEQ ID NO: 88, CDR2 SEQ ID NO: 89, CDR3 SEQ ID NO: 90, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 90.

[009] On the other hand, this document provides a binding protein comprising a binding domain, said binding domain being composed of a variable region of the α chain of the T cell receptor (TCR) and a variable region of the β chain of the TCR, wherein: 1) in the variable region of the α chain, CDR1 comprises the amino acid sequence represented by SEQ ID NO: 3, CDR2 by SEQ ID NO: 4, CDR3 by SEQ ID NO: 5, or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 5; and in the variable region of the β chain, CDR1 comprises SEQ ID NO: 8, CDR2 SEQ ID NO: 9, CDR3 SEQ ID NO: 10, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 10;2) CDR1 of chain α comprises SEQ ID NO: 13, CDR2 SEQ ID NO: 14, CDR3 SEQ ID NO: 15, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 15; and chain β comprises SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20, respectively, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 20; 3) the α string comprises SEQ ID NO: 23, SEQ ID NO: 24 and SEQ ID NO: 25, respectively, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 25; and the β string; Petition 870250073401, dated 08 / 20 / 2025, p. 23 / 115 10 / 70 comprises SEQ ID NO: 28, SEQ ID NO: 29 and SEQ ID NO: 30, respectively, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 30; 4) the α string comprises SEQ ID NO: 33, SEQ ID NO: 34 and SEQ ID NO: 35, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 35; and the β string comprises SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 40; 5) String α comprises SEQ ID NO: 43, SEQ ID NO: 44 and SEQ ID NO: 45, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 45; and string β comprises SEQ ID NO: 48, SEQ ID NO: 49 and SEQ ID NO: 50, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 50;6) String α comprises SEQ ID NO: 53, SEQ ID NO: 54, and SEQ ID NO: 55, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% of SEQ ID NO: 55; and string β comprises SEQ ID NO: 58, SEQ ID NO: 59, and SEQ ID NO: 60, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% of SEQ ID NO: 60; 7) String α comprises SEQ ID NO: 63, SEQ ID NO: 64, and SEQ ID NO: 65, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% of SEQ ID NO: 65; and the β string comprises SEQ ID NO: 68, SEQ ID NO: 69 and SEQ ID NO: 70, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO:; Petition 870250073401, dated 08 / 20 / 2025, p. 24 / 115 11 / 70 70; 8) the α string comprises SEQ ID NO: 73, SEQ ID NO: 74 and SEQ ID NO: 75, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 75; and the β string comprises SEQ ID NO: 78, SEQ ID NO: 79 and SEQ ID NO: 80, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 80; or 9) the α string comprises SEQ ID NO: 83, SEQ ID NO: 84 and SEQ ID NO: 85, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 85; and the β string comprises SEQ ID NO: 88, SEQ ID NO: 89 and SEQ ID NO: 90, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% with SEQ ID NO: 90.

[0010] In some embodiments, in the said binding protein: 1) the variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 2 or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 2; the variable region of the β chain comprises the amino acid sequence represented by SEQ ID NO: 7 or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 7; 2) the variable region of the α chain comprises SEQ ID NO: 12 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 12; the β chain comprises SEQ ID NO: 17 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 17; 3) the chain Petition 870250073401, dated 08 / 20 / 2025, p. 25 / 115 12 / 70 α comprises SEQ ID NO: 22 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 22; the β string comprises SEQ ID NO: 27 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 27; 4) the α string comprises SEQ ID NO: 32 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 32; the β string comprises SEQ ID NO: 37 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 37; 5) String α comprises SEQ ID NO: 42 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 42; String β comprises SEQ ID NO: 47 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 47;6) String α comprises SEQ ID NO: 52 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 52; String β comprises SEQ ID NO: 57 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 57; 7) String α comprises SEQ ID NO: 62 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 62; String β comprises SEQ ID NO: 67 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 67; 8) String α comprises SEQ ID NO: 72 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 72; String β comprises SEQ ID NO: 77 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 77; or; Petition 870250073401, dated 08 / 20 / 2025, p. 26 / 115 13 / 70 9) String α comprises SEQ ID NO: 82 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 82; String β comprises SEQ ID NO: 87 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% of SEQ ID NO: 87.

[0011] In some embodiments, said binding protein comprises the α chain of the TCR and the β chain of the TCR, wherein: 1) the α chain comprises the amino acid sequence represented by SEQ ID NO: 1 or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 1; the β chain comprises SEQ ID NO: 6 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 6; 2) the α chain comprises SEQ ID NO: 11 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 11; β string comprises SEQ ID NO: 16 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 16; 3) α string comprises SEQ ID NO: 21 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 21;4) the α chain comprises SEQ ID NO: 31 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 26; 5) the β chain comprises SEQ ID NO: 36 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 31; the β chain comprises SEQ ID NO: 36 or a sequence with at least 80%, preferably 85%, more; Petition 870250073401, dated 08 / 20 / 2025, p. 27 / 115 14 / 70 preferably 90% or 95% identity with SEQ ID NO: 36; 5) the α string comprises SEQ ID NO: 41 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 41; the β string comprises SEQ ID NO: 46 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 46; 6) the α string comprises SEQ ID NO: 51 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 51; 7) String β comprises SEQ ID NO: 56 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 56; 7) String α comprises SEQ ID NO: 61 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 61;the β string comprises SEQ ID NO: 66 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO:; 66; 8) the string α comprises SEQ ID NO: 71 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 71; the β string comprises SEQ ID NO: 76 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 76; or 9) the α string comprises SEQ ID NO: 81 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 81; the β string comprises SEQ ID NO: 86 or a sequence with at least 80%, preferably 85%, more Petition 870250073401, dated 08 / 20 / 2025, p. 28 / 115 15 / 70 preferably 90% or 95% identity with SEQ ID NO: 86.

[0012] In some embodiments, the aforementioned binding protein comes in the form of a protein with the following structure: 1) TCR molecule; 2) antibody molecule; or 3) CAR molecule.

[0013] In some embodiments, when T lymphocytes expressing the said binding protein are co-incubated with HLA-A*11:01 cells in the presence of the said antigenic peptide, or when they are co-incubated with HLA-A*11:01 cells expressing the said antigenic peptide, the said T lymphocytes specifically eliminate the HLA-A*11:01 cells.

[0014] In some embodiments, when T lymphocytes expressing the said binding protein are co-incubated with HLA-A*11:01 cells in the presence of the said antigenic peptide, or when they are co-incubated with HLA-A*11:01 cells expressing the said antigenic peptide, the said T lymphocytes produce IFN-γ and / or express CD69, or show an increase in IFN-γ production and / or CD69 expression.

[0015] In some embodiments, said binding protein further comprises a conjugate covalently or non-covalently linked to said binding domain; preferably, said conjugate is a detectable marker, a radioactive isotope or a therapeutic agent.

[0016] In another aspect, the present document provides Petition 870250073401, dated 08 / 20 / 2025, p. 29 / 115 16 / 70 an isolated nucleic acid molecule encoding said binding protein, the variable region of the α chain, the variable region of the β chain, the α chain or the β chain.

[0017] In another aspect, this document provides a vector that includes said nucleic acid molecule.

[0018] On the other hand, this document provides a host cell that expresses said binding protein or that comprises said nucleic acid molecule or vector.

[0019] In some embodiments, the host cell is a mammalian cell, preferably a human cell.

[0020] In some embodiments, the host cell is a T lymphocyte or an NK cell.

[0021] In some embodiments, the aforementioned host cell exhibits cytotoxic activity against HLA-A*11:01 cells that express the antigenic peptide VVGAVGVGK (SEQ ID NO: 91) or VVVGAVGVGK (SEQ ID NO: 92).

[0022] In another aspect, this document provides a pharmaceutical composition that includes: 1) the aforementioned binding protein, nucleic acid molecule, vector or host cell; and 2) a pharmacologically acceptable vehicle.

[0023] On the other hand, this document provides for the use of said binding protein, nucleic acid molecule, vector or host cell in the preparation of a drug for tumor treatment, and said tumor expresses said antigenic peptide.

[0024] In another aspect, the present document provides a method for the treatment of tumors in an individual, which Petition 870250073401, dated 08 / 20 / 2025, p. 30 / 115 17 / 70 comprises the administration to the said individual of a therapeutically effective quantity of said binding protein, nucleic acid molecule, vector, host cell or pharmaceutical composition.

[0025] In some embodiments, the tumor in question is selected from pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial carcinoma, and ovarian carcinoma.

[0026] In another aspect, the present document provides a detection kit that includes the aforementioned binding protein. Description of the Figures

[0027] Figure 1 shows a representative flow cytometry diagram of the selection and enrichment of HLA-A*11:01 / KRAS G12V specific T lymphocytes using pentamers, after T lymphocyte stimulation.

[0028] Figure 2A shows the cytotoxicity results of non-transduced and transduced CD8+ T cells with different TCRs specific for HLAA*11:01 / KRAS G12V against K562-A*11:01 target cells loaded with different antigenic peptides. The peptides loaded onto the target cells in the figure are, respectively: 9-amino acid G12V peptide: VVGAVGVGK (SEQ ID NO: 91), 10-amino acid G12V peptide: VVVGAVGVGK (SEQ ID NO: 92), WT peptide: VVGAGGVGK (SEQ ID NO: 93) + VVVGAGGVGK (SEQ ID NO: 94).

[0029] Figure 2B shows the cytotoxicity results of non-transduced and transduced CD8+ T cells with different TCRs specific for HLAA*11:01 / KRAS G12V against BxPC3 cells with overexpression Petition 870250073401, dated 08 / 20 / 2025, page 31 / 115 18 / 70 of HLA-A*11:01 and / or KRAS G12V. BxPC3-A1101 refers to BxPC3 cells transfected with HLA-A*11:01; BxPC3-A1101G12V refers to BxPC3 cells transfected simultaneously with HLA-A*11:01 and KRAS G12V; and BxPC3-A1101G12D refers to BxPC3 cells transfected simultaneously with HLA-A*11:01 and KRAS G12D.

[0030] Figure 3 shows the release of IFN-γ after co-incubation of TCR1-transduced T cells with peptide-laden target cells. BxPC3-A1101 refers to BxPC3 cells into which HLA-A*11:01 was introduced; BxPC3-G12V refers to BxPC3 cells into which KRAS G12V was introduced; BxPC3-A1101-G12V refers to BxPC3 cells into which HLA-A*11:01 and KRAS G12V were introduced simultaneously.

[0031] Figure 4A shows the release of IFN-γ detected by ELISPOT after co-incubation of PBMCs transduced with the designated TCR with target cells (K562A*11:01) loaded with different peptide concentrations (10^-10^ M).

[0032] Figure 4B shows the CD69 expression detected by flow cytometry after co-incubation of Jurkat cells transduced with the designated TCR with target cells (K562-A*11:01) loaded with different peptide concentrations (10^-10^ M).

[0033] Figure 4C shows the CD69 expression detected by flow cytometry after co-incubation of Jurkat cells transduced with the designated TCR with target cells (K562-A*11:01) loaded with different concentrations of the G12V-9 or G12V-10 peptides (10^-10^ M). Specific Modes of Implementation Petition 870250073401, dated 08 / 20 / 2025, page 32 / 115 19 / 70

[0034] Unless otherwise indicated, all technical and scientific terms used in this document have the meaning normally understood by a specialist in the subject matter.

[0035] The term "or" refers to a single element among the elements listed as alternatives, unless the context expressly indicates otherwise. The term "and / or" refers to any one, any two, any three, any more, or all of the elements listed as alternatives.

[0036] The term approximately refers, in general, to a variation of up to 10% above or below the specified value, for example, a variation of ±0.5%, ±1%, ±1.5%, ±2%, ±2.5%, ±3%, ±3.5%, ±4%, ±4.5%, ±5%, ±5.5%, ±6%, ±6.5%, ±7%, ±7.5%, ±8%, ±8.5%, ±9%, ±9.5% or ±10%.

[0037] The terms comprise or include mean that the elements, wholes or steps mentioned are present, but do not exclude the presence of other additional elements, wholes or steps. In this document, unless otherwise indicated, the terms comprise or include also cover situations where the invention consists only of the elements, wholes or steps mentioned. For example, when reference is made to a variable region that includes a particular sequence, such reference also aims to cover a variable region that consists of that specific sequence.

[0038] The term major histocompatibility complex (MHC) refers to a set of genes that encode the major histocompatibility antigens in animals. Currently, the structures Petition 870250073401, dated 08 / 20 / 2025, page 33 / 115 20 / 70 of the MHC class I and class II molecules have been fully elucidated, both being members of the immunoglobulin superfamily. Human MHC is called HLA (human leukocyte antigen). HLA class I molecules mainly include the protein products (heavy chain or α chain) of three functional genes: HLA-A, HLA-B, and HLA-C. Each heavy chain of HLA class I associates with β2-microglobulin (e2m), forming a heterodimer that constitutes the complete MHC class I molecule. Due to the polymorphism of the genes encoding HLA molecules, the HLA Nomenclature Committee established specific principles for allele designation.The main points include: for a given allele, the name of the genetic locus is written after the three-letter prefix HLA, separated by a hyphen, for example, HLA-A; after the locus name, an asterisk (*) is added, followed by the number of the genetic family corresponding to the allele, which reflects, whenever possible, the associated serological typing; then, a colon (:) is added and the specific number of the allele. For example: HLA-A*02:01. One of the main functions of MHC molecules is participation in antigen presentation, that is, MHC molecules bind to antigenic peptides through their peptide-binding groove, forming peptide-MHC complexes (pMHC), which are presented on the cell surface to be recognized by T lymphocytes (through the TCR), thus triggering an immune response.

[0039] The term antigenic peptide refers to a short peptide capable of binding to the binding groove on Petition 870250073401, dated 08 / 20 / 2025, page 34 / 115 21 / 70 peptide of an MHC molecule (or an HLA molecule). The antigen-binding groove of HLA class I molecules is formed by the α1 and α2 domains of the heavy chain, whose extracellular region comprises three structural domains: α1, α2, and α3. Each of the α1 and α2 domains adopts a conformation composed of an α-helix and four β-sheets. The two α-helices form the walls of the groove, while the eight β-sheets constitute its base. The length of antigenic peptides suitable for lodging in this binding groove is typically 8 to 11 amino acids. In a specific example, the antigenic peptide is a mutated fragment of the KRAS protein: VVGAVGVGK (SEQ ID NO: 91). In another specific example, the antigenic peptide is a mutated fragment of the KRAS protein: VVVGAVGVGK (SEQ ID NO: 92).

[0040] The term “peptide-antigenic complex: MHC” or “peptide-antigenic complex: HLA” refers to the complex (pMHC) formed by an MHC molecule and an antigenic peptide, in which the peptide is located in the peptide-binding groove of the MHC molecule. The TCR molecule recognizes this complex through the CDR sequences present in its binding domain, predicting a specific binding to it. The binding of the TCR molecule to the pMHC complex is MHC-dependent, that is, the TCR molecule simultaneously recognizes the antigenic peptide and the pMHC complex.

[0041] The term “T cell receptor (TCR)” refers to the functional unit responsible for antigen recognition (pMHC) by T lymphocytes, belonging to the immunoglobulin superfamily. The TCR expressed in Petition 870250073401, dated 08 / 20 / 2025, page 35 / 115 22 / 70 T cells is a membrane glycoprotein that exists as a heterodimer composed of an α chain and a β chain, or a γ chain and a δ chain. In the human body, the vast majority (90%-95%) of TCRs present in peripheral blood are heterodimers consisting of two polypeptide chains: an α chain and a β chain. Both the α chain and the β chain can be divided into a variable region (Va, νβ), a constant region (Ca, Ce), a transmembrane region, and a cytoplasmic region. The cytoplasmic regions of the α and β chains are very short, containing only a few amino acids. The constant regions (Ca, Cβ) exhibit relatively little sequence variation, and specific amino acid sequences can be found, for example, in the public database of the International Immunogenetics Information System (IMGT).The transmembrane region includes positively charged amino acid residues, allowing non-covalent interaction with negatively charged amino acid residues present in the transmembrane region of CD3 molecules, thus contributing to the stabilization of the TCR-CD3 complex structure. Analysis of the amino acid sequences of the variable regions of the TCR reveals that both Va and νβ possess three hypervariable regions, designated complementarity-determining regions (CDRs), namely CDR1, CDR2, and CDR3. Among these, CDR3 is the most variable and plays a determining role in the antigenic specificity of the TCR. In addition to the hypervariable regions, the variable regions also include four support structure regions (FR1 to FR4), similar to what occurs in antibody molecules. The determination. Petition 870250073401, dated 08 / 20 / 2025, page 36 / 115 23 / 70 of the positions of the CDR1 to CDR3 and FR1 to FR4 regions in the complete TCR sequence is based on the nomenclature defined by the IMGT, which is widely recognized and can be consulted in the IMGT public database. The variable regions of the α and β chains—namely, the three CDRs of the α chain and the three CDRs of the β chain—together form the part of the TCR responsible for specific recognition and binding to the pMHC complex (referred to in this document as the “binding domain”). In the immune system, the binding between the antigenically specific TCR and the pMHC complex triggers direct physical contact between T lymphocytes and antigen-presenting cells (APCs) or target cells, leading to T lymphocyte activation or target cell elimination. Unless otherwise indicated or implied by the context, the term TCR also encompasses functional fragments with antigenic specificity, such as the Va and Ve variable regions linked by a short peptide.

[0042] The term “antibody” is used in this document in its broadest sense, encompassing immunoglobulins or other molecules that include one or more antigen-binding domains with binding specificity, being proteins or polypeptides that demonstrate binding specificity to a specific antigen. Specific examples of antibodies may include complete antibodies (e.g., classic four-chain molecules), single-chain antibodies, single-domain antibodies, and multispecific antibodies, among others. Classic antibody molecules are generally tetramers composed of two identical heavy chains and two identical light chains, linked together. Petition 870250073401, dated 08 / 20 / 2025, page 37 / 115 24 / 70 by disulfide bonds. Based on the differences in amino acid sequence conservation, the heavy and light chains are divided into a variable region (V), located at the N-terminal end, and a constant region (C), located at the C-terminal end. The variable region is responsible for antigen recognition and binding, while the constant region (such as the Fc fragment) participates in the activation of downstream effects, such as antibody-mediated cellular cytotoxicity (ADCC). In the variable regions of the heavy and light chains, there are three local regions whose amino acid composition and sequence exhibit the highest degree of variability; these are crucial for antibody-antigen binding and are therefore designated complementarity-determining regions (CDRs). The three complementarity-determining regions of the heavy chain are designated HCD1, HCD2, and HCD3, while those of the light chain are designated LCD1, LCD2, and LCD3.Each variable region of the heavy chain (VH) and light chain (VL) is composed of three CDRs and four support structure (FR) regions, arranged, from the N-terminal end to the C-terminal end, in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. In the present document, the antibody molecule may also include a fusion protein composed of the recombination of the variable regions of a TCR with the constant region of an antibody, simultaneously conferring the antigenic specificity of the TCR and the effector functions of the antibody's constant region.

[0043] The term “chimeric antigen receptor (CAR)” refers to a genetically modified membrane receptor molecule that can confer a. Petition 870250073401, dated 08 / 20 / 2025, p. 38 / 115 25 / 70 desired specificity to effector cells of the immune system, such as the ability to recognize and bind to specific tumor antigens. A chimeric antigen receptor is generally composed of an extracellular antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some cases, the antigen-binding domain consists of an scFv sequence or a single-domain antibody fragment, being responsible for the recognition and binding to a specific antigen. The intracellular signaling domain generally includes tyrosine-based immune receptor activation motifs (ITAMs), such as the CD3Z-derived signal transduction domain, being responsible for the activation of effector cells of the immune system and the induction of cytotoxic activity.Additionally, the chimeric antigen receptor may include, at the N-terminal end, a signal peptide responsible for intracellular targeting of the newly synthesized protein, as well as a hinge region between the antigen-binding domain and the transmembrane domain. Beyond the signal transduction domain, the intracellular signaling domain may also include a co-stimulatory domain, derived, for example, from 4-1BB or CD28 molecules.

[0044] The terms antigenic specificity, targeting, or specific binding refer to the ability of the TCR (or other fusion proteins that include its binding domain, such as CARs) to specifically recognize and bind with high affinity to the corresponding pMHC complex. Compared to other Petition 870250073401, dated 08 / 20 / 2025, page 39 / 115 Of the 26 / 70 molecules present in the environment, the TCR (or other fusion proteins that include its binding domain, such as CARs) exhibits a higher binding affinity for a specific molecule with which it possesses antigenic specificity, such as a pMHC complex. The binding affinity of the TCR to the pMHC complex can be assessed through certain measurement parameters, such as the EC50 value or the KD value.

[0045] The term “binding protein” refers to a protein with the ability to bind specifically to a specific ligand, such as an antigen. In this document, binding protein may include TCR molecules with specific binding capacity to the pMHC complex (including single-chain TCRs and soluble TCRs), fusion proteins formed between the TCR and other proteins (such as antibody molecules or chimeric antigen receptors), as well as immunoconjugates linked to detectable markers, therapeutic agents, or radioactive isotopes.

[0046] The term “fusion protein” refers to an artificially generated protein molecule (e.g., by genetic engineering techniques) composed of at least two distinct peptide segments. These peptide segments do not exist naturally or are not found in nature in the same protein molecule.Common examples of fusion proteins containing antibody fragments include multispecific antibodies, antibody-cytokine fusion proteins, antibodies labeled with enzymes for immunological detection, and chimeric antigen receptors (CARs).

[0047] When reference is made to the TCR (or its Petition 870250073401, dated 08 / 20 / 2025, page 40 / 115 27 / 70 antigen-specific fragment), the term variant used in this document designates a protein obtained from the original TCR (or its antigen-specific fragment) by introducing one or more insertions, deletions, or amino acid substitutions, while maintaining at least part of the functions of the original TCR—in particular, the relevant function, such as the ability to bind to the corresponding pMHC complex. For example, a variant of the TCR (or its antigen-specific fragment) may retain at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the pMHC complex binding capacity of the original TCR (or its antigen-specific fragment), or even exhibit a higher binding capacity than the original TCR.In some embodiments, the TCR variant (or its antigen-specific fragment) may retain at least 80%, 85%, 90%, 95%, or even 100% or more of the antigen-binding affinity of the original TCR (or its antigen-specific fragment). TCR variants (or their antigen-specific fragments) generally include amino acid changes in the supporting structural sequence of the variable region and / or the constant region, without excluding, however, the possibility of one or a few modifications in the sequence of the CDR regions. Thus, it is also understood by those skilled in the art that, based on the specific amino acid sequences of the TCR (or its antigen-specific fragment) provided in this document—including the sequences of the CDR regions, the variable regions, or the α / β chains—it is possible to obtain corresponding variants. Petition 870250073401, dated 08 / 20 / 2025, p. 41 / 115 28 / 70 by substitution, deletion, or addition of a limited number of amino acids, followed by validation or screening of the ability to bind to the corresponding pMHC complex or biological activity. These variants should also be considered to be included within the scope of the present invention.

[0048] The terms “nucleic acid molecule”, “nucleic acid”, and “polynucleotide” are used interchangeably in this document and refer to a polymer of nucleotides. These nucleotide polymers may contain natural and / or non-natural nucleotides and include (but are not limited to) DNA, RNA, and PNA. Nucleic acid sequence refers to the linear sequence of nucleotides contained in a nucleic acid molecule or in a polynucleotide.

[0049] The term vector refers to a nucleic acid molecule that can be engineered to contain a polynucleotide of interest (e.g., the coding sequence of a polypeptide of interest) or a nucleic acid molecule capable of replicating in a host cell (e.g., nucleic acid, plasmid, or virus). The vector may include one or more of the following components: an origin of replication, one or more regulatory sequences that control the expression of the polynucleotide of interest (such as promoters and / or enhancers), and / or one or more selection marker genes (such as antibiotic resistance genes and genes usable in colorimetric analyses, such as β-galactosidase). The term expression vector refers to a vector used to express a polypeptide of interest in a host cell. Petition 870250073401, dated 08 / 20 / 2025, p. 42 / 115 29 / 70

[0050] Host cell refers to a cell that can receive or has received a vector or an isolated polynucleotide. The host cell can be a prokaryotic or eukaryotic cell. Examples of eukaryotic cells include mammalian cells, such as primate or non-primate cells; fungal cells, such as yeast; plant cells; and insect cells. Non-limiting examples of mammalian cells include (but are not limited to) CHO cells, HEK-293 cells, BHK cells, or PER-C6 cells, as well as cells derived from them, such as 293-6E, CHO-DG44, CHO-K1, CHO-S, and CHO-DS cells. In some embodiments, the host cell is used for the production of the protein of interest, for example, the α and / or β chain of the TCR provided in this document can be secreted by mammalian cells.In other embodiments, the host cell acquires a specific function after expressing the TCR molecule provided in this document; for example, after expressing said TCR molecule in T cells, these cells acquire the ability to recognize and eliminate target cells expressing a specific antigenic peptide. The host cell may be a single cell or cell line, including cells that have been transfected in vivo with the nucleic acid molecule or expression vector provided in this document. The host cell includes the descendants of a single host cell, and these descendants may not be entirely identical to the original progenitor cell (in terms of morphology or genomic DNA complementarity) due to natural, accidental, or other mutations. Petition 870250073401, dated 08 / 20 / 2025, page 43 / 115 30 / 70 induced.

[0051] The term individual includes animals, such as mammals, including (but not limited to) primates, rodents, apes, felines, canines, equines, bovines, swine, ovines, caprines, laboratory mammalian animals, livestock mammalian animals, mammalian animals used in sporting activities, and mammalian pets. Individuals may be male or female and may belong to any appropriate age range, including infants, juveniles, young adults, adults, or seniors. In some instances, the term individual refers to an individual who requires diagnosis or treatment of a disease or pathological condition. In some cases, the individual receiving the diagnosis or treatment may be a patient suffering from a condition associated with that diagnosis or treatment, or who is at risk of developing such a condition. In specific instances, the individual is a human being, such as a human patient.This term can generally be used interchangeably with patient, individual under evaluation, or individual under treatment.

[0052] When referring to a pharmaceutical composition, the term pharmaceutically acceptable vehicle designates substances such as solid or liquid diluents, excipients, antioxidants, stabilizers, among others, that can be safely administered, are suitable for administration to humans and / or animals without excessive adverse effects, and are also appropriate for maintaining the activity of the drug or active agent contained therein. Petition 870250073401, dated 08 / 20 / 2025, page 44 / 115 31 / 70

[0053] When referring to the treatment of a disease, the term "effective dose" designates the amount of an active molecule (such as an antibody) sufficient to elicit, in the individual's organism, a biological or medical response desired by the clinical professional. The "effective dose" to be administered can be determined by a technical professional in the field, taking into account factors such as route of administration, body weight, age, clinical condition of the individual, among others. For example, in the case of protein-based medications, the typical daily dose can vary between 0.01 mg and 100 mg of the active ingredient per kilogram of body weight. For immune effector cells that express the TCR provided in this document (such as T lymphocytes), the number of cells administered per infusion can vary, for example, from about 1x10⁶ to about 1x10¹² cells or even more. In certain embodiments, administration can be done with fewer than 1x10⁶ T lymphocytes.Methods of delivering the active molecules provided in this document (such as TCRs, antibodies, or fusion proteins) or immune effector cells include, but are not limited to, injection, for example, intravenously, intramuscularly, intra-arterially, subcutaneously, or intraperitoneally.

[0054] When referring to amino acid or nucleotide sequences, the term “sequence identity” (also called “sequence homology”) refers to the degree of correspondence between two amino acid or nucleotide sequences (e.g., a query sequence and a reference sequence), usually expressed as a percentage. Typically, before calculating the percentage Petition 870250073401, dated 08 / 20 / 2025, p. 45 / 115 32 / 70 of identity between two amino acid or nucleotide sequences, the alignment of the sequences is performed first and, if necessary, gaps are introduced. If, at a given position in the alignment, the amino acid residues or nucleotides of the two sequences are identical, there is considered to be a match or coincidence at that position; if they are different, there is considered to be a discrepancy or incompatibility at that position. In certain algorithms, sequence identity is obtained by dividing the number of coincident positions by the total number of positions in the alignment window. In other algorithms, the number of gaps and / or the length of the gaps are also considered in the calculation of sequence identity. For the purposes of the present invention, the public alignment software BLAST (available at ncbi.nlm.nih.(gov), employing predefined settings to obtain the best sequence alignment and calculate the identity between two amino acid or nucleotide sequences. In certain embodiments, the expression “at least 80% sequence identity” as described in this document includes, but is not limited to, cases of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or even 100% sequence identity.

[0055] This document provides isolated or purified binding proteins with antigenic specificity for antigen-peptide-MHC complexes (in which the peptide Petition 870250073401, dated 08 / 20 / 2025, page 46 / 115 33 / 70 antigenic features amino acid mutations relative to the wild-type sequence), such as T cell receptors (TCRs), antibodies, or CARs, with the antigenic peptide being derived from a mutated KRAS protein.

[0056] This document also provides polypeptides and proteins associated with the aforementioned TCR or its binding domain, as well as corresponding nucleic acid molecules, vectors (such as recombinant expression vectors), host cells (such as T lymphocytes), and associated pharmaceutical compositions.

[0057] This document also provides methods and kits for detecting the presence of tumors in an individual, as well as methods for treating or preventing tumors in that individual. T-cell receptor (TCR)

[0058] This document provides isolated or purified T cell receptors (TCRs) with antigenic specificity for the peptide-MHC complex, wherein the antigenic peptide has an amino acid mutation site relative to the wild-type sequence, is derived from a mutated KRAS protein, and includes (1) VVGAVGVGK (SEQ ID NO: 91) or (2) VVVGAVGVGK (SEQ ID NO: 92), or consists of these sequences. Given that MHC class I molecules do not impose a strict limitation on the length of the antigenic peptide, the inventors of this document foresee that, based on the antigenic peptide sequences provided herein, one or two amino acid residues may be added or deleted (particularly at the ends) while maintaining the binding capacity of binding proteins or Petition 870250073401, dated 08 / 20 / 2025, p. 47 / 115 34 / 70 TCR molecules described in this document are linked to MHC complexes formed with these antigenic peptide variants.

[0059] The TCRs provided in this document may be in the form of αβ heterodimers or in single-chain form (scTCR). Examples of the single-chain form may include αβ TCR polypeptides with the structures Va-L-νβ, νβ-L-Va, Va—Ca—L-νβ or Va-L-νβCe, where Va and Ve represent, respectively, the variable regions of the α and β chains of the TCR, Ca and Ce are the constant regions of the α and β chains of the TCR, and L is a linker sequence, usually consisting of a short peptide. The linker sequence may be a conventional sequence in the field, frequently used in antibody engineering and TCR engineering. The TCRs provided in this document may also take the form of water-soluble TCR molecules, which do not contain the transmembrane regions of the α and β chains.

[0060] In some embodiments, this document provides TCRs with antigenic specificity for the peptide-MHC complex consisting of VVGAVGVGK (SEQ ID NO: 91) or VVVGAVGVGK (SEQ ID NO: 92). The CDR3 of the variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 5, 15, 25, 36, 45, 55, 65, 75 or 85, or an amino acid sequence having at least 80% identity, preferably at least 85% identity, more preferably 90% or 95% identity with the amino acid sequence represented by SEQ ID NO: 5, 15, 25, 36, 45, 55, 65, 75 or 85; the CDR3 of the variable region of the β chain comprises the amino acid sequence Petition 870250073401, dated 08 / 20 / 2025, p. 48 / 115 35 / 70 represented by SEQ ID NO: 10, 20, 30, 40, 50, 60, 70, 80 or 90, or an amino acid sequence that exhibits at least 80% identity, preferably at least 85% identity, more preferably 90% or 95% identity with the amino acid sequence represented by SEQ ID NO: 10, 20, 30, 40, 50, 60, 70, 80 or 90. Preferably, the MHC molecule is of the HLA-A*11:01 type.

[0061] Additionally, in the variable region of the α chain, CDR1 comprises the amino acid sequence represented by SEQ ID NO: 3, CDR2 comprises the amino acid sequence represented by SEQ ID NO: 3, and CDR3 comprises the amino acid sequence represented by SEQ ID NO: 5, or an amino acid sequence that has at least 80% identity with the sequence represented by SEQ ID NO: 5, preferably at least 85%, more preferably 90% or 95% identity; CDR1 comprises the amino acid sequence represented by SEQ ID NO: 13, CDR2 by SEQ ID NO: 14, and CDR3 by SEQ ID NO: 15, or an amino acid sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 15; CDR1 comprises SEQ ID NO: 23, CDR2 SEQ ID NO: 24 and CDR3 SEQ ID NO: 25, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 25;CDR1 comprises SEQ ID NO: 33, CDR2 SEQ ID NO: 34 and CDR3 SEQ ID NO: 35, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 35; CDR1 comprises SEQ ID NO: 43, CDR2 SEQ ID NO: 44 and CDR3 SEQ ID NO: 45, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 35; Petition 870250073401, dated 08 / 20 / 2025, p. 49 / 115 36 / 70 identity with SEQ ID NO: 45; CDR1 comprises SEQ ID NO: 53, CDR2 SEQ ID NO: 54 and CDR3 SEQ ID NO: 55, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 55; CDR1 comprises SEQ ID NO: 63, CDR2 SEQ ID NO: 64 and CDR3 SEQ ID NO: 65, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 65; CDR1 comprises SEQ ID NO: 73, CDR2 SEQ ID NO: 74 and CDR3 SEQ ID NO: 75, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 75; or CDR1 comprises SEQ ID NO: 83, CDR2 SEQ ID NO: 84 and CDR3 SEQ ID NO: 85, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 85.In the variable region of the β chain, CDR1 comprises the amino acid sequence represented by SEQ ID NO: 8, CDR2 by SEQ ID NO: 9 and CDR3 by SEQ ID NO: 10, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 10; CDR1 comprises SEQ ID NO: 18, CDR2 SEQ ID NO: 19 and CDR3 SEQ ID NO: 20, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 20; CDR1 comprises SEQ ID NO: 28, CDR2 SEQ ID NO: 29 and CDR3 SEQ ID NO: 30, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 30; CDR1 comprises SEQ ID NO: 38, CDR2 SEQ ID NO: 39 and CDR3 SEQ ID NO: 40, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO:. Petition 870250073401, dated 08 / 20 / 2025, p. 50 / 115 37 / 70 40; CDR1 comprises SEQ ID NO: 48, CDR2 SEQ ID NO: 49 and CDR3 SEQ ID NO: 50, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 50; CDR1 comprises SEQ ID NO: 58, CDR2 SEQ ID NO: 59 and CDR3 SEQ ID NO: 60, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 60; CDR1 comprises SEQ ID NO: 68, CDR2 SEQ ID NO: 69 and CDR3 SEQ ID NO: 70, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 70; CDR1 comprises SEQ ID NO: 78, CDR2 SEQ ID NO: 79 and CDR3 SEQ ID NO: 80, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 80;or CDR1 comprises SEQ ID NO: 88, CDR2 SEQ ID NO: 89 and CDR3 SEQ ID NO: 90, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 90. In the variable region of the β chain, CDR1 includes the amino acid sequence represented by SEQ ID NO: 8, CDR2 includes SEQ ID NO: 9 and CDR3 includes SEQ ID NO: 10, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 10; CDR1 includes SEQ ID NO: 18, CDR2 includes SEQ ID NO: 19, CDR3 includes SEQ ID NO: 20, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 20; CDR1 includes SEQ ID NO: 28, CDR2 includes SEQ ID NO: 29, CDR3 includes SEQ ID NO: 30, or a sequence with at least 80%, preferably at least 85%, more; Petition 870250073401, dated 08 / 20 / 2025, p. 51 / 115 38 / 70 preferably 90% or 95% identity with SEQ ID NO: 30; CDR1 includes SEQ ID NO: 38, CDR2 includes SEQ ID NO: 39, CDR3 includes SEQ ID NO: 40, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 40; CDR1 includes SEQ ID NO: 48, CDR2 includes SEQ ID NO: 49, CDR3 includes SEQ ID NO: 50, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 50; CDR1 includes SEQ ID NO: 58, CDR2 includes SEQ ID NO: 59, CDR3 includes SEQ ID NO: 60, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 60; CDR1 includes SEQ ID NO: 68, CDR2 includes SEQ ID NO: 69, CDR3 includes SEQ ID NO: 70, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 70;CDR1 includes SEQ ID NO: 78, CDR2 includes SEQ ID NO: 79, CDR3 includes SEQ ID NO: 80, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 80; or CDR1 includes SEQ ID NO: 88, CDR2 includes SEQ ID NO: 89, CDR3 includes SEQ ID NO: 90, or a sequence with at least 80%, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 90.

[0062] Furthermore, in the described TCR, the variable region of the α chain comprises: CDR1 containing the amino acid sequence represented by SEQ ID NO: 3, CDR2 containing the sequence represented by SEQ ID NO: 4 and CDR3 containing the Petition 870250073401, dated 08 / 20 / 2025, p. 52 / 115 39 / 70 sequence represented by SEQ ID NO: 5, or a sequence with at least 80% identity with SEQ ID NO: 5, preferably at least 85%, more preferably 90% or 95% identity; and the variable region of the β chain comprises: CDR1 containing the sequence represented by SEQ ID NO: 8, CDR2 by SEQ ID NO: 9 and CDR3 by SEQ ID NO: 10, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 10. The variable region of the α chain may further comprise: CDR1 with SEQ ID NO: 13, CDR2 with SEQ ID NO: 14 and CDR3 with SEQ ID NO: 15, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 15; where the β chain comprises: CDR1 with SEQ ID NO: 18, CDR2 with SEQ ID NO: 19 and CDR3 with SEQ ID NO: 20, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 20.The α string may also comprise: CDR1 with SEQ ID NO: 23, CDR2 with SEQ ID NO: 24 and CDR3 with SEQ ID NO: 25, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 25; and the β string: CDR1 with SEQ ID NO: 28, CDR2 with SEQ ID NO: 29 and CDR3 with SEQ ID NO: 30, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 30. The α string may also contain: CDR1 with SEQ ID NO: 33, CDR2 with SEQ ID NO: 34 and CDR3 with SEQ ID NO: 35, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 35; while the β string: CDR1 with SEQ ID NO: 38, CDR2 with SEQ ID NO: 39 and CDR3 with SEQ ID NO: 40, or a sequence. Petition 870250073401, dated 08 / 20 / 2025, p. 53 / 115 40 / 70 with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 40. The α string may also contain: CDR1 with SEQ ID NO: 43, CDR2 with SEQ ID NO: 44 and CDR3 with SEQ ID NO: 45, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 45; and the β string: CDR1 with SEQ ID NO: 48, CDR2 with SEQ ID NO: 49 and CDR3 with SEQ ID NO: 50, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 50. Additionally, the α string may contain: CDR1 with SEQ ID NO: 53, CDR2 with SEQ ID NO: 54 and CDR3 with SEQ ID NO: 55, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 55; and the β string: CDR1 with SEQ ID NO: 58, CDR2 with SEQ ID NO: 59 and CDR3 with SEQ ID NO: 60, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 60.The α string may also comprise: CDR1 with SEQ ID NO: 63, CDR2 with SEQ ID NO: 64 and CDR3 with SEQ ID NO: 65, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 65; and the β string: CDR1 with SEQ ID NO: 68, CDR2 with SEQ ID NO: 69 and CDR3 with SEQ ID NO: 70, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 70. The α string may also contain: CDR1 with SEQ ID NO: 73, CDR2 with SEQ ID NO: 74 and CDR3 with SEQ ID NO: 75, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 75; and the β string: CDR1 with SEQ ID NO: 78, CDR2 with SEQ ID. Petition 870250073401, dated 08 / 20 / 2025, p. 54 / 115 41 / 70 NO: 79 and CDR3 with SEQ ID NO: 80, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 80. Alternatively, the α string may comprise: CDR1 with SEQ ID NO: 83, CDR2 with SEQ ID NO: 84 and CDR3 with SEQ ID NO: 85, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 85; and the β string: CDR1 with SEQ ID NO: 88, CDR2 with SEQ ID NO: 89 and CDR3 with SEQ ID NO: 90, or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 90.

[0063] In some specific embodiments, in the described TCR, the α chain comprises the amino acid sequence represented by SEQ ID NO: 1 or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 1; and the β chain comprises the amino acid sequence represented by SEQ ID NO: 6 or a sequence with at least 80% identity, preferably at least 85%, more preferably 90% or 95% identity with SEQ ID NO: 6. The α chain may also comprise SEQ ID NO: 11 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 11; and the β string may comprise SEQ ID NO: 16 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 16.String α may also comprise SEQ ID NO: 21 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 21; and string β may comprise SEQ ID NO: 26 or a... Petition 870250073401, dated 08 / 20 / 2025, p. 55 / 115 42 / 70 sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 26. Alternatively, the α string may comprise SEQ ID NO: 31 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 31; and the β string may comprise SEQ ID NO: 36 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 36. The α string may also comprise SEQ ID NO: 41 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 41; and the β string may comprise SEQ ID NO: 46 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 46.String α may comprise SEQ ID NO: 51 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 51; and string β may comprise SEQ ID NO: 56 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 56. String α may also comprise SEQ ID NO: 61 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 61; and the β string may comprise SEQ ID NO: 66 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 66. The α string may comprise SEQ ID NO: 71 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 71; and the β string may comprise SEQ ID NO: 76 or a... Petition 870250073401, dated 08 / 20 / 2025, p. 56 / 115 43 / 70 sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 76. Or, the variable region of the α string may comprise SEQ ID NO: 81 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 81; and the β string may comprise SEQ ID NO: 86 or a sequence with at least 80%, preferably 85%, more preferably 90% or 95% identity with SEQ ID NO: 86.

[0064] It will be understood by a professional in the field that, based on the specific sequences provided in this document, it is possible to obtain variants of the TCR molecules described herein by means of substitutions, deletions or additions of a limited number of amino acid residues, followed by validation or screening of the ability to bind to the corresponding pMHC complex or its biological activity. These variants should also be considered included within the scope of this document. For example, the TCR molecules provided in this document may present, in their total length sequence, in the variable region or in the CDR sequences, at least 1 and at most 10 amino acid alterations, and in certain cases the number of alterations does not exceed 5, 4, 3, 2 or even only 1 amino acid residue.For example, at least 1 and at most 10 amino acid changes can be introduced into the variable sequence of the α or β chain, and in certain cases the number of changes does not exceed 5, 4, 3, 2, or 1 residue. Additionally, the CDR sequences of the variable regions of the α or β chains may contain, in total, no more than 5, 4, 3, 2, or 1 alteration. Petition 870250073401, dated 08 / 20 / 2025, p. 57 / 115 44 / 70 amino acid.

[0065] It is expected that the TCRs (or their antigenically specific fragments) described in this document may include conservative amino acid substitutions. Conservative amino acid substitutions are generally described as the replacement of one amino acid residue with another of similar chemical structure, resulting in little or no impact, or minimal impact, on the function, activity, or other biological properties of the polypeptide. Conservative amino acid substitutions are well known in the technical field.Conservative substitutions can, for example, involve replacing one amino acid with another belonging to the same group as the following (a) to (e): (a) small, aliphatic, nonpolar or weakly polar residues: Ala, Ser, Thr, Pro and Gly; (b) polar residues with a negative charge and their respective amides (no charge): Asp, Asn, Glu and Gln; (c) polar residues with a positive charge: His, Arg and Lys; (d) large, nonpolar aliphatic residues: Met, Leu, Ile, Val and Cys; (e) aromatic residues: Phe, Tyr and Trp.

[0066] In certain embodiments, the TCRs provided in this document (or their antigen-specific fragments) may additionally include post-translational modifications. Examples of post-translational protein modifications include: phosphorylation, acetylation, methylation, ADP-ribosylation, ubiquitination, glycosylation, carbonylation, ubiquitin-like modifications, biotinylation, or the addition of polypeptide side chains or hydrophobic groups. Thus, the modified TCRs (or their antigen-specific fragments) Petition 870250073401, dated 08 / 20 / 2025, page 58 / 115 45 / 70 antigenic) may include non-peptidic components, such as lipids, polysaccharides or monosaccharides, as well as phosphate groups. One form of glycosylation is, for example, sialylation modification, in which one or more sialic acid groups are conjugated to the polypeptide. Sialic acid groups improve the solubility and serum half-life of proteins, while reducing their potential immunogenicity.

[0067] When the N-terminal end of the TCR amino acid sequence provided in this document is a methionine residue (M), it is known to professionals in the field that, during the recombinant protein production process, this methionine can be removed. Fusion proteins and immunoconjugates

[0068] This document also provides fusion proteins that include the variable region of the α and / or β chain of the TCR molecule provided here, especially their CDR sequences.

[0069] In certain embodiments, the aforementioned fusion protein is in the form of a single-chain TCR (scTCR). For example, by linking the variable region of the α chain to the variable region of the β chain via a linker sequence, a complete binding domain with antigenic specificity for the corresponding pMHC complex can be formed.

[0070] In certain embodiments, the variable regions of the α and / or β chain of the TCR molecule provided in this document, especially their CDR sequences, can be used to form multispecific TCR molecules. In certain embodiments, the aforementioned Petition 870250073401, dated 08 / 20 / 2025, p. 59 / 115 46 / 70 fusion protein includes at least two functional parts: a first functional part with antigenic specificity for a first pMHC complex, and a second functional part having antigenic specificity identical to or different from the first.

[0071] In certain embodiments, the variable regions of the α and / or β chain of the TCR molecule provided in this document, especially their CDR sequences, can be used to form multispecific fusion proteins. In certain embodiments, said fusion protein includes at least two functional parts: a first functional part with antigenic specificity for a pMHC complex, and a second functional part with antigenic specificity or targeting capability different from the first part. In certain embodiments, the second functional part may be a targeting domain, capable of specifically recognizing and binding to specific tumor antigens, tumor-associated antigens, or other molecules present on the surface of target cells.Examples include antibodies or their antigen-binding fragments (such as scFv), hormones, growth factors, cytokines, as well as any other natural or non-natural ligands that bind to cell surface receptors, such as the epidermal growth factor receptor (EGFR), CD28, the platelet-derived growth factor receptor (PDGFR), the nicotinic acetylcholine receptor (nAChR), among others.

[0072] In certain embodiments, the binding domain of an antibody molecule (e.g., a Petition 870250073401, dated 08 / 20 / 2025, page 60 / 115 The classic tetrameric antibody (47 / 70) can be replaced by the TCR molecule provided in this document (or by the variable regions of the α and β chains, or even by the binding domain formed by them), in order to form a recombinant antibody molecule with the antigenic specificity of that TCR. In certain embodiments, the variable region of the α chain of the TCR molecule is used to replace the two variable regions of the heavy chains of an antibody, binding to the respective constant regions of the heavy chains; simultaneously, the variable region of the β chain replaces the two variable regions of the light chains of the antibody, binding to the respective constant regions of the light chains.In certain embodiments, the variable region of the β chain of the TCR molecule is used to replace the two variable regions of the heavy chains of an antibody, binding to the respective constant regions of the heavy chains; simultaneously, the variable region of the α chain replaces the two variable regions of the light chains of the antibody, binding to the respective constant regions of the light chains. In certain embodiments, the variable region of the α chain and the variable region of the β chain of the TCR molecule are used to replace, respectively, a variable region of the heavy chain and a variable region of the light chain of an antibody, leaving one of the original antigen-binding domains of the antibody unchanged. In this way, a bispecific recombinant antibody molecule is obtained, capable of recognizing both the pMHC complex and the original target antigen of the antibody. The recombinant antibody molecule thus formed can... Petition 870250073401, dated 08 / 20 / 2025, page 61 / 115 48 / 70 perform typical antibody effector functions through their constant region (such as the Fc fragment), including, for example, mediating complement-dependent cellular cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and facilitating phagocytosis. Additionally, fusion to the Fc fragment can increase the half-life of TCR molecules (or the variable regions of the α and β chains, or the binding domain they form) in the body, allowing for longer intervals between administrations when these molecules are used as therapeutic agents. In certain embodiments, the aforementioned Fc fragment can be derived from the constant region of an immunoglobulin, such as IgG1, IgG2, or IgG4.

[0073] In certain embodiments, the TCR molecules provided in this document (or the variable regions of the α and β chains, or the binding domain formed by them) can be used as an extracellular binding domain in the construction of chimeric antigen receptors (CARs). For example, the variable regions of the α and β chains can be linked via a linker sequence, forming a binding molecule similar to an scFv, which replaces the conventional extracellular binding domain of a CAR, and is then linked to the transmembrane region and intracellular signaling domains. This CAR construct is directed to the pMHC complex recognized by the original TCR molecule and, through the intracellular signaling domains of the CAR, activates the T cell that expresses it, triggering the desired immunological effects, such as the destruction of target cells.

[0074] In certain embodiments, the TCR molecule Petition 870250073401, dated 08 / 20 / 2025, p. 62 / 115 49 / 70 (or the variable regions of the α and β chains, or the binding domain formed by them) can be linked to a conjugate to form an immunoconjugate, said conjugate being, for example, a detection tag, a therapeutic agent, a screening marker, among others.

[0075] In certain embodiments, the TCR molecule (or the variable regions of the α and β chains, or the binding domain formed by them) can be linked to a protein tag, forming a fusion protein. Protein tags can include purification tags and detection tags. Purification tags include, but are not limited to: His6 tag, Flag tag, MBP tag, GST tag, SUMO tag, among others. Detection tags can be used to indicate the presence or quantity of the TCR molecule (or the variable regions of the α and β chains, or the binding domain formed by them) in a sample, or even to track the location of this molecule within the organism or cells of the individual. Examples of detection tags include various enzymes used in immunochemical assays, such as horseradish peroxidase (HRP) and alkaline phosphatase (ALP), as well as fluorescent proteins, such as GFP (green fluorescent protein).Due to the specific binding capacity of the TCR molecule (or the variable regions of the α and β chains, or the binding domain formed by them) to the corresponding pMHC complex, the amount of the TCR molecule (or the variable regions of the α and β chains, or the binding domain formed by them) can be determined by measuring the amount of the detection tag attached to the TCR. Petition 870250073401, dated 08 / 20 / 2025, p. 63 / 115 50 / 70 Consequently, it is possible to infer the amount of the corresponding pMHC complex present in the sample. When the corresponding pMHC complex is used as a tumor marker, the aforementioned fusion protein can be employed for tumor detection and diagnosis.

[0076] In other embodiments, the TCR molecule provided in this document (or the variable regions of the α and β chains, or the binding domain formed by them) can be linked to cytokines or therapeutic proteins, forming fusion proteins. In this case, the specific binding capacity of the TCR molecule (or the variable regions of the α and β chains, or the binding domain formed by them) to the corresponding pMHC complex can be used to target the cytokine or therapeutic protein specifically to certain tissues or cells, thus enabling the desired therapeutic effect of the cytokine or therapeutic protein.

[0077] In certain embodiments, the TCR molecule (or the variable regions of the α and β chains, or the binding domain formed by them) can be conjugated to chemotherapeutic agents, such as asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, among others, in order to allow the targeted delivery of these agents to specific cells or tissues through the antigenic specificity of the TCR.

[0078] In certain embodiments, the TCR molecule (or the variable regions of the α and β chains, or the binding domain formed by them) can be conjugated to isotopes Petition 870250073401, dated 08 / 20 / 2025, p. 64 / 115 51 / 70 radioactive materials, such as 3H, 14C or 35S, for screening or therapeutic purposes. Host cells for expression of TCR molecules

[0079] This document also provides host cells that express the TCR molecule provided in this document (or the variable regions of the α and β chains, or the binding domain formed by them).

[0080] The host cells used refer to any type of cell capable of expressing the TCR molecule provided in this document (or the variable regions of the α and β chains, or the binding domain formed by them). Preferably, the host cell expresses the complete TCR molecule, including the variable and constant regions of the α and β chains, as well as the transmembrane and intracellular regions. The host cell can be a eukaryotic or prokaryotic cell. Preferably, the host cell is a mammalian cell. Most preferably, the host cell is a human cell. Although the host cell can be of any cell type, originate from any tissue type, and belong to any developmental stage, it is preferred that the host cell be a peripheral blood lymphocyte (PBL) or a peripheral blood mononuclear cell (PBMC).Even more preferably, the host cell is a T lymphocyte. For the purposes of this document, T cells may be any T cells, such as cultured T cells, for example, primary T cells or T cells from cultured cell lines, such as Jurkat, SupTl, among others, or T cells obtained from mammals. When obtained. Petition 870250073401, dated 08 / 20 / 2025, page 65 / 115 In mammals, T cells (52 / 70) can be isolated from various sources, including but not limited to blood, bone marrow, lymph nodes, thymus, or other tissues or fluids. T cells can also be enriched or purified. T cells can be of any type and at any stage of development, including but not limited to: double-positive CD4+ / CD8+ T cells, CD4+ helper T cells (such as Th1 and Th2 cells), CD4+ T cells, CD8+ T cells (e.g., cytotoxic T cells), tumor-infiltrating lymphocytes (TILs), memory T cells (e.g., central memory T cells and effector memory T cells), naive T cells, among others.

[0081] This document also provides host cells that express the CAR provided in this document. Preferably, the host cell is a human cell, especially a human T cell or a human NK cell.

[0082] The functionality of host cells expressing TCR or CAR (such as T cells) can be assessed by various methods. In certain embodiments, the cytotoxic capacity of host cells expressing TCR or CAR (such as T cells) can be assessed by incubating these cells with target cells and measuring the quantity or activity of the target cells, for example, by detecting LDH release. In certain embodiments, the immune effect of host cells expressing TCR or CAR (such as T cells) can be assessed by incubating these cells with target cells and measuring IFN-γ secretion or CD69 expression by the cells. Petition 870250073401, dated 08 / 20 / 2025, page 66 / 115 53 / 70 host plants. Pharmaceutical compositions and therapeutic methods

[0083] The TCR molecules provided in this document (or the variable regions of the α and β chains, or the binding domain formed by them), as well as the fusion proteins or immunoconjugates that include them, may be formulated with acceptable pharmaceutical vehicles to compose a pharmaceutical composition intended for administration to an individual for the prevention or treatment of tumors.

[0084] In certain embodiments, the TCR molecules provided in this document (or the variable regions of the α and β chains, or the binding domain formed by them), as well as the fusion proteins or immunoconjugates that include them, can be administered in combination with one or more other drugs, such as antitumor agents.

[0085] In some embodiments, the disease or condition to be treated is a tumor, especially a tumor that expresses the antigenic peptides VVGAVGVGK (SEQ ID NO: 91) or VVVGAVGVGK (SEQ ID NO: 92). These tumors include, but are not limited to: acute lymphoblastic leukemia, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, anal cancer, anal canal cancer or anorectal cancer, eye cancer, intrahepatic cholangiocarcinoma, joint cancer, cervical cancer, gallbladder cancer or pleural mesothelioma, nasal cancer, nose cancer, or middle ear cancer, oral cancer, vaginal cancer, vulvar cancer, chronic lymphocytic leukemia, chronic myeloid cancer, colorectal cancer, endometrial cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumors, Petition 870250073401, dated 08 / 20 / 2025, page 67 / 115 54 / 70 glioma, Hodgkin's lymphoma, hypopharyngeal cancer, renal cancer, laryngeal cancer, hepatic cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharyngeal cancer, non-Hodgkin's lymphoma, oropharyngeal cancer, ovarian cancer, penile cancer, pancreatic cancer, peritoneal cancer, omental cancer and mesenteric cancer, pharyngeal cancer, prostate cancer, rectal cancer, renal cancer, skin cancer, small bowel cancer, soft tissue cancer, gastric cancer, testicular cancer, thyroid cancer, uterine cancer, ureteral cancer and bladder cancer. Preferred cancers include pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer, ovarian cancer, prostate cancer, among others.

[0086] Nucleic acid molecules encoding the TCR molecules provided in this document (or the variable regions of the α and β chains, or the binding domain formed by them), as well as fusion proteins or immunoconjugates that include them, including expression vectors containing such nucleic acid molecules, and host cells (such as T cells or CAR cells) transfected with such nucleic acid molecules or expression vectors, can also be used in various ways for the aforementioned therapeutic purposes. For example, expression vectors can be introduced into the individual's body by known gene therapy methods, promoting the expression of the desired protein or polypeptide (such as the TCR molecules provided in this document, or the variable regions of the α and β chains, or the binding domain formed by them, Petition 870250073401, dated 08 / 20 / 2025, page 68 / 115 55 / 70 as well as the fusion proteins or immunoconjugates that include them), in order to achieve the intended therapeutic effect.

[0087] The effective dose for this application may depend on the severity of the disease and the overall state of the patient's immune system. The administration regimen may also vary depending on the disease state and the individual's conditions, generally ranging from a single bolus administration or continuous infusion to multiple daily administrations (e.g., every 4 to 6 hours). An experienced clinician can, for example, easily determine if an individual is a candidate for this treatment using clinical trials, physical examinations, and the individual's family history. Diagnostic or treatment kits

[0088] The TCR molecules provided in this document (or the variable regions of the α and β chains, or the binding domain formed by them), as well as the fusion proteins or immunoconjugates that include them, can specifically bind to the corresponding pMHC complex present in a sample. By detecting the amount of the ternary complex formed (i.e., TCR-antigenic peptide-MHC molecule), it is possible to conveniently determine the amount (or presence) of the corresponding pMHC complex in the sample.

[0089] To this end, as described above, the TCR molecules provided in this document (or the variable regions of the α and β chains, or the binding domain formed by them) can be coupled to various detection tags, facilitating their identification by various Petition 870250073401, dated 08 / 20 / 2025, page 69 / 115 56 / 70 methods, including but not limited to bioluminescence, fluorescence, radioactive labeling, or the production of enzymatic reaction products. After determining the amount of the corresponding pMHC complex in the sample, comparison with normal levels found in healthy individuals can be used to assess the disease status or severity in the individual who provided the sample. Repeated monitoring over time of variations in the amount of the corresponding pMHC complex during the individual's treatment can also be used to assess the effectiveness of the therapy, thus providing a basis for adjusting the therapeutic regimen as needed.

[0090] The TCR molecules provided in this document (or the variable regions of the α and β chains, or the binding domain formed by them), as well as the fusion proteins or immunoconjugates that include them, or the host cells that express them, may be packaged in containers to form diagnostic or treatment kits. These containers may take the form of boxes, vials, small bottles, tubes, bags or other suitable forms known in the technical field. These containers may be made of plastic, glass, foil, metal foil or other materials suitable for the preservation of pharmaceuticals. When necessary, the container may be supplied together with an instruction leaflet.The instruction leaflet may include information on the use of TCR molecules (or the variable regions of the α and β chains, or the binding domain they form), the compositions containing them, and the host cells for the treatment or prevention of... Petition 870250073401, dated 08 / 20 / 2025, pp. 70 / 115 57 / 70 tumors. This information may include, for example: descriptions of therapeutic agents (such as TCR molecules, nucleic acid molecules, host cells, among others); dosage regimens for the treatment or prevention of neoplasms; precautions; warnings; indications; contraindications; adverse effects; pharmacological data in animals; clinical trials; and / or bibliographic references. The instruction leaflet may be printed directly on the container (if present), or presented as a label affixed to the container, or provided as a separate document on paper, booklet, card or foldable material included inside the container or delivered together with it. Experimental materials and reagents: 1. PBMC of healthy individuals 2. Target peptide: A*11:01 KRAS-G12V-9 peptide: VVGAVGVGK (SEQ ID NO: 91) A*11:01 KRAS-G12V-10 peptide: VVVGAVGVGK (SEQ ID NO: 92) 3. Brilliant Violet 510™ anti-human CD3 Antibody: Biolegend 300448 4. APC antibody anti-human CD8a: BioLegend 300912 5. PE-KRAS-G12V-Pentamer: PROIMMUNE 6. Chromium Next GEM Single Cell V(D)J v1.1 Reagent Kits 7. Lentiviral vector 8. Polybrene Viral Enhancer: Merck Millipore TR1003-G 9. Anti-CD3 / CD28 magnetic beads: novoprotein GMPB038 10. X-VIVO 15: lonza 04418q Petition 870250073401, dated 08 / 20 / 2025, page 71 / 115 58 / 70 11. OKM-100: CansBio sj18 12. RPMI 1640: gibco 11875-093 13. LDH reagent kit: dojindo 14. Human IFN-γ Reagent Kit: Excell Bio EH008-96 15. IFN-γ ELISPOT: Mabtech 3420-4AST-10 16. APC anti-human CD69 Antibody: Biolegend 310910 Equipment and Instruments Flow cytometer: BD LSRFortessa Flow cytometry classifier: SONY SH800S Microplate reader (spectrophotometer): Molecular Devices SpectraMax i3x Imaging system for ELISPOT: Bio-sys Bioreader 6000-Ee. FlowJo graphing and analysis software. GraphPad Prism 8.0.1 Implementation Examples

[0091] After stimulating T cells from three healthy donors with dendritic cells loaded with the mutated peptide KRAS G12V 9 (VVGAVGVGK) (SEQ ID NO: 91), the proportion of A*11:01-KRAS G12V specific T cells was evaluated by pentamer staining and flow cytometry analysis using the BD LSRFortessa. Subsequently, the specific T cells were enriched and selected using the SONY SH800S flow cytometer, and the data were analyzed with FlowJo software. The resulting flow cytometry graph is shown in Figure 1. The enriched cells were subjected to 10x single-cell sequencing, obtaining the paired chains of TCRa and TCRe.

[0092] A lentiviral vector containing the Petition 870250073401, dated 08 / 20 / 2025, page 72 / 115 59 / 70 TCR gene of the present invention and its translation into T lymphocytes. T cells transduced with different TCRs were co-incubated for 16 hours with (1) K562 cells expressing HLA-A*11:01 loaded with different peptides (G12V-9: VVGAVGVGK (SEQ ID NO: 91), G12V-10: VVVGAVGVGK (SEQ ID NO: 92), WT peptide: VVGAGGVGK (SEQ ID NO: 93) + VVVGAGGVGK (SEQ ID NO: 94)) and (2) BxPC3 cells expressing HLA-A*11:01, co-expressing HLA-A*11:01 and KRASG12V, or co-expressing HLA-A*11:01 and KRAS-G12D (effector cell ratio: (target cell = 5:1). The cytotoxic capacity of the different TCRs was evaluated by detecting LDH release. Statistical analysis of the data was performed using Graphpad Prism 8.0.1 software, and the results are shown in Figures 2A and 2B.T lymphocytes transduced with different TCRs demonstrated effective specific cytotoxic activity against target cells expressing HLA-A*11:01 loaded with KRAS G12V-9 or KRAS G12V-10 peptides, as well as against cells overexpressing KRAS G12V.

[0093] The release of IFN-γ after stimulation of T cells transduced with the specific TCR with the KRAS G12V-9 peptide (VVGAVGVGK) (SEQ ID NO: 91), in a 1:1 ratio between effector and target cells, is shown in Figure 3. Primary T cells expressing the exemplary TCR of this disclosure produced significant amounts of IFN-γ only in the presence of specific stimulation by the target.

[0094] T cells transduced with the specific TCR were co-incubated with target cells loaded with different concentrations of the KRAS G12V-9 peptide. Petition 870250073401, dated 08 / 20 / 2025, page 73 / 115 60 / 70 (VVGAVGVGK) (SEQ ID NO: 91), with IFN-γ release (number of spots) and CD69 expression used to evaluate the EC50 of different TCRs, as shown in Figures 4A and 4B. The EC50 concentration for the recognition of the KRAS G12V-9 peptide by the TCRs ranged from 1 nM to 10 nM. As illustrated in Figure 4C, TCR1 showed an approximately 10-fold difference between the EC50 values ​​for the recognition of the KRAS G12V-9 and G12V-10 peptides, with the EC50 for the 9th peptide being 2.24 nM and for the 10th peptide being 31.3 nM.

[0095] Some of the amino acid sequences mentioned in this document are presented below. Amino acid sequence of the α chain of TCR1 MRQVARVIVFLTLSTLSLAKTTQPISMDSYEGQEVNITCSHNNIATNDYITWYQQFPSQ GPRFIIQGYKTKVTNEVASLFIPADRKSSTLSLPRVSLSDTAVYYCLVGALSSSWYGQN FVFGPGTRLSVLPYIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITD KTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFE TDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 1) Amino acid sequence of the variable (V) region of the α chain of TCR1 LAKTTQPISMDSYEGQEVNITCSHNNIATNDYITWYQQFPSQGPRFIIQGYKTKVTNEV ASLFIPADRKSSTLSLPRVSLSDTAVYYCLVGALSSSWYGQNFVFGPGTRLSVLP (SEQ ID NO: 2) Amino acid sequence of CDR1 of the α chain of TCR1 NIATNDY (SEQ ID NO: 3) Amino acid sequence of CDR2 of the α chain of TCR1 GYKTK (SEQ ID NO: 4) Amino acid sequence of CDR3 of the α chain of TCR1 LVGALSSSWYGQNFV (SEQ ID NO: 5) Amino acid sequence of the β chain of TCR1 Petition 870250073401, dated 08 / 20 / 2025, page 74 / 115 61 / 70 MGCRLLCCVVFCLLQAGPLDTAVSQTPKYLVTQMGNDKSIKCEQNLGHDTMYWYKQDSK KFLKIMFSYNNKELIINETVPNRFSPKSPDKAHLNLHINSLELGDSAVYFCASSQSGAQ DGYTFGSGTRLTVVEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSW WVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLS ENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLV SALVLMAMVKRKDF (SEQ ID NO: 6) Amino acid sequence of the variable region (V) of the TCR1 β chain DTAVSQTPKYLVTQMGNDKSIKCEQNLGHDTMYWYKQDSKKFLKIMFSYNNKELIINET VPNRFSPKSPDKAHLNLHINSLELGDSAVYFCASSQSGAQDGYTFGSGTRLTVV (SEQ ID NO: 7) Amino acid sequence of CDR1 of the β chain of TCR1 LGHDT (SEQ ID NO: 8) Amino acid sequence of CDR2 of the β chain of TCR1 YNNKEL (SEQ ID NO: 9) Amino acid sequence of CDR3 of the β chain of TCR1 ASSQSGAQDGYT (SEQ ID NO: 10) Amino acid sequence of the α chain of TCR2 MAMLLGASVLILWLQPDWVNSQQKNDDQQVKQNSPSLSVQEGRISILNCDYTNSMFDYF LWYKKYPAEGPTFLISISSIKDKNEDGRFTVFLNKSAKHLSLHIVPSQPGDSAVYFCAA KDNAGNMLTFGGGTRLMVKPHIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKD SDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVK LVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 11) Amino acid sequence of the V region of the α chain of TCR2 DQQVKQNSPSLSVQEGRISILNCDYTNSMFDYFLWYKKYPAEGPTFLISISSIKDKNED GRFTVFLNKSAKHLSLHIVPSQPGDSAVYFCAAKDNAGNMLTFGGGTRLMVKP (SEQ ID NO: 12) Amino acid sequence of CDR1 of the α chain of TCR2 NSMFDY (SEQ ID NO: 13) Amino acid sequence of CDR2 of the α chain of TCR2 Petition 870250073401, dated 08 / 20 / 2025, pp. 75 / 115 62 / 70 ISSIKDK (SEQ ID NO: 14) Amino acid sequence of CDR3 of the α chain of TCR2 AAKDNAGNMLT (SEQ ID NO: 15) Amino acid sequence of the β chain of TCR2 MGSRLLCWVLLCLLGAGPVKAGVTQTPRYLIKTRGQQVTLSCSPISGHRSVSWYQQTPG QGLQFLFEYFSETQRNKGNFPGRFSGRQFSNSRSEMNVSTLELGDSALYLCASSLGTAE AFFGQGTRLTVVEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWV NGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSEN DEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSA LVLMAMVKRKDF (SEQ ID NO: 16) Amino acid sequence of the V region of the β chain of TCR2 KAGVTQTPRYLIKTRGQQVTLSCSPISGHRSVSWYQQTPGQGLQFLFEYFSETQRNKGN FPGRFSGRQFSNSRSEMNVSTLELGDSALYLCASSLGTAEAFFGQGTRLTVV (SEQ ID NO: 17) Amino acid sequence of CDR1 of the β chain of TCR2 SGHRS (SEQ ID NO: 18) Amino acid sequence of CDR2 of the β chain of TCR2 YFSETQ (SEQ ID NO: 19) Amino acid sequence of CDR3 of the β chain of TCR2 ASSLGTAEAF (SEQ ID NO: 20) Amino acid sequence of the α chain of TCR3 MAMLLGASVLILWLQPDWVNSQQKNDDQQVKQNSPSLSVQEGRISILNCDYTNSMFDYF LWYKKYPAEGPTFLISISSIKDKNEDGRFTVFLNKSAKHLSLHIVPSQPGDSAVYFCAA NSGYALNFGKGTSLLVTPHIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSD VYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLV EKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 21) Amino acid sequence of the V region of the α chain of TCR3 DQQVKQNSPSLSVQEGRISILNCDYTNSMFDYFLWYKKYPAEGPTFLISISSIKDKNED GRFTVFLNKSAKHLSLHIVPSQPGDSAVYFCAANSGYALNFGKGTSLLVTP (SEQ ID NO: 22) Petition 870250073401, dated 08 / 20 / 2025, page 76 / 115 63 / 70 Amino acid sequence of CDR1 of the α chain of TCR3 NSMFDY (SEQ ID NO: 23) Amino acid sequence of CDR2 of the α chain of TCR3 ISSIKDK (SEQ ID NO: 24) Amino acid sequence of CDR3 from the α chain of TCR3 AANSGYALN (SEQ ID NO: 25) Amino acid sequence of the β chain of TCR3 MGSRLLCWVLLCLLGAGPVKAGVTQTPRYLIKTRGQQVTLSCSPISGHRSVSWYQQTPG QGLQFLFEYFSETQRNKGNFPGRFSGRQFSNSRSEMNVSTLELGDSALYLCASSLGGVG NEQFFGPGTRLTVLEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSW WVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLS ENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLV SALVLMAMVKRKDSRG (SEQ ID NO: 26) Amino acid sequence of the V region of the β chain of TCR3 KAGVTQTPRYLIKTRGQQVTLSCSPISGHRSVSWYQQTPGQGLQFLFEYFSETQRNKGN FPGRFSGRQFSNSRSEMNVSTLELGDSALYLCASSLGGVGNEQFFGPGTRLTVL (SEQ ID NO: 27) Amino acid sequence of CDR1 of the TCR3 β chain SGHRS (SEQ ID NO: 28) Amino acid sequence of CDR2 of the TCR3 β chain YFSETQ (SEQ ID NO: 29) Amino acid sequence of CDR3 of the β chain of TCR3 ASSLGGVGNEQF (SEQ ID NO: 30) Amino acid sequence of the α chain of TCR4 MMKSLRVLLVILWLQLSWVWSQQKEVEQNSGPLSVPEGAIASLNCTYSDRGSQSFFWYR QYSGKSPELIMFIYSNGDKEDGRFTAQLNKASQYVSLLIRDSQPSDSATYLCAVERGST LGRLYFGRGTQLTVWPDIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVY ITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEK SFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 31) Amino acid sequence of the V region of the α chain of TCR4 Petition 870250073401, dated 08 / 20 / 2025, page 77 / 115 64 / 70 QKEVEQNSGPLSVPEGAIASLNCTYSDRGSQSFFWYRQYSGKSPELIMFIYSNGDKEDG RFTAQLNKASQYVSLLIRDSQPSDSATYLCAVERGSTLGRLYFGRGTQLTVWP (SEQ ID NO: 32) Amino acid sequence of CDR1 of the TCR4 α chain DRGSQS (SEQ ID NO: 33) Amino acid sequence of CDR2 of the α chain of TCR4 IYSNGD (SEQ ID NO: 34) Amino acid sequence of CDR3 of the α chain of TCR4 AVERGSTLGRLY (SEQ ID NO: 35) Amino acid sequence of the β chain of TCR4 MGTSLLCWVVLGFLGTDSVSTDHTGAGVSQSPRYKVTKRGQDVTLRCDPISSHATLYWY QQALGQGPEFLTYFNYEAQPDKSGLPSDRFSAERPEGSISTLTIQRTEQRDSAMYRCAS SLSSPTGGPINEQFFGPGTRLTVLEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATG FYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHF RCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILL GKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 36) Amino acid sequence of the V region of the TCR4 β chain GAGVSQSPRYKVTKRGQDVTLRCDPISSHATLYWYQQALGQGPEFLTYFNYEAQPDKSG LPSDRFSAERPEGSISTLTIQRTEQRDSAMYRCASSLSSPTGGPINEQFFGPGTRLTVL (SEQ ID NO: 37) Amino acid sequence of CDR1 of the TCR4 β chain SSHAT (SEQ ID NO: 38) Amino acid sequence of CDR2 of the β chain of TCR4 FNYEAQ (SEQ ID NO: 39) Amino acid sequence of CDR3 of the β chain of TCR4 ASSLSSPTGGPINEQF (SEQ ID NO: 40) Amino acid sequence of the α chain of TCR5 MKTFAGFSFLFLWLQLDCMSRGEDVEQSLFLSVREGDSSVINCTYTDSSSTYLYWYKQE PGAGLQLLTYIFSNMDMKQDQRLTVLLNKKDKHLSLRIADTQTGDSAIYFCAESPGGGA DGLTFKGTHLIIQPYIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYI Petition 870250073401, dated 08 / 20 / 2025, page 78 / 115 65 / 70 TDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKS FETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 41) Amino acid sequence of the V region of the TCR5 α chain GEDVEQSLFLSVREGDSSVINCTYTDSSSTYLYWYKQEPGAGLQLLTYIFSNMDMKQDQ RLTVLLNKKDKHLSLRIADTQTGDSAIYFCAESPGGGADGLTFGKGTHLIIQP (SEQ ID NO: 42) Amino acid sequence of CDR1 of the TCR5 α chain DSSSTY (SEQ ID NO: 43) Amino acid sequence of CDR2 of the TCR5 α chain IFSNMDM (SEQ ID NO: 44) Amino acid sequence of CDR3 of the TCR5 α chain AESPGGGADGLT (SEQ ID NO: 45) Amino acid sequence of the β chain of TCR5 MLLLLLLLGPGSGLGAVVSQHPSWVICKSGTSVKIECRSLDFQATTMFWYRQFPKQSLM LMATSNEGSKATYEQGVEKDKFLINESLTLSTLTVTSAHPEDSSFYICSAPRGWAAGV YGYTFGSGTRLTVVEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSW WVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLS ENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLV SALVLMAMVKRKDF (SEQ ID NO: 46) Amino acid sequence of the V region of the β chain of TCR5 GAVVSQHPSWVICKSGTSVKIECRSLDFQATTMFWYRQFPKQSLMLMATSNEGSKATYE QGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYICSAPRGWAAGVYGYTFGSGTRLTVV (SEQ ID NO: 47) Amino acid sequence of CDR1 of the TCR5 β chain DFQATT (SEQ ID NO: 48) Amino acid sequence of CDR2 of the TCR5 β chain SNEGSKA (SEQ ID NO: 49) Amino acid sequence of CDR3 of the β chain of TCR5 SAPRGWAAGVYGYT (SEQ ID NO: 50) Amino acid sequence of the α chain of TCR6 Petition 870250073401, dated 08 / 20 / 2025, pp. 79 / 115 66 / 70 MLLELIPLLGIHFVLRTARAQSVTQPDIHITVSEGASLELRCNYSYGATPYLFWYVQSP GQGLQLLLKYFSGDTLVQGIKGFEAEFKRSQSSFNLRKPSVHWSDAAEYFCAVGASREY GNKLVFGAGTILRVKSYIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVY ITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEK SFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 51) Amino acid sequence of the V region of the TCR6 α chain AQSVTQPDIHITVSEGASLELRCNYSYGATPYLFWYVQSPGQGLQLLLKYFSGDTLVQG IKGFEAEFKRSQSSFNLRKPSVHWSDAAEYFCAVGASREYGNKLVFGAGTILRVKS (SEQ ID NO: 52) Amino acid sequence of CDR1 of the α chain of TCR6 YGATPY (SEQ ID NO: 53) Amino acid sequence of CDR2 of the α chain of TCR6 YFSGDTLV (SEQ ID NO: 54) Amino acid sequence of CDR3 of the α chain of TCR6 AVGASREYGNKLV (SEQ ID NO: 55) Amino acid sequence of the β chain of TCR6 MDTRVLCCAVICLLGAGLSNAGVMQNPRHLVRRRGQEARLRCSPMKGHSHVYWYRQLPE EGLKFMVYLQKENIIDESGMPKERFSAEFPKEGPSILRIQQVVRGDSAAYFCASSPGGL LHFGNGTRLTVTEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSEN DEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSA LVLMAMVKRKDF (SEQ ID NO: 56) Amino acid sequence of the V region of the TCR6 β chain NAGVMQNPRHLVRRRGQEARLRCSPMKGHSHVYWYRQLPEEGLKFMVYLQKENIIDESG MPKERFSAEFPKEGPSILRIQQVVRGDSAAYFCASSPGGLLHFGNGTRLTVT (SEQ ID NO: 57) Amino acid sequence of CDR1 of the TCR6 β chain KGHSH (SEQ ID NO: 58) Amino acid sequence of CDR2 of the β chain of TCR6 LQKENI (SEQ ID NO: 59) Petition 870250073401, dated 08 / 20 / 2025, pp. 80 / 115 67 / 70 Amino acid sequence of CDR3 of the β chain of TCR6 ASSPGGLLH (SEQ ID NO: 60) Amino acid sequence of the α chain of TCR7 MAMLLGASVLILWLQPDWVNSQQKNDDQQVKQNSPSLSVQEGRISILNCDYTNSMFDYF LWYKKYPAEGPTFLISISSIKDKNEDGRFTVFLNKSAKHLSLHIVPSQPGDSAVYFCAG KTNTGNQFYFGTGTSLTVIPNIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKD SDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVK LVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 61) Amino acid sequence of the V region of the α chain of TCR7 DQQVKQNSPSLSVQEGRISILNCDYTNSMFDYFLWYKKYPAEGPTFLISISSIKDKNED GRFTVFLNKSAKHLSLHIVPSQPGDSAVYFCAGKTNTGNQFYFGTGTSLTVIP (SEQ ID NO: 62) Amino acid sequence of CDR1 of the α chain of TCR7 NSMFDY (SEQ ID NO: 63) Amino acid sequence of CDR2 of the α chain of TCR7 ISSIKDK (SEQ ID NO: 64) Amino acid sequence of CDR3 of the α chain of TCR7 AGKTNTGNQFY (SEQ ID NO: 65) Amino acid sequence of the β chain of TCR7 MGSRLLCWVLLCLLGAGPVKAGVTQTPRYLIKTRGQQVTLSCSPISGHRSVSWYQQTPG QGLQFLFEYFSETQRNKGNFPGRFSGRQFSNSRSEMNVSTLELGDSALYLCASSSGHPE AFFGQGTRLTVVEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWV NGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSEN DEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSA LVLMAMVKRKDF (SEQ ID NO: 66) Amino acid sequence of the V region of the TCR7 β chain KAGVTQTPRYLIKTRGQQVTLSCSPISGHRSVSWYQQTPGQGLQFLFEYFSETQRNKGN FPGRFSGRQFSNSRSEMNVSTLELGDSALYLCASSSGHPEAFFGQGTRLTVV (SEQ ID NO: 67) Amino acid sequence of CDR1 of the β chain of TCR7 Petition 870250073401, dated 08 / 20 / 2025, page 81 / 115 68 / 70 SGHRS (SEQ ID NO: 68) Amino acid sequence of CDR2 of the TCR7 β chain YFSETQ (SEQ ID NO: 69) Amino acid sequence of CDR3 of the TCR7 β chain ASSSGHPEAF (SEQ ID NO: 70) Amino acid sequence of the α chain of TCR8 METALLGVSLVILWLQLARVNSQQGEEDPQALSIQEGENATMNCSYKTSINLQWYRQNS GRGLVHLILIRSNEREKHSGRLRVTLDTSKKSSLLITASRAADTASYFCATDAGGGAD GLTFGKGTHLIIQPYIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYIT DKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSF ETDTNLNFQNLSVIGFRILLLKVAGFNLLMSEQRL (Sequence ID: 17) amino acids of the V region of the α chain of the TCR8 SQQGEEDPQALSIQGENATMNCSYKTSINNLQWYRQNSGRGLVHLILILIRSNEREKHSG RLRVTLDTSKKSSLLITASRAADTASYFCATDAGGADGLTFGKGTHLIIQP (SEQ ID NO: 72) Amino acid sequence of CDR1 of the α chain of TCR8 TSINN (SEQ ID NO: 73) Amino acid sequence of the CDR2 of the α chain of TCR8 IRSNERE (SEQ ID NO: 74) Amino acid sequence of the CDR3 of the α chain of TCR8 ATDAGGGADGLT (SEQ ID NO: 75) Amino acid sequence of the β chain of TCR8 MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVYWYQQSLD QGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGDSALYFCASSESRDS GNTIYFGEGSWLTVVEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELS WWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGL SENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVL VSALVLMAMVKRKDF (SEQ ID NO: 76) Amino acid sequence of the V region of the β chain of TCR8 DSGVTQTPKHLITATGQRVTLRCSPRSGDLSVYWYQQSLDQGLQFLIQYYNGEERAKGN Petition 870250073401, dated 08 / 20 / 2025, page 82 / 115 69 / 70 ILERFSAQQFPDLHSELNLSSLELGDSALYFCASSESRDSGNTIYFGEGSWLTVV (SEQ ID NO: 77) Amino acid sequence of CDR1 of the TCR8 β chain SGDLS (SEQ ID NO: 78) Amino acid sequence of CDR2 of the TCR8 β chain YYNGEE (SEQ ID NO: 79) Amino acid sequence of CDR3 of the TCR8 β chain ASSESRDSGNTIY (SEQ ID NO: 80) Amino acid sequence of the α chain of TCR9 METLLGVSLVILWLQLARVNSQQGEEDPQALSIQEGENATMNCSYKTSINNLQWYRQNS GRGLVHLILIRSNEREKHSGRLRVTLDTSKKSSSLLITASRAADTASYFCATDSGGGAD GLTFGKGTHLIIQPYIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYIT DKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSF ETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 81) Amino acid sequence of the V region of the α chain of TCR9 SQQGEEDPQALSIQEGENATMNCSYKTSINNLQWYRQNSGRGLVHLILIRSNEREKHSG RLRVTLDTSKKSSSLLITASRAADTASYFCATDSGGGADGLTFGKGTHLIIQP (SEQ ID NO: 82) Amino acid sequence of CDR1 of the α chain of TCR9 TSINN (SEQ ID NO: 83) Amino acid sequence of CDR2 of the α chain of TCR9 IRSNERE (SEQ ID NO: 84) Amino acid sequence of CDR3 of the α chain of TCR9 ATDSGGGADGLT (SEQ ID NO: 85) Amino acid sequence of the β chain of TCR9 MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVYWYQQSLD QGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGDSALYFCASTPGRDS GNTIYFGEGSWLTVVEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELS WWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGL SENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVL Petition 870250073401, dated 08 / 20 / 2025, page 83 / 115 70 / 70 VSALVLMAMVKRKDF (SEQ ID NO: 86) Amino acid sequence of the V region of the β chain of TCR9 DSGVTQTPKHLITATGQRVTLRCSPRSGDLSVYWYQQSLDQGLQFLIQYYNGEERAKGN ILERFSAQQFPDLHSELNLSSLELGDSALYFCASTPGRDSGNTIYFGEGSWLTVV (SEQ ID NO: 87) Amino acid sequence of CDR1 of the TCR9 β chain SGDLS (SEQ ID NO: 88) Amino acid sequence of CDR2 of the TCR9 β chain YYNGEE (SEQ ID NO: 89) Amino acid sequence of CDR3 of the TCR9 β chain ASTPGRDSGNTIY (SEQ ID NO: 90) Petition 870250073401, dated 08 / 20 / 2025, p. 84 / 115

Claims

1 / 17 CLAIMS 1. A binding protein, characterized in that it comprises a binding domain specific for an antigenic peptide: HLA complex, said binding domain being constituted by the variable region of the α chain of the T cell receptor (TCR) and the variable region of the β chain of the TCR, wherein: said antigenic peptide includes the amino acid sequence VVGAVGVGK (SEQ ID NO: 91); said HLA is HLA-A*11:01; The CDR3 of the variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 65, 5, 15, 25, 35, 45, 55, 75 or 85, or an amino acid sequence with at least 80% or 90% identity with the sequences represented by SEQ ID NO: 65, 5, 15, 25, 35, 45, 55, 75 or 85.

1. The CDR3 of the variable region of the β chain comprises the amino acid sequence represented by SEQ ID NO: 70, 10, 20, 30, 40, 50, 60, 80 or 90, or an amino acid sequence with at least 80% or 90% identity with the sequences represented by SEQ ID NO: 70, 10, 20, 30, 40, 50, 60, 80 or 90.

2. A binding protein according to claim 1, characterized in that the antigenic peptide is VVGAVGVGK (SEQ ID NO: 91) or VVVGAVGVGK (SEQ ID NO: 92).

3. A binding protein according to claim 1, characterized in that the variable region of the α chain comprises: 1) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 63, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 64, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 65, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 65; 2) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 3, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 4, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 5, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 5; 3) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 13, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 14, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 15, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 15; 4) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 23, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 24, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 25, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 25; 5) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 33, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 34, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 35, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 35; 6) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 43, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 44, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 45, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 45; 7) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 53, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 54, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 55, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 55; 8) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 73, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 74, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 75, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 75; or 9) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 83, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 84, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 85, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by Petition 870250076270, dated 08 / 28 / 2025, page 9 / 23 4 / 17 SEQ ID NO:

85. In the variable region of the β chain: 1) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 68, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 69, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 70, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 70;2) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 8, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 9, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 10, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 10; 3) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 18, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 19, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 20, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 20;4) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 28, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 29, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 30, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 30; Petition 870250076270, dated 08 / 28 / 2025, p. 10 / 23 5 / 17 5) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 38, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 39, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 40, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 40;6) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 48, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 49, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 50, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 50; 7) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 58, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 59, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 60, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 60;8) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 78, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 79, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 80, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 80;or 9) CDR1 comprising the amino acid sequence represented by SEQ ID NO: 88, CDR2 comprising the sequence Petition 870250076270, dated 08 / 28 / 2025, p. 11 / 23 6 / 17 of amino acids represented by SEQ ID NO: 89, and CDR3 comprises the amino acid sequence represented by SEQ ID NO: 90, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO:

90.

4. Binding protein, according to claim 1, characterized in that: 1) In the variable region of the α chain, CDR1 comprises the amino acid sequence represented by SEQ ID NO: 63, CDR2 comprises the amino acid sequence represented by SEQ ID NO: 64, and CDR3 comprises the amino acid sequence represented by SEQ ID NO: 65, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 65;1) In the variable region of the β chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 68, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 69, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 70, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 70; 2) In the variable region of the α chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 3, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 4, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 5, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 5;In the variable region of the β chain, CDR1 comprises the amino acid sequence represented by SEQ ID NO: 8, CDR2 comprises the amino acid sequence represented by SEQ ID NO: 9, and CDR3 comprises the amino acid sequence represented by SEQ ID NO: 10, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 10; 3) In the variable region of the α chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 13, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 14, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 15, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 15;In the variable region of the β chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 18, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 19, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 20, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 20; 4) In the variable region of the α chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 23, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 24, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 25, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 25;in the variable region of the β chain, CDR1 shall comprise the amino acid sequence represented by SEQ ID NO: 28, CDR2 shall comprise the amino acid sequence represented by SEQ ID NO: 29, and CDR3 shall comprise the amino acid sequence represented by SEQ ID NO: 30, or an amino acid sequence with at least 80% or 90% identity to the sequence represented by SEQ ID NO: 30; 5) In the variable region of the α chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 33, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 34, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 35, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 35;In the variable region of the β chain, CDR1 comprises the amino acid sequence represented by SEQ ID NO: 38, CDR2 comprises the amino acid sequence represented by SEQ ID NO: 39, and CDR3 comprises the amino acid sequence represented by SEQ ID NO: 40, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 40; 6) In the variable region of the α chain, CDR1 comprises the amino acid sequence represented by SEQ ID NO: 43, CDR2 comprises the amino acid sequence represented by SEQ ID NO: 44, and CDR3 comprises the amino acid sequence represented by SEQ ID NO: 45, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 45;in the variable region of the β chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 48, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 49, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 50, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 50; 7) In the variable region of the α chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 53, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 54, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 55, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 55;In the variable region of the β chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 58, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 59, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 60, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 60; 8) In the variable region of the α chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 73, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 74, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 75, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 75;in the variable region of the β chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 78, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 79, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 80, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 80; or Petition 870250076270, dated 08 / 28 / 2025, p. 15 / 23 10 / 17 9) In the variable region of the α chain, CDR1 comprises the amino acid sequence represented by SEQ ID NO: 83, CDR2 comprises the amino acid sequence represented by SEQ ID NO: 84, and CDR3 comprises the amino acid sequence represented by SEQ ID NO: 85, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO: 85;in the variable region of the β chain, CDR1 comprising the amino acid sequence represented by SEQ ID NO: 88, CDR2 comprising the amino acid sequence represented by SEQ ID NO: 89, and CDR3 comprising the amino acid sequence represented by SEQ ID NO: 90, or an amino acid sequence with at least 80% or 90% identity with the sequence represented by SEQ ID NO:

90.

5. Binding protein, according to claim 1, characterized in that: 1) The variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 2, or an amino acid sequence with at least 85% or 90% identity with the sequence represented by SEQ ID NO: 2; the variable region of the β chain comprises the amino acid sequence represented by SEQ ID NO: 7, or an amino acid sequence with at least 85% or 90% identity with the sequence represented by SEQ ID NO: 7;2) The variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 12, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 12; the variable region of the β chain comprises the amino acid sequence represented by SEQ ID NO: 17, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 17; 3) The variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 22, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 22; the variable region of the β chain shall comprise the amino acid sequence represented by SEQ ID NO: 27, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 27;4) The variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 32, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 32; the variable region of the β chain comprises the amino acid sequence represented by SEQ ID NO: 37, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 37; 5) The variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 42, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 42; the variable region of the β chain comprises the amino acid sequence represented by SEQ ID NO: 47, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 47;6) The variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 52, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 52; Petition 870250076270, dated 08 / 28 / 2025, p. 17 / 23 12 / 17 the variable region of the β chain comprises the amino acid sequence represented by SEQ ID NO: 57, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 57; 7) The variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 62, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 62; the variable region of the β chain shall comprise the amino acid sequence represented by SEQ ID NO: 67, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 67;8) The variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 72, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 72; the variable region of the β chain comprises the amino acid sequence represented by SEQ ID NO: 77, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 77; or 9) The variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 82, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 82; the variable region of the β chain comprises the amino acid sequence represented by SEQ ID NO: 87, or an amino acid sequence with at least 85% or 90% identity to the sequence represented by SEQ ID NO: 87;Preferably, the aforementioned binding protein Petition 870250076270, dated 08 / 28 / 2025, p. 18 / 23 13 / 17 comprises the TCR α chain and the TCR β chain, in which: 1) The α chain comprises the amino acid sequence represented by SEQ ID NO: 1, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 1; the β chain comprises the amino acid sequence represented by SEQ ID NO: 6, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 6; 2) The α chain comprises the amino acid sequence represented by SEQ ID NO: 11, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 11;The β chain comprises the amino acid sequence represented by SEQ ID NO: 16, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 16; 3) The α chain comprises the amino acid sequence represented by SEQ ID NO: 21, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 21; the β chain comprises the amino acid sequence represented by SEQ ID NO: 26, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 26;4) The α chain comprises the amino acid sequence represented by SEQ ID NO: 31, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 31; the β chain comprises the amino acid sequence represented by SEQ ID NO: 36, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 36; 5) The α chain comprises the amino acid sequence represented by SEQ ID NO: 41, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 41;The β chain comprising the amino acid sequence represented by SEQ ID NO: 46, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 46; 6) The α chain comprises the amino acid sequence represented by SEQ ID NO: 51, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 51; the β chain comprising the amino acid sequence represented by SEQ ID NO: 56, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 56; 7) The α chain comprises the amino acid sequence represented by SEQ ID NO: 61, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 61;The β chain comprises the amino acid sequence represented by SEQ ID NO: 66, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 66; 8) The α chain comprises the amino acid sequence represented by SEQ ID NO: 71, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 71; the β chain comprises the amino acid sequence represented by SEQ ID NO: 76, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 76;or 9) The variable region of the α chain comprises the amino acid sequence represented by SEQ ID NO: 81, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO: 81; the β chain comprises the amino acid sequence represented by SEQ ID NO: 86, or an amino acid sequence with at least 85% identity, more preferably 90% identity, with the sequence represented by SEQ ID NO:

86.

6. Binding protein, according to claim 1, characterized in that it comprises: 1) a TCR molecule; 2) an antibody molecule; or 3) a CAR molecule.

7. Binding protein, according to claim 1, characterized in that it further comprises a conjugate covalently or non-covalently linked to said domain. Petition 870250076270, dated 08 / 28 / 2025, p. 21 / 23 16 / 17 connection;Preferably, said conjugate is a detectable marker, a radioactive isotope, or a therapeutic agent.

8. Isolated nucleic acid molecule, characterized in that it encodes the binding protein, the variable region of the α chain, the variable region of the β chain, the α chain, or the β chain, as defined in claim 1.

9. Vector, characterized in that it comprises the nucleic acid molecule as defined in claim 8.

10. Host cell, characterized in that it expresses the binding protein as defined in claim 1 or comprises the nucleic acid molecule as defined in claim 8 or the vector as defined in claim 9; preferably, said host cell is a mammalian cell, more preferably a human cell;Preferably, said host cell is a T cell or an NK cell.

11. Pharmaceutical composition, characterized in that it comprises: 1) The binding protein as defined in claim 1, the nucleic acid molecule as defined in claim 8, the vector as defined in claim 9 or the host cell as defined in claim 10;and 2) An acceptable pharmaceutical vehicle.

12. Use of the binding protein, as defined in claim 1, of the nucleic acid molecule as defined in claim 8, of the vector as defined in claim 9 or of the host cell as defined in claim 10, characterized in that it is directed to the preparation of a medicament for the treatment of tumors, wherein said tumor expresses an antigenic peptide, said antigenic peptide being VVGAVGVGK (SEQ ID NO: 91) or VVVGAVGVGK (SEQ ID NO: 92).

13. Use, according to claim 12, characterized in that the tumor is selected from pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, endometrial cancer and ovarian cancer. Petition 870250076270, dated 08 / 28 / 2025, page 23 / 23;

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