Antigen recognition constructs that bind specific peptides with determinable affinity, and T cell receptors with antigen specificity for KRAS, as well as corresponding nucleic acid sequences, vectors, host cells, pharmaceutical compositions, and kits

Abstract

The invention relates inter alia to an antigen recognition construct that binds a specific peptide with a determinable affinity, a T cell receptor with antigen specificity for KRAS, a nucleic acid sequence encoding said antigen recognition construct or said T cell receptor, a vector comprising said nucleic acid sequence, and a host cell comprising said antigen recognition construct or said T cell receptor. The invention also relates to the antigen recognition construct or T cell receptor, the nucleic acid sequence, the vector, or the host cell for use in medicine or in the prevention and / or treatment of disease. Furthermore, the invention relates to methods of treating disease, as well as pharmaceutical compositions and kits.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims priority to European Patent Application No. 22152794.8, filed January 21, 2022, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present invention relates to an antigen recognition construct that binds the peptide VVGAVGVGK (SEQ ID NO: 1) with a determinable affinity, a T cell receptor (TCR) with antigen specificity for mutant KRAS, a nucleic acid sequence encoding said antigen recognition construct or said T cell receptor, a respective vector comprising the nucleic acid sequence, and a host cell comprising the antigen recognition construct or T cell receptor. The present invention also relates to the antigen recognition construct or T cell receptor, the nucleic acid sequence, the vector, or the host cell for use in medicine or for use in the prevention and / or treatment of a disease. Furthermore, the present invention relates to the use of the antigen recognition construct or T cell receptor, the nucleic acid sequence, the vector, or the host cell for the manufacture of a medicament for treating a disease. The present invention also relates to a method of treating a disease, comprising the step of administering a therapeutically effective amount of the antigen recognition construct or T cell receptor, the nucleic acid sequence, the vector, or the host cell. In addition, the present invention also relates to pharmaceutical compositions comprising the antigen recognition constructs or T cell receptors, nucleic acid sequences, vectors, or host cells of the invention, and respective kits for use in medicine. [Background technology]

[0003] Ras family proteins are small GTPases that are involved in the transmission of signals within cells, including, for example, the transmission of cell growth.Examples of RAS proteins include KRAS (also called CK-RAS, CFC2, K-RAS2A, KRAS2B, K-RAS4A, K-RAS4B, KI-RAS, KRAS1, KRAS2, NS, NS3, RALD, RASK2, K-ras, KRAS proto-oncogene, GTPase, and c-Ki-ras2), HRAS, and NRAS.Mutations in RAS proteins that inhibit negative growth signaling can lead to the sustained proliferation of cells.

[0004] When activated, mutant KRAS binds guanosine-5'-triphosphate (GTP) and converts GTP to guanosine-5'-diphosphate (GDP). The mutant KRAS protein product can be constitutively activated.

[0005] Mutant KRAS proteins can be expressed in any of a variety of human cancers, such as pancreatic cancer (e.g., pancreatic carcinoma), colorectal cancer, lung cancer (e.g., lung adenocarcinoma), endometrial cancer, ovarian cancer (e.g., ovarian epithelial carcinoma), prostate cancer, melanoma, thyroid cancer, and breast cancer, as well as in some cases of myeloid leukemia, such as AML. Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there is a need for new therapies that target mutant RAS proteins.It is therefore an object of the present invention to provide such treatments. [Means for solving the problem]

[0007] This object is achieved, inter alia, by antigen recognition constructs, TCRs, nucleic acids, vectors, host cells, methods, compositions and kits having the features of the respective independent claims.

[0008] In a first aspect, the present invention provides an antigen recognition construct which binds the peptide VVGAVGVGK (SEQ ID NO: 1) with a determinable affinity, wherein the antigen recognition construct comprises a complementarity determining region 3 (CDR3) of the α chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 16, 4, 22, and 28, and / or wherein the antigen recognition construct comprises a complementarity determining region 3 (CDR3) of the β chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 19, 7, 25, and 31.

[0009] In a second aspect, the present invention provides a T cell receptor (TCR) having antigen specificity for mutant KRAS, the TCR comprising: (a) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:8; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 9; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 11; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or (b) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 17; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or (c) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:2; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO:3; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:5; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:6, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 21; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 23; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 27; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and It comprises a β chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0010] In a third aspect, the present invention provides a nucleic acid sequence encoding an antigen recognition construct or a T cell receptor.

[0011] In a fourth aspect, the present invention provides a vector comprising the nucleic acid sequence.

[0012] In a fifth aspect, the present invention provides a host cell comprising an antigen recognition construct or a T cell receptor, a nucleic acid sequence, or a vector of the invention.

[0013] In a sixth aspect, the present invention provides an antigen recognition construct or T cell receptor, a nucleic acid sequence, a vector, or a host cell of the invention for use in medicine or in the prevention and / or treatment of disease.

[0014] In a seventh aspect, the present invention provides the use of an antigen recognition construct or T cell receptor, a nucleic acid sequence, a vector, or a host cell for the manufacture of a medicament for treating a disease.

[0015] In an eighth aspect, the present invention provides a method of treating a disease comprising administering a therapeutically effective amount of an antigen recognition construct or T cell receptor, or a nucleic acid sequence, or a vector, or a host cell of the present invention.

[0016] In a ninth aspect, the present invention provides a pharmaceutical composition comprising an antigen recognition construct or a T cell receptor, a nucleic acid sequence, a vector, or a host cell of the invention.

[0017] In a tenth aspect, the present invention provides a kit for use in medicine comprising an antigen recognition construct or a T cell receptor, or a nucleic acid sequence, or a vector, or a host cell of the invention.

[0018] The invention will be better understood with reference to the detailed description considered in conjunction with the non-limiting examples and drawings. [Brief description of the drawings]

[0019] [Figure 1] FIG. 1 shows TCR or mock transduced peripheral blood leukocytes (PBLs) from human donors co-cultured with KRASG12V expressing cell lines (intact or transduced with HLA-A*11:01) or cultured alone ("T cells"). PMA and ionomycin stimulation ("P / I") was used as a positive control for T cell activation. IFNγ secretion in culture supernatants upon T cell activation was measured by ELISA. [Diagram 2] Figure 2 shows TCR-transduced PBLs from human donors co-cultured with HLA-A*11:01 expressing cells loaded with descending concentrations (10-6M to 10-12M) of the recognition peptide (VVGAVGVGK). IFNγ secretion in culture supernatants upon T cell activation was measured by ELISA. Normalized IFNγ secretion curves are shown. [Diagram 3] Figure 3 shows the expression of TCR on the surface of TCR-transduced CD8+ T cells from two donors as analyzed by flow cytometry. TCR expression was measured by staining cells with anti-mouse TCR β chain or HLA-A*11:01-VVGAVGVGK dextramer ("Dex"). TCR expression is expressed as mean fluorescence intensity (MFI) normalized to the TCR of CT1. [Figure 4] Figure 4 shows TCR-transduced human PBLs co-cultured with HLA-A*11:01 expressing cell lines. CFPAC-1 cells expressed KRASG12V ("CFPAC-1-A11") or K-562 cells were loaded with the recognition peptide (VVGAVGVGK, 10-6M) ("K562-A11+G12V"). Unloaded K-562 cells served as a negative control ("K562-A11"). Protein secretion in culture supernatants upon T cell activation was measured by multi-analyte bead flow assay. [Diagram 5] FIG. 5 shows SEQ ID NOs: 32-41, which show the full-length sequences of the α and β chains in TCR4-13, 3-13, 3-14, 3-7, and 3-10 of the present invention. The variable regions are underlined, and the constant regions are bolded. The term "variable region" may also be referred to as "variable domain" as used herein, and both terms may be used interchangeably. The term "constant region" may also be referred to as "constant domain" as used herein, and both terms may be used interchangeably. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] As mentioned above, in a first aspect, the present invention is directed to an antigen recognition construct which binds the peptide VVGAVGVGK (SEQ ID NO: 1) with a determinable affinity, the antigen recognition construct comprising a complementarity determining region 3 (CDR3) of the α chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 16, 4, 22, and 28, and / or the antigen recognition construct comprising a complementarity determining region 3 (CDR3) of the β chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 19, 7, 25, and 31. Thus, the first aspect of the invention also includes an antigen recognition construct which binds the peptide VVGAVGVGK (SEQ ID NO:1) with a determinable affinity, wherein the antigen recognition construct comprises a complementarity determining region 3 (CDR3) of the α chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 16, 4, 22, and 28, or wherein the antigen recognition construct comprises a complementarity determining region 3 (CDR3) of the β chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 19, 7, 25, and 31.The first aspect of the invention may also be directed to an antigen recognition construct that binds the peptide VVGAVGVGK (SEQ ID NO: 1) with a determinable affinity, the antigen recognition construct comprising a complementarity determining region 3 (CDR3) of the α chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 16, 4, 22, and 28, and the antigen recognition construct comprising a complementarity determining region 3 (CDR3) of the β chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 19, 7, 25, and 31. The first aspect of the invention may also be directed to an antigen recognition construct that binds the peptide VVGAVGVGK (SEQ ID NO:1) with a determinable affinity, wherein the antigen recognition construct comprises a complementarity determining region 3 (CDR3) of the α chain having 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:10, and / or wherein the antigen recognition construct comprises a complementarity determining region 3 (CDR3) of the β chain having 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:13.

[0021] The peptide VVGAVGVGK (SEQ ID NO: 1) is a mutant KRAS peptide, i.e., the region of amino acids 8 to 16 of KRAS carrying the point mutation G12V (KRAS G12V) mutant KRAS peptide. Thus, as used herein, the term "mutant KRAS" or "mutation target" may specifically refer to the G12V point mutant at amino acids 8-16 of KRAS. The peptide VVGAVGVGK (SEQ ID NO: 1) is thus a mutant KRAS epitope, respectively. Thus, the antigen recognition construct or TCR in the present invention binds with determinable affinity the mutant KRAS epitope / peptide of VVGAVGVGK (SEQ ID NO: 1) (KRAS G12V ) has the ability to bind.

[0022] As used herein, the term "with a determinable affinity" refers to an antigen recognition construct or T cell receptor of the present invention that recognizes each peptide with a specific affinity, i.e., at least 10 4 M -1 As used herein, the term "affinity constant" refers to the equilibrium association constant Ka. Lower affinities are generally less important in practical applications because they can no longer be accurately recorded by conventional measurement methods. An antigen-recognizing construct or T cell receptor can bind with an affinity constant of at least 10, which corresponds to an equilibrium dissociation constant Kd of, for example, 100 μM. 4 M -1 The binding affinity of the antigen recognition construct or T cell receptor to each peptide can be determined by one of skill in the art using a number of methods, for example, using fluorescence titration, using competitive ELISA, or using surface plasmon resonance techniques.

[0023] The term "epitope" or "antigenic epitope" includes any molecule, structure, amino acid sequence, or protein determinant that is recognized and specifically bound by a cognate binding molecule, such as an immunoglobulin, T cell receptor (TCR), chimeric antigen receptor, or other binding molecule, domain, or protein. Epitopic determinants generally comprise chemically active surface groupings of molecules such as amino acids or sugar side chains and may have specific three dimensional structural characteristics, as well as specific charge characteristics.

[0024] The antigen recognition construct in the first aspect of the invention may be an antibody or a fragment thereof, or a T cell receptor (TCR) or a fragment thereof.

[0025] Thus, it is within the scope of the first aspect of the invention that the antigen recognition construct is an antibody or a fragment thereof. The term "antibody" in its various grammatical forms is used herein to refer to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antibody binding site or paratope. Such molecules are also referred to as "antigen-binding fragments" of immunoglobulin molecules. The present invention further provides antibodies or antigen-binding portions thereof that specifically bind to the antigens described herein. The antibody can be any type of immunoglobulin known in the art. For example, the antibody can be any isotype, e.g., IgA, IgD, IgE, IgG, IgM, etc. The antibody can be monoclonal or polyclonal. The antibody can be an antibody of natural origin, e.g., an antibody isolated and / or purified from a mammal, e.g., mouse, rabbit, goat, horse, chicken, hamster, human, etc. Alternatively, the antibody can be a genetically engineered antibody, e.g., a humanized antibody or a chimeric antibody. The antibody can be in monomeric or multimeric form.

[0026] A "T cell" or "T lymphocyte" is a cell of the immune system that matures in the thymus and produces a T cell receptor (TCR). T cells are classified as naive ("T N"; not exposed to antigen; T CM increased expression of CD62L, CCR7, CD28, CD3, CD127, and CD45RA, and decreased or absent expression of CD45RO compared to control T cells), including stem cell memory T cells (T M ) (antigen-experienced and long-lived), as well as effector cells (antigen-experienced and cytotoxic). M In addition, central memory T cells (T EM , CD62L, CCR7, CD28, CD95, CD45RO, and CD127), and effector memory T cells (T EM effector T cells (T E ) expresses CD45RA and is associated with T CM CD4+ refers to antigen-experienced CD8+ cytotoxic T lymphocytes that have reduced expression of CD62L, CCR7, and CD28 compared to CD4+, and are positive for granzymes and perforin. CD4+ cells affect the activity of other immune cells by releasing cytokines. CD4+ T cells can activate and suppress adaptive immune responses, and which of the two functions is elicited may depend on the presence of other cells and signals. T cells can be harvested using known techniques, and various subpopulations or combinations thereof can be enriched or depleted by known techniques, for example, affinity binding to antibodies, flow cytometry, immunomagnetic selection, and the like. Other example T cells include regulatory T cells, such as CD4+CD25+(Foxp3+) regulatory T cells and Treg17 cells, as well as Tr1, Th3, and Qa-1 restricted T cells.

[0027] "T cell receptor" (TCR) refers to a member of the immunoglobulin superfamily having a variable binding domain, a constant domain, a transmembrane region, and a short cytoplasmic tail, and capable of specifically binding to antigenic peptides bound to an MHC receptor, see, e.g., Janeway et al., Immunobiology: The Immune System in Health and Disease, 3rd Ed., Current Biology Publications, p. 433, 1997. TCRs are found on the surface of cells or in soluble form and generally comprise a heterodimer having an α and β chain (also known as TCRα and TCRβ, respectively), or a γ and δ chain (also known as TCRγ and TCRδ, respectively). Polynucleotides encoding the binding proteins of the disclosure, such as TCRs, can be codon optimized to enhance expression in a particular host cell, such as a cell of the immune system, a hematopoietic stem cell, a T cell, a primary T cell, a T cell line, a NK cell, or a natural killer T cell (Scholten el al., Clin. Immunol. 119:135, 2006).

[0028] The terms "complementarity determining region" and "CDR" are synonymous with "hypervariable region" or "HVR" and are known in the art to refer to amino acid sequences in immunoglobulin or TCR variable regions that confer antigen specificity and / or binding affinity and are separated from each other in the primary amino acid sequence by framework regions. Generally, there are three CDRs in each TCR α chain variable region (αCDR1, αCDR2, αCDR3) and three CDRs in each TCR β chain variable region (βCDR1, βCDR2, βCDR3). In TCRs, CDR3 is considered to be the main CDR responsible for recognition of processed antigen. Generally, CDR1 and CDR2 interact primarily or exclusively with MHC.

[0029] The antigen recognition construct was approximately 1 × 10 -6 Median effective concentration EC less than M 50and capable of specifically binding the peptide VVGAVGVGK (SEQ ID NO: 1). In a specific example, the antigen recognition construct is capable of specifically binding the peptide VVGAVGVGK (SEQ ID NO: 1) at about 1×10 -8 Less than M, about 2 x 10 -8 Less than M or about 6 x 10 -8 EC below M 50 and capable of specifically binding the peptide VVGAVGVGK (SEQ ID NO: 1). 50 The value of can be determined by the procedure performed in Example 2 described herein.

[0030] As used herein, the term "specifically binds" refers to a binding between an antigen recognition construct (e.g., a TCR receptor) and a target peptide that is more than 10 4 M -1 (The on-rate in this association reaction [k on ] and off rate [k off ]) a (i.e., the equilibrium association constant for a particular binding interaction in units of 1 / M), while not significantly associating or binding with any other molecules or components in a sample.

[0031] The antigen recognition construct in the first aspect of the present invention, which binds the peptide VVGAVGVGK (SEQ ID NO: 1), may be presented by an MHC I molecule. For example, the MHC I molecule may be an HLA-A molecule. The HLA-A molecule may be, for example, HLA-A*11:01. An example amino acid sequence of HLA-A*11:01 is IMGT / HLA Accession No. HLA00043 (see https: / / www.ebi.ac.uk / ipd / imgt / hla / alleles / allele / ?accession=HLA00043).

[0032] There are two classes of MHC molecules: MHC class I and MHC class II. Peptide-MHC class I complexes are recognized by CD8+ T cells bearing the appropriate T cell receptor (TCR), whereas peptide-MHC class II molecule complexes are recognized by CD4+ T cells bearing the appropriate TCR. Both types of CD8 and CD4 T cell-dependent responses jointly and synergistically contribute to antitumor effects, so the identification and characterization of tumor-associated and tumor-specific antigens and their corresponding T cell receptors are important in the development of cancer immunotherapies, such as vaccines and cell therapies.

[0033] It is within the scope of the first aspect of the invention that the antigen recognition construct is capable of binding peptides with at least 80% antigen specificity. It is within the scope of the first aspect of the invention that the antigen recognition construct is capable of binding peptides with at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% antigen specificity.

[0034] As used herein, the term "antigen specificity" means that the antigen recognition construct is capable of specifically binding to and immunologically recognizing a mutant target, e.g., mutant KRAS. This may refer to the ability to specifically recognize an antigen as a unique molecular entity and distinguish it from others with exquisite precision. For example, the antigen recognition construct may be capable of expressing approximately 1×10 6 cells / ml of the antigen recognition construct when co-cultured with (a) antigen-negative HLA-A11:01 target cells instantaneously treated with a low concentration of the mutant target peptide (e.g., about 0.05 ng / mL to about 5 ng / mL, 0.05 ng / mL, 0.1 ng / mL, 0.5 ng / mL, 1 ng / mL, 5 ng / mL, or a range defined by any two of the above values), or (b) antigen-negative HLA-A11:01 target cells into which a nucleotide sequence encoding the mutant target has been introduced such that the target cells express the mutant target. 4 ~Approx. 1×10 5 T cells may be considered to have "antigen specificity" for the mutant target if they secrete IFNγ at least about 200 pg / mL or more (e.g., 200 pg / mL or more, 300 pg / mL or more, 400 pg / mL or more, 500 pg / mL or more, 600 pg / mL or more, 700 pg / mL or more, 1,000 pg / mL or more, 5,000 pg / mL or more, 7,000 pg / mL or more, 10,000 pg / mL or more, 20,000 pg / mL or more, or a range defined by any two of the above values). Cells expressing the antigen recognition constructs of the present invention may also secrete IFNγ when co-cultured with antigen-negative HLA-A11:01 target cells pulsed with high concentrations of the mutant target peptide.

[0035] Any antibody molecule that specifically binds KRAS can be used herein.Antibody molecule can be, for example, a polyclonal antibody, a monoclonal antibody, or a fragment typically derived from a monoclonal antibody, such as a bivalent antigen-binding antibody fragment, a monovalent antigen-binding antibody fragment, etc.Examples of suitable bivalent antibody fragments are (Fab)2'-fragments, bivalent single-chain Fv fragments, or bivalent single-domain camelid antibodies (also known as nanobodies), which can be obtained by making such single-domain camelid antibodies as fusion proteins with linkers between two single-domain camelid antibodies.Examples of suitable monovalent antibody fragments include, but are not limited to, Fab fragments, Fv fragments, or single-chain Fv fragments (scFv).

[0036] Specifically, as described above, the antigen recognition construct may be a T cell receptor (TCR), which may comprise a complementarity determining region 1 (CDR1) of the α chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 14, 2, 20, and 26, and / or a complementarity determining region 1 (CDR1) of the β chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 5, 23, and 29. Furthermore, the T cell receptor may comprise a complementarity determining region 1 (CDR1) of the α chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NO:8, and / or the T cell receptor comprises a complementarity determining region 1 (CDR1) of the β chain having 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:11.

[0037] Further, the T cell receptor may comprise a complementarity determining region 2 (CDR2) of the α chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 15, 3, 21, and 27; and / or the T cell receptor may comprise a complementarity determining region 2 (CDR2) of the β chain having 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%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 18, 6, 24, and 30. Further, the T cell receptor may comprise a complementarity determining region 2 (CDR2) of the α chain having 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:9, and / or the T cell receptor may comprise a complementarity determining region 2 (CDR2) of the β chain having 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:12.

[0038] Also, in the first aspect of the present invention, the T cell receptor may comprise a complementarity determining region 3 (CDR3) of the α chain having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 16, 4, 22, and 28, and / or the T cell receptor may comprise a complementarity determining region 3 (CDR3) of the β chain having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 19, 7, 25, and 31. Also, in the first aspect of the present invention, the T cell receptor may comprise a complementarity determining region 3 (CDR3) of the α chain having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 10, and / or the T cell receptor may comprise a complementarity determining region 3 (CDR3) of the β chain having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 13. The T cell receptor may comprise a complementarity determining region 1 (CDR1) of the α chain having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 14, 2, 20, and 26, and / or a complementarity determining region 1 (CDR1) of the β chain having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 5, 23, and 29.The T cell receptor may comprise a complementarity determining region 1 (CDR1) of the α chain having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:8, and / or the T cell receptor may comprise a complementarity determining region 1 (CDR1) of the β chain having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:11. The T cell receptor may comprise a complementarity determining region 2 (CDR2) of the α chain having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 15, 3, 21, and 27, and / or the T cell receptor may comprise a complementarity determining region 2 (CDR2) of the β chain having at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 18, 6, 24, and 30.

[0039] The T cell receptor in the first aspect of the present invention is (a) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:8; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; or (b) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 15; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; or (c) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:2; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO:3; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and It may comprise an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:28.

[0040] The T cell receptor in the first aspect of the present invention is (a) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or (b) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or (c) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:5; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:6, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (d) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or (e) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and It may comprise a β chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0041] The T cell receptor in the first aspect of the present invention is (a) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:8; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 9; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 11; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or (b) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 17; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or (c) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:2; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO:3; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:5; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:6, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 21; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 23; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 27; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and It may comprise a β chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0042] The T cell receptor in the first aspect of the present invention is (a) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 8, 9, and 10, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 11, 12, and 13; or (b) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 14, 15, and 16, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 17, 18, and 19; or (c) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 2, 3, and 4, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 5, 6, and 7; or (d) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 20, 21, and 22, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 23, 24, and 25; or (e) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 26, 27, and 28, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 29, 30, and 31.

[0043] The T cell receptor in the first aspect of the present invention is (a) an amino acid sequence which has at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 32, and / or an amino acid sequence which has at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 33, or (b) an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 34, and / or an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 35, or (c) an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 36, and / or an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 37, or (d) an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 38, and / or an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 39, or (e) an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO:40, and / or an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO:41. The variable domains or regions of each SEQ ID NO: are indicated by underlining in Table 2 and Figure 5 herein.

[0044] The T cell receptor in the first aspect of the present invention is (a) an α chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 32, and / or a β chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 33, or (b) an α chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 34, and / or a β chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 35, or (c) an α chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 36, and / or a β chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 37, or (d) an α chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 38, and / or a β chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 39, or (e) an alpha chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 40, and / or or a β-strand comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:41.

[0045] In yet a further aspect, the present invention provides a T cell receptor (TCR) having antigen specificity for mutant KRAS, the TCR comprising: (a) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:8; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; or (b) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 15; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; or (c) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:2; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO:3; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and It comprises an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:28.

[0046] In yet a further aspect, the present invention provides a T cell receptor (TCR) having antigen specificity for mutant KRAS, the TCR comprising: (a) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or (b) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or (c) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:5; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:6, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (d) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or (e) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and It comprises a β chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0047] In a second aspect, the present invention provides a T cell receptor (TCR) having antigen specificity for mutant KRAS, the TCR comprising: (a) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:8; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 9; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 11; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or (b) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 17; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or (c) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:2; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO:3; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:5; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:6, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 21; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 23; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 27; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and It may comprise a β chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:31.

[0048] In a second aspect, the present invention provides a T cell receptor (TCR) having antigen specificity for mutant KRAS, the TCR comprising: (a) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 8, 9, and 10, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 11, 12, and 13; or (b) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 14, 15, and 16, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 17, 18, and 19; or (c) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 2, 3, and 4, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 5, 6, and 7; or (d) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 20, 21, and 22, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 23, 24, and 25; or (e) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 26, 27, and 28, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 29, 30, and 31.

[0049] In a second aspect, the present invention provides a T cell receptor (TCR) having antigen specificity for mutant KRAS, the TCR comprising: (a) an amino acid sequence which has at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 32, and / or an amino acid sequence which has at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 33, or (b) an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 34, and / or an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 35, or (c) an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 36, and / or an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 37, or (d) an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 38, and / or an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 39, or (e) an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO:40, and / or an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the variable domain of SEQ ID NO:41. The variable domains or regions of each SEQ ID NO: are indicated by underlining in Table 2 and Figure 5 herein.

[0050] In a second aspect, the present invention provides a T cell receptor (TCR) with antigen specificity for a mutant KRAS, the TCR having: (a) a binding affinity of at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% to the amino acid sequence of SEQ ID NO: 32. an α chain comprising a sequence having at least 99% sequence identity and / or a β chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 33; or (b) an α chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 34, and / or a β chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 35, or (c) an α chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 36, and / or a β chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 37, or (d) an α chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 38, and / or a β chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 39, or (e) an alpha chain comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 40, and / or or a β-strand comprising a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:41.

[0051] The scope of the invention includes TCRs comprising at least one αTCR chain and / or βTCR chain, wherein said αTCR chain has a sequence similar to that of SEQ ID NO: 32, 34, 36, 38 or 40, at least 50%, at least 60%, at least 70%, at least 80%, 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 at least 10%. and / or the above-mentioned βTCR chain comprises a sequence having at least 50%, at least 60%, at least 70%, at least 80%, 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 100% sequence identity to the amino acid sequence of SEQ ID NO: 33, 35, 37, 39, or 41.

[0052] The scope of the present invention includes functional variants of the antigen recognition constructs or TCRs of the present invention described herein. As used herein, the term "functional variant" refers to an antigen recognition construct or TCR that has substantial or significant sequence identity or similarity with a parent antigen recognition construct or TCR, which functional variant retains the biological activity of the variant antigen recognition construct or TCR. Functional variants include, for example, variants of the antigen recognition constructs or TCRs described herein (parent antigen recognition constructs or TCRs) that retain the ability of the parent antigen recognition construct or TCR to specifically bind to a mutant target, such as a mutant KRAS, with a similar, similar, or higher degree of antigen specificity as the parent antigen recognition construct or TCR. With respect to the parent antigen recognition construct or TCR, a functional variant can be, for example, at least about 30%, 50%, 75%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more identical in amino acid sequence to the parent antigen recognition construct or TCR.

[0053] As used herein, the term "sequence identity" or "identity" refers to the percentage of residues that are pairwise identical, based on the number of residues in the longer of the two sequences, following homologous alignment of the sequence of a polypeptide of the invention with a sequence of interest.

[0054] The percentage of sequence homology or sequence identity can be determined herein, for example, using the BLASTP program version blastp2.2.5 (November 16, 2002; see Altschul, S F et al. (1997) Nucl. Acids Res. 25, 3389-3402). The percentage of homology is determined based on the alignment of the entire polypeptide sequence including each sequence (matrix: BLOSUM 62, gap cost: 11.1, cutoff value: 10 -3It is based on the alignment score (set to 0.05). It is calculated as the percentage of the number of resulting "positives" (homologous amino acids) in the BLASTP program output divided by the total number of amino acids selected by the program for the alignment.

[0055] Functional variants may, for example, comprise the amino acid sequence of parent antigen recognition construct or TCR that comprises at least one conservative amino acid substitution. Conservative amino acid substitutions are known in the art and include amino acid substitutions that replace one amino acid with a given physical and / or chemical property with another amino acid with the same chemical or physical property. For example, conservative amino acid substitutions may be an acidic amino acid (e.g., Asp or Glu) substituted with another acidic amino acid, an amino acid with a non-polar side chain substituted with another amino acid with a non-polar side chain (e.g., Ala, Gly, Val, lle, Leu, Met, Phe, Pro, Trp, Val, etc.), a basic amino acid (Lys, Arg, etc.) substituted with another basic amino acid, an amino acid with a polar side chain substituted with another amino acid with a polar side chain (Asn, Cys, Gln, Ser, Thr, Tyr, etc.), etc.

[0056] The term "KRAS" refers to Kirsten Rat Sarcoma Virus, the protein sequence of which is deposited, for example, under UniProtKB Accession No. P01116 (RASK_HUMAN).

[0057] Returning to the aspects of the present invention, in a third aspect, the present invention is directed to a nucleic acid sequence encoding an antigen recognition construct or a T cell receptor according to the first or second aspect of the present invention.

[0058] As used herein, the term "nucleic acid" includes "polynucleotides," "oligonucleotides," and "nucleic acid molecules," and generally refers to a polymer of DNA or RNA that may be single-stranded or double-stranded, that may be synthetic or obtained from natural sources (e.g., isolated and / or purified), that may contain natural, non-natural, or altered nucleotides, and that may contain natural, non-natural, or altered internucleotide linkages, such as phosphoramidate or phosphorothioate linkages in place of phosphodiesters found between the nucleotides of unmodified oligonucleotides.

[0059] In a fourth aspect, the present invention is directed to a vector comprising a nucleic acid sequence according to the third aspect of the invention.

[0060] In the context of the present invention, the term "vector" encompasses DNA molecules, such as plasmids, bacteriophages, phagemids, viruses, or other vehicles, which contain one or more heterologous or recombinant nucleotide sequences (e.g., the nucleic acid molecules of the present invention described above, also under the control of a functional promoter and, optionally, an enhancer) and can function as a vector in the sense understood by those skilled in the art. Suitable phage and viral vectors include, but are not limited to, lambda (X) bacteriophage, EMBL bacteriophage, simian virus 40, bovine papilloma virus, Epstein-Barr virus, adenovirus, herpes virus, vaccinia virus, Moloney murine leukemia virus, Harvey murine sarcoma virus, mouse mammary tumor virus, lentivirus, and Rous sarcoma virus.

[0061] Desirably, the vector is an expression vector or a recombinant expression vector. The term "recombinant expression vector" in the context of the present invention refers to a nucleic acid construct that expresses mRNA, protein, or polypeptide in a suitable host cell. The recombinant expression vector of the present invention can be any suitable recombinant expression vector and can be used to transform or transfect any suitable host. Suitable vectors include those designed for growth and propagation or for expression, or both, such as plasmids and viruses. Examples of animal expression vectors include pEUK-Cl, pMAM, and pMAMneo. In a specific example, the recombinant expression vector is a viral vector, such as a retroviral vector. The recombinant expression vector includes regulatory sequences, such as initiation and termination codons for transcription and translation, specific for the type of host cell (e.g., bacteria, fungi, plants, or animals) into which the vector is introduced and expression of the nucleic acid of the present invention is effected. Additionally, the vector of the present invention can include one or more marker genes that allow for the selection of transformed or transfected hosts. The recombinant expression vector may comprise a native or standard promoter operably linked to a nucleotide sequence encoding a construct of the invention or a nucleotide sequence that is complementary to or hybridizes to a nucleotide sequence encoding a construct of the invention. The choice of promoter includes, for example, strong promoters, weak promoters, inducible promoters, tissue-specific promoters, and development-specific promoters. The promoter may be a non-viral promoter or a viral promoter. The recombinant expression vector of the present invention may be designed for either transient expression, stable expression, or both. Also, the recombinant expression vector may be made for constitutive or inducible expression.

[0062] The invention is further described below with reference to any, some or all of these aspects, and it will be understood by those skilled in the art that even if only one of these aspects is referenced, this reference includes reference to all other aspects of the invention, where applicable.

[0063] In a fifth aspect, the present invention is directed to a host cell comprising an antigen recognition construct or a T cell receptor according to the first or second aspect of the invention, or a nucleic acid sequence according to the third aspect of the invention, or a vector according to the fourth aspect of the invention.

[0064] Specifically, the host cell of the present invention comprises a nucleic acid or vector as described herein above. The host cell can be a eukaryotic cell, such as a plant, animal, fungus, or algae, or a prokaryotic cell, such as a bacterium or a protozoan. The host cell can be a cultured cell, or a primary cell, i.e., a cell directly isolated from an organism, such as a human. The host cell can be an adherent cell, or a suspension cell, i.e., a cell that grows in suspension. For the purpose of producing recombinant TCR, polypeptide, or protein, the host cell is, for example, a mammalian cell. In another specific example, the host cell is a human cell. The host cell can be of any cell type, originate from any type of tissue, and be at any developmental stage, while the host cell can be a peripheral blood leukocyte (PBL) or a peripheral blood mononuclear cell (PBMC). In another specific example, the host cell is a T cell. The T cells can be any T cells, such as cultured T cells, e.g., primary T cells, or T cells from cultured T cell lines, e.g., Jurkat, SupT1, etc., or T cells obtained from a mammal, specifically T cells or T cell precursors from a human patient. When obtained from a mammal, the T cells can be obtained from a number of sources, including, but not limited to, blood, bone marrow, lymph nodes, thymus, or other tissues or body fluids. The T cells can also be enriched or purified. In another specific example, the T cells are human T cells. In another specific example, the T cells are T cells isolated from a human. The T cells can be any type of T cell, and can be at any stage of development, including, but not limited to, CD4 positive and / or CD8 positive, CD4 positive helper T cells, e.g., Th1 and Th2 cells, CD8 positive T cells (e.g., cytotoxic T cells), tumor infiltrating lymphocytes (TILs), memory T cells, naive T cells, etc. In another specific example, the T cell is a CD8 positive T cell or a CD4 positive T cell.

[0065] In a specific example, the host cell of the present invention is a lymphocyte, specifically a T lymphocyte, such as a CD4 or CD8 positive T cell.Furthermore, the host cell may specifically be a tumor-reactive T cell specific for mutant KRAS expressing tumor cells.

[0066] In a sixth aspect, the present invention is directed to an antigen recognition construct or a T cell receptor according to the first or second aspect of the invention, or a nucleic acid sequence according to the third aspect of the invention, or a vector according to the fourth aspect of the invention, or a host cell according to the fifth aspect of the invention, for use in medicine.

[0067] In a seventh aspect, the present invention is directed to an antigen recognition construct or a T cell receptor according to the first or second aspect of the invention, or a nucleic acid sequence according to the third aspect of the invention, or a vector according to the fourth aspect of the invention, or a host cell according to the fifth aspect of the invention, for use in the prevention and / or treatment of a disease.

[0068] As used herein, the terms "treat" and "prevent" and derivatives thereof, such as "treatment" or "prevention", do not necessarily mean 100% or complete treatment or prevention. Rather, there are various degrees of treatment or prevention that one skilled in the art would recognize as having potential benefit or therapeutic effect. In this regard, the method of the present invention can provide any amount of treatment or prevention at any level in mammalian cancer. Furthermore, the treatment or prevention provided by the method of the present invention can include treatment or prevention of one or more conditions or symptoms in the cancer being treated or prevented. For example, the treatment or prevention can include promoting tumor regression. Also, for purposes of this specification, "prevention" can include delaying the onset of cancer, or a symptom or condition thereof.

[0069] In the sixth or seventh aspect of the invention, the disease may be a malignant or benign tumor disease.

[0070] The term "tumor" or "tumor disease" in the context of the present invention refers to diseases selected from, for example, melanoma, hepatocellular carcinoma, intrahepatic and extrahepatic cholangiocarcinoma, squamous cell carcinoma, adenocarcinoma and undifferentiated carcinoma of the head, neck, lung or esophagus, colorectal carcinoma, chondrosarcoma, osteosarcoma, medulloblastoma, neuroblastoma, non-squamous cell carcinoma of the head or neck, ovarian tumor, lymphoma, acute and chronic lymphocytic leukemia, acute and chronic myeloid leukemia, bladder cancer, prostate cancer, pancreatic adenocarcinoma, breast cancer and gastric cancer. In specific examples, diseases treated by the products and / or methods of the present invention include melanoma, non-small cell lung cancer, pancreatic adenocarcinoma and cholangiocarcinoma.

[0071] In the sixth or seventh aspect of the present invention, the disease may be a tumor expressing mutant KRAS. Specifically, the disease may be an advanced stage tumor expressing mutant KRAS.

[0072] With regard to the sixth or seventh aspect of the invention, the disease may be selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, pancreatic cancer, colorectal cancer, endometrial cancer, biliary tract cancer, liver cancer, myeloma, prostate cancer, stomach cancer, kidney cancer, bone cancer, soft tissue cancer, head and neck cancer, glioblastoma multiforme, astrocytoma, melanoma, lung cancer, esophageal cancer, gastric cancer, breast cancer, ovarian cancer, mesothelioma cancer, bladder cancer, anal cancer, chondrosarcoma cancer, osteosarcoma cancer, sarcoma cancer, adenoma cancer, primitive neuroectodermal cancer (primitive neuroectodermal tumor (PNET)), and combinations thereof.

[0073] Lung cancer can be, but is not limited to, squamous cell carcinoma of the lung, non-small cell lung cancer, and small cell lung cancer. In another specific example, breast cancer can be, but is not limited to, ductal carcinoma, tubular breast cancer, medullary breast cancer, and combinations thereof. In yet another specific example, gastric cancer can be gastric adenocarcinoma. Turning to sarcoma cancer, sarcoma cancer can be, but is not limited to, chondrosarcoma cancer, osteosarcoma cancer, and combinations thereof. Also, adenoma cancer can include, but is not limited to, gastric adenocarcinoma, pancreatic adenocarcinoma, and combinations thereof.

[0074] The eighth aspect of the present invention is directed to the use of the antigen recognition construct or T cell receptor in the first or second aspect of the present invention, or the nucleic acid sequence in the third aspect of the present invention, or the vector in the fourth aspect of the present invention, or the host cell in the fifth aspect of the present invention for the manufacture of a medicament for treating a disease. The disease can be, but is not limited to, a malignant tumor disease or a benign tumor disease. In yet another specific example, the disease can be a tumor that expresses mutant KRAS. The disease is, but is not limited to, an advanced stage tumor that expresses mutant KRAS.

[0075] Regarding the eighth aspect of the present invention, the disease may be selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, pancreatic cancer, colorectal cancer, endometrial cancer, biliary tract cancer, liver cancer, myeloma, prostate cancer, stomach cancer, kidney cancer, bone cancer, soft tissue cancer, head and neck cancer, glioblastoma multiforme, astrocytoma, melanoma, lung cancer, esophageal cancer, gastric cancer, breast cancer, ovarian cancer, mesothelioma cancer, bladder cancer, anal cancer, chondrosarcoma cancer, osteosarcoma cancer, sarcoma cancer, adenoma cancer, primitive neuroectodermal cancer (primitive neuroectodermal tumor (PNET)), and combinations thereof. The lung cancer may be, but is not limited to, squamous cell carcinoma of the lung, non-small cell lung cancer, and small cell lung cancer. In another specific example, the breast cancer may be, but is not limited to, ductal carcinoma, tubular breast cancer, medullary breast cancer, and combinations thereof. In yet another specific example, gastric cancer can be gastric adenocarcinoma.Looking at sarcoma cancer, sarcoma cancer can be, but is not limited to, chondrosarcoma cancer, osteosarcoma cancer, and combinations thereof.Also, adenoma cancer can include, but is not limited to, gastric adenocarcinoma, pancreatic adenocarcinoma, and combinations thereof.

[0076] The ninth aspect of the present invention is directed to a method for treating a disease, comprising administering a therapeutically effective amount of an antigen recognition construct or a T cell receptor in the first or second aspect of the present invention, or a nucleic acid sequence in the third aspect of the present invention, or a vector in the fourth aspect of the present invention, or a host cell in the fifth aspect of the present invention. The disease can be, but is not limited to, a malignant tumor disease or a benign tumor disease. In yet another specific example, the disease can be a tumor expressing mutant KRAS. The disease is, but is not limited to, an advanced stage tumor expressing mutant KRAS.

[0077] Regarding the ninth aspect of the present invention, the disease may be selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, pancreatic cancer, colorectal cancer, endometrial cancer, biliary tract cancer, liver cancer, myeloma, prostate cancer, stomach cancer, kidney cancer, bone cancer, soft tissue cancer, head and neck cancer, glioblastoma multiforme, astrocytoma, melanoma, lung cancer, esophageal cancer, gastric cancer, breast cancer, ovarian cancer, mesothelioma cancer, bladder cancer, anal cancer, chondrosarcoma cancer, osteosarcoma cancer, sarcoma cancer, adenoma cancer, primitive neuroectodermal cancer (primitive neuroectodermal tumor (PNET)), and combinations thereof. The lung cancer may be, but is not limited to, squamous cell carcinoma of the lung, non-small cell lung cancer, and small cell lung cancer. In another specific example, the breast cancer may be, but is not limited to, ductal carcinoma, tubular breast cancer, medullary breast cancer, and combinations thereof. In yet another specific example, gastric cancer can be gastric adenocarcinoma.Looking at sarcoma cancer, sarcoma cancer can be, but is not limited to, chondrosarcoma cancer, osteosarcoma cancer, and combinations thereof.Also, adenoma cancer can include, but is not limited to, gastric adenocarcinoma, pancreatic adenocarcinoma, and combinations thereof.

[0078] More specifically, the treatment of diseases, e.g., tumors, can be performed using any suitable cancer treatment, such as small molecule chemotherapy agents or immunotherapy treatment. Immunotherapy treatment can include administering to the patient a therapeutically effective amount of an adoptive cellular therapy agent or an agent that specifically binds mutant KRAS.

[0079] Examples of cell therapy agents can be genetically modified cells of the immune system, such as T cells or natural killer (NK) cells. Such genetically modified cells include chimeric antigen receptor T cells (CAR T cells, see Jakobsen & Gjerstorff “CAR T-Cell Cancer Therapy Targeting Surface Cancer / Testis Antigens”, Front. Immunol. September 2, 2020, Article 01568, doi:10.3389 / fimmu.2020.01568), or genetically modified T cells that specifically bind mutant KRAS. The genetically modified cells can be autologous cells from the patient to be treated, but also allogeneic cells, i.e., cells derived from a “universal” donor cell, rather than cells obtained from the intended patient. The "universal" donor cells may be derived from cells of natural origin, such as T cells or NK cells from a human donor (see, for example, the review article by Perez et al., Off-the-Shelf Allogeneic T Cell Therapies for Cancer: Opportunities and Challenges Using Naturally Occurring "Universal" Donor T Cells, Front. Immunol., November 11, 2020, Article 583716, https: / / doi.org / 10.3389 / fimmu.2020.583716). However, it is also possible to derive such "universal" donor cells from induced pluripotent stem cells (iPSCs) (see review article by Flahou et al., "Fit-For-All iPSC-Derived Cell Therapies and Their Evaluation in Humanized Mice With NK Cell Immunity", Front. Immunol., April 2, 2021, Article 662360, https: / / doi.org / 10.3389 / fimmu.2021.662360).When genetically modified T cells are used as a cell therapy, the T cells can be of any appropriate phenotype, such as, but not limited to, CD8+ T cells, CD4+ T cells, or a combination thereof. Whether autologous (patient-derived) or allogeneic T cells are used, the T cells can express a recombinant T cell receptor (TCR) that specifically binds mutant KRAS.

[0080] When cellular products / agents such as genetically modified T cells are used in the methods of treatment of the invention, such cells can be used in any suitable dosage (therapeutically effective amount). The dosage of T cells administered to a patient, defined as the total number of T cells, is about 0.5×10 7 T cells ~ approx. 1 x 10 10 An example dose of T cells administered to a patient, defined as the total number of T cells, is about 0.75×10 8 T cells, approximately 1 x 10 8 T cells, approximately 1 x 10 9 T cells, approximately 3 x 10 9 T cells, approximately 4 x 10 9 T cells, approximately 5 x 10 9 T cells, approximately 6 x 10 9 T cells, approximately 7 x 10 9 T cells, approximately 8 x 10 9 T cells, or approximately 9 × 10 9 The dose of T cells administered to a patient, defined as the total number of T cells, can thus be about 1×10 9 cells ~ approx. 9 x 10 9 range of cells, or approximately 3 x 10 9 cells ~ approx. 9 x 10 9 It should be noted that the term "about" as used herein with respect to the dosage / number of cells used for administration is meant to include deviations of up to 1%, up to 2%, up to 3%, up to 4%, up to 5% from the respective value, or deviations of 10% or less from the given value. This includes, for example, "about 1×10 9 The dose of "T cells" was 1 × 10 9 % ± 10% range of total cells, i.e., 0.9 × 10 9 ~1.1×109 This means that the T cells may include T cells expressing a mutant KRAS-binding TCR.

[0081] In accordance with the above disclosure, the present invention also provides a pharmaceutical composition comprising an antigen recognition construct or a T cell receptor according to the first or second aspect of the invention, or a nucleic acid sequence according to the third aspect of the invention, or a vector according to the fourth aspect of the invention, or a host cell according to the fifth aspect of the invention.

[0082] The pharmaceutical composition may be in any suitable form (depending on the desired method of administration to a patient). It may be provided in a unit dosage form, generally in a sealed container, or as part of a kit. Such a kit will usually (but not necessarily) include instructions for use. It may include a plurality of the above-mentioned unit dosage forms. Suitable compositions and methods of administration are known to those skilled in the art, see, for example, Johnson et al., Blood. July 16, 2009, 114(3):535-46, regarding clinical trial numbers NCI-07-C-0175 and NCI-07-C-0174. Thus, the cells may be supplied as part of a sterile pharmaceutical composition, which may usually include a pharma- ceutical acceptable carrier. For example, the TCR-transfected T cells of the present invention may be provided in a pharmaceutical composition together with a pharma-ceutical acceptable carrier. The pharma-ceutical acceptable carrier may be a cream, emulsion, gel, liposome, nanoparticle, or ointment.

[0083] The pharmaceutical compositions may be adapted for administration by any suitable route, such as parenteral (including subcutaneous, intramuscular, or intravenous), enteral (including oral or rectal), inhalation or intranasal routes, etc. Such compositions may be prepared by any method known in the art of formulation, for example by mixing the active ingredient with the carrier or excipient under sterile conditions.

[0084] In a specific example of the pharmaceutical composition of the present invention, the total number of T cells contained in the composition is about 0.75×10 8 T cells, approximately 1 x 108 T cells, approximately 1 x 10 9 T cells, approximately 3 x 10 9 T cells, approximately 4 x 10 9 T cells, approximately 5 x 10 9 T cells, approximately 6 x 10 9 T cells, approximately 7 x 10 9 T cells, approximately 8 x 10 9 T cells, or approximately 9 × 10 9 It may be a T cell.

[0085] The pharmaceutical composition may further comprise one or more pharma- ceutically acceptable carriers. Any pharma- ceutically acceptable carrier may be used as long as the carrier does not affect the viability of the administered T cells and the carrier is suitable for the selected route of administration of the pharmaceutical composition. The pharma- ceutically acceptable carrier may be a saline solution, optionally containing a component capable of improving the viability of T cells expressing mutant KRAS-binding TCR, such as human serum albumin. The mutant KRAS-binding T cells may also be stored in frozen form, for example at temperatures between -20°C and -80°C, after their production. In this case, the pharmaceutical composition may comprise a cryoprotectant added to protect the cells from damage due to the freezing process. Examples of cryoprotectants that may be used in the freezing of the pharmaceutical composition comprising the transduced T cells herein include glycerol, DMSO. These cryoprotectants may be used with crystalloid solutions, such as commercially available HypoThermosol or PlasmaLyte-A solutions, which are approved for infusion and available in pharmaceutical grade. Other possible media that can be used as carriers for the pharmaceutical composition are the "CryoStor family" of media, i.e., animal protein-free cryopreservation synthetic media commercially available from Biolife Solutions, such as CyroStor2 (CS2, optimized freezing medium preformulated with 2% DMSO), CyroStor5 (CS5, optimized freezing medium preformulated with 5% DMSO), or CyroStor10 (CS10, optimized freezing medium preformulated with 10% DMSO).

[0086] We now turn to a kit of the invention, such a kit for use in medicine comprising a pharmaceutical composition comprising an antigen recognition construct or a T cell receptor according to the first or second aspect of the invention, or a nucleic acid sequence according to the third aspect of the invention, or a vector according to the fourth aspect of the invention, or a host cell according to the fifth aspect of the invention. The kit may be, but is not limited to, a diagnostic kit for selecting patients for treatment of tumors whose cells express mutant KRAS.

[0087] The present invention is further illustrated by the following non-limiting examples.

[0088] As used herein, the sequences are shown in Tables 1 and 2 below.

[0089] Table 1 shows the sequences used herein. [Table 1]

[0090] Table 2 shows further sequences used herein. [Table 2] JPEG2025504883000003.jpg97153 The variable regions are underlined and the constant regions are bolded. The term "variable region" as used herein may also be referred to as "variable domain" and both terms may be used interchangeably. The term "constant region" as used herein may also be referred to as "constant domain" and both terms may be used interchangeably.

[0091] These sequences of SEQ ID NOs: 32 to 41 are also shown in FIG. 5 herein.

[0092] In the constant domains of TCRs as described herein and in Table 2, for example, "minimal murinization" can be performed by substituting four positions in the human alpha chain and five positions in the human beta chain with the respective mouse amino acids, e.g., by substituting mouse residues Ser90, Asp91, Val92, and Pro93 in the human alpha chain, and mouse residues Lys18, Ala22, Ile133, Ala136, and His139 in the human beta chain.

[0093] Alternatively, fully humanized sequences may be used for the constant domains, as described herein and shown in Table 2. Such humanized sequences for the α chain are deposited, for example, under accession number UniProtKB-P01848 (TRAC_HUMAN), and humanized sequences for the β chain are deposited, for example, under accession number UniProtKB-A0A5B9 (TRBC2_HUMAN). EXAMPLES

[0094] Example 1 TCR or mock transduced peripheral blood leukocytes (PBLs) from human donors were transduced with mutant KRAS (KRAS G12V ) expressing cell lines (intact or transduced with HLA-A*11:01) or cultured alone ("T cells"). PMA and ionomycin stimulation ("P / I") was used as a positive control for T cell activation. IFNγ secretion in culture supernatants upon T cell activation was measured by sandwich ELISA. The results of this example are shown in Figure 1 included herein.

[0095] The inventors of the present invention have always additionally generated data for two control TCRs from human donors and immunized mice, named herein CT1 and CT2. These controls are according to Cafri et al. ("Memory T cells targeting oncogenic mutations detected in peripheral blood of epithelial cancer patients", Nat. Commun. 10, 449, 2019) and from Wang et al. ("Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors", Cancer Immunol. Res. 2016 Mar; 4(3): 204-14. doi: 10.1158 / 2326-6066. CIR-15-0188) (see also WO 2016 / 085904 and WO 2019 / 112941).

[0096] Example 2 TCR-transduced PBLs from human donors and decreasing concentrations (10 -6 M~10 -12 The T cells were co-cultured with HLA-A*11:01 expressing cells loaded with the recognition peptide (VVGAVGVGK, SEQ ID NO: 1) of T cell activator M. IFNγ secretion in the culture supernatant upon T cell activation was measured by sandwich ELISA. The normalized IFNγ secretion curve is shown in FIG. 2 included in the present specification.

[0097] Example 3 Expression of TCR on the surface of TCR-transduced CD8+ T cells from two donors was analyzed by flow cytometry. The results are shown herein in FIG. 3. TCR expression was measured by staining cells with anti-mouse TCR β chain or HLA-A*11:01-VVGAVGVGK dextramer ("Dex"). TCR expression was expressed as mean fluorescence intensity (MFI) normalized to the TCR of CT1.

[0098] Example 4 TCR-transduced human PBLs were co-cultured with HLA-A*11:01 expressing cell lines. The results are shown herein in Figure 4. G12V CFPAC-1 cells ("CFPAC-1-A11") or K-562 cells expressing the recognition peptide (VVGAVGVGK, 10 -6 M) ("K562-A11+G12V"). Unloaded K-562 cells served as a negative control ("K562-A11"). Protein secretion in the culture supernatant upon T cell activation was measured by the LEGENDplex Multi-Analyte Flow Assay Kit (Biolegend) using a human CD8 / NK population according to the manufacturer's instructions.

[0099] material and method Animal immunization KRAS G12V To generate CD8+ T cell responses against epitopes, humanized TCR / HLA class I transgenic mice derived from ABabDII mice described by Li et al. (2010, Nature Medicine 16, 1029-1034) were used for immunization with peptides or adenoviral vectors.

[0100] For peptide immunization, mice were immunized with KRAS mAb emulsified in incomplete Freund's adjuvant supplemented with CpG1826 oligonucleotide. G12V Monthly subcutaneous priming and boosting was performed with the peptide VVGAVGVGK.

[0101] Adenoviral immunization delivered mice with KRAS expression vector under the control of the CMV promoter. G12V A human type 5 (dE1 / E3) adenovirus vector expressing a minigene (encoding amino acids 1-35) was injected intraperitoneally.

[0102] Specific T cell responses were assessed in vitro using KRAS G12V The responses were monitored by restimulating peripheral blood with peptide or minigene-expressing cell lines.

[0103] TCR identification and characterization Splenocytes from responder mice were restimulated in vitro as described, and antigen-specific activated CD3+CD8+CD137+ T cells were selected for cDNA library preparation and single-cell TCR sequencing using 10xGenomics technology according to the manufacturer's protocol. Expanded TCR clonotypes were cloned into retroviral vectors and transduced into human peripheral blood lymphocytes.

[0104] The invention is further illustrated by the following non-limiting paragraphs. 1. An antigen recognition construct that binds the peptide VVGAVGVGK (SEQ ID NO:1) with a determinable affinity, The antigen recognition construct comprises a complementarity determining region 3 (CDR3) of the alpha chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 10, 16, 22, and 28, and / or The antigen recognition construct comprises a complementarity determining region 3 (CDR3) of a β chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 13, 19, 25, and 31. 2. The antigen recognition construct according to item 1, wherein the antigen recognition construct is an antibody or a fragment thereof, or a T cell receptor (TCR) or a fragment thereof. 3. The antigen recognition construct is approximately 1 x 10 -6 EC below M 50 Item 3. The antigen recognition construct according to item 1 or 2, which specifically binds the peptide VVGAVGVGK (SEQ ID NO: 1). 4. EC 50 The antigen recognition construct described in item 3, wherein the value is determined by the procedure performed in Example 2. 5. The antigen recognition construct according to any one of items 1 to 4, wherein the antigen recognition construct binds a peptide presented by an MHC I molecule. 6. The antigen recognition construct according to item 5, wherein the MHC I molecule is an HLA-A molecule. 7. The antigen recognition construct described in item 6, wherein the HLA-A molecule is HLA-A*11:01. 8. The antigen recognition construct according to any one of items 1 to 7, wherein the antigen recognition construct binds the peptide VVGAVGVGK (SEQ ID NO: 1) with at least 80% antigen specificity. 9. The antigen recognition construct according to any one of items 1 to 8, wherein the antigen recognition construct is a T cell receptor (TCR). 10. The T cell receptor of item 9, wherein the T cell receptor comprises a complementarity determining region 1 (CDR1) of the alpha chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 20, and 26, and / or the T cell receptor comprises a complementarity determining region 1 (CDR1) of the beta chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 11, 17, 23, and 29. 11. The T cell receptor of clause 9 or 10, wherein the T cell receptor comprises a complementarity determining region 2 (CDR2) of the alpha chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 9, 15, 21, and 27, and / or the T cell receptor comprises a complementarity determining region 2 (CDR2) of the beta chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 12, 18, 24, and 30. 12. The T cell receptor according to any one of items 9 to 11, wherein the T cell receptor comprises a complementarity determining region 3 (CDR3) of the alpha chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 10, 16, 22, and 28, and / or the T cell receptor comprises a complementarity determining region 3 (CDR3) of the beta chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 13, 19, 25, and 31. 13. The T cell receptor according to any one of items 9 to 12, wherein the T cell receptor comprises a complementarity determining region 1 (CDR1) of the α chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 8, 14, 20, and 26, and / or the T cell receptor comprises a complementarity determining region 1 (CDR1) of the β chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 11, 17, 23, and 29. 14. The T cell receptor according to any one of items 9 to 13, wherein the T cell receptor comprises a complementarity determining region 2 (CDR2) of the α chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 9, 15, 21, and 27, and / or the T cell receptor comprises a complementarity determining region 2 (CDR2) of the β chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 12, 18, 24, and 30. 15. (a) CDR1 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 2; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO:3; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; or (b) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:8; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; or (c) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 15; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and 15. The T cell receptor according to any one of items 9 to 14, comprising an α chain CDR3 that comprises or consists of the amino acid sequence of SEQ ID NO:28. 16. (a) a CDR1 of a β chain comprising or consisting of the amino acid sequence of SEQ ID NO:5; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:6, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (b) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or (c) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or (d) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or (e) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and 16. The T cell receptor according to any one of items 9 to 15, comprising a β chain CDR3 that comprises or consists of the amino acid sequence of SEQ ID NO:31. 17. (a) CDR1 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 2; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO:3; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:5; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:6, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (b) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:8; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 9; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 11; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or (c) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 17; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 21; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 23; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 27; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and 17. The T cell receptor according to any one of items 9 to 16, comprising a β chain CDR3 that comprises or consists of the amino acid sequence of SEQ ID NO:31. 18. A T cell receptor (TCR) having antigen specificity for mutant KRAS, the TCR comprising: (a) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:2; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO:3; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; or (b) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:8; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 9; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; or (c) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 15; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21; and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27; and A T cell receptor (TCR) comprising an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:28. 19. A T cell receptor (TCR) having antigen specificity for mutant KRAS, the TCR comprising: (a) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:5; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:6, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (b) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 11; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or (c) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or (d) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or (e) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 29; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and A T cell receptor (TCR) comprising a CDR3 of a β chain comprising or consisting of the amino acid sequence of SEQ ID NO:31. 20. A T cell receptor (TCR) having antigen specificity for mutant KRAS, the TCR comprising: (a) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:2; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO:3; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:5; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO:6, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (b) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO:8; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 9; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 11; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 13, or (c) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 15; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 17; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 19, or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 21; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 23; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and A CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 25, or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26; CDR2 of the alpha chain comprising or consisting of the amino acid sequence of SEQ ID NO: 27; an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; CDR1 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 29; A CDR2 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and A T cell receptor (TCR) comprising a CDR3 of a β chain comprising or consisting of the amino acid sequence of SEQ ID NO:31. 21. A nucleic acid sequence encoding the antigen recognition construct or the T cell receptor according to any one of items 1 to 20. 22. A vector comprising the nucleic acid sequence according to item 21. 23. A host cell comprising the antigen recognition construct or T cell receptor according to any one of items 1 to 20, or the nucleic acid sequence according to item 21, or the vector according to item 22. 24. An antigen recognition construct or a T cell receptor according to any one of paragraphs 1 to 20, or a nucleic acid sequence according to paragraph 21, or a vector according to paragraph 22, or a host cell according to paragraph 23, for use in medicine. 25. An antigen recognition construct or T cell receptor according to any one of clauses 1 to 20, or a nucleic acid sequence according to clause 21, or a vector according to clause 22, or a host cell according to clause 23, for use in the prevention and / or treatment of a disease. 26. The antigen recognition construct or T cell receptor, or the nucleic acid sequence, or the vector, or the host cell according to clause 25, wherein the disease is a malignant tumor disease or a benign tumor disease. 27. The antigen recognition construct or T cell receptor, or the nucleic acid sequence, or the vector, or the host cell according to clause 25 or 26, wherein the disease is a tumor expressing mutant KRAS. 28. The antigen recognition construct or T cell receptor, or the nucleic acid sequence, or the vector, or the host cell according to clause 27, wherein the disease is an advanced stage tumor expressing mutant KRAS. 29. The antigen recognition construct or T cell receptor, or nucleic acid sequence, or vector, or host cell according to any one of claims 25 to 28, wherein the disease is selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, pancreatic cancer, colorectal cancer, endometrial cancer, biliary tract cancer, liver cancer, myeloma, prostate cancer, stomach cancer, kidney cancer, bone cancer, soft tissue cancer, head and neck cancer, glioblastoma multiforme, astrocytoma, melanoma, lung cancer, esophageal cancer, gastric cancer, breast cancer, ovarian cancer, mesothelioma cancer, bladder cancer, anal cancer, chondrosarcoma cancer, osteosarcoma cancer, sarcoma cancer, adenoma cancer, primitive neuroectodermal cancer (primitive neuroectodermal tumor (PNET)), and combinations thereof. 30. The antigen recognition construct or T cell receptor, or nucleic acid sequence, or vector, or host cell according to paragraph 29, wherein the lung cancer is selected from the group consisting of squamous cell carcinoma of the lung, non-small cell lung cancer, and small cell lung cancer. 31. The antigen recognition construct or T cell receptor, or nucleic acid sequence, or vector, or host cell according to paragraph 29, wherein the breast cancer is selected from the group consisting of ductal breast cancer, tubular breast cancer, medullary breast cancer, and combinations thereof. 32. The antigen recognition construct or T cell receptor, or nucleic acid sequence, or vector, or host cell according to paragraph 29, wherein the gastric cancer is gastric adenocarcinoma. 33. The antigen recognition construct or T cell receptor, or nucleic acid sequence, or vector, or host cell according to paragraph 29, wherein the sarcoma cancer is selected from the group consisting of chondrosarcoma cancer, osteosarcoma cancer, and combinations thereof. 34. The antigen recognition construct or T cell receptor, or nucleic acid sequence, or vector, or host cell according to clause 29, wherein the adenoma carcinoma is selected from the group consisting of gastric adenocarcinoma, pancreatic adenocarcinoma, and combinations thereof. 35. Use of the antigen recognition construct or T cell receptor according to any one of paragraphs 1 to 20, or the nucleic acid sequence according to paragraph 21, or the vector according to paragraph 22, or the host cell according to paragraph 23, for the manufacture of a medicament for treating a disease. 36. The use of an antigen recognition construct or a T cell receptor, or a nucleic acid sequence, or a vector, or a host cell according to clause 35, wherein the disease is a malignant tumor disease or a benign tumor disease. 37. The use of an antigen recognition construct or a T cell receptor, or a nucleic acid sequence, or a vector, or a host cell according to clause 35 or 36, wherein the disease is a tumor expressing a mutated KRAS. 38. The use of an antigen recognition construct or a T cell receptor, or a nucleic acid sequence, or a vector, or a host cell according to clause 37, wherein the disease is an advanced stage tumor expressing mutant KRAS. 39. The use of the antigen recognition construct or T cell receptor, or the nucleic acid sequence, or the vector, or the host cell according to any one of paragraphs 35 to 38, wherein the disease is selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, pancreatic cancer, colorectal cancer, endometrial cancer, biliary tract cancer, liver cancer, myeloma, prostate cancer, stomach cancer, kidney cancer, bone cancer, soft tissue cancer, head and neck cancer, glioblastoma multiforme, astrocytoma, melanoma, lung cancer, esophageal cancer, gastric cancer, breast cancer, ovarian cancer, mesothelioma cancer, bladder cancer, anal cancer, chondrosarcoma cancer, osteosarcoma cancer, sarcoma cancer, adenoma cancer, primitive neuroectodermal cancer (primitive neuroectodermal tumor (PNET)), and combinations thereof. 40. The use of an antigen recognition construct or T cell receptor, or a nucleic acid sequence, or a vector, or a host cell according to paragraph 39, wherein the lung cancer is selected from the group consisting of squamous cell carcinoma of the lung, non-small cell lung cancer, and small cell lung cancer. 41. The use of the antigen recognition construct or T cell receptor, or the nucleic acid sequence, or the vector, or the host cell according to paragraph 39, wherein the breast cancer is selected from the group consisting of ductal carcinoma, tubular breast carcinoma, medullary breast carcinoma, and combinations thereof. 42. The use of an antigen recognition construct or T cell receptor, or a nucleic acid sequence, or a vector, or a host cell according to paragraph 39, wherein the gastric cancer is gastric adenocarcinoma. 43. The use of an antigen recognition construct or T cell receptor, or a nucleic acid sequence, or a vector, or a host cell according to paragraph 39, wherein the sarcoma cancer is selected from the group consisting of chondrosarcoma cancer, osteosarcoma cancer, and combinations thereof. 44. The use of an antigen recognition construct or T cell receptor, or a nucleic acid sequence, or a vector, or a host cell according to clause 39, wherein the adenoma cancer is selected from the group consisting of gastric adenocarcinoma, pancreatic adenocarcinoma, and combinations thereof. 45. A method for treating a disease, comprising the step of administering a therapeutically effective amount of the antigen recognition construct or T cell receptor described in any one of paragraphs 1 to 20, or the nucleic acid sequence described in paragraph 21, or the vector described in paragraph 22, or the host cell described in paragraph 23. 46. ​​The method for treating a disease according to clause 45, wherein the disease is a malignant tumor disease or a benign tumor disease. 47. The method for treating a disease according to clause 45 or 46, wherein the disease is a tumor expressing mutant KRAS. 48. The method of treating a disease according to clause 47, wherein the disease is an advanced stage tumor expressing mutant KRAS. 49. The method for treating a disease according to any one of clauses 45 to 48, wherein the disease is selected from the group consisting of Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, pancreatic cancer, colorectal cancer, endometrial cancer, biliary tract cancer, liver cancer, myeloma, prostate cancer, stomach cancer, kidney cancer, bone cancer, soft tissue cancer, head and neck cancer, glioblastoma multiforme, astrocytoma, melanoma, lung cancer, esophageal cancer, gastric cancer, breast cancer, ovarian cancer, mesothelioma cancer, bladder cancer, anal cancer, chondrosarcoma cancer, osteosarcoma cancer, sarcoma cancer, adenoma cancer, primitive neuroectodermal cancer (primitive neuroectodermal tumor (PNET)), and combinations thereof. 50. The method for treating a disease according to paragraph 49, wherein the lung cancer is selected from the group consisting of squamous cell carcinoma of the lung, non-small cell lung cancer, and small cell lung cancer. 51. The method of treating a disease according to clause 49, wherein the breast cancer is selected from the group consisting of ductal carcinoma, tubular breast cancer, medullary breast cancer, and combinations thereof. 52. The method for treating a disease according to item 49, wherein the gastric cancer is gastric adenocarcinoma. 53. The method of treating a disease according to clause 49, wherein the sarcoma cancer is selected from the group consisting of chondrosarcoma cancer, osteosarcoma cancer, and combinations thereof. 54. The method of treating a disease according to clause 49, wherein the adenoma cancer is selected from the group consisting of gastric adenocarcinoma, pancreatic adenocarcinoma, and combinations thereof. 55. A pharmaceutical composition comprising the antigen recognition construct or T cell receptor according to any one of items 1 to 20, or the nucleic acid sequence according to item 21, or the vector according to item 22, or the host cell according to item 23. 56. A kit for use in medicine, comprising the antigen recognition construct or T cell receptor according to any one of items 1 to 20, or the nucleic acid sequence according to item 21, or the vector according to item 22, or the host cell according to item 23. 57. The kit of paragraph 56, wherein the kit is a diagnostic kit for selecting patients for treatment of tumors whose cells express mutant KRAS.

[0105] It will be readily apparent to those skilled in the art that various substitutions and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention.

[0106] All patents and publications mentioned in this specification are indicative of the level of those skilled in the art to which this invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0107] As used herein, the term "about" means ±20% of the indicated range, value, or configuration, unless otherwise indicated. As used herein, the terms "a" and "an" should be understood to refer to "one or more" of the listed configuration. The use of alternative forms (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternative forms. As used herein, the terms "including," "having," and "comprising" are used interchangeably, and these terms and variations thereof are intended to be interpreted in a non-limiting manner.

[0108] The present invention illustratively described herein can be suitably implemented without any element or limitation not specifically disclosed herein. Thus, for example, terms such as "comprises", "includes", "includes" and the like are to be interpreted broadly and without limitation. Furthermore, the terms and expressions used herein are used as terms for describing and not for limiting purposes, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described, or portions thereof, but it is recognized that various modifications are possible within the scope of the invention described. Thus, although the present invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the invention embodied and disclosed herein may be adopted by those skilled in the art, and such modifications and variations are considered to be within the scope of the present invention. The present invention is described broadly and generically herein. Also, each of the narrower species and subclassifications falling within the generic disclosure is also part of the present invention. This includes a generic description of the invention with a presupposition or negative limitation of excluding any limitation from the genus, regardless of whether the implementation is specifically described herein. Moreover, those skilled in the art will recognize that while features or aspects of the invention are described in Markush groups, the invention is also described thereby in any individual member or subgroup member of the Markush group. Further embodiments of the invention will become apparent from the following claims.

Claims

1. An antigen recognition construct that binds the peptide VVGAVGVGK (SEQ ID NO: 1) with a determinable affinity, The antigen recognition construct comprises a complementarity determining region 3 (CDR3) of the alpha chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 16, 4, 22, and 28; and / or The antigen recognition construct comprises a complementarity determining region 3 (CDR3) of a β chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 19, 7, 25, and 31.

2. The antigen-recognition construct according to claim 1 , wherein the antigen-recognition construct is an antibody or a fragment thereof, or a T-cell receptor (TCR) or a fragment thereof.

3. The antigen recognition construct is about 1 x 10 －６ EC less than M ５０ And peptide VVG The antigen recognition construct according to claim 1 or 2, which specifically binds AVGVGK (SEQ ID NO: 1), preferably wherein the EC 50 value is determined by the procedure carried out in Example 2.

4. The antigen recognition construct according to claim 1 or 2, wherein the antigen recognition construct binds the peptide presented by an MHC I molecule, preferably the MHC I molecule is an HLA-A molecule, more preferably the HLA-A molecule is HLA-A*11:01, and / or the antigen recognition construct binds the peptide VVGAVGVGK (SEQ ID NO: 1) with at least 80% antigen specificity.

5. The antigen recognition construct according to claim 1 , wherein the antigen recognition construct is a T cell receptor (TCR).

6. The T cell receptor comprises a complementarity determining region 1 (CDR1) of the α chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 14, 2, 20, and 26, and / or the T cell receptor comprises a complementarity determining region 1 (CDR1) of the β chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 5, 23, and 29, and / or the T cell receptor comprises an complementarity determining region 1 (CDR1) of the β chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 15, 3, 21, and 27. and / or the T cell receptor comprises a complementarity determining region 2 (CDR2) of the α chain having at least 90% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 18, 6, 24, and 30, and a complementarity determining region 3 (CDR3) of the α chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 16, 4, 22, and 28, and or the T cell receptor comprises a complementarity determining region 3 (CDR3) of the β chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 19, 7, 25, and 31, and the T cell receptor comprises a complementarity determining region 1 (CDR1) of the α chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 14, 2, 20, and 26; and / or the T cell receptor comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 11, 17, 5, 23, and 29. and / or the T cell receptor comprises a complementarity determining region 2 (CDR2) of the α chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 15, 3, 21, and 27, and / or the T cell receptor comprises a complementarity determining region 2 (CDR2) of the β chain having at least 95% sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 18, 6, 24, and 30.The T cell receptor of claim 5.

7. (a) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 8, an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 9, and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; or (b) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 15, and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; or (c) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 2, an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20, an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21, and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26, an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27, and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; and / or (a) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 11, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 13; or (b) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; or (c) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; or (d) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; or (e) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 29, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 31; and / or (a) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 8, an α-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 9, an α-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10, a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 11, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 13; or (b) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, an α-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 15, an α-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16, a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; or (c) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 2, an α-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, an α-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (d) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20, an α-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21, an α-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22, a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; or (e) an α chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26, an α chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27, an α chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28, a β chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 29, a β chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and comprising a CDR3 of the β chain comprising or consisting of the amino acid sequence of SEQ ID NO: 31; and / or (a) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 8, 9, and 10, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 11, 12, and 13; or (b) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 14, 15, and 16, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 17, 18, and 19; or (c) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 2, 3, and 4, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 5, 6, and 7; or (d) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 20, 21, and 22, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 23, 24, and 25; or (e) an alpha chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 26, 27, and 28, and a beta chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 29, 30, and 31; and / or (a) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 32, and / or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 33, or (b) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 34, and / or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 35; or (c) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 36, and / or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 37; or (d) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 38, and / or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 39; or (e) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 40, and / or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 41; and / or (a) an α chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 32, and / or a β chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 33; or (b) an α chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 34, and / or a β chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 35; or (c) an α chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 36, and / or a β chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 37; or (d) an α chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 38, and / or a β chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 39; or (e) A T cell receptor described in claim 5 or 6, comprising an alpha chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 40, and / or a beta chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:

41.

8. A T cell receptor (TCR) having antigen specificity for mutant KRAS, The TCR is (a) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 8, an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 9, and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10; or (b) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 15, and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16; or (c) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 2, an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4; or (d) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20, an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21, and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22; or (e) an alpha chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26, an alpha chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27, and an alpha chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28; or The TCR is (a) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 11, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 13; or (b) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; or (c) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 7; or (d) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; or (e) a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 29, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 31; or The TCR is (a) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 8, an α-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 9, an α-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 10, a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 11, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 12, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 13; or (b) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 14, an α-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 15, an α-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 16, a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 17, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 18, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; or (c) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 2, an α-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 3, an α-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 4, a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 5, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 6, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 7, or (d) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 20, an α-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 21, an α-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 22, a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 23, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 24, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 25; or (e) an α-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 26, an α-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 27, an α-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 28, a β-chain CDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 29, a β-chain CDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 30, and a β-chain CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 31; or The TCR is (a) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 8, 9, and 10, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 11, 12, and 13; or (b) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 14, 15, and 16, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 17, 18, and 19; or (c) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 2, 3, and 4, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 5, 6, and 7; or (d) an α chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 20, 21, and 22, and a β chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 23, 24, and 25; or (e) an alpha chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 26, 27, and 28, and a beta chain comprising CDR sequences comprising the amino acid sequences of SEQ ID NOs: 29, 30, and 31; or The TCR is (a) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 32, and / or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 33, or (b) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 34, and / or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 35; or (c) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 36, and / or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 37; or (d) an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 38, and / or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 39; or (e) comprising an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 40, and / or an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the variable domain of SEQ ID NO: 41; or The TCR is (a) an α chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 32, and / or a β chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 33; or (b) an α chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 34, and / or a β chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 35; or (c) an α chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 36, and / or a β chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 37; or (d) an α chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 38, and / or a β chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 39; or (e) A T cell receptor (TCR) comprising an alpha chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 40, and / or a beta chain comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:

41.

9. A nucleic acid sequence encoding the antigen recognition construct or T cell receptor of claim 1 or 8, or a vector comprising said nucleic acid sequence.

10. A host cell comprising an antigen recognition construct or T cell receptor according to claim 1 or 8, or comprising a nucleic acid sequence encoding an antigen recognition construct or T cell receptor according to claim 1 or 8, or a vector comprising said nucleic acid sequence.

11. An antigen recognition construct or T cell receptor according to claim 1 or 8, or a nucleic acid sequence encoding the antigen recognition construct or T cell receptor according to claim 1 or 8, or a vector comprising said nucleic acid sequence, or a host cell comprising said antigen recognition construct, said T cell receptor, said nucleic acid sequence or said vector, for use in medicine.

12. 10. The antigen recognition construct or T cell receptor according to claim 1 or 8, or a nucleic acid sequence encoding the antigen recognition construct or T cell receptor according to claim 1 or 8, or a vector comprising said nucleic acid sequence, or a host cell comprising said antigen recognition construct, said T cell receptor, said nucleic acid sequence, or said vector, for use in the prevention and / or treatment of a disease, wherein preferably said disease is a malignant tumor disease or a benign tumor disease, and / or preferably said disease is a tumor expressing mutant KRAS, and / or preferably said disease is an advanced stage tumor expressing mutant KRAS, and / or preferably said disease is Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, pancreatic cancer, colorectal cancer, endometrial cancer, biliary tract cancer, liver cancer, myeloma, prostate cancer, stomach cancer, kidney cancer, bone cancer, soft tissue cancer, head and neck cancer, glioblastoma multiforme, astrocytoma, the cancer is selected from the group consisting of melanoma, lung cancer, esophageal cancer, gastric cancer, breast cancer, ovarian cancer, mesothelioma cancer, bladder cancer, anal cancer, chondrosarcoma cancer, osteosarcoma cancer, sarcoma cancer, adenoma cancer, primitive neuroectodermal carcinoma (primitive neuroectodermal tumor (PNET)), and a combination thereof; more preferably, the lung cancer is selected from the group consisting of squamous cell carcinoma of the lung, non-small cell lung cancer, and small cell lung cancer; or more preferably, the breast cancer is selected from the group consisting of ductal carcinoma, tubular breast carcinoma, medullary breast carcinoma, and a combination thereof; or more preferably, the gastric cancer is gastric adenocarcinoma; or more preferably, the sarcoma cancer is selected from the group consisting of chondrosarcoma cancer, osteosarcoma cancer, and a combination thereof; or more preferably, the adenoma cancer is selected from the group consisting of gastric adenocarcinoma, pancreatic adenocarcinoma, and a combination thereof.

13. A pharmaceutical composition comprising an antigen recognition construct or T cell receptor described in claim 1 or 8, or a nucleic acid sequence encoding the antigen recognition construct or T cell receptor described in claim 1 or 8, or a vector containing said nucleic acid sequence, or a host cell containing said antigen recognition construct, said T cell receptor, said nucleic acid sequence or said vector.

14. A kit for use in medicine comprising an antigen recognition construct or T cell receptor according to claim 1 or 8, or a nucleic acid sequence encoding the antigen recognition construct or T cell receptor according to claim 1 or 8, or a vector comprising said nucleic acid sequence, or a host cell comprising said antigen recognition construct, said T cell receptor, said nucleic acid sequence or said vector.

15. 15. The kit of claim 14, wherein the kit is a diagnostic kit for selecting patients for treatment of tumors whose cells express mutant KRAS.

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