T cell receptors for targeting mutant RAS and compositions thereof

Abstract

The present invention provides compositions and methods for treating cancers associated with mutant RAS. In one embodiment, the present invention provides T cell receptors that bind to specific mutant RAS peptide fragments in the context of a specific HLA type. In one embodiment, the present invention provides multispecific (e.g., bispecific) antibodies comprising T cell receptors that bind to specific mutant RAS peptide fragments in the context of a specific HLA type.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 375,969, filed September 16, 2022, and U.S. Provisional Patent Application No. 63 / 375,464, filed September 13, 2022, the disclosures of which are incorporated herein by reference in their entireties.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under CA204261 and CA016521 awarded by the National Institutes of Health. The U.S. Government has certain rights in this invention. [Background technology]

[0003] Somatic mutations have been identified as a common driver of carcinogenesis. Activating point mutations in the Ras gene were the first somatic point mutations identified in human cancer. RAS mutations are the most common somatic mutations in human cancer and are involved in the pathogenesis of a variety of prevalent malignancies, including lung adenocarcinoma, colorectal adenocarcinoma, and pancreatic ductal adenocarcinoma. Mutant RAS is uniquely expressed by cancer cells and is considered a critical driver mutation for tumor growth and survival, making it an attractive target for cancer therapy. These mutations typically involve codon 12 of the RAS protein, and the amino acid change is highly conserved, most commonly resulting from G12C, G12D, G12R, and G12V amino acid substitutions. Pathogenic RAS mutations are gain-of-function mutations that cause constitutive activation of intracellular GTPase signaling, promoting cell proliferation. RAS mutations may be frequently observed in certain cancer types. For example, G12D and G12V mutations are present in 60% to 70% of pancreatic cancers and 20% to 30% of colorectal cancers. Unfortunately, there are no effective pharmacological inhibitors of RAS oncoproteins.

[0004] Therefore, there is a need in the art for compositions and methods for the treatment of mutant RAS-associated cancers. The present invention addresses and fulfills these and other needs. Summary of the Invention

[0005] In various embodiments, the present invention provides compositions comprising a T cell receptor (TCR) that specifically binds to a mutant RAS (mRAS) peptide in the context of an HLA-C*08:02 molecule.

[0006] In some embodiments, the mRAS peptide comprises a mutation at a position corresponding to G12 relative to wild-type RAS. In some embodiments, the mutation in the mRAS peptide corresponds to a G12D mutation relative to wild-type RAS.

[0007] In some embodiments, the TCR comprises at least one CDR selected from TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV6-5 CDR1, TRBV6-5 CDR2, or TRBV6-5 CDR3. In some embodiments, the TCR comprises TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3.

[0008] In some embodiments, the TCR comprises at least one CDR selected from: TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV5-6 CDR1, TRBV5-6 CDR2, or TRBV5-6 CDR3. In some embodiments, the TCR comprises TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3.

[0009] In some embodiments, the composition comprises a fusion polypeptide comprising a TCR alpha chain and a TCR beta chain.

[0010] In some embodiments, the fusion polypeptide comprises a linker domain. In some embodiments, the linker domain is a cleavable linker domain.

[0011] In one embodiment, the present invention also provides a composition comprising an isolated nucleic acid molecule encoding a composition of the present invention.

[0012] In another embodiment, the invention provides cells modified to express a TCR that specifically binds to an mRAS peptide in the context of HLA-C*08:02.

[0013] In some embodiments, the mRAS peptide comprises a mutation at a position corresponding to G12 relative to wild-type RAS. In some embodiments, the mutation in the mRAS peptide corresponds to a G12D mutation relative to wild-type RAS.

[0014] In some embodiments, the cells are modified to express a fusion polypeptide comprising a TCR alpha chain and a TCR beta chain, hi some embodiments, the cells are genetically modified by introduction of an isolated nucleic acid molecule encoding a polypeptide comprising at least one of a TCR alpha chain and a TCR beta chain.

[0015] In some embodiments, the cell is an immune cell, hi some embodiments, the immune cell is selected from the group consisting of a T cell, an NK cell, or an NKT cell.

[0016] In some embodiments, the cells are autologous to a subject with a RAS-associated cancer.

[0017] In some embodiments, the cells are autologous to a subject with the HLA-C*08:02 type.

[0018] In one embodiment, the present invention also provides a method of treating a subject having a cancer associated with mRAS, comprising administering to the subject a cell of the present invention.

[0019] In some embodiments, the subject has a cancer selected from pancreatic cancer, pancreatic ductal adenocarcinoma (PDA), colon cancer, colorectal adenocarcinoma, myeloma, multiple myeloma, lung adenocarcinoma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia (AML), urothelial carcinoma, gastric adenocarcinoma and cervical adenocarcinoma, head and neck squamous cell carcinoma (SCC), diffuse large B-cell lymphoma (DLBCL), esophageal adenocarcinoma, chronic lymphocytic leukemia (CLL), lung SCC, small cell lung cancer (SCLC), renal papillary cancer, hepatocellular carcinoma (HCC), breast cancer, cervical SCC, ovarian adenocarcinoma, adrenal carcinoma, prostate cancer, neuroblastoma, glioblastoma multiforme (GBM), medulloblastoma, renal cell carcinoma (RCC), esophageal SCC, osteosarcoma, sarcoma, small intestinal neuroendocrine tumor (NET), or a combination thereof.

[0020] In some embodiments, the methods include identifying the HLA type of the subject.

[0021] In some embodiments, the methods include isolating one or more cells of a subject and modifying the one or more cells to express a TCR.

[0022] In some embodiments, the method comprises modifying one or more cells to express a TCR by contacting the one or more cells with an isolated nucleic acid molecule encoding one or more of a TCR alpha chain and a TCR beta chain.

[0023] In another aspect, the present invention provides a multispecific polypeptide comprising a first domain that specifically binds to an mRAS peptide in the context of an HLA-C*08:02 molecule and at least one second binding domain that specifically binds to a second target epitope or antigen.

[0024] In some embodiments, the first domain comprises a TCR. In some embodiments, the TCR is any TCR described herein. [Brief explanation of the drawings]

[0025] The following detailed description of preferred embodiments of the invention will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, there are shown in the drawings preferred embodiments. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

Figure 1A

Figure 1B

Figure 2A

Figure 2B

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

[0026] The present invention relates to compositions and methods for treating cancers associated with mutant RAS (mRAS). Somatic mutations within RAS result in a form of non-self antigen, making RAS-mutated tumors susceptible to immune-based therapeutic approaches, including, but not limited to, adoptive T-cell therapy. T cells possess unique T-cell receptors (TCRs) that can recognize subtle mutations within intracellular proteins that may be expressed and presented on HLA molecules by tumor cells.

[0027] The present invention is applicable to any member of the RAS oncogenic protein family, including, but not limited to, KRAS, NRAS, and HRAS. The RAS hotspot mutations described herein (e.g., mutations at position G12) are commonly found in KRAS-, NRAS-, and HRAS-related cancers. Furthermore, the amino acid sequences of the RAS peptides described herein are conserved among all RAS family members. Therefore, the mutant RAS peptides and TCRs described herein are applicable in inducing an immune response against mutant RAS family members to treat cancers associated with mutant RAS family members. As used herein, "RAS" is intended to encompass any member of the RAS protein family.

[0028] The present invention is based, in part, on the identification of antigenic, HLA-restricted variant RAS peptides. The RAS peptides described herein can be used as immunogenic compositions for inducing an immune response against mRAS. In one embodiment, the present invention relates to immunogenic compositions, such as vaccines, comprising the antigenic mRAS peptides described herein or nucleic acid molecules encoding the antigenic mRAS peptides described herein.

[0029] The present invention is also based, in part, on the identification of T cell receptor (TCR) sequences that specifically recognize HLA-restricted mutant RAS antigens. The TCR sequences described herein recognize common mutant RAS antigens in the context of frequently occurring HLA types. In certain aspects, the present invention relates to compositions comprising isolated TCRs or nucleic acid molecules encoding isolated TCRs that specifically bind to RAS, mRAS, or fragments thereof. In one embodiment, the composition comprises cells, e.g., home-grown or allogeneic T cells, that have been genetically modified to express a TCR that specifically binds to RAS, mRAS, or a fragment thereof.

[0030] In some aspects, the invention relates to an antibody comprising an isolated TCR or fragment thereof, or a nucleic acid molecule encoding an antibody comprising an isolated TCR or fragment thereof that specifically binds to RAS, mRAS, or a fragment thereof. In some embodiments, the antibody is a bispecific antibody, e.g., an engineered bispecific monoclonal antibody or a bispecific T cell engager (BiTE).

[0031] In one aspect, the present invention relates to a method for treating or preventing mRAS-associated cancer using a composition described herein. In one aspect, the present invention relates to a method for treating or preventing mRAS-associated cancer using an antibody (e.g., a bispecific antibody) comprising a TCR or a fragment thereof described herein. In one embodiment, the present invention relates to a method using TCR therapy, e.g., adoptive TCR therapy. In one embodiment, the method comprises administering to a subject with an mRAS-associated cancer at least one T cell genetically modified to express a TCR that specifically binds to RAS, mRAS, or a fragment thereof. In one embodiment, the method comprises administering to the subject an immunogenic composition comprising an mRAS peptide described herein or a nucleic acid molecule encoding an mRAS peptide. In one embodiment, the method comprises administering to the subject an immunogenic composition comprising antigen-presenting cells (APCs), such as dendritic cells, loaded with one or more mRAS peptides described herein or one or more nucleic acid molecules encoding one or more mRAS peptides.

[0032] Exemplary mRAS-associated cancers treatable by the compositions and methods of the present invention include pancreatic ductal adenocarcinoma (PDA), colon cancer, colorectal adenocarcinoma, myeloma, multiple myeloma, lung cancer, lung adenocarcinoma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia (AML), urothelial carcinoma, gastric adenocarcinoma and cervical adenocarcinoma, head and neck squamous cell carcinoma (SCC), diffuse large B-cell lymphoma (DLBCL), esophageal adenocarcinoma, chronic lymphocytic leukemia (CLL), lung SCC, small cell lung cancer (SCLC), renal papillary carcinoma (RPC), and thyroid cancer. These include, but are not limited to, hepatocellular carcinoma (HCC), breast cancer, cervical SCC, ovarian adenocarcinoma, adrenal carcinoma, prostate cancer, neuroblastoma, glioblastoma multiforme (GBM), medulloblastoma, renal cell carcinoma (RCC), esophageal SCC, osteosarcoma, sarcoma, and small intestinal neuroendocrine tumors (NETs).

[0033] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described.

[0034] As used herein, each of the following terms has the meaning associated with it in this section.

[0035] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0036] The terms "inhibit" and "inhibition," as used herein, mean to reduce, suppress, attenuate, or block an activity or function by at least about 10% relative to a control value. In some embodiments, the activity is inhibited or blocked by at least about 50% compared to a control value. In some embodiments, the activity is inhibited or blocked by at least about 75%. In some embodiments, the activity is inhibited or blocked by at least about 95%.

[0037] The terms "effective amount" and "therapeutically effective amount" refer to an amount of an agent sufficient to produce a desired biological result. That result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. An appropriate "effective amount" in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

[0038] The terms "patient," "subject," "individual," and the like are used interchangeably herein and refer to any animal, in some embodiments a mammal, and in some embodiments a human, having a complement system, including humans in need of treatment for or susceptible to a condition or its sequelae. Individuals can include, for example, dogs, cats, pigs, cows, sheep, goats, horses, rats, monkeys, and mice, as well as humans.

[0039] The term "abnormal," when used in reference to an organism, tissue, cell, or component thereof, refers to an organism, tissue, cell, or component thereof that differs in at least one observable or detectable characteristic (e.g., age, treatment, time of day, etc.) from an organism, tissue, cell, or component thereof that exhibits the respective "normal" (expected / homeostatic) characteristic. A characteristic that is normal or expected for one cell, tissue type, or subject may be abnormal for a different cell or tissue type.

[0040] "Activated," as used herein, refers to a state of T cells that have received sufficient stimulation to induce detectable cell proliferation. Activation can also be associated with the induction of cytokine production and detectable effector function. The term "activated T cells" refers, inter alia, to T cells that are undergoing cell division.

[0041] A "disease" is a condition in a subject in which the subject is unable to maintain homeostasis, and in which the subject's health continues to deteriorate if the disease is not improved.

[0042] In contrast, a "disorder" in a subject is a condition in which the subject is able to maintain homeostasis, but in which the subject's condition is less favorable than it would be in the absence of the disorder. If left untreated, the disorder does not necessarily cause further deterioration of the subject's condition.

[0043] A disease or disorder is "alleviated" if the severity of a sign or symptom of the disease or disorder, the frequency with which a patient experiences such sign or symptom, or both, is reduced.

[0044] The term "cancer," as used herein, is defined as a disease characterized by the rapid and uncontrolled growth of abnormal cells. Cancer cells can spread locally or to other parts of the body through the bloodstream and lymphatic system. Examples of various cancers include, but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, etc.

[0045] The term "anti-tumor effect," as used herein, refers to a biological effect that may be manifested by a reduction in tumor volume, a reduction in tumor cell number, a reduction in the number of metastases, an increase in life expectancy, or an improvement in various physiological symptoms associated with a cancerous condition. An "anti-tumor effect" may also be manifested by the ability of the peptides, polynucleotides, cells, and antibodies of the present invention in preventing tumor development in the first place.

[0046] As used herein, the term "autologous" is intended to refer to any material obtained from an individual with the intent to later be reintroduced into that same individual.

[0047] "Allogeneic" refers to the graft being obtained from a different animal of the same species.

[0048] "Xenogeneic" refers to the graft being obtained from an animal of a different species.

[0049] An "effective amount" or "therapeutically effective amount" of a compound is the amount of the compound sufficient to confer a beneficial effect on the subject to which it is administered.

[0050] As used herein, "instructional material" includes publications, records, drawings, or any other medium of expression that can be used to communicate the usefulness of the compounds, compositions, vectors, or delivery systems of the invention in kits for providing relief from various diseases or disorders described herein. Optionally, or alternatively, the instructional material can describe one or more methods of alleviating a disease or disorder in a mammalian cell or tissue. The instructional material of the kits of the invention can be, for example, affixed to a container containing the identified compound, composition, vector, or delivery system of the invention, or shipped together with a container containing the identified compound, composition, vector, or delivery system. Alternatively, the instructional material can be shipped separately from the container, with the intention that the recipient use the instructional material in conjunction with the compound.

[0051] As used herein, "operably linked" or "operably linked" may mean that the expression of a gene is under the control of a promoter that is spatially connected to it. The promoter may be located 5' (upstream) or 3' (downstream) of the gene under its control. The distance between the promoter and the gene may be approximately the same as the distance between the promoter and the gene it controls in the gene from which the promoter is derived. As is known in the art, variations in this distance may be tolerated without loss of promoter function.

[0052] A "therapeutic treatment" is a treatment administered to a subject who exhibits symptoms of a disease or disorder with the intent of diminishing or eliminating those symptoms.

[0053] As used herein, "treating a disease or disorder" means that a reduction in the frequency and / or severity of the signs and / or symptoms of the disease or disorder is experienced by the patient.

[0054] The terms "biological sample," "sample," or "specimen," as used herein, are intended to encompass any sample containing cells, tissues, or bodily fluids in which nucleic acid or polypeptide expression can be detected. A biological sample may contain any biological material suitable for detecting a biomarker of interest and may include cellular and / or non-cellular material obtained from an individual. Examples of such biological samples include, but are not limited to, blood, lymph, bone marrow, biopsies, and smears. Samples that are liquid in nature are referred to as "body fluids." Biological samples can be obtained from a patient by various techniques, including, for example, by scraping or swabbing an area or by using a needle to obtain a bodily fluid. Methods for collecting various body samples are well known in the art.

[0055] "CDR" is defined as the amino acid sequence of the complementarity determining region of a TCR or TCR chain.

[0056] As used herein, "immunoassay" refers to any binding assay that uses an antibody capable of specifically binding to a target molecule to detect and quantitate the target molecule.

[0057] The term "specifically binds," when used herein in reference to a polypeptide (e.g., a TCR or TCR chain), means that the polypeptide recognizes and binds to a specific target molecule, but does not substantially recognize or bind to other molecules in a sample. In some cases, the terms "specific binding" or "specifically binding" are used to indicate that recognition and binding are dependent on the presence of a particular structure (e.g., an antigenic determinant or epitope) on the target molecule.

[0058] The term "antibody" encompasses any antibody protein construct comprising at least one antibody variable domain containing at least one antigen-binding site (ABS). Antibodies include, but are not limited to, immunoglobulins of the IgA, IgG, IgE, IgD, and IgM types (and their subtypes). The overall structure of immunoglobulin G (IgG) antibodies, constructed from two identical heavy (H) chain polypeptides and two identical light (L) chain polypeptides, is well established and highly conserved among mammals (Padlan (1994) Mol. Immunol. 31:169-217).

[0059] A typical antibody or immunoglobulin (Ig) is a protein comprising four polypeptide chains: two heavy (H) chains and two light (L) chains. Each chain is divided into a constant region and a variable domain. The heavy (H) chain variable domain is abbreviated herein as VH, and the light (L) chain variable domain is abbreviated herein as VL. These domains, domains related to them, and domains derived from them may be referred to herein as immunoglobulin chain variable domains. The VH and VL domains (also referred to as VH and VL regions) can be further subdivided into regions called "complementarity-determining regions" ("CDRs"), interspersed with more conserved regions called "framework regions" ("FRs"). The framework and complementarity-determining regions are precisely defined (Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, (1991) NIH Publication Number 91-3242). Other numbering conventions for CDR sequences exist, such as those presented by Chothia et al. (1989) Nature 342: 877-883 and those compiled by IMGT.org. In a typical antibody, each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. A typical antibody tetramer, consisting of two immunoglobulin heavy chains and two immunoglobulin light chains, is formed by the immunoglobulin heavy chains and immunoglobulin light chains interconnected by, for example, disulfide bonds, and the heavy chains similarly connected. The heavy chain constant region contains three domains, CH1, CH2, and CH3. The light chain constant region consists of one domain, CL. The heavy chain variable domain and the light chain variable domain are binding domains that interact with antigens.The constant regions of the antibodies typically mediate the binding of the antibody to host tissues or host factors, including various immune system cells (e.g., effector cells) and the first component (C1q) of the classical complement system.

[0060] "Specificity" refers to the number of different antigens or antigenic determinants to which a particular antibody or antigen-binding fragment thereof can bind. Antibody specificity refers to the antibody's ability to recognize a particular antigen as a unique molecular entity and distinguish it from other antigens. An antibody that "specifically binds" to an antigen or epitope is a term well understood in the art. A molecule is said to exhibit "specific binding" if it reacts with a particular target antigen or epitope more frequently, more rapidly, for a longer duration, and / or with greater affinity than it reacts with another target. An antibody "specifically binds" to a target antigen or epitope if it binds with greater affinity, avidity, more rapidly, and / or for a longer duration than it binds to other substances.

[0061] The antibodies of the present invention encompass multispecific polypeptides and multispecific antibodies. A "multispecific polypeptide" or "multispecific antibody" is a molecule capable of binding to multiple different epitopes, simultaneously or sequentially. Typically, epitopes do not occur on the same antigen. Thus, a multispecific polypeptide or multispecific antibody has the ability to selectively bind to epitopes present on different antigens via multiple different binding domains. This is in contrast to a typical monospecific polypeptide or monospecific antibody, which does not have this ability. Rather, a "monospecific polypeptide" or "monospecific antibody" has specific binding affinity for only one antigen, but may have multiple binding sites for that antigen (e.g., a fully human IgG antibody has a valency of 2, while other antibodies may have a higher valency, but are still classified as monospecific antibodies if they recognize only one antigen). Thus, a multispecific polypeptide or multispecific antibody of the present invention binds to multiple different antigens simultaneously and / or sequentially.

[0062] In some embodiments of the present invention, the polypeptide or antibody is a bispecific polypeptide or antibody. A "bispecific polypeptide" or "bispecific antibody" is a polypeptide or antibody that can bind to two different epitopes simultaneously and / or sequentially. Typically, the epitopes do not occur on the same antigen. Thus, a bispecific polypeptide or bispecific antibody has the ability to selectively bind to two different epitopes present on two different antigens via two different binding domains. This is in contrast to conventional monospecific polypeptides or monospecific antibodies that do not have this ability. Thus, a bispecific polypeptide or bispecific antibody of the present invention binds to two different antigens simultaneously and / or sequentially.

[0063] "Affinity" is expressed as the dissociation equilibrium constant (KD) between an antigen and an antigen-binding polypeptide and is a measure of the binding strength between an antigenic determinant and an antigen-binding site on an antibody (or antigen-binding fragment thereof): the lower the KD value, the stronger the binding strength between the antigenic determinant and the antigen-binding polypeptide. Alternatively, affinity can be expressed as an affinity constant (KA), where KA is 1 / KD. Affinity can be determined by known methods depending on the particular antigen of interest. For example, KD can be determined by surface plasmon resonance.

[0064] 10 -6 A KD value of less than 0.05 is considered to indicate binding. Specific binding of an antibody or antigen-binding fragment thereof to an antigen or antigenic determinant can be determined by any suitable known method, including, for example, Scatchard analysis and / or competitive binding assays, such as radioimmunoassays (RIA), enzyme-linked immunosorbent assays (EIA) and sandwich competition assays, equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance, or spectroscopy (e.g., using fluorescence assays), as well as different modifications thereof known in the art.

[0065] "Avidity" is a measure of the strength of binding between an antibody or antigen-binding fragment thereof and an associated antigen. Avidity is related to both the affinity between an antigenic determinant and its antigen-binding site on the antibody and the number of associated binding sites present on the antibody.

[0066] The "coding region" of a gene consists of the nucleotide residues of the coding strand of that gene and the nucleotides of the non-coding strand of that gene that are homologous or complementary, respectively, to the coding region of an mRNA molecule produced by transcription of that gene.

[0067] The "coding region" of an mRNA molecule also consists of nucleotide residues of the mRNA molecule that match the anticodon region of a transfer RNA molecule or that encode a stop codon during translation of the mRNA molecule. Thus, a coding region may include nucleotide residues that contain codons for amino acid residues that are not present in the mature protein encoded by the mRNA molecule (e.g., amino acid residues in a protein export signal sequence).

[0068] "Differentially decreased expression" or "down-regulation" refers to a decrease in the level of a biomarker product that is at least 10% or more, e.g., 20%, 30%, 40%, or 50%, 60%, 70%, 80%, 90% lower or less, and / or a 2.0-fold, 1.8-fold, 1.6-fold, 1.4-fold, 1.2-fold, 1.1-fold, or less fold decrease, relative to a control, including any whole or partial increment therebetween.

[0069] "Differentially increased expression" or "upregulation" refers to a level of a biomarker product that is at least 10% or more, e.g., 20%, 30%, 40%, or 50%, 60%, 70%, 80%, 90% higher or more, and / or 1.1-fold, 1.2-fold, 1.4-fold, 1.6-fold, 1.8-fold, 2.0-fold higher or more, relative to a control, including any whole or partial increment therebetween.

[0070] As used herein with reference to nucleic acids, "complementary" refers to the broad concept of sequence complementarity between regions of two nucleic acid strands or between two regions of the same nucleic acid strand. It is known that an adenine residue in a first nucleic acid region can form specific hydrogen bonds ("base pairing") with a residue in a second nucleic acid region antiparallel to the first region when the residue is thymine or uracil. Similarly, it is known that a cytosine residue in a first nucleic acid strand can base pair with a residue in a second nucleic acid strand antiparallel to the first strand when the residue is guanine. A first region of nucleic acid is complementary to a second region of the same or a different nucleic acid if, when the two regions are aligned in an antiparallel orientation, at least one nucleotide residue in the first region can base pair with a residue in the second region. In some embodiments, the first region comprises a first portion and the second region comprises a second portion, and when the first and second portions are aligned in antiparallel, at least about 50%, and / or at least about 75%, or at least about 90%, or at least about 95% of the nucleotide residues in the first portion are capable of base pairing with nucleotide residues in the second portion. In some embodiments, all nucleotide residues in the first portion are capable of base pairing with nucleotide residues in the second portion.

[0071] The term "DNA" as used herein is defined as deoxyribonucleic acid.

[0072] "Encoding" refers to the inherent property of, and the biological properties resulting from, a particular nucleotide sequence within a polynucleotide, such as a gene, cDNA, or mRNA, to serve as a template for the synthesis of other polymers and macromolecules in biological processes, having a defined nucleotide sequence (i.e., rRNA, tRNA, and mRNA) or a defined amino acid sequence. That is, a gene encodes a protein when a protein is produced in a cell or other biological system by transcription and translation of the mRNA corresponding to that gene. Both the coding strand, which is the nucleotide sequence identical to the mRNA sequence and usually shown in a sequence listing, and the non-coding strand, which is used as a template for transcription of the gene or cDNA, are said to encode the protein or other product of that gene or cDNA.

[0073] Unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. References to a nucleotide sequence encoding a protein or RNA can also include introns, to the extent that in some forms the nucleotide sequence encoding the protein may contain introns.

[0074] The term "hybridoma," as used herein, refers to a cell resulting from the fusion of a B lymphocyte with a fusion partner, such as a myeloma cell. Hybridomas can be cloned and maintained indefinitely in cell culture, and are capable of producing monoclonal antibodies. Hybridomas can also be considered hybrid cells.

[0075] "Isolated" means changed or removed from the natural state. For example, a nucleic acid or peptide that occurs naturally under normal conditions in an organism is not "isolated," but the same nucleic acid or peptide that has been partially or completely separated from the coexisting materials of its natural setting is "isolated." An isolated nucleic acid or protein may exist in a substantially purified form, or it may exist in a non-native environment, such as a host cell.

[0076] An "isolated nucleic acid" refers to a nucleic acid segment or fragment that is separated from sequences that flank it in its naturally occurring state; i.e., a DNA fragment that is removed from sequences that normally flank the fragment, i.e., the sequences that flank the fragment in the genome in which it occurs in nature. The term also applies to nucleic acids that have been substantially purified from other components that naturally accompany the nucleic acid, i.e., the RNA or DNA or proteins that naturally accompany the nucleic acid in the cell. Thus, the term includes, for example, recombinant DNA incorporated into a vector, an autonomously replicating plasmid or virus, or into the genomic DNA of a prokaryote or eukaryote, and recombinant DNA that exists as a separate molecule free from other sequences (i.e., as cDNA, or as genomic or cDNA fragments produced by PCR or restriction enzyme digestion). It also includes recombinant DNA that is part of a hybrid gene that encodes additional polypeptide sequences.

[0077] In connection with the present invention, the following abbreviations are used for commonly occurring nucleobases: "A" refers to adenosine, "C" refers to cytosine, "G" refers to guanosine, "T" refers to thymidine, and "U" refers to uridine.

[0078] The term "polynucleotide" as used herein is defined as a chain of nucleotides. Furthermore, a nucleic acid is a polymer of nucleotides. Therefore, as used herein, nucleic acid and polynucleotide are interchangeable. Those skilled in the art have general knowledge that a nucleic acid is a polynucleotide, and that a polynucleotide can hybridize to a monomeric "nucleotide." A monomeric nucleotide can hybridize to a nucleoside. As used herein, polynucleotide encompasses, but is not limited to, all nucleic acid sequences obtained by any means available in the art, including, but not limited to, recombinant means, i.e., cloning a nucleic acid sequence from a recombinant library or a cellular genome using conventional cloning techniques and PCR, etc., and synthetic means.

[0079] "Lentivirus" as used herein refers to a genus of the Retroviridae family. Lentiviruses are unique among retroviruses in that they can infect non-dividing cells; they can deliver a significant amount of genetic information into the DNA of host cells, making them one of the most efficient gene delivery vectors. HIV, SIV, and FIV are all examples of lentiviruses. Lentivirus-derived vectors provide a means to achieve significant levels of gene transfer in vivo.

[0080] As used herein, the terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, but there is no limit to the maximum number of amino acids that can comprise a protein or peptide sequence. A polypeptide encompasses any peptide or protein containing two or more amino acids linked together by peptide bonds. As used herein, the term refers to both short chains, commonly referred to in the art as peptides, oligopeptides, and oligomers, and longer chains, commonly referred to in the art as polypeptides or proteins. "Polypeptide" specifically includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, polypeptide variants, modified polypeptides, derivatives, analogs, and fusion proteins. These polypeptides include natural peptides, recombinant polypeptides, synthetic peptides, or combinations thereof.

[0081] The term "RNA" as used herein is defined as ribonucleic acid.

[0082] The term "recombinant DNA," as used herein, is defined as DNA that is produced by joining pieces of DNA from different sources.

[0083] The term "recombinant polypeptide," as used herein, is defined as a polypeptide produced using recombinant DNA methods.

[0084] As used herein, "conjugated" refers to the covalent attachment of one molecule to a second molecule.

[0085] "Homologous" refers to sequence similarity or sequence identity between two polypeptides or two nucleic acid molecules. If a position in both compared sequences is occupied by the same base or amino acid monomer subunit, for example, if a position in each of two DNA molecules is occupied by adenine, the molecules are homologous at that position. The percent homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences, divided by the number of positions compared, multiplied by 100. For example, if 6 out of 10 positions in two sequences are matched or homologous, the two sequences are 60% homologous. As an example, the DNA sequences ATTGCC and TATGGC share 50% homology. Generally, comparisons are performed when the two sequences are aligned to maximize homology.

[0086] A "variant," as the term is used herein, refers to a nucleic acid or peptide sequence that differs in sequence from a reference nucleic acid or peptide sequence, respectively, but retains essential biological properties of the reference molecule. Sequence changes in a nucleic acid variant may not change the amino acid sequence of a peptide encoded by the reference nucleic acid, or may result in amino acid substitutions, additions, deletions, fusions, and truncations. Changes in the sequence of a peptide variant are typically limited or conservative, such that the sequences of the reference peptide and variant are similar overall and, in many regions, identical. A variant and reference peptide may differ in amino acid sequence by one or more substitutions, additions, or deletions, in any combination. A nucleic acid or peptide variant may be naturally occurring, such as an allelic variant, or may be a variant that is not known to occur naturally. Non-naturally occurring variants of nucleic acids and peptides can be generated by mutagenesis or by direct synthesis. In various embodiments, the variant sequence is at least 99%, at least 98%, at least 97%, at least 96%, at least 95%, at least 94%, at least 93%, at least 92%, at least 91%, at least 90%, at least 89%, at least 88%, at least 87%, at least 86%, at least 85% identical to the reference sequence.

[0087] The term "regulating," as used herein, can refer to any method of altering the level or activity of a substrate. Non-limiting examples of regulation with respect to proteins include affecting expression (including transcription and / or translation), affecting folding, affecting degradation or protein turnover, and affecting protein localization. Non-limiting examples of regulation with respect to enzymes further include affecting enzyme activity. A "regulator" refers to a molecule whose activity includes affecting the level or activity of a substrate. Regulators can be direct or indirect. Regulators can function to activate, inhibit, or regulate their substrate.

[0088] As used herein, a "scanning window" refers to a segment of adjacent positions within which a sequence can be evaluated independently of adjacent sequences. The scanning window is typically shifted incrementally along the length of the sequence being evaluated, with each new segment being evaluated independently. The incremental shift can be one or more positions.

[0089] "Vector," as used herein, may refer to a nucleic acid sequence that includes an origin of replication. A vector may be a plasmid, a bacteriophage, a bacterial artificial chromosome, or a yeast artificial chromosome. A vector may be a DNA vector or an RNA vector. A vector may be a self-replicating extrachromosomal vector or a vector that integrates into a host genome.

[0090] As used herein, "substantially purified" cells are cells that are essentially free of other cell types. Substantially purified cells also refer to cells that have been separated from other cell types with which the cells are normally associated in their natural state. In some cases, a substantially purified cell population refers to a homogenous cell population. In other cases, the term simply refers to cells that have been separated from the cells with which they are naturally associated in their natural state. In some embodiments, the cells are cultured in vitro. In other embodiments, the cells are not cultured in vitro.

[0091] Ranges: Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed not only each individual numerical value within that range but also all possible subranges. For example, description of a range such as 1 to 6 should be considered to have specifically disclosed not only each individual numerical value within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6, but also subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc. This applies regardless of the breadth of the range.

[0092] explanation The present invention relates to compositions and methods for treating mRAS-associated cancers. In various embodiments, the compositions and methods described herein can be used to kill cancer cells, reduce tumor size, inhibit tumor growth, inhibit tumor metastasis, slow tumor progression or severity, and the like.

[0093] In one aspect, the present invention relates to an immunogenic composition comprising an antigenic mRAS peptide that stimulates or induces an anti-mRAS immune response. In one embodiment, the mRAS peptide comprises a fragment of mRAS. In one embodiment, the mRAS peptide comprises an amino acid sequence of approximately 5 to 15 amino acids. In one embodiment, the mRAS peptide comprises an amino acid sequence having a mutation at position G12 compared to wild-type RAS. For example, in one embodiment, the mRAS peptide comprises an amino acid sequence of approximately 5 to 15 amino acids and includes a G12C, G12D, G12R, or G12V mutation compared to wild-type RAS.

[0094] In one embodiment, the present invention provides an isolated nucleic acid molecule encoding an mRAS peptide described herein. In one embodiment, the present invention provides a cell, such as an antigen-presenting cell, comprising an mRAS peptide described herein or a nucleic acid molecule encoding an mRAS peptide.

[0095] In one aspect, the invention relates to a polypeptide comprising one or more TCR chains (e.g., a TCR alpha chain, a TCR beta chain, a TCR delta chain, and a TCR gamma chain) that, alone or together, specifically bind to RAS, mRAS, or a fragment thereof. In one embodiment, the TCR comprises a TCR alpha chain and a TCR beta chain, and the TCR specifically binds to RAS, mRAS, or a fragment thereof. Hereinafter, reference to "TCR" refers to the heterodimeric TCR, individual TCR chains (e.g., a TCR alpha chain, a TCR beta chain, a TCR delta chain, and a TCR gamma chain), and functional portions and variants thereof.

[0096] In one embodiment, the TCR specifically binds to mRAS comprising a mutation at position G12 relative to wild-type RAS. For example, in one embodiment, the TCR specifically binds to mRAS comprising a G12D mutation relative to wild-type RAS. In one embodiment, the TCR specifically binds to a fragment of mRAS comprising a mutation at the position corresponding to G12. In one embodiment, the TCR specifically binds to an mRAS fragment in the context of a particular HLA type. In one embodiment, the composition comprises a fusion polypeptide comprising a TCR α chain and a TCR β chain that together form a heterodimeric TCR. In one embodiment, the fusion polypeptide comprises a cleavable linker between the TCR α chain and the TCR β chain.

[0097] In one embodiment, the invention provides an isolated nucleic acid molecule encoding a TCR described herein. In one embodiment, the invention provides a cell, such as a T cell, that has been modified to express a TCR described herein.

[0098] In one aspect, the invention provides an antibody comprising at least one TCR or fragment thereof described herein that specifically binds to RAS, mRAS (e.g., mRAS comprising a G12C mutation, a G12D mutation, a G12R mutation, or a G12V mutation relative to wild-type RAS), or a fragment thereof. In some embodiments, the antibody is a bispecific antibody, e.g., an engineered bispecific monoclonal antibody or a bispecific T cell engager (BiTE).

[0099] In one aspect, the present invention provides a composition comprising at least one TCR or fragment thereof described herein that specifically binds to RAS, mRAS (e.g., mRAS that comprises a G12C, G12D, G12R, or G12V mutation relative to wild-type RAS), or a fragment thereof. In some embodiments, the composition further comprises a second TCR that specifically binds to mRAS that comprises a G12C, G12D, G12R, or G12V mutation relative to wild-type RAS.

[0100] In one embodiment, the present invention provides a method for treating or preventing an mRAS-associated cancer in a subject who has, is suspected of having, or is at risk of developing an mRAS-associated cancer. Exemplary mRAS-associated cancers that are treatable or preventable by the compositions and methods of the present invention include pancreatic cancer, pancreatic ductal adenocarcinoma (PDA), colon cancer, colorectal adenocarcinoma, myeloma, multiple myeloma, lung adenocarcinoma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia (AML), urothelial carcinoma, gastric adenocarcinoma, and cervical adenocarcinoma, head and neck squamous cell carcinoma (SCC), diffuse large B-cell lymphoma (DLBCL), esophageal adenocarcinoma, chronic lymphocytic leukemia (CLL), lung cancer, lung SCC, small cell lung cancer (SCLC), renal papillary carcinoma (RPC), and thyroid cancer. These include, but are not limited to, hepatocellular carcinoma (HCC), breast cancer, cervical SCC, ovarian adenocarcinoma, adrenal carcinoma, prostate cancer, neuroblastoma, glioblastoma multiforme (GBM), medulloblastoma, renal cell carcinoma (RCC), esophageal SCC, osteosarcoma, sarcoma, and small intestinal neuroendocrine tumors (NETs).

[0101] In one embodiment, the method includes administering to a subject an immunogenic composition comprising an mRAS peptide, a nucleic acid molecule encoding an mRAS peptide, or at least one cell comprising an mRAS peptide or a nucleic acid molecule encoding an mRAS peptide. In one embodiment, the method includes administering antigen-presenting cells, such as dendritic cells, loaded with one or more mRAS peptides or one or more nucleic acid molecules encoding one or more mRAS peptides. In some embodiments, the antigen-presenting cells are autologous cells or are derived from autologous cells. For example, in one embodiment, the method includes isolating autologous cells from the subject; culturing the autologous cells in vitro; loading the isolated autologous cells with one or more mRAS peptides or one or more nucleic acid molecules encoding one or more mRAS peptides to generate antigen-presenting cells that present the mRAS peptides described herein; and administering the antigen-presenting cells to the subject. In some embodiments, the specific type of mRAS peptide used in the method depends on the specific HLA type of the subject or cells.

[0102] In one embodiment, the method includes administering to a subject a composition comprising a TCR, a nucleic acid molecule encoding a TCR, or at least one cell expressing a TCR, wherein the TCR specifically binds to RAS, mRAS, or a fragment thereof. In one embodiment, the method includes adoptive TCR therapy, in which autologous T cells are genetically modified to express a TCR described herein and administered to the subject to induce an immune response against cancer cells presenting mRAS or a fragment thereof. For example, in one embodiment, the method includes isolating autologous cells from the subject; culturing the autologous cells in vitro; genetically modifying the isolated autologous cells to express a TCR described herein; and administering the genetically modified cells to the subject. In some embodiments, the specific type of TCR used in the method depends on the specific HLA type of the subject or cells.

[0103] mRAS peptides and vaccines In some embodiments, the present invention provides a composition comprising an antigenic mRAS peptide. In one embodiment, the mRAS peptide stimulates or induces an anti-mRAS immune response in a subject.

[0104] In one embodiment, the mRAS peptide comprises a mutation at position G12 relative to wild-type RAS. In one embodiment, the mRAS peptide comprises a G12C, G12D, G12R, or G12V mutation relative to wild-type RAS. In some embodiments, the mRAS peptide is a short fragment of full-length mRAS.

[0105] In one embodiment, the mRAS peptide has a length of about 8 to about 24 amino acid residues, or about 9 to about 11 amino acid residues. In an embodiment of the present invention, the mRAS peptide contains a mutation corresponding to G12 compared to wild-type mRAS, and the mRAS peptide has a length of about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 amino acid residues.

[0106] Exemplary antigenic mRAS peptides of the invention are provided in Table 1. In one embodiment, the antigenic mRAS peptide comprises SEQ ID NO:231.

[0107] In one embodiment, the present invention provides an immunogenic composition for inducing an immune response against mRAS in a subject. For example, in one embodiment, the immunogenic composition is a vaccine. For a composition to be useful as a vaccine, it must induce an immune response against mRAS in a cell, tissue, or mammal (e.g., a human). In some cases, the vaccine induces a protective immune response in a mammal. As used herein, an "immunogenic composition" may include an antigen (e.g., an mRAS peptide), a nucleic acid encoding the antigen, a cell expressing or presenting the antigen or a cellular component, or a combination thereof. In some embodiments, the composition comprises or encodes all or a portion of any peptide antigen described herein, or a functional equivalent in terms of immunogenicity. In other embodiments, the composition is in the form of a mixture containing an additional immunostimulatory agent or a nucleic acid encoding such an agent. Immunostimulatory agents include, but are not limited to, additional antigens, immunomodulatory agents, antigen-presenting cells, lipid nanoparticles, or adjuvants. In other embodiments, one or more of the additional agents, in any combination, are covalently bound to the antigen or immunostimulatory agent.

[0108] In the context of the present invention, the term "vaccine" refers to a composition that induces an immune response when administered to an animal. In some embodiments, the induced immune response provides protective immunity. Vaccines of the present invention can vary in the composition of nucleic acid and / or cellular components. In a non-limiting example, a vaccine containing or encoding an mRAS peptide antigen can be formulated with an adjuvant. Of course, it should be understood that the various compositions described herein can further comprise additional components. For example, one or more vaccine components can be contained in lipids, liposomes, or lipid nanoparticles. In another non-limiting example, a vaccine can include one or more adjuvants. Exemplary adjuvants include, but are not limited to, α-interferon, γ-interferon, platelet-derived growth factor (PDGF), TNFα, TNFβ, GM-CSF, epidermal growth factor (EGF), cutaneous T-cell-attracting chemokine (CTACK), epithelial thymus-expressed chemokine (TECK), mucosal-associated epithelial chemokine (MEC), IL-12, IL-15, MHC, CD80, CD86.Other genes that may be useful adjuvants include those encoding MCP-I, MIP-Ia, MIP-Ip, IL-8, RANTES, L-selectin, P-selectin, E-selectin, CD34, GlyCAM-1, MadCAM-1, LFA-1, VLA-1, Mac-1, pl50.95, PECAM, ICAM-1, ICAM-2, ICAM-3, CD2, LFA-3, M-CSF, G-CSF, IL-4, variants of IL-18, CD40, CD40L, vascular growth factor (VGF), and IL-18. factor), fibroblast growth factor, IL-7, nerve growth factor, vascular endothelial growth factor, Fas, TNF receptor, Fit, Apo-1, p55, WSL-I, DR3, TRAMP, Apo-3, AIR, LARD, NGRF, DR4, DR5, KILLER, TRAIL-R2, TRICK2, DR6, caspase ICE, Fos, c-jun, Sp-I, Ap-I, Ap-2, p38, p65Rel, MyD88, IRAK, TRAF6, IkB, inactive NIK, SAP K, SAP-I, JNK, interferon response genes gene), NFkB, Bax, TRAIL, TRAILrec, TRAILrecDRC5, TRAIL-R3, TRAIL-R4, RANK, RANK ligand, Ox40, Ox40 ligand, NKG2D, MICA, MICB, NKG2A, NKG2B, NKG2C, NKG2E, NKG2F, TAP1, TAP2, anti-CTLA4-sc, anti-LAG3-Ig, anti-TIM3-Ig, and functional fragments thereof.

[0109] The vaccines of the present invention, and their various components, may be prepared and / or administered by any of the methods disclosed herein or as would be known to those of skill in the art in light of the present disclosure.

[0110] The induction of immunity by an mRAS peptide antigen can be detected in vivo or in vitro by observing the response of all or any part of the immune system in the host against mRAS.

[0111] The present invention encompasses cells that have been exposed to or otherwise "pulsed" with an antigen (e.g., an mRAS peptide antigen). For example, antigen-presenting cells (APCs), such as dendritic cells (DCs), can be antigen (Ag)-loaded in vitro, e.g., by ex vivo culture in the presence of antigen, or by exposure to antigen in vivo.

[0112] Those skilled in the art will also readily appreciate that APCs can be "pulsed" by exposing them to an antigen for a period of time sufficient to promote presentation of the antigen on the surface of the APC. For example, APCs can be exposed to an antigen in the form of a small peptide fragment known as an antigenic peptide, which is "pulsed" directly onto the outside of the APC. Alternatively, APCs can be incubated with an antigenic peptide, which is ingested by the APC. The APC then presents the antigenic peptide on its surface. Antigens in peptide form can be exposed to cells by standard "pulsing" techniques, such as those described herein and known in the art.

[0113] Antigen-loaded APCs, also known as "pulsed APCs," of the present invention are produced by exposing APCs to antigen in vitro or in vivo. When pulsing APCs in vitro, the APCs can be plated in a culture dish and exposed to antigen in a sufficient amount and for a sufficient time to allow the antigen to bind to the APCs. The amount and time required to achieve antigen binding to APCs can be determined using methods known in the art or methods disclosed elsewhere herein. Other methods known to those skilled in the art, such as immunoassays and binding assays, may also be used to detect the presence of antigen on APCs after exposure to the antigen.

[0114] In another embodiment of the present invention, APCs can be transfected with a vector that allows APCs to express a specific peptide. The peptide expressed by APCs can then be processed and presented on the MHC receptor on the cell surface. The transfected APCs can then be used as an immunogenic composition to generate an immune response against the protein encoded by the vector.

[0115] As described elsewhere herein, vectors can be prepared containing specific polynucleotides that encode and express peptides against which an immunogenic response is desired. In one embodiment, retroviral vectors are used for cell infection. In one embodiment, adenoviral vectors are used for cell infection.

[0116] In another embodiment, vectors can be targeted to APCs by modifying the viral vector to encode a protein or portion thereof that is recognized by a receptor on the APC, and once the APC receptor is occupied by the vector, endocytosis of the vector is initiated, allowing processing and presentation of the antigen encoded by the viral vector nucleic acid.

[0117] As contemplated herein, various methods can be used to transfect a polynucleotide into a host cell. These methods include, but are not limited to, calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, colloidal dispersion systems (i.e., macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes). These methods are understood in the art and are described in the published literature to enable one of ordinary skill in the art to practice these methods.

[0118] In another embodiment, a polynucleotide encoding an antigen can be cloned into an expression vector, and the vector can be introduced into an APC to generate an alternatively loaded APC. Various types of vectors and methods for introducing nucleic acids into cells are discussed in available published literature. For example, an expression vector can be introduced into a host cell by physical, chemical, or biological means. See, for example, Sambrook et al. (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and in Ausubel et al. (1997, Current Protocols in Molecular Biology, John Wiley & Sons, New York). It is readily apparent that introduction of an expression vector containing an antigen-encoding polynucleotide results in pulsed cells.

[0119] The present invention encompasses various methods for pulsing APCs, including, but not limited to, loading APCs with peptide antigens or with cDNA or mRNA encoding peptide antigens. However, the present invention should not be construed as limited to the particular form of antigen used to pulse APCs. Rather, the present invention encompasses other methods known in the art for generating antigen-loaded APCs. In one embodiment, APCs are transfected with mRNA encoding a well-defined antigen. mRNA corresponding to a gene product of known sequence can be rapidly produced in vitro using appropriate primers and reverse transcriptase polymerase chain reaction (RT-PCR) coupled with a transcription reaction. Transfection of APCs with mRNA offers advantages over other antigen-loading techniques for generating pulsed APCs. For example, the ability to amplify RNA from minute amounts of tissue, i.e., tumor tissue, extends the use of APCs for vaccination to a large number of patients.

[0120] There are numerous methods that can be used to engineer DCs and other APCs, including mRNA-based delivery, DNA plasmid-based delivery, and the like, all of which are encompassed by the present invention, i.e., any delivery system can be used to engineer immune cells to express the mRAS peptides described herein.

[0121] It is understood that the antigenic compositions of the present invention can be produced by methods well known in the art, including, but not limited to, chemical synthesis by solid-phase synthesis and purification from other products of chemical reactions by HPLC, or production by expression of a nucleic acid sequence (e.g., a DNA sequence) encoding a peptide antigen of the present invention in an in vitro translation system or in living cells. Additionally, the antigenic composition can include cellular components isolated from a biological sample. The antigenic composition can be isolated, dialyzed to remove one or more undesired low-molecular-weight molecules, and / or lyophilized to facilitate formulation into a desired solvent. Furthermore, it is understood that additional amino acids, mutations, chemical modifications, etc., may be present in the vaccine component without substantially interfering with antibody recognition of the epitope sequence. The peptide sequences can be synthesized by methods known to those skilled in the art, such as peptide synthesis using an automated peptide synthesizer, such as those available from Applied Biosystems, Inc., Foster City, CA (Foster City, CA).

[0122] Longer peptides or polypeptides can also be prepared, for example, by recombinant means. In certain embodiments, nucleic acids encoding the antigenic compositions and / or components described herein can be used to produce antigenic compositions in vitro or in vivo, for example, for the various compositions and methods of the invention. For example, in certain embodiments, the nucleic acid encoding the antigen is contained in a vector, for example, within a recombinant cell. The nucleic acid can be expressed to produce a peptide or polypeptide comprising the antigenic sequence. The peptide or polypeptide can be secreted from the cell or can be contained as part of or within the cell.

[0123] In certain embodiments, an immune response can be enhanced by transfecting or inoculating a mammal with a nucleic acid encoding an antigen. After administration of the nucleic acid to the target mammal, one or more cells contained within the target mammal express the sequence encoded by the nucleic acid. The vaccine may take the form of, for example, a nucleic acid (e.g., cDNA or RNA) encoding all or part of the peptide or polypeptide sequence of the antigen. In vivo expression by the nucleic acid can be via, for example, a plasmid-type vector, a viral vector, or a viral / plasmid construct vector.

[0124] In another embodiment, the nucleic acid comprises a coding region that encodes all or part of a sequence encoding a suitable antigen, or an immunologically functional equivalent. Of course, the nucleic acid may also comprise and / or encode additional sequences, including, but not limited to, sequences comprising one or more immunomodulators or adjuvants.

[0125] In some embodiments, an immunologic composition comprises immune cells stimulated by APCs loaded or pulsed with one or more mRAS peptide antigens described herein. For example, in one embodiment, the immunologic composition comprises stimulated T cells cultured with and activated by APCs loaded or pulsed with one or more mRAS peptide antigens described herein. In one embodiment, the stimulated cells are obtained from naive cells (e.g., naive T cells) and then cultured with and activated by APCs loaded or pulsed with one or more mRAS peptide antigens described herein. In some embodiments, the naive cells are autologous or allogenic to the ultimate recipient of the stimulated cells. In one embodiment, the naive cells and APCs are both derived from the same subject. In one embodiment, the naive cells and APCs are derived from different subjects within the same species.

[0126] Methods for detecting the induction of cytotoxic T lymphocytes are well known. Foreign substances that enter the body are presented to T cells and B cells by the action of APCs. T cells that respond specifically to the antigen presented by APCs differentiate into cytotoxic T cells (also called cytotoxic T lymphocytes or CTLs) upon stimulation with the antigen. These antigen-stimulated cells then proliferate. This process is called "activation" of T cells. Therefore, CTL induction by epitopes of polypeptides, peptides, or combinations thereof can be evaluated by presenting epitopes of polypeptides, peptides, or combinations thereof to T cells using APCs and detecting the induction of CTLs. Furthermore, APCs have the ability to activate B cells, CD4+ T cells, CD8+ T cells, macrophages, eosinophils, and NK cells.

[0127] Methods for evaluating the CTL induction activity using dendritic cells (DCs) as APCs are well known in the art. DCs are a representative APC with robust CTL induction activity. In the method of the present invention, an epitope of a polypeptide or peptide, or a combination thereof, is first expressed by DCs, and then the DCs are contacted with T cells. Detection of T cells with cytotoxic effects against the cells of interest after contact with DCs indicates that the epitope of the polypeptide or peptide, or a combination thereof, has the activity of inducing cytotoxic T cells. Furthermore, the induced immune response can also be examined by measuring IFN-γ produced and released by CTLs in the presence of antigen-presenting cells bearing immobilized peptides or peptide combinations, visualized with an anti-IFN-γ antibody, such as in an ELISPOT assay.

[0128] In addition to DCs, peripheral blood mononuclear cells (PBMCs) can also be used as APCs. It has been reported that culturing PBMCs in the presence of GM-CSF and IL-4 enhances the induction of CTLs. Similarly, it has been shown that CTLs can be induced by culturing PBMCs in the presence of keyhole limpet hemocyanin (KLH) and IL-7.

[0129] Antigens confirmed to have CTL-inducing activity by these methods are antigens that activate DCs and subsequently induce CTLs. Furthermore, CTLs that acquire cytotoxicity through antigen presentation by APCs can be used as vaccines against antigen-related disorders.

[0130] The induction of immunity by expression of the mRAS peptide antigen can be further confirmed by observing the induction of antibody production against mRAS. For example, if an experimental animal is immunized with a composition encoding the antigen, and antibodies against the antigen are induced, and the antibodies suppress antigen-related pathology, the composition is determined to induce immunity.

[0131] The induction of immunity by expression of the mRAS peptide antigen can be further confirmed by observing the induction of CD4+ T cells. Although CD4+ T cells can also lyse target cells, they primarily serve to induce other types of immune responses, including CTL and antibody production. Helper types of CD4+ T cells include Th1 cells, Th2 cells, Th9 cells, Th17 cells, regulatory T cells, or follicular helper T (T fh ) cells. Each subtype of CD4+ T cell provides help for a specific type of immune response. In one embodiment, the composition selectively induces follicular helper T cells, which drive potent antibody responses.

[0132] mRAS-specific TCR In some embodiments, the present invention provides a polypeptide comprising a TCR or a fragment thereof that specifically binds to RAS, mRAS, or a fragment thereof. In one embodiment, the polypeptide comprises a TCR or a fragment thereof that specifically binds to RAS, mRAS, or a fragment thereof in the context of a particular HLA type.

[0133] In some embodiments, the invention provides antibodies (e.g., bispecific antibodies) comprising a TCR or fragment thereof that specifically binds to RAS, mRAS, or a fragment thereof. In other embodiments, the invention provides antibodies comprising a first TCR or fragment thereof that specifically binds to RAS, mRAS, or a fragment thereof, and a second TCR or fragment thereof that specifically binds to a different RAS, mRAS, or fragment thereof.

[0134] In some embodiments, the invention provides compositions comprising a TCR or fragment thereof that specifically binds to RAS, mRAS, or a fragment thereof. In other embodiments, the invention provides compositions comprising a first TCR or fragment thereof that specifically binds to RAS, mRAS, or a fragment thereof, and a second TCR or fragment thereof that specifically binds to a different RAS, mRAS, or a fragment thereof.

[0135] In various embodiments, the TCR is an artificial TCR.

[0136] In one embodiment, the TCR specifically binds to mRAS that comprises a mutation at position G12 relative to wild-type RAS. In some embodiments, the TCR specifically binds to mRAS that comprises a G12C mutation, a G12D mutation, a G12R mutation, or a G12V mutation relative to wild-type RAS. For example, in some embodiments, the TCR specifically binds to mRAS that comprises a G12D mutation relative to wild-type RAS.

[0137] In one embodiment, the TCR specifically binds to a fragment of mRAS containing a mutation at the position corresponding to G12.

[0138] In one embodiment of the present invention, a TCR has antigen specificity for an mRAS peptide of any length and a mutation at G12, as described above. For example, a TCR may have antigen specificity for an mRAS peptide having a mutation corresponding to G12 and having a length of about 8 to about 24 amino acid residues, or about 9 to about 11 amino acid residues. In an embodiment of the present invention, a TCR may have antigen specificity for an mRAS peptide having a mutation corresponding to G12 and having a length of about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 amino acid residues. Exemplary mRAS peptides having a mutation corresponding to G12 and specifically binding to a TCR can be found in Table 1.

[0139] In some embodiments, TCR specifically binds to mRAS peptide in the context of a specific HLA molecule. For example, in some embodiments, TCR specifically binds to mRAS peptide in the context of HLA-C*08:02 molecule. Other HLA molecules corresponding to mRAS peptides can be found in Table 1. [Table 1]

[0140] HLA-C*08:02 G12D In one embodiment, the TCR specifically binds to an mRAS peptide having a G12D mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12D mutation at a position corresponding to RAS G12 in the context of an HLA-C*08:02 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising GADGVGKSA (SEQ ID NO: 231). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising GADGVGKSA (SEQ ID NO: 231) in the context of an HLA-C*08:02 molecule.

[0141] HLA-A*02:01 G12C In one embodiment, the TCR specifically binds to an mRAS peptide having a G12C mutation at the position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12C mutation at the position corresponding to RAS G12 in the context of an HLA-A*02:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising KLVVVGACGV (SEQ ID NO: 1). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising KLVVVGACGV (SEQ ID NO: 1) in the context of an HLA-A*02:01 molecule.

[0142] HLA-A*02:01 G12D In one embodiment, the TCR specifically binds to an mRAS peptide having a G12D mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12D mutation at a position corresponding to RAS G12 in the context of an HLA-A*02:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising KLVVVGADGV (SEQ ID NO: 2). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising KLVVVGADGV (SEQ ID NO: 2) in the context of an HLA-A*02:01 molecule.

[0143] HLA-A*02:01 G12R In one embodiment, the TCR specifically binds to an mRAS peptide having a G12R mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12R mutation at a position corresponding to RAS G12 in the context of an HLA-A*02:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising KLVVVGARGV (SEQ ID NO: 3). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising KLVVVGARGV (SEQ ID NO: 3) in the context of an HLA-A*02:01 molecule.

[0144] HLA-A*02:01 G12V In one embodiment, the TCR specifically binds to an mRAS peptide having a G12V mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12V mutation at a position corresponding to RAS G12 in the context of an HLA-A*02:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising KLVVVGAVGV (SEQ ID NO: 4). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising KLVVVGAVGV (SEQ ID NO: 4) in the context of an HLA-A*02:01 molecule.

[0145] HLA-A*11:01 G12C In one embodiment, the TCR specifically binds to an mRAS peptide having a G12C mutation at the position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12C mutation at the position corresponding to RAS G12 in the context of an HLA-A*11:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGACGVGK (SEQ ID NO: 5) or VVVGACGVGK (SEQ ID NO: 6). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGACGVGK (SEQ ID NO: 5) or VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0146] HLA-A*11:01 G12D In one embodiment, the TCR specifically binds to an mRAS peptide having a G12D mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12D mutation at a position corresponding to RAS G12 in the context of an HLA-A*11:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGADGVGK (SEQ ID NO: 7) or VVVGADGVGK (SEQ ID NO: 8). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVVGADGVGK (SEQ ID NO: 7) or VVGADGVGK (SEQ ID NO: 8) in the context of an HLA-A*11:01 molecule.

[0147] HLA-A*11:01 G12R In one embodiment, the TCR specifically binds to an mRAS peptide having a G12R mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12R mutation at a position corresponding to RAS G12 in the context of an HLA-A*11:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGARGVGK (SEQ ID NO: 9) or VVVGARGVGK (SEQ ID NO: 10). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGARGVGK (SEQ ID NO: 9) or VVVGARGVGK (SEQ ID NO: 10) in the context of an HLA-A*11:01 molecule.

[0148] HLA-A*11:01 G12V In one embodiment, the TCR specifically binds to an mRAS peptide having a G12V mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12V mutation at a position corresponding to RAS G12 in the context of an HLA-A*11:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVVGAVGVGK (SEQ ID NO: 11) or VVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*11:01 molecule.

[0149] HLA-A*03:01 G12C In one embodiment, the TCR specifically binds to an mRAS peptide having a G12C mutation at the position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12C mutation at the position corresponding to RAS G12 in the context of an HLA-A*03:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGACGVGK (SEQ ID NO: 5) or VVVGACGVGK (SEQ ID NO: 6). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGACGVGK (SEQ ID NO: 5) or VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*03:01 molecule.

[0150] HLA-A*03:01 G12D In one embodiment, the TCR specifically binds to an mRAS peptide having a G12D mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12D mutation at a position corresponding to RAS G12 in the context of an HLA-A*03:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGADGVGK (SEQ ID NO: 7) or VVVGADGVGK (SEQ ID NO: 8). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGADGVGK (SEQ ID NO: 7) or VVVGADGVGK (SEQ ID NO: 8) in the context of an HLA-A*03:01 molecule.

[0151] HLA-A*03:01 G12R In one embodiment, the TCR specifically binds to an mRAS peptide having a G12R mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12R mutation at a position corresponding to RAS G12 in the context of an HLA-A*03:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGARGVGK (SEQ ID NO: 9) or VVVGARGVGK (SEQ ID NO: 10). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGARGVGK (SEQ ID NO: 9) or VVVGARGVGK (SEQ ID NO: 10) or in the context of an HLA-A*03:01 molecule.

[0152] HLA-A*03:01 G12V In one embodiment, the TCR specifically binds to an mRAS peptide having a G12V mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12V mutation at a position corresponding to RAS G12 in the context of an HLA-A*03:01 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12) or in the context of an HLA-A*03:01 molecule.

[0153] HLA-B*07:02 G12C In one embodiment, the TCR specifically binds to an mRAS peptide having a G12C mutation at the position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12C mutation at the position corresponding to RAS G12 in the context of an HLA-B*07:02 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising GACGVGKSAL (SEQ ID NO: 13). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising GACGVGKSAL (SEQ ID NO: 13) in the context of an HLA-B*07:02 molecule.

[0154] HLA-B*07:02 G12D In one embodiment, the TCR specifically binds to an mRAS peptide having a G12D mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12D mutation at a position corresponding to RAS G12 in the context of an HLA-B*07:02 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising GADGVGKSAL (SEQ ID NO: 14). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising GADGVGKSAL (SEQ ID NO: 14) in the context of an HLA-B*07:02 molecule.

[0155] HLA-B*07:02 G12R In one embodiment, the TCR specifically binds to an mRAS peptide having a G12R mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12R mutation at a position corresponding to RAS G12 in the context of an HLA-B*07:02 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising GARGVGKSAL (SEQ ID NO: 15). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising GARGVGKSAL (SEQ ID NO: 15) in the context of an HLA-B*07:02 molecule.

[0156] HLA-B*07:02 G12V In one embodiment, the TCR specifically binds to an mRAS peptide having a G12V mutation at a position corresponding to RAS G12. In one embodiment, the TCR specifically binds to an mRAS peptide having a G12V mutation at a position corresponding to RAS G12 in the context of an HLA-B*07:02 molecule. For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising GAVGVGKSAL (SEQ ID NO: 16). For example, in one embodiment, the TCR specifically binds to an mRAS peptide comprising GAVGVGKSAL (SEQ ID NO: 16) in the context of an HLA-B*07:02 molecule.

[0157] TCR831 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0158] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises TCR alpha variable 39 (TRAV39-01*01; also referred to as "TRAV39") CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV39 CDR1, which comprises the following amino acid sequence: STTSDRL (SEQ ID NO: 17).

[0159] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV39 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV39 CDR2, wherein the TRAV39 CDR2 comprises the following amino acid sequence: VLLSNGAVK (SEQ ID NO: 18).

[0160] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV39 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV39 CDR3, and the TRAV39 CDR3 comprises the following amino acid sequence: CAVDKDGGYQKVTF (SEQ ID NO: 19).

[0161] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV39 CDR1, a TRAV39 CDR2, and a TRAV39 CDR3.

[0162] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV39. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV39, which comprises the following amino acid sequence: ELKVEQNPLFLSMQEGKNYTIYCNYSTTSDRLYWYRQDPGKSLESLFVLLSNGAVKQEGRLMASLDTKARLSTLHITAAVHDLSATYFCAVDKDGGYQKVTFGTGTKLQVIP (SEQ ID NO: 20).

[0163] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 21).

[0164] In one embodiment, the TCR comprises a TCR alpha chain comprising the following amino acid sequence: MKKLLAMILWLQLDRLSGELKVEQNPLFLSMQEGKNYTIYCNYSTTSDRLYWYRQDPGKSLESLFVLLSNGAVKQEGRLMASLDTKARLSTLHITAAVHDLSATYFCAVDKDGGYQKVTFGTGTKLQVIPNIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 22).

[0165] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0166] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR β chain variable region 20-1 (TRBV20-1*01; also referred to as "TRBV20") CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV20-1 CDR1, which comprises the following amino acid sequence: LDFQATTM (SEQ ID NO: 23).

[0167] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV20-1 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV20-1 CDR2, wherein the TRBV20-1 CDR2 comprises the following amino acid sequence: TSNEGSKAT (SEQ ID NO: 24).

[0168] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV20-1 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV20-1 CDR3, and the TRBV20-1 CDR3 comprises the following amino acid sequence: CSASPRAGQLSSYNSPLHF (SEQ ID NO: 25).

[0169] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV20-1 CDR1, a TRBV20-1 CDR2, and a TRBV20-1 CDR3.

[0170] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRBV20-1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRBV20-1, and the variable domain of TRBV20-1 comprises the following amino acid sequence: GAVVSQHPSWVICKSGTSVKIECRSLDFQATTMFWYRQFPKQSLMLMATSNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYICSASPRAGQLSSYNSPLHFGNGTRLTV (SEQ ID NO: 26).

[0171] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF (SEQ ID NO: 27).

[0172] In one embodiment, the TCR comprises a TCR beta chain comprising the following amino acid sequence: MLLLLLLLGPGISLLLPGSLAGSGLGAVVSQHPSWVICKSGTSVKIECRSLDFQATTMFWYRQFPKQSLMLMATSNEGSKATYEQGVEKDKFLINHASLTLSTLTVTSAHPEDSSFYICSASPRAGQLSSYNSPLHFGNGTRLTVTEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF (SEQ ID NO: 28)

[0173] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV39 CDR1, TRAV39 CDR2, and TRAV39 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV20-1 CDR1, TRBV20-1 CDR2, and TRBV20-1 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV39 CDR1, TRAV39 CDR2, and TRAV39 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV20-1 CDR1, TRBV20-1 CDR2, and TRBV20-1 CDR3, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV39 CDR1, TRAV39 CDR2, and TRAV39 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV20-1 CDR1, TRBV20-1 CDR2, and TRBV20-1 CDR3, and binds to an mRAS peptide comprising VVVGAVGVGK (sequence number 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV39 CDR1, TRAV39 CDR2, and TRAV39 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV20-1 CDR1, TRBV20-1 CDR2, and TRBV20-1 CDR3, and binds to an mRAS peptide comprising VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0174] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV39 CDR1, TRAV39 CDR2, and TRAV39 CDR3, and (b) a TCR beta chain comprising TRBV20-1 CDR1, TRBV20-1 CDR2, and TRBV20-1 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV39 CDR1, TRAV39 CDR2, and TRAV39 CDR3, and (b) a TCR beta chain comprising TRBV20-1 CDR1, TRBV20-1 CDR2, and TRBV20-1 CDR3, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV39 CDR1, TRAV39 CDR2, and TRAV39 CDR3, and (b) a TCR beta chain comprising TRBV20-1 CDR1, TRBV20-1 CDR2, and TRBV20-1 CDR3, and binds to an mRAS peptide comprising VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV39 CDR1, TRAV39 CDR2, and TRAV39 CDR3, and (b) a TCR beta chain comprising TRBV20-1 CDR1, TRBV20-1 CDR2, and TRBV20-1 CDR3, and binds to an mRAS peptide comprising VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0175] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises at least one CDR selected from the group consisting of: TRAV39-CDR1: SEQ ID NO: 17; TRAV39-CDR2: SEQ ID NO: 18; TRAV39-CDR3: SEQ ID NO: 19; TRBV20-1-CDR1: SEQ ID NO: 23; TRBV20-1-CDR2: SEQ ID NO: 24; and TRBV20-1-CDR3: SEQ ID NO: 25, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV39-CDR1: SEQ ID NO: 17; TRAV39-CDR2: SEQ ID NO: 18; TRAV39-CDR3: SEQ ID NO: 19; TRBV20-1-CDR1: SEQ ID NO: 23; TRBV20-1-CDR2: SEQ ID NO: 24; and TRBV20-1-CDR3: SEQ ID NO: 25, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV39-CDR1: SEQ ID NO: 17; TRAV39-CDR2: SEQ ID NO: 18; TRAV39-CDR3: SEQ ID NO: 19; TRBV20-1-CDR1: SEQ ID NO: 23; TRBV20-1-CDR2: SEQ ID NO: 24; and TRBV20-1-CDR3: SEQ ID NO: 25, or one or more variants thereof, which bind to an mRAS peptide comprising VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV39-CDR1: SEQ ID NO: 17; TRAV39-CDR2: SEQ ID NO: 18; TRAV39-CDR3: SEQ ID NO: 19; TRBV20-1-CDR1: SEQ ID NO: 23; TRBV20-1-CDR2: SEQ ID NO: 24; and TRBV20-1-CDR3: SEQ ID NO: 25, or one or more variants thereof, which bind to an mRAS peptide comprising VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0176] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises all of the CDRs selected from the group consisting of: TRAV39-CDR1: SEQ ID NO: 17; TRAV39-CDR2: SEQ ID NO: 18; TRAV39-CDR3: SEQ ID NO: 19; TRBV20-1-CDR1: SEQ ID NO: 23; TRBV20-1-CDR2: SEQ ID NO: 24; and TRBV20-1-CDR3: SEQ ID NO: 25, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV39-CDR1: SEQ ID NO: 17; TRAV39-CDR2: SEQ ID NO: 18; TRAV39-CDR3: SEQ ID NO: 19; TRBV20-1-CDR1: SEQ ID NO: 23; TRBV20-1-CDR2: SEQ ID NO: 24; and TRBV20-1-CDR3: SEQ ID NO: 25, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV39-CDR1: SEQ ID NO: 17; TRAV39-CDR2: SEQ ID NO: 18; TRAV39-CDR3: SEQ ID NO: 19; TRBV20-1-CDR1: SEQ ID NO: 23; TRBV20-1-CDR2: SEQ ID NO: 24; and TRBV20-1-CDR3: SEQ ID NO: 25, or one or more variants thereof, and binds to an mRAS peptide comprising VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV39-CDR1: SEQ ID NO: 17; TRAV39-CDR2: SEQ ID NO: 18; TRAV39-CDR3: SEQ ID NO: 19; TRBV20-1-CDR1: SEQ ID NO: 23; TRBV20-1-CDR2: SEQ ID NO: 24; and TRBV20-1-CDR3: SEQ ID NO: 25, or one or more variants thereof, and binds to an mRAS peptide comprising VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0177] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a GSG-T2A domain. In one embodiment, GSG-T2A comprises the following amino acid sequence: GSGEGRGSLTCGDVEENPGP (SEQ ID NO: 29).

[0178] In one embodiment, the composition comprises a fusion protein comprising the following amino acid sequence: (SEQ ID NO: 30).

[0179] TCR833 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0180] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 12-1 (TRAV12-1*01, also referred to as "TRAV12-1") CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV12-1 CDR1, which comprises the following amino acid sequence: SNSASQSF (SEQ ID NO: 31).

[0181] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV12-1 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV12-1 CDR2, wherein the TRAV12-1 CDR2 comprises the following amino acid sequence: SVYSSGNE (SEQ ID NO: 32).

[0182] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV12-1 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV12-1 CDR3, and the TRAV12-1 CDR3 comprises the following amino acid sequence: CAVNPPDTGFQKLVF (SEQ ID NO: 33).

[0183] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at the position corresponding to RAS G12 comprises a TRAV12-1 CDR1, a TRAV12-1 CDR2, and a TRAV12-1 CDR3.

[0184] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV12-1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV12-1, which variable domain comprises the following amino acid sequence: RKEVEQDPGPFNVPEGATVAFNCTYSNSASQSFFWYRQDCRKEPKLLMSVYSSGNEDGRFTAQLNRASQYISLLIRDSKLSDSATYLCAVNPPDTGFQKLVFGTGTRLLVSP (SEQ ID NO: 34).

[0185] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, the constant domain comprising the following amino acid sequence: IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 35).

[0186] In one embodiment, the TCR comprises a TCR alpha chain comprising the following amino acid sequence: MISLRVLLVILWLQLSWVWSQRKEVEQDPGPFNVPEGATVAFNCTYSNSASQSFFWYRQDCRKEPKLLMSVYSSGNEDGRFTAQLNRASQYISLLIRDSKLSDSATYLCAVNPPDTGFQKLVFGTGTRLLVSPNIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 36).

[0187] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0188] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR β chain variable region 28 (TRBV28*01; also referred to as "TRBV28") CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV28 CDR1, which comprises the following amino acid sequence: DMDHENM (SEQ ID NO: 37).

[0189] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV28 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV28 CDR2, wherein the TRBV28 CDR2 comprises the following amino acid sequence: FSYDVKME (SEQ ID NO: 38).

[0190] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV28 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV28 CDR3, and the TRBV28 CDR3 comprises the following amino acid sequence: CASSLSFRQGLREQYF (SEQ ID NO: 39).

[0191] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3.

[0192] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV28. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV28, which variable domain comprises the following amino acid sequence: MGIRLLCRVAFCFLAVGLVDVKVTQSSRYLVKRTGEKVFLECVQDMDHENMFWYRQDPGLGLRLIYFSYDVKMKEKGDIPEGYSVSREKKERFSLILESASTNQTSMYLCASSLSFRQGLREQYFGPGTRLTVT (SEQ ID NO: 40).

[0193] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 41).

[0194] In one embodiment, the TCR comprises a TCR beta chain comprising the following amino acid sequence: MGIRLLCRVAFCFLAVGLVDVKVTQSSRYLVKRTGEKVFLECVQDMDHENMFWYRQDPGLGLRLIYFSYDVKMKEKGDIPEGYSVSREKKERFSLILESASTNQTSMYLCASSLSFRQGLREQYFGPGTRLTVTEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 42).

[0195] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising VVVGAVGVGK (sequence number 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising VVVGACGVGK (sequence number 6) in the context of an HLA-A*11:01 molecule.

[0196] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0197] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises at least one of the CDRs selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, which bind to an mRAS peptide comprising VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, which bind to an mRAS peptide comprising VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0198] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises all of the CDRs selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, and binds to an mRAS peptide comprising VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, and binds to an mRAS peptide comprising VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0199] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a GSG-T2A domain. In one embodiment, GSG-T2A comprises the following amino acid sequence: GSGEGRGSLTCGDVEENPGP (SEQ ID NO: 43).

[0200] In one embodiment, the composition comprises a fusion protein comprising the following amino acid sequence: (SEQ ID NO: 44).

[0201] TCR897 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0202] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 17 (TRAV17) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR1, which comprises the following amino acid sequence: KTSINNL (SEQ ID NO: 45).

[0203] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR2, wherein the TRAV17 CDR2 comprises the following amino acid sequence: LIRSNEREK (SEQ ID NO: 46).

[0204] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR3, and the TRAV17 CDR3 comprises the following amino acid sequence: CATDPGGFKTIF (SEQ ID NO: 47).

[0205] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at the position corresponding to RAS G12 comprises TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3.

[0206] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV17. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV17, which comprises the following amino acid sequence: SQQGEEDPQALSIQEGENATMNCSYKTSINNLQWYRQNSGRGLVHLILIRSNEREKHSGRLRVTLDTSKKSSSLLITASRAADTASYFCATD (SEQ ID NO: 169).

[0207] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 48).

[0208] In one embodiment, the TCR comprises a TCR alpha chain comprising the following amino acid sequence: METLLGVSLVILWLQLARVNSQQGEEDPQALSIQEGENATMNCSYKTSINNLQWYRQNSGRGLVHLILIRSNEREKHSGRLRVTLDTSKKSSSLLITASRAADTASYFCATDPGGFKTIFGAGTRLFVKANIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 49).

[0209] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0210] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR beta chain variable region 11-2 (TRBV11-2) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR1, which comprises the following amino acid sequence: ISGHATL (SEQ ID NO: 50).

[0211] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR2, wherein the TRBV11-2 CDR2 comprises the following amino acid sequence: QFQNNGVV (SEQ ID NO: 51).

[0212] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR3, and the TRBV11-2 CDR3 comprises the following amino acid sequence: CASSLYGGSISYEQYF (SEQ ID NO: 52).

[0213] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR1, a TRBV11-2 CDR2, and a TRBV11-2 CDR3.

[0214] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV11-2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV11-2, the variable domain of TRBV11-2 comprising the following amino acid sequence: EAGVAQSPRYKIIEKRQSVAFWCNPISGHATLYWYQQILGQGPKLLIQFQNNGVVDDSQLPKDRFSAERLKGVDSTLKIQPAKLEDSAVYLCASSL (SEQ ID NO: 170).

[0215] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 53).

[0216] In one embodiment, the TCR comprises a TCR beta chain comprising the following amino acid sequence: MGTRLCWAALCLLGAELTEAGVAQSPRYKIIEKRQSVAFWCNPISGHATLYWYQQILGQGPKLLIQFQNNGVVDDSQLPKDRFSAERLKGVDSTLKIQPAKLEDSAVYLCASSLYGGSISYEQYFGPGTRLTVTEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 54).

[0217] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising a G12V, G12C, or G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGAVGVGK (sequence number 11) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGACGVGK (sequence number 5) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGADGVGK (sequence number 7) in the context of an HLA-A*11:01 molecule.In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGARGVGK (sequence number 9) in the context of an HLA-A*11:01 molecule.

[0218] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising a G12V, G12C, or G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGACGVGK (SEQ ID NO: 5) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGADGVGK (sequence number 7) in the context of an HLA-A*11:01 molecule.In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGARGVGK (sequence number 9) in the context of an HLA-A*11:01 molecule.

[0219] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V, G12C, or G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, which bind to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, which bind to an mRAS peptide comprising VVGACGVGK (SEQ ID NO: 5) in the context of an HLA-A*11:01 molecule.In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, which bind to an mRAS peptide comprising VVGADGVGK (SEQ ID NO: 7) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, which bind to an mRAS peptide comprising VVGARGVGK (SEQ ID NO: 9) in the context of an HLA-A*11:01 molecule.

[0220] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V, G12C, or G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising VVGACGVGK (SEQ ID NO: 5) in the context of an HLA-A*11:01 molecule.In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising VVGADGVGK (SEQ ID NO: 7) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising VVGARGVGK (SEQ ID NO: 9) in the context of an HLA-A*11:01 molecule.

[0221] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a GSG-T2A domain. In one embodiment, GSG-T2A comprises the following amino acid sequence: GSGEGRGSLTCGDVEENPGP (SEQ ID NO: 55).

[0222] In one embodiment, the composition comprises a fusion protein comprising the following amino acid sequence: (SEQ ID NO: 56).

[0223] TCR896 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12V mutation at the position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0224] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 19 (TRAV19) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV19 CDR1, which comprises the following amino acid sequence: ETRDTTYYL (SEQ ID NO: 57).

[0225] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV19 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV19 CDR2, wherein the TRAV19 CDR2 comprises the following amino acid sequence: RRNSFDEQNE (SEQ ID NO: 58).

[0226] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV19 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV19 CDR3, wherein the TRAV19 CDR3 comprises the following amino acid sequence: CALSEAGTYKYIF (SEQ ID NO: 59).

[0227] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at the position corresponding to RAS G12 comprises TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3.

[0228] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV19. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV19, which variable domain comprises the following amino acid sequence: AQKVTQAQTEISVVEKEDVTLDCVYETRDTTYYLFWYKQPPSGELVFLIRRNSFDEQNEISGRYSWNFQKSTSSFNFTITASQVVDSAVYFCALSE (SEQ ID NO: 171).

[0229] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 60).

[0230] In one embodiment, the TCR comprises a TCR alpha chain comprising the following amino acid sequence: MLTASLLRAVIASICVVSSMAQKVTQAQTEISVVEKEDVTLDCVYETRDTTYYLFWYKQPPSGELVFLIRRNSFDEQNEISGRYSWNFQKSTSSFNFTITASQVVDSAVYFCALSEAGTYKYIFGTGTRLKVLANIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 61).

[0231] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0232] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR beta chain variable region 9 (TRBV9) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR1, which comprises the following amino acid sequence: RSGDLSV (SEQ ID NO: 62).

[0233] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR2, wherein the TRBV9 CDR2 comprises the following amino acid sequence: QYYNGEER (SEQ ID NO: 63).

[0234] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR3, and the TRBV9 CDR3 comprises the following amino acid sequence: CASSVAGGGQETQYF (SEQ ID NO: 64).

[0235] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR1, a TRBV9 CDR2, and a TRBV9 CDR3.

[0236] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV9. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV9, which comprises the following amino acid sequence: DSGVTQTPKHLITATGQRVTLRCSPRSGDLSVYWYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGDSALYFCASSV (SEQ ID NO: 172).

[0237] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 65).

[0238] In one embodiment, the TCR comprises a TCR beta chain comprising the following amino acid sequence: MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVYWYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGDSALYFCASSVAGGGQETQYFGPGTRLLVLEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 66).

[0239] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3, and binds to an mRAS peptide comprising a G12V mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*03:01 molecule.

[0240] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3, and binds to an mRAS peptide comprising a G12V mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*03:01 molecule.

[0241] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises at least one of the CDRs selected from the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*03:01 molecule.

[0242] In another embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at the position corresponding to RAS G12 comprises all of the CDRs of the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs of the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof, binds to an mRAS peptide having a G12V mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs of the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*03:01 molecule.

[0243] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a GSG-T2A domain. In one embodiment, GSG-T2A comprises the following amino acid sequence: GSGEGRGSLTCGDVEENPGP (SEQ ID NO: 67).

[0244] In one embodiment, the composition comprises a fusion protein comprising the following amino acid sequence: (SEQ ID NO: 68).

[0245] TCR847 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0246] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 17 (TRAV17) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR1, which comprises the following amino acid sequence: KTSINNL (SEQ ID NO: 69).

[0247] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR2, wherein the TRAV17 CDR2 comprises the following amino acid sequence: LIRSNEREK (SEQ ID NO: 70).

[0248] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR3, and the TRAV17 CDR3 comprises the following amino acid sequence: CATFPNFGNEKLTF (SEQ ID NO: 71).

[0249] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at the position corresponding to RAS G12 comprises TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3.

[0250] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV17. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV17, which comprises the following amino acid sequence: SQQGEEDPQALSIQEGENATMNCSYKTSINNLQWYRQNSGRGLVHLILIRSNEREKHSGRLRVTLDTSKKSSSLLITASRAADTASYFCATF (SEQ ID NO: 173).

[0251] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 72).

[0252] In one embodiment, the TCR comprises a TCR alpha chain comprising the following amino acid sequence: METLLGVSLVILWLQLARVNSQQGEEDPQALSIQEGENATMNCSYKTSINNLQWYRQNSGRGLVHLILIRSNEREKHSGRLRVTLDTSKKSSSLLITASRAADTASYFCATFPNFGNEKLTFGTGTRLTIIPNIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (sequence number 73).

[0253] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0254] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR beta chain variable region 10-3 (TRBV10-3) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV10-3 CDR1, which comprises the following amino acid sequence: TENHRYM (SEQ ID NO: 74).

[0255] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV10-3 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV10-3 CDR2, wherein the TRBV10-3 CDR2 comprises the following amino acid sequence: YSYGVKDT (SEQ ID NO: 75).

[0256] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV10-3 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV10-3 CDR3, and the TRBV10-3 CDR3 comprises the following amino acid sequence: CAISESERYYEQYF (SEQ ID NO: 76).

[0257] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV10-3 CDR1, a TRBV10-3 CDR2, and a TRBV10-3 CDR3.

[0258] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV10-3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV10-3, the variable domain of TRBV10-3 comprising the following amino acid sequence: DAGITQSPRHKVTETGTPVTLRCHQTENHRYMYWYRQDPGHGLRLIHYSYGVKDTDKGEVSDGYSVSRSKTEDFLLTLESATSSQTSVYFCAISE (SEQ ID NO: 174).

[0259] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 77).

[0260] In one embodiment, the TCR comprises a TCR beta chain comprising the following amino acid sequence: MGTRLFFYVALCLLWTGHMDAGITQSPRHKVTETGTPVTLRCHQTENHRYMYWYRQDPGHGLRLIHYSYGVKDTDKGEVSDGYSVSRSKTEDFLLTLESATSSQTSVYFCAISESERYYEQYFGPGTRLTVTEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (sequence number 78).

[0261] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV10-3 CDR1, TRBV10-3 CDR2, and TRBV10-3 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV10-3 CDR1, TRBV10-3 CDR2, and TRBV10-3 CDR3, and binds to an mRAS peptide comprising a G12R mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV10-3 CDR1, TRBV10-3 CDR2, and TRBV10-3 CDR3, and binds to an mRAS peptide comprising GARGVGKSAL (SEQ ID NO: 15) in the context of an HLA-B*07:02 molecule.

[0262] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV10-3 CDR1, TRBV10-3 CDR2, and TRBV10-3 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV10-3 CDR1, TRBV10-3 CDR2, and TRBV10-3 CDR3, and binds to an mRAS peptide comprising a G12R mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV10-3 CDR1, TRBV10-3 CDR2, and TRBV10-3 CDR3, and binds to an mRAS peptide comprising GARGVGKSAL (SEQ ID NO: 15) in the context of an HLA-B*07:02 molecule.

[0263] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12R mutation at the position corresponding to RAS G12 comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 69; TRAV17-CDR2: SEQ ID NO: 70; TRAV17-CDR3: SEQ ID NO: 71; TRBV10-3-CDR1: SEQ ID NO: 74; TRBV10-3-CDR2: SEQ ID NO: 75; and TRBV10-3-CDR3: SEQ ID NO: 76, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 69; TRAV17-CDR2: SEQ ID NO: 70; TRAV17-CDR3: SEQ ID NO: 71; TRBV10-3-CDR1: SEQ ID NO: 74; TRBV10-3-CDR2: SEQ ID NO: 75; and TRBV10-3-CDR3: SEQ ID NO: 76, or one or more variants thereof, and binds to an mRAS peptide comprising a G12R mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 69; TRAV17-CDR2: SEQ ID NO: 70; TRAV17-CDR3: SEQ ID NO: 71; TRBV10-3-CDR1: SEQ ID NO: 74; TRBV10-3-CDR2: SEQ ID NO: 75; and TRBV10-3-CDR3: SEQ ID NO: 76, or one or more variants thereof, which binds to an mRAS peptide comprising GARGVGKSAL (SEQ ID NO: 15) in the context of an HLA-B*07:02 molecule.

[0264] In another embodiment, a TCR that specifically binds to an mRAS peptide having a G12R mutation at the position corresponding to RAS G12 comprises all of the CDRs of the group consisting of: TRAV17-CDR1: SEQ ID NO: 69; TRAV17-CDR2: SEQ ID NO: 70; TRAV17-CDR3: SEQ ID NO: 71; TRBV10-3-CDR1: SEQ ID NO: 74; TRBV10-3-CDR2: SEQ ID NO: 75; and TRBV10-3-CDR3: SEQ ID NO: 76, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs of the group consisting of: TRAV17-CDR1: SEQ ID NO: 69; TRAV17-CDR2: SEQ ID NO: 70; TRAV17-CDR3: SEQ ID NO: 71; TRBV10-3-CDR1: SEQ ID NO: 74; TRBV10-3-CDR2: SEQ ID NO: 75; and TRBV10-3-CDR3: SEQ ID NO: 76, or one or more variants thereof, and binds to an mRAS peptide containing a G12R mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs of the group consisting of: TRAV17-CDR1: SEQ ID NO: 69; TRAV17-CDR2: SEQ ID NO: 70; TRAV17-CDR3: SEQ ID NO: 71; TRBV10-3-CDR1: SEQ ID NO: 74; TRBV10-3-CDR2: SEQ ID NO: 75; and TRBV10-3-CDR3: SEQ ID NO: 76, or one or more variants thereof, and binds to an mRAS peptide comprising GARGVGKSAL (SEQ ID NO: 15) in the context of an HLA-B*07:02 molecule.

[0265] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a GSG-T2A domain. In one embodiment, GSG-T2A comprises the following amino acid sequence: GSGEGRGSLTCGDVEENPGP (SEQ ID NO: 79).

[0266] In one embodiment, the composition comprises a fusion protein comprising the following amino acid sequence: (SEQ ID NO: 80).

[0267] TCR864 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0268] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 4 (TRAV4) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR1, which comprises the following amino acid sequence: NNIATNDYI (SEQ ID NO: 81).

[0269] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR2, and the TRAV4 CDR2 comprises the following amino acid sequence: QGYKTKV (SEQ ID NO: 82).

[0270] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR3, and the TRAV4 CDR3 comprises the following amino acid sequence: CLVGDFNSNSGYALNF (SEQ ID NO: 83).

[0271] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR1, a TRAV4 CDR2, and a TRAV4 CDR3.

[0272] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRAV4. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRAV4, wherein the variable domain of TRAV4 comprises the following amino acid sequence: LAKTTQPISMDSYEGQEVNITCSHNNIATNDYITWYQQFPSQGPRFIIQGYKTKVTNEVASLFIPADRKSSTLSLPRVSLSDTAVYYCLVGD (SEQ ID NO: 175).

[0273] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 84).

[0274] In one embodiment, the TCR comprises a TCR alpha chain comprising the following amino acid sequence: MRQVARVIVFLTLSTLSLAKTTQPISMDSYEGQEVNITCSHNNIATNDYITWYQQFPSQGPRFIIQGYKTKVTNEVASLFIPADRKSSTLSLPRVSLSDTAVYYCLVGDFNSNSGYALNFGKGTSLLVTPHIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 85)

[0275] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0276] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR beta chain variable region 7-2 (TRBV7-2) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV7-2 CDR1, which comprises the following amino acid sequence: ISGHTAL (SEQ ID NO: 86).

[0277] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV7-2 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV7-2 CDR2, wherein the TRBV7-2 CDR2 comprises the following amino acid sequence: YFQGNSAP (SEQ ID NO: 87).

[0278] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV7-2 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV7-2 CDR3, and the TRBV7-2 CDR3 comprises the following amino acid sequence: CASKVYGYTF (SEQ ID NO: 88).

[0279] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV7-2 CDR1, a TRBV7-2 CDR2, and a TRBV7-2 CDR3.

[0280] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV7-2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV7-2, which comprises the following amino acid sequence: GAGVSQSPSNKVTEKGKDVELRCDPISGHTALYWYRQRLGQGLEFLIYFQGNSAPDKSGLPSDRFSAERTGESVSTLTIQRTQQEDSAVYLCASK (SEQ ID NO: 176).

[0281] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12R mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12R mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF (SEQ ID NO: 89).

[0282] In one embodiment, the TCR comprises a TCR beta chain comprising the following amino acid sequence: MGTRLLFWVAFCLLGAYHTGAGVSQSPSNKVTEKGKDVELRCDPISGHTALYWYRQRLGQGLEFLIYFQGNSAPDKSGLPSDRFSAERTGESVSTLTIQRTQQEDSAVYLCASKVYGYTFGSGTRLTVVEDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF (sequence number 90).

[0283] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV7-2 CDR1, TRBV7-2 CDR2, and TRBV7-2 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV7-2 CDR1, TRBV7-2 CDR2, and TRBV7-2 CDR3, and binds to an mRAS peptide comprising a G12R mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV7-2 CDR1, TRBV7-2 CDR2, and TRBV7-2 CDR3, and binds to an mRAS peptide comprising GARGVGKSAL (SEQ ID NO: 15) in the context of an HLA-B*07:02 molecule.

[0284] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV7-2 CDR1, TRBV7-2 CDR2, and TRBV7-2 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV7-2 CDR1, TRBV7-2 CDR2, and TRBV7-2 CDR3, and binds to an mRAS peptide comprising a G12R mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV7-2 CDR1, TRBV7-2 CDR2, and TRBV7-2 CDR3, and binds to an mRAS peptide comprising GARGVGKSAL (sequence number 15) in the context of an HLA-B*07:02 molecule.

[0285] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12R mutation at the position corresponding to RAS G12 comprises at least one CDR selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 81; TRAV4-CDR2: SEQ ID NO: 82; TRAV4-CDR3: SEQ ID NO: 83; TRBV7-2-CDR1: SEQ ID NO: 86; TRBV7-2-CDR2: SEQ ID NO: 87; and TRBV7-2-CDR3: SEQ ID NO: 88, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 81; TRAV4-CDR2: SEQ ID NO: 82; TRAV4-CDR3: SEQ ID NO: 83; TRBV7-2-CDR1: SEQ ID NO: 86; TRBV7-2-CDR2: SEQ ID NO: 87; and TRBV7-2-CDR3: SEQ ID NO: 88, or one or more variants thereof, and binds to an mRAS peptide comprising a G12R mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 81; TRAV4-CDR2: SEQ ID NO: 82; TRAV4-CDR3: SEQ ID NO: 83; TRBV7-2-CDR1: SEQ ID NO: 86; TRBV7-2-CDR2: SEQ ID NO: 87; and TRBV7-2-CDR3: SEQ ID NO: 88, or one or more variants thereof, which binds to an mRAS peptide comprising GARGVGKSAL (SEQ ID NO: 15) in the context of an HLA-B*07:02 molecule.

[0286] In another embodiment, a TCR that specifically binds to an mRAS peptide having a G12R mutation at the position corresponding to RAS G12 comprises all of the CDRs of the group consisting of: TRAV4-CDR1: SEQ ID NO: 81; TRAV4-CDR2: SEQ ID NO: 82; TRAV4-CDR3: SEQ ID NO: 83; TRBV7-2-CDR1: SEQ ID NO: 86; TRBV7-2-CDR2: SEQ ID NO: 87; and TRBV7-2-CDR3: SEQ ID NO: 88, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs of the group consisting of: TRAV4-CDR1: SEQ ID NO: 81; TRAV4-CDR2: SEQ ID NO: 82; TRAV4-CDR3: SEQ ID NO: 83; TRBV7-2-CDR1: SEQ ID NO: 86; TRBV7-2-CDR2: SEQ ID NO: 87; and TRBV7-2-CDR3: SEQ ID NO: 88, or one or more variants thereof, and binds to an mRAS peptide containing a G12R mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs of the group consisting of: TRAV4-CDR1: SEQ ID NO: 81; TRAV4-CDR2: SEQ ID NO: 82; TRAV4-CDR3: SEQ ID NO: 83; TRBV7-2-CDR1: SEQ ID NO: 86; TRBV7-2-CDR2: SEQ ID NO: 87; and TRBV7-2-CDR3: SEQ ID NO: 88, or one or more variants thereof, and binds to an mRAS peptide comprising GARGVGKSAL (SEQ ID NO: 15) in the context of an HLA-B*07:02 molecule.

[0287] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a GSG-T2A domain. In one embodiment, GSG-T2A comprises the following amino acid sequence: GSGEGRGSLTCGDVEENPGP (SEQ ID NO: 91).

[0288] In one embodiment, the composition comprises a fusion protein comprising the following amino acid sequence: (SEQ ID NO: 92).

[0289] TCR1074 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0290] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 4 (TRAV4*01; also referred to as "TRAV4") CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR1, which comprises the following amino acid sequence: NIATNDY (SEQ ID NO: 188).

[0291] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR2, wherein the TRAV4 CDR2 comprises the following amino acid sequence: GYKTK (SEQ ID NO: 189).

[0292] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR3, and the TRAV4 CDR3 comprises the following amino acid sequence: LVGDIDQAGTALI (SEQ ID NO: 190).

[0293] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR1, a TRAV4 CDR2, and a TRAV4 CDR3.

[0294] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRAV4. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRAV4, which comprises the following amino acid sequence: MRQVARVIVFLTLSTLSLAKTTQPISMDSYEGQEVNITCSHNNIATNDYITWYQQFPSQGPRFIIQGYKTKVTNEVASLFIPADRKSSTLSLPRVSLSDTAVYYCLVGDIDQAGTALIFGKGTTLSVSS (SEQ ID NO: 191).

[0295] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: NIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 192).

[0296] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0297] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR β chain variable region 6-5 (TRBV6-5*01; also referred to as "TRBV6-5") CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV6-5 CDR1, which comprises the following amino acid sequence: MNHEY (SEQ ID NO: 194).

[0298] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV6-5 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV6-5 CDR2, wherein the TRBV6-5 CDR2 comprises the following amino acid sequence: SVGAGI (SEQ ID NO: 195).

[0299] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV6-5 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV6-5 CDR3, wherein the TRBV6-5 CDR3 comprises the following amino acid sequence: ASARDSNQPQH (SEQ ID NO: 196).

[0300] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV6-5 CDR1, a TRBV6-5 CDR2, and a TRBV6-5 CDR3.

[0301] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV6-5. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV6-5, which variable domain comprises the following amino acid sequence: MSIGLLCCAALSLLWAGPVNAGVTQTPKFQVLKTGQSMTLQCAQDMNHEYMSWYRQDPGMGLRLIHYSVGAGITDQGEVPNGYNVSRSTTEDFPLRLLSAAPSQTSVYFCASARDSNQPQHFGDGTRLSIL (SEQ ID NO: 197).

[0302] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF (SEQ ID NO: 198).

[0303] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3, and binds to an mRAS peptide comprising GADGVGKSA (sequence number 231) in the context of an HLA-C*08:02 molecule.

[0304] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3, and binds to an mRAS peptide comprising GADGVGKSA (sequence number 231) in the context of an HLA-C*08:02 molecule.

[0305] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises at least one CDR selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 190; TRBV6-5-CDR1: SEQ ID NO: 194; TRBV6-5-CDR2: SEQ ID NO: 195; and TRBV6-5-CDR3: SEQ ID NO: 196, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 190; TRBV6-5-CDR1: SEQ ID NO: 194; TRBV6-5-CDR2: SEQ ID NO: 195; and TRBV6-5-CDR3: SEQ ID NO: 196, or one or more variants thereof, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 190; TRBV6-5-CDR1: SEQ ID NO: 194; TRBV6-5-CDR2: SEQ ID NO: 195; and TRBV6-5-CDR3: SEQ ID NO: 196, or one or more variants thereof, which binds to an mRAS peptide comprising GADGVGKSA (SEQ ID NO: 231) in the context of an HLA-C*08:02 molecule.

[0306] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises all of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 190; TRBV6-5-CDR1: SEQ ID NO: 194; TRBV6-5-CDR2: SEQ ID NO: 195; and TRBV6-5-CDR3: SEQ ID NO: 196, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 190; TRBV6-5-CDR1: SEQ ID NO: 194; TRBV6-5-CDR2: SEQ ID NO: 195; and TRBV6-5-CDR3: SEQ ID NO: 196, or one or more variants thereof, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 190; TRBV6-5-CDR1: SEQ ID NO: 194; TRBV6-5-CDR2: SEQ ID NO: 195; and TRBV6-5-CDR3: SEQ ID NO: 196, or one or more variants thereof, and binds to an mRAS peptide comprising GADGVGKSA (SEQ ID NO: 231) in the context of an HLA-C*08:02 molecule.

[0307] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a BspEI-T2A-AvrII domain. In one embodiment, BspEI-T2A-AvrII comprises the following amino acid sequence: SGGSGSGEGRGSLTCGDVEENPGPR (SEQ ID NO: 193).

[0308] TCR1085 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0309] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 4 (TRAV4*01; also referred to as "TRAV4") CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR1, which comprises the following amino acid sequence: NIATNDY (SEQ ID NO: 188).

[0310] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR2, wherein the TRAV4 CDR2 comprises the following amino acid sequence: GYKTK (SEQ ID NO: 189).

[0311] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR3, and the TRAV4 CDR3 comprises the following amino acid sequence: LVGDTDQAGTALI (SEQ ID NO: 210).

[0312] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR1, a TRAV4 CDR2, and a TRAV4 CDR3.

[0313] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRAV4. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRAV4, wherein the variable domain of TRAV4 comprises the following amino acid sequence: MRQVARVIVFLTLSTLSLAKTTQPISMDSYEGQEVNITCSHNNIATNDYITWYQQFPSQGPRFIIQGYKTKVTNEVASLFIPADRKSSTLSLPRVSLSDTAVYYCLVGDIDQAGTALIFGKGTTLSVSS (SEQ ID NO: 211).

[0314] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: NIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 192).

[0315] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0316] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR beta chain variable region 5-6 (TRBV5-6) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV5-6 CDR1, which comprises the following amino acid sequence: SGHDT (SEQ ID NO: 212).

[0317] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV5-6 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV5-6 CDR2, wherein the TRBV5-6 CDR2 comprises the following amino acid sequence: YYEEEE (SEQ ID NO: 213).

[0318] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV5-6 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV5-6 CDR3, wherein the TRBV5-6 CDR3 comprises the following amino acid sequence: ASSLGEGRLTGYT (SEQ ID NO: 214).

[0319] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3.

[0320] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV5-6. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV5-6, which comprises the following amino acid sequence: MGPGLLCWALLCLLGAGLVDAGVTQSPTHLIKTRGQQVTLRCSPKSGHDTVSWYQQALGQGPQFIFQYYEEEERQRGNFPDRFSGHQFPNYSSELNVNALLLGDSALYLCASSLGEGRLYGYTFGSGTRLTVV (SEQ ID NO: 215).

[0321] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF (SEQ ID NO: 198).

[0322] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3, and binds to the GADGVGKSA (sequence number 231) mRAS peptide in the context of an HLA-C*08:02 molecule.

[0323] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3, and binds to an mRAS peptide comprising GADGVGKSA (sequence number 231) in the context of an HLA-C*08:02 molecule.

[0324] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises at least one of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 210; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 214, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 210; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 214, or one or more variants thereof, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 210; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 214, or one or more variants thereof, which binds to an mRAS peptide comprising GADGVGKSA (SEQ ID NO: 231) in the context of an HLA-C*08:02 molecule.

[0325] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises all of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 210; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 214, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 210; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 214, or one or more variants thereof, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 210; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 214, or one or more variants thereof, and binds to an mRAS peptide comprising GADGVGKSA (SEQ ID NO: 231) in the context of an HLA-C*08:02 molecule.

[0326] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a BspEI-T2A-AvrII domain. In one embodiment, BspEI-T2A-AvrII comprises the following amino acid sequence: SGGSGSGEGRGSLTCGDVEENPGPR (SEQ ID NO: 193).

[0327] TCR1086 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0328] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 4 (TRAV4*01; also referred to as "TRAV4") CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR1, which comprises the following amino acid sequence: NIATNDY (SEQ ID NO: 188).

[0329] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR2, wherein the TRAV4 CDR2 comprises the following amino acid sequence: GYKTK (SEQ ID NO: 189).

[0330] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR3, and the TRAV4 CDR3 comprises the following amino acid sequence: LVGDMDQAGTALI (SEQ ID NO: 222).

[0331] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV4 CDR1, a TRAV4 CDR2, and a TRAV4 CDR3.

[0332] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRAV4. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRAV4, wherein the variable domain of TRAV4 comprises the following amino acid sequence: MRQVARVIVFLTLSTLSLAKTTQPISMDSYEGQEVNITCSHNNIATNDYITWYQQFPSQGPRFIIQGYKTKVTNEVASLFIPADRKSSTLSLPRVSLSDTAVYYCLVGDNQAGTALIFGKGTTLSVSS (SEQ ID NO: 223).

[0333] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: NIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 192).

[0334] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0335] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR beta chain variable region 5-6 (TRBV5-6) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV5-6 CDR1, which comprises the following amino acid sequence: SGHDT (SEQ ID NO: 212).

[0336] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV5-6 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV5-6 CDR2, wherein the TRBV5-6 CDR2 comprises the following amino acid sequence: YYEEEE (SEQ ID NO: 213).

[0337] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV5-6 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV5-6 CDR3, wherein the TRBV5-6 CDR3 comprises the following amino acid sequence: ASSLGQGIFNSPLH (SEQ ID NO: 224).

[0338] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3.

[0339] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV5-6. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV5-6, which variable domain comprises the following amino acid sequence: MGPGLLCWALLCLLGAGLVDAGVTQSPTHLIKTRGQQVTLRCSPKSGHDTVSWYQQALGQGPQFIFQYYEEEERQRGNFPDRFSGHQFPNYSSELNVNALLLGDSALYLCASSLGQGIFNSPLHFGNGTRLTVT (SEQ ID NO: 225).

[0340] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF (SEQ ID NO: 198).

[0341] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3, and binds to an mRAS peptide comprising GADGVGKSA (sequence number 231) in the context of an HLA-C*08:02 molecule.

[0342] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3, and (b) a TCR beta chain comprising TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3, and binds to an mRAS peptide comprising GADGVGKSA (sequence number 231) in the context of an HLA-C*08:02 molecule.

[0343] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises at least one of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 222; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 224, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 222; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 224, or one or more variants thereof, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 222; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 224, or one or more variants thereof, which binds to an mRAS peptide comprising GADGVGKSA (SEQ ID NO: 231) in the context of an HLA-C*08:02 molecule.

[0344] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises all of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 222; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 224, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 222; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 224, or one or more variants thereof, and binds to an mRAS peptide comprising a G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV4-CDR1: SEQ ID NO: 188; TRAV4-CDR2: SEQ ID NO: 189; TRAV4-CDR3: SEQ ID NO: 222; TRBV5-6-CDR1: SEQ ID NO: 212; TRBV5-6-CDR2: SEQ ID NO: 213; and TRBV5-6-CDR3: SEQ ID NO: 224, or one or more variants thereof, and binds to an mRAS peptide comprising GADGVGKSA (SEQ ID NO: 231) in the context of an HLA-C*08:02 molecule.

[0345] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a BspEI-T2A-AvrII domain. In one embodiment, BspEI-T2A-AvrII comprises the following amino acid sequence: SGGSGSGEGRGSLTCGDVEENPGPR (SEQ ID NO: 193).

[0346] TCR1020 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0347] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 12-1 (TRAV12-1*01, also referred to as "TRAV12-1") CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV12-1 CDR1, which comprises the following amino acid sequence: SNSASQSF (SEQ ID NO: 31).

[0348] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV12-1 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV12-1 CDR2, wherein the TRAV12-1 CDR2 comprises the following amino acid sequence: SVYSSGNE (SEQ ID NO: 32).

[0349] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV12-1 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV12-1 CDR3, and the TRAV12-1 CDR3 comprises the following amino acid sequence: CAVNPPDTGFQKLVF (SEQ ID NO: 33).

[0350] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at the position corresponding to RAS G12 comprises a TRAV12-1 CDR1, a TRAV12-1 CDR2, and a TRAV12-1 CDR3.

[0351] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV12-1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV12-1, which variable domain comprises the following amino acid sequence: RKEVEQDPGPFNVPEGATVAFNCTYSNSASQSFFWYRQDCRKEPKLLMSVYSSGNEDGRFTAQLNRASQYISLLIRDSKLSDSATYLCAVNPPDTGFQKLVFGTGTRLLVSP (SEQ ID NO: 34).

[0352] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 35).

[0353] In one embodiment, the TCR comprises a TCR alpha chain comprising the following amino acid sequence: MISLRVLLVILWLQLSWVWSQRKEVEQDPGPFNVPEGATVAFNCTYSNSASQSFFWYRQDCRKEPKLLMSVYSSGNEDGRFTAQLNRASQYISLLIRDSKLSDSATYLCAVNPPDTGFQKLVFGTGTRLLVSPNIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 36).

[0354] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0355] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR β chain variable region 28 (TRBV28*01; also referred to as "TRBV28") CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV28 CDR1, which comprises the following amino acid sequence: DMDHENM (SEQ ID NO: 37).

[0356] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV28 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV28 CDR2, wherein the TRBV28 CDR2 comprises the following amino acid sequence: FSYDVKME (SEQ ID NO: 38).

[0357] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV28 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV28 CDR3, and the TRBV28 CDR3 comprises the following amino acid sequence: CASSLSFRQGLREQYF (SEQ ID NO: 39).

[0358] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3.

[0359] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV28. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV28, which variable domain comprises the following amino acid sequence: MGIRLLCRVAFCFLAVGLVDVKVTQSSRYLVKRTGEKVFLECVQDMDHENMFWYRQDPGLGLRLIYFSYDVKMKEKGDIPEGYSVSREKKERFSLILESASTNQTSMYLCASSLSFRQGLREQYFGPGTRLTVT (SEQ ID NO: 40).

[0360] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 41).

[0361] In one embodiment, the TCR comprises a TCR beta chain comprising the following amino acid sequence: MGIRLLCRVAFCFLAVGLVDVKVTQSSRYLVKRTGEKVFLECVQDMDHENMFWYRQDPGLGLRLIYFSYDVKMKEKGDIPEGYSVSREKKERFSLILESASTNQTSMYLCASSLSFRQGLREQYFGPGTRLTVTEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 42)

[0362] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising VVVGAVGVGK (sequence number 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising VVVGACGVGK (sequence number 6) in the context of an HLA-A*11:01 molecule.

[0363] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3, and (b) a TCR beta chain comprising TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3, and binds to an mRAS peptide comprising VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0364] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises at least one of the CDRs selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, which bind to an mRAS peptide comprising VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, which bind to an mRAS peptide comprising VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0365] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises all of the CDRs selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V or G12C mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, and binds to an mRAS peptide comprising VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV12-1-CDR1: SEQ ID NO: 31; TRAV12-1-CDR2: SEQ ID NO: 32; TRAV12-1-CDR3: SEQ ID NO: 33; TRBV28-CDR1: SEQ ID NO: 37; TRBV28-CDR2: SEQ ID NO: 38; and TRBV28-CDR3: SEQ ID NO: 39, or one or more variants thereof, and binds to an mRAS peptide comprising VVVGACGVGK (SEQ ID NO: 6) in the context of an HLA-A*11:01 molecule.

[0366] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a GSG-T2A domain. In one embodiment, GSG-T2A comprises the following amino acid sequence: GSGEGRGSLTCGDVEENPGP (SEQ ID NO: 43).

[0367] In one embodiment, the composition comprises a fusion protein comprising the following amino acid sequence: (SEQ ID NO: 44).

[0368] TCR1022 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12V mutation at the position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0369] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 19 (TRAV19) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV19 CDR1, which comprises the following amino acid sequence: ETRDTTYYL (SEQ ID NO: 57).

[0370] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV19 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV19 CDR2, wherein the TRAV19 CDR2 comprises the following amino acid sequence: RRNSFDEQNE (SEQ ID NO: 58).

[0371] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV19 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV19 CDR3, wherein the TRAV19 CDR3 comprises the following amino acid sequence: CALSEAGTYKYIF (SEQ ID NO: 59).

[0372] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at the position corresponding to RAS G12 comprises TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3.

[0373] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV19. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV19, which variable domain comprises the following amino acid sequence: AQKVTQAQTEISVVEKEDVTLDCVYETRDTTYYLFWYKQPPSGELVFLIRRNSFDEQNEISGRYSWNFQKSTSSFNFTITASQVVDSAVYFCALSE (SEQ ID NO: 171).

[0374] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 60).

[0375] In one embodiment, the TCR comprises a TCR alpha chain comprising the following amino acid sequence: MLTASLLRAVIASICVVSSMAQKVTQAQTEISVVEKEDVTLDCVYETRDTTYYLFWYKQPPSGELVFLIRRNSFDEQNEISGRYSWNFQKSTSSFNFTITASQVVDSAVYFCALSEAGTYKYIFGTGTRLKVLANIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 61).

[0376] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0377] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR beta chain variable region 9 (TRBV9) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR1, which comprises the following amino acid sequence: RSGDLSV (SEQ ID NO: 62).

[0378] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR2, wherein the TRBV9 CDR2 comprises the following amino acid sequence: QYYNGEER (SEQ ID NO: 63).

[0379] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR3, and the TRBV9 CDR3 comprises the following amino acid sequence: CASSVAGGGQETQYF (SEQ ID NO: 64).

[0380] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV9 CDR1, a TRBV9 CDR2, and a TRBV9 CDR3.

[0381] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV9. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV9, which comprises the following amino acid sequence: DSGVTQTPKHLITATGQRVTLRCSPRSGDLSVYWYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGDSALYFCASSV (SEQ ID NO: 172).

[0382] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 65).

[0383] In one embodiment, the TCR comprises a TCR beta chain comprising the following amino acid sequence: MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVYWYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGDSALYFCASSVAGGGQETQYFGPGTRLLVLEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 66).

[0384] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3, and binds to an mRAS peptide comprising a G12V mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*03:01 molecule.

[0385] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3, and binds to an mRAS peptide comprising a G12V mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3, and (b) a TCR beta chain comprising TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*03:01 molecule.

[0386] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises at least one of the CDRs selected from the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*03:01 molecule.

[0387] In another embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at the position corresponding to RAS G12 comprises all of the CDRs of the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs of the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof, binds to an mRAS peptide having a G12V mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs of the group consisting of: TRAV19-CDR1: SEQ ID NO: 57; TRAV19-CDR2: SEQ ID NO: 58; TRAV19-CDR3: SEQ ID NO: 59; TRBV9-CDR1: SEQ ID NO: 62; TRBV9-CDR2: SEQ ID NO: 63; and TRBV9-CDR3: SEQ ID NO: 64, or one or more variants thereof, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) or VVVGAVGVGK (SEQ ID NO: 12) in the context of an HLA-A*03:01 molecule.

[0388] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a GSG-T2A domain. In one embodiment, GSG-T2A comprises the following amino acid sequence: GSGEGRGSLTCGDVEENPGP (SEQ ID NO: 67).

[0389] In one embodiment, the composition comprises a fusion protein comprising the following amino acid sequence: (SEQ ID NO: 68).

[0390] TCR898 In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR alpha chain.

[0391] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR alpha chain variable region 17 (TRAV17) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR1, which comprises the following amino acid sequence: KTSINNL (SEQ ID NO: 45).

[0392] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR2, wherein the TRAV17 CDR2 comprises the following amino acid sequence: LIRSNEREK (SEQ ID NO: 46).

[0393] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRAV17 CDR3, and the TRAV17 CDR3 comprises the following amino acid sequence: CATDPGGFKTIF (SEQ ID NO: 47).

[0394] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at the position corresponding to RAS G12 comprises TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3.

[0395] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV17. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises the variable domain of TRAV17, which comprises the following amino acid sequence: SQQGEEDPQALSIQEGENATMNCSYKTSINNLQWYRQNSGRGLVHLILIRSNEREKHSGRLRVTLDTSKKSSSLLITASRAADTASYFCATD (SEQ ID NO: 169).

[0396] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: NIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKCVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (SEQ ID NO: 232).

[0397] In one embodiment, the TCR comprises a TCR alpha chain comprising the following amino acid sequence: METLLGVSLVILWLQLARVNSQQGEEDPQALSIQEGENATMNCSYKTSINNLQWYRQNSGRGLVHLILIRSNEREKHSGRLRVTLDTSKKSSSLLITASRAADTASYFCATDPGGFKTIFGAGTRLFVKANIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKCVLDMRSMDFKSNSAVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS (sequence number 233).

[0398] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises one or more of the following: CDR1, CDR2, and CDR3 of the TCR β chain.

[0399] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TCR beta chain variable region 11-2 (TRBV11-2) CDR1. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR1, which comprises the following amino acid sequence: ISGHATL (SEQ ID NO: 50).

[0400] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR2, wherein the TRBV11-2 CDR2 comprises the following amino acid sequence: QFQNNGVV (SEQ ID NO: 51).

[0401] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR3. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR3, and the TRBV11-2 CDR3 comprises the following amino acid sequence: CASSLYGGSISYEQYF (SEQ ID NO: 52).

[0402] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a TRBV11-2 CDR1, a TRBV11-2 CDR2, and a TRBV11-2 CDR3.

[0403] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV11-2. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a variable domain of TRBV11-2, the variable domain of TRBV11-2 comprising the following amino acid sequence: EAGVAQSPRYKIIEKRQSVAFWCNPISGHATLYWYQQILGQGPKLLIQFQNNGVVDDSQLPKDRFSAERLKGVDSTLKIQPAKLEDSAVYLCASSL (SEQ ID NO: 170).

[0404] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain. In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises a constant domain, and the constant domain comprises the following amino acid sequence: EDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVCTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (SEQ ID NO: 234).

[0405] In one embodiment, the TCR comprises a TCR beta chain comprising the following amino acid sequence: MGTRLCWAALCLLGAELTEAGVAQSPRYKIIEKRQSVAFWCNPISGHATLYWYQQILGQGPKLLIQFQNNGVVDDSQLPKDRFSAERLKGVDSTLKIQPAKLEDSAVYLCASSLYGGSISYEQYFGPGTRLTVTEDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVCTDPQPLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG (sequence number 235).

[0406] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising a G12V, G12C, or G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGAVGVGK (sequence number 11) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGACGVGK (sequence number 5) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGADGVGK (sequence number 7) in the context of an HLA-A*11:01 molecule.In one embodiment, the TCR comprises (a) a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGARGVGK (sequence number 9) in the context of an HLA-A*11:01 molecule.

[0407] In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising a G12V, G12C, or G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGACGVGK (SEQ ID NO: 5) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGADGVGK (sequence number 7) in the context of an HLA-A*11:01 molecule.In one embodiment, the TCR comprises (a) a TCR alpha chain comprising TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3, and (b) a TCR beta chain comprising TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3, and binds to an mRAS peptide comprising VVGARGVGK (sequence number 9) in the context of an HLA-A*11:01 molecule.

[0408] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V, G12C, or G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, which bind to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, which bind to an mRAS peptide comprising VVGACGVGK (SEQ ID NO: 5) in the context of an HLA-A*11:01 molecule.In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, which bind to an mRAS peptide comprising VVGADGVGK (SEQ ID NO: 7) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises at least one CDR selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, which bind to an mRAS peptide comprising VVGARGVGK (SEQ ID NO: 9) in the context of an HLA-A*11:01 molecule.

[0409] In one embodiment, a TCR that specifically binds to an mRAS peptide having a G12 mutation at a position corresponding to RAS G12 comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising a G12V, G12C, or G12D mutation at the position relative to RAS G12. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising VVGAVGVGK (SEQ ID NO: 11) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising VVGACGVGK (SEQ ID NO: 5) in the context of an HLA-A*11:01 molecule.In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising VVGADGVGK (SEQ ID NO: 7) in the context of an HLA-A*11:01 molecule. In one embodiment, the TCR comprises all of the CDRs selected from the group consisting of: TRAV17-CDR1: SEQ ID NO: 45; TRAV17-CDR2: SEQ ID NO: 46; TRAV17-CDR3: SEQ ID NO: 47; TRBV11-2-CDR1: SEQ ID NO: 50; TRBV11-2-CDR2: SEQ ID NO: 51; and TRBV11-2-CDR3: SEQ ID NO: 52, or one or more variants thereof, and binds to an mRAS peptide comprising VVGARGVGK (SEQ ID NO: 9) in the context of an HLA-A*11:01 molecule.

[0410] In one embodiment, the composition comprises a fusion protein encoding the TCR α chain and TCR β chain described above. In one embodiment, the fusion protein comprises a linker domain separating the TCR α chain and the TCR β chain. In one embodiment, the linker domain is a cleavable linker domain. For example, in one embodiment, the linker domain comprises a GSG-T2A domain. In one embodiment, GSG-T2A comprises the following amino acid sequence: GSGEGRGSLTCGDVEENPGP (SEQ ID NO: 55).

[0411] In one embodiment, the composition comprises a fusion protein comprising the following amino acid sequence: (SEQ ID NO: 236).

[0412] In one embodiment, the composition comprises a fusion protein comprising a linker domain separating the TCR alpha and beta chains. In one embodiment, the linker domain is a cleavable linker domain. Any suitable linker domain may be used so that the function of the alpha and beta chains is maintained.

[0413] In some embodiments, the composition comprises a peptide or polypeptide (e.g., a TCR or an antibody comprising the same) comprising an amino acid sequence that is substantially homologous to the amino acid sequence of a TCR or portion thereof described herein and retains the function of the original amino acid sequence. For example, in some embodiments, the amino acid sequence has a degree of identity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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 99.5% to the original amino acid sequence.

[0414] In some embodiments, the composition comprises a peptide having one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more mutations (such as point mutations) relative to the amino acid sequence of a TCR or portion thereof described herein.

[0415] In some embodiments, the TCR comprises an amino acid sequence having at least about 85% amino acid identity to one or more of the CDR sequences described herein. The invention encompasses TCRs having CDR sequences that are at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 99%, or 100% identical to the CDR sequences described herein.

[0416] In one embodiment, the composition comprises a polypeptide having a CDR sequence at least about 85% identical to a CDR sequence set forth herein. The invention encompasses polypeptides having CDR sequences that are at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 99%, or 100% identical to a CDR sequence set forth herein.

[0417] The peptides of the present invention may be produced using chemical methods. For example, peptides can be synthesized by solid-phase synthesis (Roberge JY et al (1995) Science 269: 202-204), cleaved from the resin, and purified by preparative high-performance liquid chromatography. Automated synthesis may also be achieved, for example, using an ABI 431 A Peptide Synthesizer (PerkinElmer) according to instructions provided by the manufacturer. Peptides may alternatively be produced by recombinant means or by cleavage from a longer polypeptide. Amino acid analysis or sequencing may confirm the composition of the peptide.

[0418] Variants of the polypeptides of the present invention may be (i) variants in which one or more amino acid residues are substituted with conserved or non-conserved amino acid residues, whether or not the substituted amino acid residues are those encoded by the genetic code; (ii) variants in which one or more modified amino acid residues are present, e.g., residues modified by the attachment of a substituent group; (iii) variants in which the polypeptide is an alternatively spliced ​​variant of a polypeptide of the present invention; (iv) fragments of the polypeptide; and / or (v) variants in which the polypeptide is fused to another polypeptide, such as a leader sequence or secretory sequence, or a sequence used for purification (e.g., a His tag) or detection (e.g., an Sv5 epitope tag). Fragments include polypeptides generated via proteolytic cleavage (including multisite proteolysis) of the original sequence. Variants may also be post-translationally, i.e., chemically modified. Such variants are deemed to be within the scope of those skilled in the art given the teachings herein.

[0419] As is known in the art, "similarity" between two polypeptides is determined by comparing the amino acid sequence of one polypeptide and its conservative amino acid sequence substitutes with the sequence of a second polypeptide. A variant is defined to include a polypeptide sequence that differs from the original sequence. For example, in some embodiments, the polypeptide sequence differs from the original sequence in fewer than 40% of the residues per segment of interest. In some embodiments, the polypeptide sequence differs from the original sequence in fewer than 25% of the residues per segment of interest. In some embodiments, the polypeptide sequence differs from the original sequence by fewer than 10% of the residues per segment of interest. In some embodiments, the polypeptide sequence differs from the original protein sequence by only a few residues per segment of interest while remaining sufficiently homologous to the original sequence to preserve the functionality of the original sequence and / or its ability to bind to ubiquitin or ubiquitinated proteins. The present invention encompasses amino acid sequences that are at least 60%, 65%, 70%, 72%, 74%, 76%, 78%, 80%, 90%, or 95% similar or identical to the original amino acid sequence. The degree of identity between two polypeptides can be determined using computer algorithms and methods well known to those skilled in the art. For example, the identity between two amino acid sequences can be determined using the BLASTP algorithm [BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md. 20894, Altschul, S., et al., J. Mol. Biol. 215: 403-410 (1990)].

[0420] Polypeptides of the present invention may be post-translationally modified. For example, post-translational modifications within the scope of the present invention include signal peptide cleavage, glycosylation, acetylation, isoprenylation, proteolysis, myristoylation, protein folding, and protein processing. Some modifications and processing events require the introduction of additional biological machinery. For example, processing events such as signal peptide cleavage and core glycosylation can be examined by adding dog microsomal membranes or Xenopus egg extract (U.S. Pat. No. 6,103,489) to a standard translation reaction.

[0421] Polypeptides of the invention may contain unnatural amino acids formed by post-translational modification or by introducing unnatural amino acids during translation. Various approaches are available for introducing unnatural amino acids during protein translation. For example, specialized tRNAs, such as tRNAs with suppressor properties (suppressor tRNAs), are used in the process of site-directed non-native amino acid replacement (SNAAR). SNAARs require unique codons on the mRNA and the suppressor tRNA, which target the non-native amino acid to a unique site during protein synthesis (as described in WO 90 / 05785). However, the suppressor tRNA must not be recognizable by the aminoacyl-tRNA synthetase present in the protein translation system. In certain cases, non-native amino acids can be formed after aminoacylation of the tRNA molecule using chemical reactions that specifically modify native amino acids but do not significantly alter the functional activity of the aminoacylated tRNA. These reactions are referred to as post-aminoacylation modifications. For example, lysine (tRNA) linked to its cognate tRNA LYS ) may be modified with an amine-specific photoaffinity label.

[0422] The peptides of the present invention may be converted into pharmaceutical salts by reaction with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, and the like, or organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, benezenesulfonic acid, and toluenesulfonic acid.

[0423] nucleic acid molecule In one aspect, the present invention provides a composition comprising an isolated nucleic acid molecule encoding one or more of the peptides or polypeptides described herein. For example, in one aspect, a composition comprises DNA, RNA, mRNA, or cDNA encoding one or more of the peptides or polypeptides described herein.

[0424] In one embodiment, a composition comprises one or more isolated nucleic acid molecules encoding one or more antigenic mRAS peptides described herein. For example, in one embodiment, a composition comprises one or more isolated nucleic acid molecules encoding one or more antigenic mRAS peptides comprising an amino acid sequence selected from SEQ ID NOs: 1-16 and 231.

[0425] In one aspect, the present invention provides a composition comprising an isolated nucleic acid molecule encoding one or more of the peptides or polypeptides described herein. For example, in one aspect, a composition comprises DNA, RNA, mRNA, or cDNA encoding one or more of the peptides or polypeptides described herein.

[0426] In one embodiment, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence selected from SEQ ID NOs: 1 to 92, 188 to 198, 210 to 215, 222 to 225, and 231 to 236. In one embodiment, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having significant homology to an amino acid sequence selected from SEQ ID NOs: 1 to 92, 188 to 198, 210 to 215, 222 to 225, and 231 to 236. For example, in certain embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having at least 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% identity to an amino acid sequence selected from SEQ ID NOs: 1-92, 188-198, 210-215, 222-225, and 231-236. In certain embodiments, the nucleic acid molecule comprises a nucleic acid sequence encoding an amino acid sequence having one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more mutations (such as point mutations) relative to an amino acid sequence selected from SEQ ID NOs: 1-92, 188-198, 210-215, 222-225, and 231-236.

[0427] In one embodiment, the composition comprises one or more isolated nucleic acid molecules encoding one or more TCRs described herein, one or more CDRs described herein, one or more alpha chains described herein, one or more beta domains described herein, one or more variable domains described herein, one or more constant domains described herein, one or more linkers described herein, or one or more fusion proteins described herein.

[0428] A nucleic acid molecule encoding TCR831 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV39 CDR1, TRAV39 CDR2, and TRAV39 CDR3. In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV39 CDR1 comprising the amino acid sequence of SEQ ID NO: 17, TRAV39 CDR2 comprising the amino acid sequence of SEQ ID NO: 18, and TRAV39 CDR3 comprising the amino acid sequence of SEQ ID NO: 19. In one embodiment, the nucleic acid sequence encoding TRAV39 CDR1 comprises ACCACTTCAGA (SEQ ID NO: 93). In one embodiment, the nucleic acid sequence encoding TRAV39 CDR2 comprises TTGCTATCAAATGGAGCAGTG (SEQ ID NO: 94). In one embodiment, the nucleic acid sequence encoding TRAV39 CDR3 comprises GCCGTGGACAAGGATGGGGGTTACC (SEQ ID NO: 95).

[0429] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising the variable domain of TRAV39 comprising the amino acid sequence of SEQ ID NO:20. In one embodiment, the nucleic acid sequence encoding the variable domain of TRAV39 comprises: ATGAAGAAGCTACTAGCAATGATTCTGTGGCTTCAACTAGACCGGTTAAGTGGAGAGCTGAAAGTGGAACAAAACCCTCTGTTCCTGAGCATGCAGGAGGGAAAAAACTATACCATCTACTGCAATTATTCAACCACTTCAGACAGACTGTATTGGTACAGGCAGGATCCTGGGAAAAGTCTGGAATCTCTGTTTGTGTTGCTATCAAATGGAGCAGTGAAGCAGGAGGGACGATTAATGGCCTCACTTGATACCAAAGCCCGTCTCAGCACCCTCCACATCACAGCTGCCGTGCATGACCTCTCTGCCACCTACTTCTGTGCCGTGGACAAGGATGGGGGTTACCAGAAAGTTACCTTTGGAACTGGAACAAAGCTCCAAGTCATCCCAA (SEQ ID NO: 96).

[0430] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO:21. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: ATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGTTGGACATGCGCAGCATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCCGGGTTTAATCTGCTCATGACGCTGCGGCTGTGGTCCAGC (SEQ ID NO: 97).

[0431] In one embodiment, the nucleic acid molecule encodes a TCR alpha chain comprising the amino acid sequence of SEQ ID NO: 22. In one embodiment, the nucleic acid sequence encoding the TCR alpha chain comprises: (SEQ ID NO: 98).

[0432] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV20-1 CDR1, TRBV20-1 CDR2, and TRBV20-1 CDR3. In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV20-1 CDR1 comprising the amino acid sequence of SEQ ID NO: 23, TRBV20-1 CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and TRBV20-1 CDR3 comprising the amino acid sequence of SEQ ID NO: 25. In one embodiment, the nucleic acid sequence encoding TRBV20-1 CDR1 comprises GACTTTCAGGCCACAACT (SEQ ID NO: 99). In one embodiment, the nucleic acid sequence encoding TRBV20-1 CDR2 comprises TCCAATGAGGGCTCCAAGGCC (SEQ ID NO: 100). In one embodiment, the nucleic acid sequence encoding the TRBV20-1 CDR3 comprises AGTGCTAGCCCACGGGCGGGACAGTTGAGCTCCTATAATTCACCCCTCCAC (SEQ ID NO: 101).

[0433] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising the variable domain of TRBV20-1 comprising the amino acid sequence of SEQ ID NO:26. In one embodiment, the nucleic acid sequence encoding the variable domain of TRBV20-1 comprises: ATGCTGCTGCTTCTGCTGCTTCTGGGGCCAGGTATAAGCCTCCTTCTACCTGGGAGCTTGGCAGGCTCCGGGCTTGGTGCTGTCGTCTCTCAACATCCGAGCTGGGTTATCTGTAAGAGTGGAACCTCTGTGAAGATCGAGTGCCGTTCCCTGGACTTTCAGGCCACAACTATGTTTTGGTATCGTCAGTTCCCGAAACAGAGTCTCATGCTGATGGCAACTTCCAATGAGGGCTCCAAGGCCACATACGAGCAAGGCGTCGAGAAGGACAAGTTTCTCATCAACCATGCAAGCCTGACCTTGTCCACTCTGACAGTGACCAGTGCCCATCCTGAAGACAGCAGCTTCTACATCTGCAGTGCTAGCCCACGGGCGGGACAGTTGAGCTCCTATAATTCACCCCTCCACTTTGGGAATGGGACCAGGCTCACTGTGAC (SEQ ID NO: 102).

[0434] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR beta chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO: 27. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: (SEQ ID NO: 103).

[0435]

[0436] In one embodiment, the nucleic acid molecule encodes a fusion protein encoding a TCR alpha chain and a TCR beta chain. In one embodiment, the isolated nucleic acid molecule encodes a fusion protein comprising a linker domain between the TCR alpha chain and the TCR beta chain. In one embodiment, the nucleic acid molecule encodes a GSG-T2A linker domain comprising the amino acid sequence of SEQ ID NO: 29. In one embodiment, the nucleic acid sequence encoding the GSG-T2A linker domain comprises: GGCAGCGGAGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCT (SEQ ID NO: 105).

[0437]

[0438] A nucleic acid molecule encoding TCR833 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3. In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1 comprising the amino acid sequence of SEQ ID NO: 32, TRAV12-1 CDR2 comprising the amino acid sequence of SEQ ID NO: 32, and TRAV12-1 CDR3 comprising the amino acid sequence of SEQ ID NO: 33. In one embodiment, the nucleic acid sequence encoding TRAV12-1 CDR1 comprises AACAGTGCTCTCTCAGTCT (SEQ ID NO: 107). In one embodiment, the nucleic acid sequence encoding TRAV12-1 CDR2 comprises GTATACTCCAGTGGTAAC (SEQ ID NO: 108). In one embodiment, the nucleic acid sequence encoding the TRAV12-1 CDR3 comprises GCGGTGAACCCCCCGGACACAGGCTTTCAGAAACTTGTA (SEQ ID NO: 109).

[0439] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising the variable domain of TRAV12-1 comprising the amino acid sequence of SEQ ID NO:34. In one embodiment, the nucleic acid sequence encoding the variable domain of TRAV12-1 comprises: ATGATATCCTTGAGAGTTTTACTGGTGATCCTGTGGCTTCAGTTAAGCTGGGTTTGGAGCCAACGGAAGGAGGTGGAGCAGGATCCTGGACCCTTCAATGTTCCAGAGGGAGCCACTGTCGCTTTCAACTGTACTTACAGCAACAGTGCTTCTCAGTCTTTCTTCTGGTACAGACAGGATTGCAGGAAAGAACCTAAGTTGCTGATGTCCGTATACTCCAGTGGTAACGAAGATGGAAGGTTTACAGCACAGCTCAATAGAGCCAGCCAGTATATTTCCCTGCTCATCAGAGACTCCAAGCTCAGTGATTCAGCCACCTACCTCTGTGCGGTGAACCCCCCGGACACAGGCTTTCAGAAACTTGTATTTGGAACTGGCACCCGACTTCTGGTCAGTCCAA (SEQ ID NO: 110).

[0440] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO:35. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: ATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGTTGGACATGCGCAGCATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCCGGGTTTAATCTGCTCATGACGCTGCGGCTGTGGTCCAGC (SEQ ID NO: 111).

[0441] In one embodiment, the nucleic acid molecule encodes a TCR alpha chain comprising the amino acid sequence of SEQ ID NO: 36. In one embodiment, the nucleic acid sequence encoding the TCR alpha chain comprises: (SEQ ID NO: 112).

[0442] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3. In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV28 CDR1 comprising the amino acid sequence of SEQ ID NO: 37, TRBV28 CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and TRBV28 CDR3 comprising the amino acid sequence of SEQ ID NO: 39. In one embodiment, the nucleic acid sequence encoding TRBV28 CDR1 comprises ATGGACCATGAAAAT (SEQ ID NO: 113). In one embodiment, the nucleic acid sequence encoding TRBV28 CDR2 comprises TCATATGATGTTAAAATG (SEQ ID NO: 114). In one embodiment, the nucleic acid sequence encoding TRBV28 CDR3 comprises GCCAGCAGTTTATCCTTCCGGCAGGGCCTTCGCGAGCAGTAC (SEQ ID NO: 115).

[0443] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising the variable domain of TRBV28 comprising the amino acid sequence of SEQ ID NO:40. In one embodiment, the nucleic acid sequence encoding the variable domain of TRBV28 comprises: ATGGGAATCAGGCTCCTGTGTCGTGTGGCCTTTTGTTTCCTGGCTGTAGGCCTCGTAGATGTGAAAGTAACCCAGAGCTCGAGATATCTAGTCAAAAGGACGGGAGAGAAAGTTTTTCTGGAATGTGTCCAGGATATGGACCATGAAAATATGTTCTGGTATCGACAAGACCCAGGTCTGGGGCTACGGCTGATCTATTTCTCATATGATGTTAAAATGAAAGAAAAAGGAGATATTCCTGAGGGGTACAGTGTCTCCAGAGAGAAGAAGGAGCGCTTCTCCCTGATTCTGGAGTCCGCCAGCACCAACCAGACATCTATGTACCTCTGTGCCAGCAGTTTATCCTTCCGGCAGGGCCTTCGCGAGCAGTACTTCGGGCCGGGCACCAGGCTCACGGTCACA (SEQ ID NO: 116).

[0444] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR beta chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO: 41. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: (SEQ ID NO: 117).

[0445] In one embodiment, the nucleic acid molecule encodes a TCR β chain comprising the amino acid sequence of SEQ ID NO:42.In one embodiment, the nucleic acid sequence comprising the TCRβ chain comprises the following: ATGGGAATCAGGCTCCTGTGTCGTGTGGCCTTTTGTTTCCTGGCTGTAGGCCTCGTAGATGTGAAAGTAACCCAGAGCTCGAGATATCTAGTCAAAAGGACGGGAGAGAAAGTTTTTCTGGAATGTGTCCAGGATATGGACCATGAAAATATGTTCTGGTATCGACAAGACCCAGGTCTGGGGCTACGGCTGATCTATTTCTCATATGATGTTAAAATGAAAGAAAAAGGAGATATTCCTGAGGGGTACAGTGTCTCCAGAGAGAAGAAGGAGCGCTTCTCCCTGATTCTGGAGTCCGCCAGCACCAACCAGACATCTATGTACCTCTGTGCCAGCAGTTTATCCTTCCGGCAGGGCCTTCGCGAGCAGTACTTCGGGCCGGGCACCAGGCTCACGGTCACAGAGGACCTGAAAAACGTGTTCCCACCCGAGGTCGCTGTGTTTGAGCCATCAGAAGCAGAGATCTCCCACACCCAAAAGGCCACACTGGTGTGCCTGGCCACAGGCTTCTACCCCGACCACGTGGAGCTGAGCTGGTGGGTGAATGGGAAGGAGGTGCACAGTGGGGTCAGCACAGACCCGCAGCCCCTCAAGGAGCAGCCCGCCCTCAATGACTCCAGATACTGCCTGAGCAGCCGCCTGAGGGTCTCGGCCACCTTCTGGCAGAACCCCCGCAACCACTTCCGCTGTCAAGTCCAGTTCTACGGGCTCTCGGAGAATGATGAGTGGACACAAGATAGGGCCAAACCTGTCACCCAGATCGTCAGCGCCGAGGCCTGGGGTAGAGCAGACTGTGGCTTCACCTCCGAGTCTTACCAGCAAGGGGTCCTGTCTGCCACCATCCTCTATGAGATCTTGCTAGGGAAGGCCACCTTGTATGCCGTGCTGGTCAGTGCCCTCGTGCTGATGGCCATGGTCAAGAGAAAGGATTCCAGAGGCTGA (SEQ ID NO: 118).

[0446] In one embodiment, the nucleic acid molecule encodes a fusion protein encoding a TCR alpha chain and a TCR beta chain. In one embodiment, the isolated nucleic acid molecule encodes a fusion protein comprising a linker domain between the TCR alpha chain and the TCR beta chain. In one embodiment, the nucleic acid molecule encodes a GSG-T2A linker domain comprising the amino acid sequence of SEQ ID NO: 43. In one embodiment, the nucleic acid sequence encoding the GSG-T2A linker domain comprises: GGCAGCGGAGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCT (SEQ ID NO: 119).

[0447]

[0448] A nucleic acid molecule encoding TCR897 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3. In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV17 CDR1 comprising the amino acid sequence of SEQ ID NO: 45, TRAV17 CDR2 comprising the amino acid sequence of SEQ ID NO: 46, and TRAV17 CDR3 comprising the amino acid sequence of SEQ ID NO: 47. In one embodiment, the nucleic acid sequence encoding TRAV17 CDR1 comprises ACTAGTATAAACAAT (SEQ ID NO: 121). In one embodiment, the nucleic acid sequence encoding TRAV17 CDR2 comprises ATACGTTCAAATGAAAGAGAG (SEQ ID NO: 122). In one embodiment, the nucleic acid sequence encoding TRAV17 CDR3 comprises TGTGCTACGGACCCTGGAGGCTTCAAAACTATCTTT (SEQ ID NO: 123).

[0449] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO:48. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: ATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGTTGGACATGCGCAGCATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCCGGGTTTAATCTGCTCATGACGCTGCGGCTGTGGTCCAGC (SEQ ID NO: 124).

[0450] In one embodiment, the nucleic acid molecule encodes a TCR alpha chain comprising the amino acid sequence of SEQ ID NO: 49. In one embodiment, the nucleic acid sequence encoding the TCR alpha chain comprises: (SEQ ID NO: 125).

[0451] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV11-2 CDR1, TRBV11-2 CDR2, and TRBV11-2 CDR3. In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV11-2 CDR1 comprising the amino acid sequence of SEQ ID NO: 50, TRBV11-2 CDR2 comprising the amino acid sequence of SEQ ID NO: 51, and TRBV11-2 CDR3 comprising the amino acid sequence of SEQ ID NO: 52. In one embodiment, the nucleic acid sequence encoding TRBV11-2 CDR1 comprises TCTGGCCATGCTACC (SEQ ID NO: 126). In one embodiment, the nucleic acid sequence encoding TRBV11-2 CDR2 comprises TTTCAGAATAACGGTGTA (SEQ ID NO: 127). In one embodiment, the nucleic acid sequence encoding the TRBV11-2 CDR3 comprises TGTGCCAGCAGCTTATATGGGGGGTCGATCTCCTACGAGCAGTACTTC (SEQ ID NO: 128).

[0452] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR beta chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO: 53. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: (SEQ ID NO: 129).

[0453] In one embodiment, the nucleic acid molecule encodes a TCR β chain comprising the amino acid sequence of SEQ ID NO:54.In one embodiment, the nucleic acid sequence comprising the TCRβ chain comprises the following: ATGGGCACCAGGCTCCTCTGCTGGGCGGCCCTCTGTCTCCTGGGAGCAGAACTCACAGAAGCTGGAGTTGCCCAGTCTCCCAGATATAAGATTATAGAGAAAAGGCAGAGTGTGGCTTTTTGGTGCAATCCTATATCTGGCCATGCTACCCTTTACTGGTACCAGCAGATCCTGGGACAGGGCCCAAAGCTTCTGATTCAGTTTCAGAATAACGGTGTAGTGGATGATTCACAGTTGCCTAAGGATCGATTTTCTGCAGAGAGGCTCAAAGGAGTAGACTCCACTCTCAAGATCCAGCCTGCAAAGCTTGAGGACTCGGCCGTGTATCTCTGTGCCAGCAGCTTATATGGGGGGTCGATCTCCTACGAGCAGTACTTCGGGCCGGGCACCAGGCTCACGGTCACAGAGGACCTGAAAAACGTGTTCCCACCCGAGGTCGCTGTGTTTGAGCCATCAGAAGCAGAGATCTCCCACACCCAAAAGGCCACACTGGTGTGCCTGGCCACAGGCTTCTACCCCGACCACGTGGAGCTGAGCTGGTGGGTGAATGGGAAGGAGGTGCACAGTGGGGTCAGCACAGACCCGCAGCCCCTCAAGGAGCAGCCCGCCCTCAATGACTCCAGATACTGCCTGAGCAGCCGCCTGAGGGTCTCGGCCACCTTCTGGCAGAACCCCCGCAACCACTTCCGCTGTCAAGTCCAGTTCTACGGGCTCTCGGAGAATGATGAGTGGACACAAGATAGGGCCAAACCTGTCACCCAGATCGTCAGCGCCGAGGCCTGGGGTAGAGCAGACTGTGGCTTCACCTCCGAGTCTTACCAGCAAGGGGTCCTGTCTGCCACCATCCTCTATGAGATCTTGCTAGGGAAGGCCACCTTGTATGCCGTGCTGGTCAGTGCCCTCGTGCTGATGGCCATGGTCAAGAGAAAGGATTCCAGAGGCTGA (SEQ ID NO: 130).

[0454] In one embodiment, the nucleic acid molecule encodes a fusion protein encoding a TCR alpha chain and a TCR beta chain. In one embodiment, the isolated nucleic acid molecule encodes a fusion protein comprising a linker domain between the TCR alpha chain and the TCR beta chain. In one embodiment, the nucleic acid molecule encodes a GSG-T2A linker domain comprising the amino acid sequence of SEQ ID NO: 55. In one embodiment, the nucleic acid sequence encoding the GSG-T2A linker domain comprises: GGCAGCGGAGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCT (SEQ ID NO: 131).

[0455]

[0456] A nucleic acid molecule encoding TCR896 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3. In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV19 CDR1 comprising the amino acid sequence of SEQ ID NO: 57, TRAV19 CDR2 comprising the amino acid sequence of SEQ ID NO: 58, and TRAV19 CDR3 comprising the amino acid sequence of SEQ ID NO: 59. In one embodiment, the nucleic acid sequence encoding TRAV19 CDR1 comprises ACCCGTGATACTACTTATTAC (SEQ ID NO: 133). In one embodiment, the nucleic acid sequence encoding TRAV19 CDR2 comprises CGGAACTCTTTTGATGAGCAAAAT (SEQ ID NO: 134). In one embodiment, the nucleic acid sequence encoding TRAV19 CDR3 comprises TGTGCTCTGAGTGAGGCAGGAACCTACAAATACATCTTT (SEQ ID NO: 135).

[0457] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO:60. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: ATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGTTGGACATGCGCAGCATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCCGGGTTTAATCTGCTCATGACGCTGCGGCTGTGGTCCAGC (SEQ ID NO: 136).

[0458] In one embodiment, the nucleic acid molecule encodes a TCR alpha chain comprising the amino acid sequence of SEQ ID NO: 61. In one embodiment, the nucleic acid sequence encoding the TCR alpha chain comprises: (SEQ ID NO: 137).

[0459] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV9 CDR1, TRBV9 CDR2, and TRBV9 CDR3. In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV9 CDR1 comprising the amino acid sequence of SEQ ID NO: 62, TRBV9 CDR2 comprising the amino acid sequence of SEQ ID NO: 63, and TRBV9 CDR3 comprising the amino acid sequence of SEQ ID NO: 64. In one embodiment, the nucleic acid sequence encoding TRBV9 CDR1 comprises TCTGGAGACCTCTCT (SEQ ID NO: 138). In one embodiment, the nucleic acid sequence encoding TRBV9 CDR2 comprises CGGAACTCTTTTGATGAGCAAAAT (SEQ ID NO: 139). In one embodiment, the nucleic acid sequence encoding TRBV9 CDR3 comprises TGTGCTCTGAGTGAGGCAGGAACCTACAAATACATCTTT (SEQ ID NO: 140).

[0460] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR beta chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO: 65. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: (SEQ ID NO: 141).

[0461] In one embodiment, the nucleic acid molecule encodes a TCR β chain comprising the amino acid sequence of SEQ ID NO:66.In one embodiment, the nucleic acid sequence containing the TCRβ chain comprises the following: ATGGGCTTCAGGCTCCTCTGCTGTGTGGCCTTTTGTCTCCTGGGAGCAGGCCCAGTGGATTCTGGAGTCACACAAACCCCAAAGCACCTGATCACAGCAACTGGACAGCGAGTGACGCTGAGATGCTCCCCTAGGTCTGGAGACCTCTCTGTGTACTGGTACCAACAGAGCCTGGACCAGGGCCTCCAGTTCCTCATTCAGTATTATAATGGAGAAGAGAGAGCAAAAGGAAACATTCTTGAACGATTCTCCGCACAACAGTTCCCTGACTTGCACTCTGAACTAAACCTGAGCTCTCTGGAGCTGGGGGACTCAGCTTTGTATTTCTGTGCCAGCAGCGTAGCTGGGGGGGGACAAGAGACCCAGTACTTCGGGCCAGGCACGCGGCTCCTGGTGCTCGAGGACCTGAAAAACGTGTTCCCACCCGAGGTCGCTGTGTTTGAGCCATCAGAAGCAGAGATCTCCCACACCCAAAAGGCCACACTGGTGTGCCTGGCCACAGGCTTCTACCCCGACCACGTGGAGCTGAGCTGGTGGGTGAATGGGAAGGAGGTGCACAGTGGGGTCAGCACAGACCCGCAGCCCCTCAAGGAGCAGCCCGCCCTCAATGACTCCAGATACTGCCTGAGCAGCCGCCTGAGGGTCTCGGCCACCTTCTGGCAGAACCCCCGCAACCACTTCCGCTGTCAAGTCCAGTTCTACGGGCTCTCGGAGAATGATGAGTGGACACAAGATAGGGCCAAACCTGTCACCCAGATCGTCAGCGCCGAGGCCTGGGGTAGAGCAGACTGTGGCTTCACCTCCGAGTCTTACCAGCAAGGGGTCCTGTCTGCCACCATCCTCTATGAGATCTTGCTAGGGAAGGCCACCTTGTATGCCGTGCTGGTCAGTGCCCTCGTGCTGATGGCCATGGTCAAGAGAAAGGATTCCAGAGGCTGA (SEQ ID NO: 142).

[0462] In one embodiment, the nucleic acid molecule encodes a fusion protein encoding a TCR alpha chain and a TCR beta chain. In one embodiment, the isolated nucleic acid molecule encodes a fusion protein comprising a linker domain between the TCR alpha chain and the TCR beta chain. In one embodiment, the nucleic acid molecule encodes a GSG-T2A linker domain comprising the amino acid sequence of SEQ ID NO: 67. In one embodiment, the nucleic acid sequence encoding the GSG-T2A linker domain comprises: GGCAGCGGAGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCT (SEQ ID NO: 143).

[0463]

[0464] A nucleic acid molecule encoding TCR847 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV17 CDR1, TRAV17 CDR2, and TRAV17 CDR3. In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV17 CDR1 comprising the amino acid sequence of SEQ ID NO: 69, TRAV17 CDR2 comprising the amino acid sequence of SEQ ID NO: 70, and TRAV17 CDR3 comprising the amino acid sequence of SEQ ID NO: 71. In one embodiment, the nucleic acid sequence encoding TRAV17 CDR1 comprises ACTAGTATAAACAAT (SEQ ID NO: 145). In one embodiment, the nucleic acid sequence encoding TRAV17 CDR2 comprises ATACGTTCAAATGAAAGAGAG (SEQ ID NO: 146). In one embodiment, the nucleic acid sequence encoding TRAV17 CDR3 comprises GCTACTTTTCCTAACTTTGGAAATGAGAAATTAACC (SEQ ID NO: 147).

[0465] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO:72. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: ATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGTTGGACATGCGCAGCATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCCGGGTTTAATCTGCTCATGACGCTGCGGCTGTGGTCCAGC (SEQ ID NO: 148).

[0466] In one embodiment, the nucleic acid molecule encodes a TCR alpha chain comprising the amino acid sequence of SEQ ID NO: 73. In one embodiment, the nucleic acid sequence encoding the TCR alpha chain comprises: (SEQ ID NO: 149).

[0467] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV10-3 CDR1, TRBV10-3 CDR2, and TRBV10-3 CDR3. In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV10-3 CDR1 comprising the amino acid sequence of SEQ ID NO: 74, TRBV10-3 CDR2 comprising the amino acid sequence of SEQ ID NO: 75, and TRBV10-3 CDR3 comprising the amino acid sequence of SEQ ID NO: 76. In one embodiment, the nucleic acid sequence encoding TRBV10-3 CDR1 comprises GAGAACCACCGCTA (SEQ ID NO: 150). In one embodiment, the nucleic acid sequence encoding TRBV10-3 CDR2 comprises TCATATGGTGTTAAAGAT (SEQ ID NO: 151). In one embodiment, the nucleic acid sequence encoding the TRBV10-3 CDR3 comprises GCCATCAGTGAGTCGGAGCGGTACTACGAGCAGTAC (SEQ ID NO: 152).

[0468] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR beta chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO: 77. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: (SEQ ID NO: 153).

[0469] In one embodiment, the nucleic acid molecule encodes a TCR β chain comprising the amino acid sequence of SEQ ID NO:78.In one embodiment, the nucleic acid sequence comprising the TCRβ chain comprises the following: ATGGGCACAAGGTTGTTCTTCTATGTGGCCCTTTGTCTCCTGTGGACAGGACACATGGATGCTGGAATCACCCAGAGCCCAAGACACAAGGTCACAGAGACAGGAACACCAGTGACTCTGAGATGTCACCAGACTGAGAACCACCGCTATATGTACTGGTATCGACAAGACCCGGGGCATGGGCTGAGGCTGATCCATTACTCATATGGTGTTAAAGATACTGACAAAGGAGAAGTCTCAGATGGCTATAGTGTCTCCAGATCAAAGACAGAGGATTTCCTCCTCACTCTGGAGTCCGCTACCAGCTCCCAGACATCTGTGTACTTCTGTGCCATCAGTGAGTCGGAGCGGTACTACGAGCAGTACTTCGGGCCGGGCACCAGGCTCACGGTCACAGAGGACCTGAAAAACGTGTTCCCACCCGAGGTCGCTGTGTTTGAGCCATCAGAAGCAGAGATCTCCCACACCCAAAAGGCCACACTGGTGTGCCTGGCCACAGGCTTCTACCCCGACCACGTGGAGCTGAGCTGGTGGGTGAATGGGAAGGAGGTGCACAGTGGGGTCAGCACAGACCCGCAGCCCCTCAAGGAGCAGCCCGCCCTCAATGACTCCAGATACTGCCTGAGCAGCCGCCTGAGGGTCTCGGCCACCTTCTGGCAGAACCCCCGCAACCACTTCCGCTGTCAAGTCCAGTTCTACGGGCTCTCGGAGAATGATGAGTGGACACAAGATAGGGCCAAACCTGTCACCCAGATCGTCAGCGCCGAGGCCTGGGGTAGAGCAGACTGTGGCTTCACCTCCGAGTCTTACCAGCAAGGGGTCCTGTCTGCCACCATCCTCTATGAGATCTTGCTAGGGAAGGCCACCTTGTATGCCGTGCTGGTCAGTGCCCTCGTGCTGATGGCCATGGTCAAGAGAAAGGATTCCAGAGGCTGA (SEQ ID NO: 154).

[0470] In one embodiment, the nucleic acid molecule encodes a fusion protein encoding a TCR alpha chain and a TCR beta chain. In one embodiment, the isolated nucleic acid molecule encodes a fusion protein comprising a linker domain between the TCR alpha chain and the TCR beta chain. In one embodiment, the nucleic acid molecule encodes a GSG-T2A linker domain comprising the amino acid sequence of SEQ ID NO: 79. In one embodiment, the nucleic acid sequence encoding the GSG-T2A linker domain comprises: GGCAGCGGAGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCT (SEQ ID NO: 155).

[0471]

[0472] A nucleic acid molecule encoding TCR864 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3. In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV4 CDR1 comprising the amino acid sequence of SEQ ID NO: 81, TRAV4 CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and TRAV4 CDR3 comprising the amino acid sequence of SEQ ID NO: 83. In one embodiment, the nucleic acid sequence encoding TRAV4 CDR1 comprises AACATTGCTACAAATGATTAT (SEQ ID NO: 157). In one embodiment, the nucleic acid sequence encoding TRAV4 CDR2 comprises GGATACAAGACAAAA (SEQ ID NO: 158). In one embodiment, the nucleic acid sequence encoding TRAV4 CDR3 comprises CTCGTGGGTGACTTCAACTCAAATTCCGGGTATGCACTCAAC (SEQ ID NO: 159).

[0473] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO:84. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: ATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGTTGGACATGCGCAGCATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCCGGGTTTAATCTGCTCATGACGCTGCGGCTGTGGTCCAGC (SEQ ID NO: 160).

[0474] In one embodiment, the nucleic acid molecule encodes a TCR alpha chain comprising the amino acid sequence of SEQ ID NO: 85. In one embodiment, the nucleic acid sequence encoding the TCR alpha chain comprises: (SEQ ID NO: 161).

[0475] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV7-2 CDR1, TRBV7-2 CDR2, and TRBV7-2 CDR3. In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV7-2 CDR1 comprising the amino acid sequence of SEQ ID NO: 86, TRBV7-2 CDR2 comprising the amino acid sequence of SEQ ID NO: 87, and TRBV7-2 CDR3 comprising the amino acid sequence of SEQ ID NO: 88. In one embodiment, the nucleic acid sequence encoding TRBV7-2 CDR1 comprises TCAGGTCATACTGCC (SEQ ID NO: 162). In one embodiment, the nucleic acid sequence encoding TRBV7-2 CDR2 comprises TTCCAAGGCAACAGTGCA (SEQ ID NO: 163). In one embodiment, the nucleic acid sequence encoding TRBV7-2 CDR3 comprises GCCAGCAAGGTCTATGGCTACACC (SEQ ID NO: 164).

[0476] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR beta chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO: 89. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: (SEQ ID NO: 165).

[0477] In one embodiment, the nucleic acid molecule encodes a TCR β chain comprising the amino acid sequence of SEQ ID NO:90.In one embodiment, the nucleic acid sequence containing the TCRβ chain comprises the following: ATGGGCACCAGGCTCCTCTTCTGGGTGGCCTTCTGTCTCCTGGGGGCATATCACACAGGAGCTGGAGTCTCCCAGTCCCCCAGTAACAAGGTCACAGAGAAGGGAAAGGATGTAGAGCTCAGGTGTGATCCAATTTCAGGTCATACTGCCCTTTACTGGTACCGACAGAGGCTGGGGCAGGGCCTGGAGTTTTTAATTTACTTCCAAGGCAACAGTGCACCAGACAAATCAGGGCTGCCCAGTGATCGCTTCTCTGCAGAGAGGACTGGGGAATCCGTCTCCACTCTGACGATCCAGCGCACACAGCAGGAGGACTCGGCCGTGTATCTCTGTGCCAGCAAGGTCTATGGCTACACCTTCGGTTCGGGGACCAGGTTAACCGTTGTAGAGGACCTGAACAAGGTGTTCCCACCCGAGGTCGCTGTGTTTGAGCCATCAGAAGCAGAGATCTCCCACACCCAAAAGGCCACACTGGTGTGCCTGGCCACAGGCTTCTTCCCCGACCACGTGGAGCTGAGCTGGTGGGTGAATGGGAAGGAGGTGCACAGTGGGGTCAGCACGGACCCGCAGCCCCTCAAGGAGCAGCCCGCCCTCAATGACTCCAGATACTGCCTGAGCAGCCGCCTGAGGGTCTCGGCCACCTTCTGGCAGAACCCCCGCAACCACTTCCGCTGTCAAGTCCAGTTCTACGGGCTCTCGGAGAATGATGAGTGGACACAAGATAGGGCCAAACCCGTCACCCAGATCGTCAGCGCCGAGGCCTGGGGTAGAGCAGACTGTGGCTTTACCTCGGTGTCCTACCAGCAAGGGGTCCTGTCTGCCACCATCCTCTATGAGATCCTGCTAGGGAAGGCCACCCTGTATGCTGTGCTGGTCAGCGCCCTTGTGTTGATGGCCATGGTCAAGAGAAAGGATTTCTGA (SEQ ID NO: 166).

[0478] In one embodiment, the nucleic acid molecule encodes a fusion protein encoding a TCR alpha chain and a TCR beta chain. In one embodiment, the isolated nucleic acid molecule encodes a fusion protein comprising a linker domain between the TCR alpha chain and the TCR beta chain. In one embodiment, the nucleic acid molecule encodes a GSG-T2A linker domain comprising the amino acid sequence of SEQ ID NO: 91. In one embodiment, the nucleic acid sequence encoding the GSG-T2A linker domain comprises: GGCAGCGGAGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCT (SEQ ID NO: 167).

[0479]

[0480] A nucleic acid molecule encoding TCR1074 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3. In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV4 CDR1 comprising the amino acid sequence of SEQ ID NO: 188, TRAV4 CDR2 comprising the amino acid sequence of SEQ ID NO: 189, and TRAV4 CDR3 comprising the amino acid sequence of SEQ ID NO: 190. In one embodiment, the nucleic acid sequence encoding TRAV4 CDR1 comprises AACATTGCTACAAATGATTAT (SEQ ID NO: 199). In one embodiment, the nucleic acid sequence encoding TRAV4 CDR2 comprises GGATACAAGACAAAA (SEQ ID NO: 200). In one embodiment, the nucleic acid sequence encoding TRAV4 CDR3 comprises CTCGTGGGTGACATAGACCAGGCAGGAACTGCTCTGATC (SEQ ID NO: 201).

[0481] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising the variable domain of TRAV4 comprising the amino acid sequence of SEQ ID NO:191. In one embodiment, the nucleic acid sequence encoding the variable domain of TRAV4 comprises: ATGAGGCAAGTGGCGAGAGTGATCGTGTTCCTGACCCTGAGTACTTTGAGCCTTGCTAAGACCACCCAGCCCATCTCCATGGACTCATATGAAGGACAAGAAGTGAACATAACCTGTAGCCACAACAACATTGCTACAAATGATTATATCACGTGGTACCAACAGTTTCCCAGCCAAGGACCACGATTTATTATTCAAGGATACAAGACAAAAGTTACAAACGAAGTGGCCTCCCTGTTTATCCCTGCCGACAGAAAGTCCAGCACTCTGAGCCTGCCCCGGGTTTCCCTGAGCGACACTGCTGTGTACTACTGCCTCGTGGGTGACATAGACCAGGCAGGAACTGCTCTGATCTTTGGGAAGGGAACCACCTTATCAGTGAGTTCCA (SEQ ID NO: 202).

[0482] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO:192. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: aATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGTTGGACATGCGCAGCATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCAGGTTTTAACCTGCTGATGACCCTGCGGCTGTGGTCCAGC (SEQ ID NO: 203).

[0483] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3. In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV6-5 CDR1 comprising the amino acid sequence of SEQ ID NO: 194, TRBV6-5 CDR2 comprising the amino acid sequence of SEQ ID NO: 195, and TRBV6-5 CDR3 comprising the amino acid sequence of SEQ ID NO: 196. In one embodiment, the nucleic acid sequence encoding TRBV6-5 CDR1 comprises ATGAACCATGAATAC (SEQ ID NO: 205). In one embodiment, the nucleic acid sequence encoding TRBV6-5 CDR2 comprises TCAGTTGGTGCTGGTATC (SEQ ID NO: 206). In one embodiment, the nucleic acid sequence encoding the TRBV6-5 CDR3 comprises GCCAGCGCTCGGGATAGCAATCAGCCCCAGCAT (SEQ ID NO: 207).

[0484] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising the variable domain of TRBV6-5 comprising the amino acid sequence of SEQ ID NO:197. In one embodiment, the nucleic acid sequence encoding the variable domain of TRBV6-5 comprises: ATGAGCATCGGCCTCCTGTGCTGTGCAGCCTTGTCTCTCCTGTGGGCAGGTCCAGTGAATGCTGGTGTCACTCAGACCCCAAAATTCCAGGTCCTGAAGACAGGACAGAGCATGACACTGCAGTGTGCCCAGGATATGAACCATGAATACATGTCCTGGTATCGACAAGACCCAGGCATGGGGCTGAGGCTGATTCATTACTCAGTTGGTGCTGGTATCACTGACCAAGGAGAAGTCCCCAATGGCTACAATGTCTCCAGATCAACCACAGAGGATTTCCCGCTCAGGCTGCTGTCGGCTGCTCCCTCCCAGACATCTGTGTACTTCTGTGCCAGCGCTCGGGATAGCAATCAGCCCCAGCATTTTGGTGATGGGACTCGACTCTCCATCCTA (SEQ ID NO: 208).

[0485] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR beta chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO: 198. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: (SEQ ID NO: 209).

[0486] In one embodiment, the nucleic acid molecule encodes a fusion protein encoding a TCR alpha chain and a TCR beta chain. In one embodiment, the isolated nucleic acid molecule encodes a fusion protein comprising a linker domain between the TCR alpha chain and the TCR beta chain. In one embodiment, the nucleic acid molecule encodes a BspEI-T2A-AvrII linker domain comprising the amino acid sequence of SEQ ID NO: 193. In one embodiment, the nucleic acid sequence encoding the BspEI-T2A-AvrII linker domain comprises: TCCGGAGGCAGCGGAGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCTAGG (SEQ ID NO: 204).

[0487] A nucleic acid molecule encoding TCR1085 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3. In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV4 CDR1 comprising the amino acid sequence of SEQ ID NO: 188, TRAV4 CDR2 comprising the amino acid sequence of SEQ ID NO: 189, and TRAV4 CDR3 comprising the amino acid sequence of SEQ ID NO: 210. In one embodiment, the nucleic acid sequence encoding TRAV4 CDR1 comprises AACATTGCTACAAATGATTAT (SEQ ID NO: 199). In one embodiment, the nucleic acid sequence encoding TRAV4 CDR2 comprises GGATACAAGACAAAA (SEQ ID NO: 200). In one embodiment, the nucleic acid sequence encoding TRAV4 CDR3 comprises CTCGTGGGTGACACGGACCAGGCAGGAACTGCTCTGATC (SEQ ID NO: 216).

[0488] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising the variable domain of TRAV4 comprising the amino acid sequence of SEQ ID NO:211. In one embodiment, the nucleic acid sequence encoding the variable domain of TRAV4 comprises: ATGAGGCAAGTGGCGAGAGTGATCGTGTTCCTGACCCTGAGTACTTTGAGCCTTGCTAAGACCACCCAGCCCATCTCCATGGACTCATATGAAGGACAAGAAGTGAACATAACCTGTAGCCACAACAACATTGCTACAAATGATTATATCACGTGGTACCAACAGTTTCCCAGCCAAGGACCACGATTTATTATTCAAGGATACAAGACAAAAGTTACAAACGAAGTGGCCTCCCTGTTTATCCCTGCCGACAGAAAGTCCAGCACTCTGAGCCTGCCCCGGGTTTCCCTGAGCGACACTGCTGTGTACTACTGCCTCGTGGGTGACACGGACCAGGCAGGAACTGCTCTGATCTTTGGGAAGGGAACCACCTTATCAGTGAGTTCCA (SEQ ID NO: 217).

[0489] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO:192. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: aATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGTTGGACATGCGCAGCATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCAGGTTTTAACCTGCTGATGACCCTGCGGCTGTGGTCCAGC (SEQ ID NO: 203).

[0490] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3. In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV5-6 CDR1 comprising the amino acid sequence of SEQ ID NO: 212, TRBV5-6 CDR2 comprising the amino acid sequence of SEQ ID NO: 213, and TRBV5-6 CDR3 comprising the amino acid sequence of SEQ ID NO: 214. In one embodiment, the nucleic acid sequence encoding TRBV5-6 CDR1 comprises TCTGGGCATGACACT (SEQ ID NO: 218). In one embodiment, the nucleic acid sequence encoding TRBV5-6 CDR2 comprises TATTATGAGGAGGAAGAG (SEQ ID NO: 219). In one embodiment, the nucleic acid sequence encoding the TRBV5-6 CDR3 comprises GCCAGCAGCTTGGGCGAGGGACGTCTCTATGGCTACACC (SEQ ID NO: 220).

[0491] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising the variable domain of TRBV5-6 comprising the amino acid sequence of SEQ ID NO:215. In one embodiment, the nucleic acid sequence encoding the variable domain of TRBV5-6 comprises: ATGGGCCCCGGGCTCCTCTGCTGGGCACTGCTTTGTCTCCTGGGAGCAGGCTTAGTGGACGCTGGAGTCACCCAAAGTCCCACACACCTGATCAAAACGAGAGGACAGCAAGTGACTCTGAGATGCTCTCCTAAGTCTGGGCATGACACTGTGTCCTGGTACCAACAGGCCCTGGGTCAGGGGCCCCAGTTTATCTTTCAGTATTATGAGGAGGAAGAGAGACAGAGAGGCAACTTCCCTGATCGATTCTCAGGTCACCAGTTCCCTAACTATAGCTCTGAGCTGAATGTGAACGCCTTGTTGCTGGGGGACTCGGCCCTCTATCTCTGTGCCAGCAGCTTGGGCGAGGGACGTCTCTATGGCTACACCTTCGGTTCGGGGACCAGGTTAACCGTTGTA (SEQ ID NO: 221).

[0492] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR beta chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO: 198. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: (SEQ ID NO: 209).

[0493] In one embodiment, the nucleic acid molecule encodes a fusion protein encoding a TCR alpha chain and a TCR beta chain. In one embodiment, the isolated nucleic acid molecule encodes a fusion protein comprising a linker domain between the TCR alpha chain and the TCR beta chain. In one embodiment, the nucleic acid molecule encodes a BspEI-T2A-AvrII linker domain comprising the amino acid sequence of SEQ ID NO: 193. In one embodiment, the nucleic acid sequence encoding the BspEI-T2A-AvrII linker domain comprises: TCCGGAGGCAGCGGAGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCTAGG (SEQ ID NO: 204).

[0494] A nucleic acid molecule encoding TCR1086 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV4 CDR1, TRAV4 CDR2, and TRAV4 CDR3. In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV4 CDR1 comprising the amino acid sequence of SEQ ID NO: 188, TRAV4 CDR2 comprising the amino acid sequence of SEQ ID NO: 189, and TRAV4 CDR3 comprising the amino acid sequence of SEQ ID NO: 222. In one embodiment, the nucleic acid sequence encoding TRAV4 CDR1 comprises AACATTGCTACAAATGATTAT (SEQ ID NO: 199). In one embodiment, the nucleic acid sequence encoding TRAV4 CDR2 comprises GGATACAAGACAAAA (SEQ ID NO: 200). In one embodiment, the nucleic acid sequence encoding TRAV4 CDR3 comprises CTCGTGGGTGACATGGACCAGGCAGGAACTGCTCTGATC (SEQ ID NO: 226).

[0495] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising the variable domain of TRAV4 comprising the amino acid sequence of SEQ ID NO:223. In one embodiment, the nucleic acid sequence encoding the variable domain of TRAV4 comprises: ATGAGGCAAGTGGCGAGAGTGATCGTGTTCCTGACCCTGAGTACTTTGAGCCTTGCTAAGACCACCCAGCCCATCTCCATGGACTCATATGAAGGACAAGAAGTGAACATAACCTGTAGCCACAACAACATTGCTACAAATGATTATATCACGTGGTACCAACAGTTTCCCAGCCAAGGACCACGATTTATTATTCAAGGATACAAGACAAAAGTTACAAACGAAGTGGCCTCCCTGTTTATCCCTGCCGACAGAAAGTCCAGCACTCTGAGCCTGCCCCGGGTTTCCCTGAGCGACACTGCTGTGTACTACTGCCTCGTGGGTGACATGGACCAGGCAGGAACTGCTCTGATCTTTGGGAAGGGAACCACCTTATCAGTGAGTTCCA (SEQ ID NO: 227).

[0496] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO:192. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: aATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGTTGGACATGCGCAGCATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCAGGTTTTAACCTGCTGATGACCCTGCGGCTGTGGTCCAGC (SEQ ID NO: 203).

[0497] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3. In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV5-6 CDR1 comprising the amino acid sequence of SEQ ID NO: 212, TRBV5-6 CDR2 comprising the amino acid sequence of SEQ ID NO: 213, and TRBV5-6 CDR3 comprising the amino acid sequence of SEQ ID NO: 224. In one embodiment, the nucleic acid sequence encoding TRBV5-6 CDR1 comprises TCTGGGCATGACACT (SEQ ID NO: 218). In one embodiment, the nucleic acid sequence encoding TRBV5-6 CDR2 comprises TATTATGAGGAGGAAGAG (SEQ ID NO: 219). In one embodiment, the nucleic acid sequence encoding the TRBV5-6 CDR3 comprises GCCAGCAGCCTCGGACAGGGGATATTTAATTCACCCCTCCAC (SEQ ID NO: 228).

[0498] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising the variable domain of TRBV5-6 comprising the amino acid sequence of SEQ ID NO:225. In one embodiment, the nucleic acid sequence encoding the variable domain of TRBV5-6 comprises: ATGGGCCCCGGGCTCCTCTGCTGGGCACTGCTTTGTCTCCTGGGAGCAGGCTTAGTGGACGCTGGAGTCACCCAAAGTCCCACACACCTGATCAAAACGAGAGGACAGCAAGTGACTCTGAGATGCTCTCCTAAGTCTGGGCATGACACTGTGTCCTGGTACCAACAGGCCCTGGGTCAGGGGCCCCAGTTTATCTTTCAGTATTATGAGGAGGAAGAGAGACAGAGAGGCAACTTCCCTGATCGATTCTCAGGTCACCAGTTCCCTAACTATAGCTCTGAGCTGAATGTGAACGCCTTGTTGCTGGGGGACTCGGCCCTCTATCTCTGTGCCAGCAGCCTCGGACAGGGGATATTTAATTCACCCCTCCACTTTGGGAACGGGACCAGGCTCACTGTGACA (SEQ ID NO: 229).

[0499] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR beta chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO: 198. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: (SEQ ID NO: 209).

[0500] In one embodiment, the nucleic acid molecule encodes a fusion protein encoding a TCR alpha chain and a TCR beta chain. In one embodiment, the isolated nucleic acid molecule encodes a fusion protein comprising a linker domain between the TCR alpha chain and the TCR beta chain. In one embodiment, the nucleic acid molecule encodes a BspEI-T2A-AvrII linker domain comprising the amino acid sequence of SEQ ID NO: 193. In one embodiment, the nucleic acid sequence encoding the BspEI-T2A-AvrII linker domain comprises: TCCGGAGGCAGCGGAGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCTAGG (SEQ ID NO: 204).

[0501] A nucleic acid molecule encoding TCR1020 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1, TRAV12-1 CDR2, and TRAV12-1 CDR3. In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV12-1 CDR1 comprising the amino acid sequence of SEQ ID NO: 32, TRAV12-1 CDR2 comprising the amino acid sequence of SEQ ID NO: 32, and TRAV12-1 CDR3 comprising the amino acid sequence of SEQ ID NO: 33. In one embodiment, the nucleic acid sequence encoding TRAV12-1 CDR1 comprises AACAGTGCTCTCTCAGTCT (SEQ ID NO: 107). In one embodiment, the nucleic acid sequence encoding TRAV12-1 CDR2 comprises GTATACTCCAGTGGTAAC (SEQ ID NO: 108). In one embodiment, the nucleic acid sequence encoding the TRAV12-1 CDR3 comprises GCGGTGAACCCCCCGGACACAGGCTTTCAGAAACTTGTA (SEQ ID NO: 109).

[0502] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising the variable domain of TRAV12-1 comprising the amino acid sequence of SEQ ID NO:34. In one embodiment, the nucleic acid sequence encoding the variable domain of TRAV12-1 comprises: ATGATATCCTTGAGAGTTTTACTGGTGATCCTGTGGCTTCAGTTAAGCTGGGTTTGGAGCCAACGGAAGGAGGTGGAGCAGGATCCTGGACCCTTCAATGTTCCAGAGGGAGCCACTGTCGCTTTCAACTGTACTTACAGCAACAGTGCTTCTCAGTCTTTCTTCTGGTACAGACAGGATTGCAGGAAAGAACCTAAGTTGCTGATGTCCGTATACTCCAGTGGTAACGAAGATGGAAGGTTTACAGCACAGCTCAATAGAGCCAGCCAGTATATTTCCCTGCTCATCAGAGACTCCAAGCTCAGTGATTCAGCCACCTACCTCTGTGCGGTGAACCCCCCGGACACAGGCTTTCAGAAACTTGTATTTGGAACTGGCACCCGACTTCTGGTCAGTCCAA (SEQ ID NO: 110).

[0503] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO:35. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: ATATCCAGAACCCTGACCCTGCCGTGTACCAGCTGAGAGACTCTAAATCCAGTGACAAGTCTGTCTGCCTATTCACCGATTTTGATTCTCAAACAAATGTGTCACAAAGTAAGGATTCTGATGTGTATATCACAGACAAAACTGTGT TG GACATGC GCAGC ATGGACTTCAAGAGCAACAGTGCTGTGGCCTGGAGCAACAAATCTGACTTTGCATGTGCAAACGCCTTCAACAACAGCATTATTCCAGAAGACACCTTCTTCCCCAGCCCAGAAAGTTCCTGTGATGTCAAGCTGGTCGAGAAAAGCTTTGAAACAGATACGAACCTAAACTTTCAAAACCTGTCAGTGATTGGGTTCCGAATCCTCCTCCTGAAAGTGGCA GGTTTTAAC CTGCTG ATGACC CTGCGGCTGTGGTCCAGC (SEQ ID NO: 237).

[0504] In one embodiment, the nucleic acid molecule encodes a TCR alpha chain comprising the amino acid sequence of SEQ ID NO: 36. In one embodiment, the nucleic acid sequence encoding the TCR alpha chain comprises: (SEQ ID NO: 238).

[0505] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV28 CDR1, TRBV28 CDR2, and TRBV28 CDR3. In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising one or more of the following: TRBV28 CDR1 comprising the amino acid sequence of SEQ ID NO: 37, TRBV28 CDR2 comprising the amino acid sequence of SEQ ID NO: 38, and TRBV28 CDR3 comprising the amino acid sequence of SEQ ID NO: 39. In one embodiment, the nucleic acid sequence encoding TRBV28 CDR1 comprises ATGGACCATGAAAAT (SEQ ID NO: 113). In one embodiment, the nucleic acid sequence encoding TRBV28 CDR2 comprises TCATATGATGTTAAAATG (SEQ ID NO: 114). In one embodiment, the nucleic acid sequence encoding TRBV28 CDR3 comprises GCCAGCAGTTTATCCTTCCGGCAGGGCCTTCGCGAGCAGTAC (SEQ ID NO: 115).

[0506] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR β chain comprising the variable domain of TRBV28 comprising the amino acid sequence of SEQ ID NO:40. In one embodiment, the nucleic acid sequence encoding the variable domain of TRBV28 comprises: ATGGGAATCAGGCTCCTGTGTCGTGTGGCCTTTTGTTTCCTGGCTGTAGGCCTCGTAGATGTGAAAGTAACCCAGAGCTCGAGATATCTAGTCAAAAGGACGGGAGAGAAAGTTTTTCTGGAATGTGTCCAGGATATGGACCATGAAAATATGTTCTGGTATCGACAAGACCCAGGTCTGGGGCTACGGCTGATCTATTTCTCATATGATGTTAAAATGAAAGAAAAAGGAGATATTCCTGAGGGGTACAGTGTCTCCAGAGAGAAGAAGGAGCGCTTCTCCCTGATTCTGGAGTCCGCCAGCACCAACCAGACATCTATGTACCTCTGTGCCAGCAGTTTATCCTTCCGGCAGGGCCTTCGCGAGCAGTACTTCGGGCCGGGCACCAGGCTCACGGTCACA (SEQ ID NO: 116).

[0507] In one embodiment, the isolated nucleic acid molecule encodes a TCR comprising a TCR beta chain comprising a constant domain comprising the amino acid sequence of SEQ ID NO: 41. In one embodiment, the nucleic acid sequence encoding the constant domain comprises: (SEQ ID NO: 117).

[0508] In one embodiment, the nucleic acid molecule encodes a TCR β chain comprising the amino acid sequence of SEQ ID NO:42.In one embodiment, the nucleic acid sequence containing the TCRβ chain comprises the following: ATGGGAATCAGGCTCCTGTGTCGTGTGGCCTTTTGTTTCCTGGCTGTAGGCCTCGTAGATGTGAAAGTAACCCAGAGCTCGAGATATCTAGTCAAAAGGACGGGAGAGAAAGTTTTTCTGGAATGTGTCCAGGATATGGACCATGAAAATATGTTCTGGTATCGACAAGACCCAGGTCTGGGGCTACGGCTGATCTATTTCTCATATGATGTTAAAATGAAAGAAAAAGGAGATATTCCTGAGGGGTACAGTGTCTCCAGAGAGAAGAAGGAGCGCTTCTCCCTGATTCTGGAGTCCGCCAGCACCAACCAGACATCTATGTACCTCTGTGCCAGCAGTTTATCCTTCCGGCAGGGCCTTCGCGAGCAGTACTTCGGGCCGGGCACCAGGCTCACGGTCACAGAGGACCTGAAAAACGTGTTCCCACCCGAGGTCGCTGTGTTTGAGCCATCAGAAGCAGAGATCTCCCACACCCAAAAGGCCACACTGGTGTGCCTGGCCACAGGCTTCTACCCCGACCACGTGGAGCTGAGCTGGTGGGTGAATGGGAAGGAGGTGCACAGTGGGGTCAGCACAGACCCGCAGCCCCTCAAGGAGCAGCCCGCCCTCAATGACTCCAGATACTGCCTGAGCAGCCGCCTGAGGGTCTCGGCCACCTTCTGGCAGAACCCCCGCAACCACTTCCGCTGTCAAGTCCAGTTCTACGGGCTCTCGGAGAATGATGAGTGGACACAAGATAGGGCCAAACCTGTCACCCAGATCGTCAGCGCCGAGGCCTGGGGTAGAGCAGACTGTGGCTTCACCTCCGAGTCTTACCAGCAAGGGGTCCTGTCTGCCACCATCCTCTATGAGATCTTGCTAGGGAAGGCCACCTTGTATGCCGTGCTGGTCAGTGCCCTCGTGCTGATGGCCATGGTCAAGAGAAAGGATTCCAGAGGCTGA (SEQ ID NO: 118).

[0509] In one embodiment, the nucleic acid molecule encodes a fusion protein encoding a TCR alpha chain and a TCR beta chain. In one embodiment, the isolated nucleic acid molecule encodes a fusion protein comprising a linker domain between the TCR alpha chain and the TCR beta chain. In one embodiment, the nucleic acid molecule encodes a GSG-T2A linker domain comprising the amino acid sequence of SEQ ID NO: 43. In one embodiment, the nucleic acid sequence encoding the GSG-T2A linker domain comprises: GGCAGCGGAGAGGGCAGAGGAAGTCTTCTAACATGCGGTGACGTGGAGGAGAATCCCGGCCCT (SEQ ID NO: 119).

[0510]

[0511] A nucleic acid molecule encoding TCR1022 In embodiments, the isolated nucleic acid molecule encodes a TCR comprising a TCR alpha chain comprising one or more of the following: TRAV19 CDR1, TRAV19 CDR2, and TRAV19 CDR3. In embodiments, the isolated nucleic acid...

Claims

1. A composition comprising a T cell receptor (TCR) that specifically binds to a mutant RAS (mRAS) peptide in the context of an HLA-C*08:02 molecule.

2. The composition of claim 1 , wherein the mRAS peptide comprises a mutation at a position corresponding to G12 compared to wild-type RAS.

3. The composition of claim 2, wherein the mutation in the mRAS peptide corresponds to a G12D mutation compared to wild-type RAS.

4. 2. The composition of claim 1, wherein the TCR comprises at least one CDR selected from the group consisting of TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3.

5. 2. The composition of claim 1, wherein the TCR comprises TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3.

6. 2. The composition of claim 1, wherein the TCR comprises at least one CDR selected from the group consisting of TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3.

7. 2. The composition of claim 1, wherein the TCR comprises a TRAV4 CDR1, a TRAV4 CDR2, a TRAV4 CDR3, a TRBV5-6 CDR1, a TRBV5-6 CDR2, and a TRBV5-6 CDR3.

8. The composition of claim 1 , comprising a fusion polypeptide comprising a TCR α chain and a TCR β chain.

9. The composition of claim 8 , wherein the fusion polypeptide comprises a linker domain.

10. The composition of claim 9 , wherein the linker domain is a cleavable linker domain.

11. A composition comprising an isolated nucleic acid molecule encoding at least one composition according to any one of claims 1 to 10.

12. Cells engineered to express a T cell receptor (TCR) that specifically binds to a mutant RAS (mRAS) peptide in the context of HLA-C*08:

02.

13. The cell of claim 12 , wherein the mRAS peptide contains a mutation at the position corresponding to G12 compared to wild-type RAS.

14. The cell of claim 13 , wherein the mutation in the mRAS peptide corresponds to a G12D mutation compared to wild-type RAS.

15. The cell of claim 12 , modified to express a fusion polypeptide comprising a TCR α chain and a TCR β chain.

16. The cell of claim 12, which has been genetically modified by the introduction of an isolated nucleic acid molecule encoding a polypeptide comprising at least one of a TCR alpha chain and a TCR beta chain.

17. The cell of claim 12, which is an immune cell.

18. The cell of claim 17 , wherein the immune cell is selected from the group consisting of a T cell, an NK cell, and an NKT cell.

19. The cells of claim 12, which are autologous to a subject with a RAS-associated cancer.

20. The cells of claim 12, which are autologous to a subject having the HLA-C*08:02 type.

21. A method of treating a subject having a cancer associated with mRAS, comprising administering to said subject at least one cell according to any one of claims 12 to 20.

22. The subject is diagnosed with pancreatic cancer, pancreatic ductal adenocarcinoma (PDA), colon cancer, colorectal adenocarcinoma, myeloma, multiple myeloma, lung adenocarcinoma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia (AML), urothelial carcinoma, gastric adenocarcinoma and cervical adenocarcinoma, head and neck squamous cell carcinoma (SCC), diffuse large B-cell lymphoma (DLBCL), esophageal adenocarcinoma, chronic lymphocytic leukemia (CLL), lung SCC, small cell lung cancer (SCLC), renal papillary carcinoma (RPC), or rectal cancer.

22. The method of claim 21, wherein the patient has a cancer selected from the group consisting of: hepatocellular carcinoma (HCC), breast cancer, cervical SCC, ovarian adenocarcinoma, adrenal carcinoma, prostate cancer, neuroblastoma, glioblastoma multiforme (GBM), medulloblastoma, renal cell carcinoma (RCC), esophageal SCC, osteosarcoma, sarcoma, small intestinal neuroendocrine tumor (NET), and combinations thereof.

23. 22. The method of claim 21, comprising identifying the subject's HLA type.

24. 22. The method of claim 21, comprising isolating one or more cells of the subject and modifying said one or more cells to express said TCR.

25. 22. The method of claim 21, comprising modifying the one or more cells to express the TCR by contacting the one or more cells with an isolated nucleic acid molecule encoding one or more of a TCR alpha chain and a TCR beta chain.

26. A multispecific polypeptide comprising a first domain that specifically binds to a mutant RAS (mRAS) peptide in the context of an HLA-C*08:02 molecule, and at least one second binding domain that specifically binds to a second target epitope or antigen.

27. 27. The multispecific polypeptide of claim 26, wherein the mRAS peptide comprises a mutation at the position corresponding to G12 compared to wild-type RAS.

28. 28. The multispecific polypeptide of claim 27, wherein the mutation in the mRAS peptide corresponds to a G12D mutation compared to wild-type RAS.

29. 27. The multispecific polypeptide of claim 26, wherein the first domain comprises a T cell receptor (TCR).

30. 30. The multispecific polypeptide of claim 29, wherein the TCR comprises at least one CDR selected from the group consisting of TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3.

31. 30. The multispecific polypeptide of claim 29, wherein the TCR comprises TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV6-5 CDR1, TRBV6-5 CDR2, and TRBV6-5 CDR3.

32. 30. The multispecific polypeptide of claim 29, wherein the TCR comprises at least one CDR selected from the group consisting of TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3.

33. 30. The multispecific polypeptide of claim 29, wherein the TCR comprises TRAV4 CDR1, TRAV4 CDR2, TRAV4 CDR3, TRBV5-6 CDR1, TRBV5-6 CDR2, and TRBV5-6 CDR3.

Images