HLA class II-restricted DQ T cell receptor for RAS with G13D mutation

Abstract

Disclosed is an isolated or purified T cell receptor (TCR) having antigen specificity for a mutant human RAS amino acid sequence in which glycine at position 13 is substituted with aspartic acid. The TCR can recognize G13D RAS presented by HLA-DQ heterodimers. Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions, are also provided. Also disclosed are methods for detecting the presence of cancer in a mammal and methods for treating or preventing cancer in a mammal.

Description

[Technical Field]

[0001] Cross-reference of related applications This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 086,674, filed October 2, 2020, which is incorporated herein by reference in its entirety.

[0002] Description of federally supported research or development This invention was made with government support from the National Institutes of Health and the National Cancer Institute under project number ZIABC010984. The government reserves certain rights in this invention.

[0003] References to electronically submitted literature The computer-readable nucleotide / amino acid sequence listing submitted concurrently with this specification and identified below is incorporated herein by reference in its entirety: a 411,856-byte ASCII (text) file named "757694_ST25.txt" dated September 23, 2021. [Background technology]

[0004] Some cancers, especially when they become metastatic and unresectable, offer very limited treatment options. For example, despite advances in surgical, chemotherapy, and radiation therapy, many cancers, such as those of the pancreas, colorectal, lung, endometrium, ovarian, and prostate, may have a poor prognosis. Therefore, there is an unmet need for further cancer treatments. [Overview of the project]

[0005] Embodiments of the present invention provide an isolated or purified T cell receptor (TCR) that has antigen specificity to a mutant human RAS amino acid sequence in which glycine at position 13 is substituted with aspartic acid, wherein the mutant human RAS amino acid sequence is the amino acid sequence of mutant human Kirsten rat sarcoma virus oncogene homolog (KRAS), mutant human Harvey rat sarcoma virus oncogene homolog (HRAS), or mutant human neuroblastoma rat sarcoma virus oncogene homolog (NRAS), and the TCR is defined by the 13th position referencing the protein of wild-type human KRAS, wild-type human HRAS, or wild-type human NRAS, respectively.

[0006] Another embodiment of the present invention is an isolated or purified polypeptide comprising a functional portion of the TCR of the present invention, wherein the functional portion comprises (a) all of SEQ ID NOs: 1-3, (b) all of SEQ ID NOs: 4-6, (c) all of SEQ ID NOs: 1-6, (d) all of SEQ ID NOs: 11-13, (e) all of SEQ ID NOs: 14-16, (f) all of SEQ ID NOs: 11-16, (g) all of SEQ ID NOs: 21-23, (h) all of SEQ ID NOs: 24-26, (i) all of SEQ ID NOs: 21-26, (j) all of SEQ ID NOs: 31-33, (k) all of SEQ ID NOs: 34-36, (l) all of SEQ ID NOs: 31-36, (m) all of SEQ ID NOs: 41-43, (n) all of SEQ ID NOs: 44-46, (o) all of SEQ ID NOs: 41-46, (p) all of SEQ ID NOs: 119-121, (q) all of SEQ ID NOs: 122-124, (r) all of SEQ ID NOs: 119-124, (s) SEQ ID NOs: All of (t) 129-131, (t) all of sequence numbers 132-134, (u) all of sequence numbers 129-134, (v) all of sequence numbers 139-141, (w) all of sequence numbers 142-144, (x) all of sequence numbers 139-144, (y) all of sequence numbers 149-151, (z) all of sequence numbers 152-154, (aa) all of sequence numbers 149-154, (bb) all of sequence numbers 159-161, The present invention provides polypeptides containing all amino acid sequences of (cc) SEQ ID NOs. 162-164, (dd) SEQ ID NOs. 159-164, (ee) SEQ ID NOs. 169-171, (ff) SEQ ID NOs. 172-174, (gg) SEQ ID NOs. 169-174, (hh) SEQ ID NOs. 179-181, (ii) SEQ ID NOs. 182-184, or (jj) SEQ ID NOs. 179-184.

[0007] Further embodiments of the present invention include: (a) a first polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 1-3 and a second polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 4-6; (b) a first polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 11-13 and a second polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 14-16; (c) a first polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 21-23 and a second polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 24-26; (d) a first polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 31-33 and a second polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 34-36; or (e) a first polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 41-43 and a second polypeptide chain comprising the amino acid sequences of SEQ ID NOs: 44-46; (f) a first polypeptide chain comprising all the amino acid sequences of SEQ ID NOs: 119-121 and a second polypeptide chain comprising all the amino acid sequences of SEQ ID NOs: 122-124; (g) a first polypeptide chain comprising all the amino acid sequences of SEQ ID NOs: 129-131 (h) an isolated or purified protein comprising the polypeptide chain of (i) a first polypeptide chain and a second polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 132-134; (j) a first polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 139-141 and a second polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 142-144; (k) a first polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 149-151 and a second polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 152-154; (l) an isolated or purified protein comprising the first polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 159-161 and a second polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 162-164; (k) a first polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 169-171 and a second polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 172-174; or (l) a first polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 179-181 and a second polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 182-184.

[0008] Further embodiments of the present invention provide related nucleic acids, recombinant expression vectors, host cells, cell populations, and pharmaceutical compositions associated with the TCR, polypeptide, and protein of the present invention.

[0009] Embodiments of the present invention provide an isolated or purified nucleic acid comprising a first nucleic acid sequence and a second nucleotide sequence from 5' to 3', wherein the first and second nucleotide sequences are, respectively, sequence numbers 7 and 8; 8 and 7; 9 and 10; 10 and 9; 17 and 18; 18 and 17; 19 and 20; 20 and 19; 27 and 28; 28 and 27; 29 and 30; 30 and 29; 37 and 38; 38 and 37; 39 and 40; 40 and 39; 47 and 48; 48 and 47; 49 and 50; 50 and 49; 125 and 126; 126 and 125; 127 and 128; 128 and 127; 135 and 136; 136 and 135; 137 and 138; 138 and 137; 145 and 146; 146 and 145; 147 and 148; 148 and 147; 155 and 156; 156 and 155; 157 and 158; 158 and 157; 165 and 166; 166 and 165; 167 and 168; 168 and 167; 175 and 176; 176 and 175; 177 and 178; 178 and 177; 185 and 186; 186 and 185; 187 and 188; 188 and 187; 65 and 66; 66 and 65; 67 and 68; 68 and 67; 69 and 70; 70 and 69; 71 and 72; 72 and 71; 73 and 74; 74 and 73; 75 and 76; 76 and 75; 77 and 78; 78 and 77; 79 and 80; 80 and 79; 81 and 82; 82 and 81; 83 and 84; 84 and 83; 85 and 86; 86 and 85; 87 and 88; 88 and 87; 89 and 90; 90 and 89; 91 and 92; 92 and 91; 93 and 94; 94 and 93; 95 and 96; 96 and 95; 97 and 98; 98 and 97; 99 and 100; 100 and 99; 101 and 102; 102 and 101; 10 3 and 104; 104 and 103; 189 and 190; 190 and 189; 191 and 192; 192 and 191; 193 and 194; 194 and 193; 195 and 196; 196 and 195; 197 and 198; 198 and 197; 199 and 200; 200 and 199; 201 and 202; 202 and 201; 203 and 204; 204 and 203; 205 and 206; 206 and 205; 207 and 208; 208 and 207; 209 and 210; 210 and 209; 211 and 212; 212 and 211; 213 and 214; 214 and 213;215 and 216; 216 and 215; 217 and 218; 218 and 217; 219 and 220; 220 and 219; 221 and 222; 222 and 221; 223 and 224; 224 and 223; 225 and 226; 226 and 225; 227 and 228; 228 and 227; 229 and 230; 230 and 229; 23 The present invention provides nucleic acids encoding the amino sequences 1 and 232; 232 and 231; 233 and 234; 234 and 233; 235 and 236; 236 and 235; 237 and 238; 238 and 237; 239 and 240; 240 and 239; 241 and 242; 242 and 241; 243 and 244; or 244 and 243.

[0010] Another embodiment of the present invention is MTEYKLVVVGAG D The present invention provides a method for producing host cells that express a TCR having antigen specificity for the peptide VGKSALTIQLIQ (SEQ ID NO: 252), comprising contacting the cells with the recombinant expression vector of the present invention under conditions that enable introduction of the vector into the cells.

[0011] A further embodiment of the present invention provides a method for producing a TCR, polypeptide, or protein of the present invention, comprising culturing a host cell or population of host cells of the present invention so as to produce the TCR, polypeptide, or protein of the present invention.

[0012] Another embodiment of the present invention provides a method for detecting the presence of cancer in a mammal, comprising (a) contacting a sample containing cancer cells with a TCR, polypeptide, protein, nucleic acid, recombinant expression vector, host cell, population, or pharmaceutical composition of the present invention, thereby forming a complex, and (b) detecting the complex, wherein the detection of the complex indicates the presence of cancer in a mammal.

[0013] Another embodiment of the present invention provides a method for inducing an immune response to cancer in a mammal, comprising administering to the mammal an amount effective in inducing an immune response to cancer in the mammal, of the TCR, polypeptide, protein, nucleic acid, recombinant expression vector, host cell, population, or pharmaceutical composition of the present invention.

[0014] Another embodiment of the present invention provides a method for treating or preventing cancer in a mammal, comprising administering to the mammal an amount effective for treating or preventing cancer in the mammal the TCR, polypeptide, protein, nucleic acid, recombinant expression vector, host cell, population, or pharmaceutical composition of the present invention. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 is a graph showing IFN-γ secretion (spot / 3e4 cells) measured by the ELISPOT assay after co-culturing effector cells with target cells. Effector cells were TILs from tumor fragments of 4400 patients (numbered F1-F8, F10-F16, and F18-F22). Target cells were dendritic cells (DCs) (i) transfected with mRNA encoding full-length (FL) G13D KRAS or the corresponding FL wild-type (WT) KRAS; (ii) pulsed with G13D 25-mer peptide (G13D LP) or the corresponding WT 25-mer peptide (WT LP); or (iii) pulsed with G13D ME "mix" (containing a combination of three predicted minimal epitopes from the mutant peptide). Effector cells (i) co-culturned with DMSO-treated DCs or (ii) cultured alone (T cells only) were used as negative controls. Effector cells treated with anti-CD3 / anti-CD28 antibodies were used as a positive control. [Figure 2A-2B]Figures 2A and 2B are graphs showing the percentage of cells expressing one or both of 4-1BB and OX40, as measured by FACS with gated CD4 cells (Figure 2A) or CD8+ cells (Figure 2B) after co-culture of effector cells and target cells. The effector cells, target cells, and control are as described in Figure 1. [Figure 3] Figure 3 is a graph showing IFN-γ secretion (spot / 3e4 cells) measured by the ELISPOT assay after co-culturing effector cells with target cells. Effector cells were (i) TILs from tumor fragments F15 and F16, either untreated or treated as follows: (a) TILs from F16 were in vitro stimulated (IVS) with DCs pulsed with G13D 25-mer peptide, or (b) TILs from F15 and F16 were combined, activated (as described in Figures 1 and 2A-2B), and then sorted for CD4+ / 41BB+ / OX40+ expression and subjected to REP; or (ii) TILs from tumor fragments F21 and F22 were combined, sorted for CD4+ / 41BB+ / OX40+ or ​​CD8+ / 41BB+ / OX40+ expression and subjected to REP. Target cells and controls are as described in Figure 1. Reactive cells were sorted into single cells in 96-well plates using FACS and then sequenced to provide TCRα and TCRβ chains. [Figure 4A-4B] Figures 4A-4B are graphs showing IFN-γ secretion (spot / 3e4 cells) measured by the ELISPOT assay after co-culturing effector cells with target cells. Target cells were DCs pulsed with a specified concentration (ng / mL) of G13D 25-mer peptide or the corresponding WT 25-mer peptide. Effector cells were the reactive cells shown in Figure 3: TILs from tumor fragment F16 after G13D IVS (Figure 4A) or TILs from tumor fragments F15 and F16 after activation were sorted for CD4+ / 41BB+ / OX40+ and REP (Figure 4B). [Figure 5]Figure 5 is a graph showing luciferase expression measured by luminescence units when effector cells and target cells were co-cultured. The effector cells were Jurkat cell lines that stably express luciferase under the transcriptional control of an NFAT promoter and also stably express the CD4 coreceptor; these cells were transduced with a virus to mRNA encoding the alpha and beta strands of the TCR, which was prepared according to the sequencing described in Figure 3. The TCRs were 4400 TCR-A1 or 4400 TCR-A2, or 4400 TCR-B1 or 4400 TCR-B2 from Example 2. The target cells were (i) transfected with full-length G13D KRAS mRNA (G13D FL) or the corresponding full-length WT KRAS mRNA (WT FL); and (ii) DCs pulsed with the G13D 25-mer peptide (G13D Mut LP) or the corresponding WT 25-mer peptide (G13 WT LP) from Example 1. Transfected cells co-cultured with DMSO-treated DCs and Jurkat cells not transfected with TCR were used as negative controls. [Figure 6]Figure 6 is a graph showing IFN-γ secretion (spot / 3e4 cells) measured by the ELISPOT assay after co-culturing effector cells with target cells. The effector cells were healthy donor PBLs transduced with retroviral vectors encoding 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-E, 4400 TCR-J, or 4400 TCR-N, or 4400 TCR-B1 or 4400 TCR-B2 from Example 2. The target cells were (i) transduced with full-length G13D KRAS mRNA (G13D FL) or the corresponding full-length WT KRAS protein (WT FL); (ii) pulsed with the G13D 25-mer peptide (G13D Mut LP) or the corresponding WT 25-mer peptide (G13 WT LP) from Example 1; or (iii) pulsed with the G12D 25-mer peptide (G12D Mut LP) or the G12V 25-mer peptide (G12V Mut LP). Effector cells co-cultured with DMSO-treated DCs were used as a negative control. Effector cells treated with anti-CD3 / anti-CD28 antibody were used as a positive control. [Figures 7A-7B] Figures 7A-7B are graphs showing the percentage of cells expressing one or both of 4-1BB and OX40, as measured by FACS with gated CD8+ cells (Figure 7A) or CD4+ cells (Figure 7B) after co-culture of effector cells and target cells. The effector cells, target cells, and control are as described in Figure 6. [Figure 8]Figure 8 is a graph showing IFN-γ secretion (spots / 3e4 cells) measured by ELISPOT assay after co-culturing effector cells with target cells. HEK cells (target cells) were either untransfected (control) or transfected with the HLA heterodimers (alpha and beta) shown independently, and then pulsed with the G13D 25-mer peptide of Example 1. Effector cells were independently healthy donor PBLs transduced with a retroviral vector encoding 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-E, 4400 TCR-J, or 4400 TCR-N of Example 2. Effector cells cultured in the presence of anti-CD3 / anti-CD28 Dynabeads were used as a positive control. [Figure 9] Figure 9 is a graph showing the percentage of cells expressing either or both of 4-1BB and OX40 measured by FACS with CD4+ / mTCR+ cells gated after co-culturing effector cells with target cells. Effector cells, target cells, and controls were as described for Figure 8. [Figure 10A-10B] Figures 10A - 10B are graphs showing IFN-γ secretion (spots / 3e4 cells) measured by ELISPOT assay (Figure 10A), and the percentage of cells expressing either or both of 4-1BB and OX40 measured by FACS with CD4+ / mTCR+ cells (Figure 10B) or CD8+ / mTCR+ cells (Figure 10C) gated after co-culturing effector cells with target cells. Effector cells were healthy donor PBLs transduced with the retroviral vector of Example 2 encoding 4400 TCR-A1. Target cells were DCs pulsed with the G13D 25-mer peptide or the corresponding WT 25-mer peptide at the designated concentration (ng / mL). Effector cells cultured alone (T only) were used as a negative control. Effector cells treated with anti-CD3 / anti-CD28 antibody were used as a positive control. [Figure 10C]Figure 10C is a graph showing the IFN-γ secretion (spots / 3e4 cells) measured by ELISPOT assay (Figure 10A), and the percentage of cells expressing one or both of 4-1BB and OX40 measured by FACS gating on CD4+ / mTCR+ cells (Figure 10B) or CD8+ / mTCR+ cells (Figure 10C) after co-culture of effector cells and target cells. The effector cells were healthy donor PBLs transduced with the retroviral vector of Example 2 encoding 4400 TCR-A1. The target cells were DCs pulsed with the indicated concentration (ng / mL) of G13D 25-mer peptide or the corresponding WT 25-mer peptide. Effector cells cultured alone (T only) were used as negative controls. Effector cells treated with anti-CD3 / anti-CD28 antibodies were used as positive controls. [Figure 11A-11B] Figures 11A-11B are graphs showing the IFN-γ secretion (spots / 3e4 cells) measured by ELISPOT assay (Figure 11A), and the percentage of cells expressing one or both of 4-1BB and OX40 measured by FACS gating on CD4+ / mTCR+ cells (Figure 11B) or CD8+ / mTCR+ cells (Figure 11C) after co-culture of effector cells and target cells. The effector cells were healthy donor PBLs transduced with the retroviral vector of Example 2 encoding 4400 TCR-A2. The target cells and controls were as described for Figures 10A-10C. [Figure 11C] Figure 11C is a graph showing the IFN-γ secretion (spots / 3e4 cells) measured by ELISPOT assay (Figure 11A), and the percentage of cells expressing one or both of 4-1BB and OX40 measured by FACS gating on CD4+ / mTCR+ cells (Figure 11B) or CD8+ / mTCR+ cells (Figure 11C) after co-culture of effector cells and target cells. The effector cells were healthy donor PBLs transduced with the retroviral vector of Example 2 encoding 4400 TCR-A2. The target cells and controls were as described for Figures 10A-10C. [Figures 12A-12B] Figures 12A-12B are graphs showing IFN-γ secretion (spot / 3e4 cells) measured by the ELISPOT assay (Figure 12A), and the percentage of cells expressing one or both of 4-1BB and OX40, measured by FACS after co-culture of effector cells and target cells, with CD4+ / mTCR+ cells (Figure 12B) or CD8+ / mTCR+ cells (Figure 12C) being gated. The effector cells were healthy donor PBLs transduced with the retroviral vector of Example 2 encoding 4400 TCR-E. The target cells and controls are as described in Figures 10A-10C. [Figure 12C] Figure 12C is a graph showing the percentage of cells expressing one or both of 4-1BB and OX40, measured by FACS after co-culture of effector cells and target cells, using ELISPOT assay (spot / 3e4 cells) (Figure 12A), and by gated FACS of CD4+ / mTCR+ cells (Figure 12B) or CD8+ / mTCR+ cells (Figure 12C). The effector cells were healthy donor PBLs transduced with the retroviral vector of Example 2 encoding 4400 TCR-E. The target cells and controls are as described in Figures 10A-10C. [Figures 13A-13B] Figures 13A-13B are graphs showing the percentage of cells expressing one or both of 4-1BB and OX40, measured by FACS after co-culture of effector cells and target cells, using ELISPOT assay (spot / 3e4 cells) (Figure 13A), and by gated FACS of CD4+ / mTCR+ cells (Figure 13B) or CD8+ / mTCR+ cells (Figure 13C). The effector cells were healthy donor PBLs transduced with the retroviral vector of Example 2 encoding 4400 TCR-J. The target cells and controls are as described in Figures 10A-10C. [Figure 13C]Figure 13C is a graph showing the percentage of cells expressing one or both of 4-1BB and OX40, measured by FACS after co-culture of effector cells and target cells, using ELISPOT assay (spot / 3e4 cells) (Figure 13A), and by gated FACS of CD4+ / mTCR+ cells (Figure 13B) or CD8+ / mTCR+ cells (Figure 13C). The effector cells were healthy donor PBLs transduced with the retroviral vector of Example 2 encoding 4400 TCR-J. The target cells and controls are as described in Figures 10A-10C. [Figures 14A-14B] Figures 14A-14B are graphs showing the percentage of cells expressing one or both of 4-1BB and OX40, measured by FACS after co-culture of effector cells and target cells, using ELISPOT assay (spot / 3e4 cells) (Figure 14A), and by gated FACS of CD4+ / mTCR+ cells (Figure 14B) or CD8+ / mTCR+ cells (Figure 14C). The effector cells were healthy donor PBLs transduced with the retroviral vector of Example 2 encoding 4400 TCR-N. The target cells and controls are as described in Figures 10A-10C. [Figure 14C] Figure 14C is a graph showing the percentage of cells expressing one or both of 4-1BB and OX40, measured by FACS after co-culture of effector cells and target cells, using IFN-γ secretion (spot / 3e4 cells) as measured by the ELISPOT assay (Figure 14A), and FACS after gating CD4+ / mTCR+ cells (Figure 14B) or CD8+ / mTCR+ cells (Figure 14C). The effector cells were healthy donor PBLs transduced with the retroviral vector of Example 2 encoding 4400 TCR-N. The target cells and controls are as described in Figures 10A-10C. [Figure 15]Figure 15 is a graph showing the luminescence ratio obtained when effector cells and target cells were co-cultured. The effector cells were Jurkat cell lines that stably expressed luciferase under the transcriptional control of the NFAT promoter and also stably expressed the CD4 coreceptor; these cells were transduced with one of the following TCRs via virus: 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-A3, 4400 TCR-J, 4400 TCR-J2, 4400 TCR-E, 4400 TCR-N, 4400 TCR-N4, 4400 TCR-N12, or 4400 TCR-N13. Target cells were (i) transfected with full-length G13D KRAS mRNA or the corresponding full-length WT KRAS mRNA; or (ii) DCs pulsed with the G13D 25-mer peptide of Example 1 or the corresponding WT 25-mer peptide. Pseudotransduction was used as a negative control. The luminescence ratio was the ratio of the luminescence value obtained with the G13D full-length gene (FL) to the luminescence value obtained with WT FL, or the ratio of the luminescence value obtained with the G13D long peptide (LP) to the luminescence value obtained with G13 WT LP. [Figure 16] Figure 16 is a graph showing the luminescence ratio obtained after co-culturing effector cells and target cells. COS7 cells (target cells) were independently transfected with either the HLA heterodimer (alpha and beta) or HLA DRA1 shown in Figure 16, and then pulsed with the G13D 25-mer peptide from Example 1. The effector cells were the same as those described in Figure 15. Untransduced Jurkat cells co-culturned with the same target cells were used as a negative control. The luminescence ratio is the ratio of the experimentally obtained luminescence readout value to the average luminescence readout value obtained in the control. [Figures 17A-17B]Figures 17A-17B are graphs showing the luminescence ratio obtained after co-culturing effector cells and target cells. The effector cells were Jurkat-NFAT-firefly luciferase CD4+ / CD8+ cell lines independently transduced with one of the following TCRs via virus: 4400 TCR-A1(17A), 4400 TCR-A2(17B), 4400 TCR-A3(17C), 4400 TCR-J(17D), 4400 TCR-J2(17E), 4400 TCR-E(17F), 4400 TCR-N(17G), 4400 TCR-N4(17H), 4400 TCR-N12(17I), or 4400 TCR-N13(17J). The target cells were DCs loaded with one of the G13D 25-mer peptides (triangle) or the corresponding WT 25-mer peptide (circle) at the concentrations (ng / mL) shown in the diagram. The luminescence ratio is the ratio of the luminescence readout obtained in the experiment to the luminescence readout obtained in the same cells co-cultured with DCs loaded with DMSO alone. [Figures 17C-17D] Figures 17C-17D are graphs showing the luminescence ratio obtained after co-culturing effector cells and target cells. The effector cells were Jurkat-NFAT-firefly luciferase CD4+ / CD8+ cell lines independently transduced with one of the following TCRs via virus: 4400 TCR-A1(17A), 4400 TCR-A2(17B), 4400 TCR-A3(17C), 4400 TCR-J(17D), 4400 TCR-J2(17E), 4400 TCR-E(17F), 4400 TCR-N(17G), 4400 TCR-N4(17H), 4400 TCR-N12(17I), or 4400 TCR-N13(17J). The target cells were DCs loaded with one of the G13D 25-mer peptides (triangle) or the corresponding WT 25-mer peptide (circle) at the concentrations (ng / mL) shown in the diagram. The luminescence ratio is the ratio of the luminescence readout obtained in the experiment to the luminescence readout obtained in the same cells co-cultured with DCs loaded with DMSO alone. [Figures 17E-17F]Figures 17E-17F are graphs showing the luminescence ratio obtained after co-culturing effector cells and target cells. The effector cells were Jurkat-NFAT-firefly luciferase CD4+ / CD8+ cell lines independently transduced with one of the following TCRs via virus: 4400 TCR-A1(17A), 4400 TCR-A2(17B), 4400 TCR-A3(17C), 4400 TCR-J(17D), 4400 TCR-J2(17E), 4400 TCR-E(17F), 4400 TCR-N(17G), 4400 TCR-N4(17H), 4400 TCR-N12(17I), or 4400 TCR-N13(17J). The target cells were DCs loaded with one of the G13D 25-mer peptides (triangle) or the corresponding WT 25-mer peptide (circle) at the concentrations (ng / mL) shown in the diagram. The luminescence ratio is the ratio of the luminescence readout obtained in the experiment to the luminescence readout obtained in the same cells co-cultured with DCs loaded with DMSO alone. [Figure 17G-17H] Figures 17G-17H are graphs showing the luminescence ratio obtained after co-culturing effector cells and target cells. The effector cells were Jurkat-NFAT-firefly luciferase CD4+ / CD8+ cell lines independently transduced with one of the following TCRs via virus: 4400 TCR-A1(17A), 4400 TCR-A2(17B), 4400 TCR-A3(17C), 4400 TCR-J(17D), 4400 TCR-J2(17E), 4400 TCR-E(17F), 4400 TCR-N(17G), 4400 TCR-N4(17H), 4400 TCR-N12(17I), or 4400 TCR-N13(17J). The target cells were DCs loaded with one of the G13D 25-mer peptides (triangle) or the corresponding WT 25-mer peptide (circle) at the concentrations (ng / mL) shown in the diagram. The luminescence ratio is the ratio of the luminescence readout obtained in the experiment to the luminescence readout obtained in the same cells co-cultured with DCs loaded with DMSO alone. [Figure 17I-17J]Figures 17I-17J are graphs showing the luminescence ratios obtained after co-culturing effector cells and target cells. The effector cells were Jurkat-NFAT-firefly luciferase CD4+ / CD8+ cell lines independently transduced with one of the following TCRs via virus: 4400 TCR-A1(17A), 4400 TCR-A2(17B), 4400 TCR-A3(17C), 4400 TCR-J(17D), 4400 TCR-J2(17E), 4400 TCR-E(17F), 4400 TCR-N(17G), 4400 TCR-N4(17H), 4400 TCR-N12(17I), or 4400 TCR-N13(17J). The target cells were DCs loaded with one of the G13D 25-mer peptides (triangle) or the corresponding WT 25-mer peptide (circle) at the concentrations (ng / mL) shown in the diagram. The luminescence ratio is the ratio of the luminescence readout obtained in the experiment to the luminescence readout obtained in the same cells co-cultured with DCs loaded with DMSO alone. [Figure 17K] Figure 17K is a graph showing the emission ratios obtained after the same experiments as those performed for Figures 17A-17J, except that the Jurkat-NFAT firefly luciferase cell line was transduced with a control plasmid (a backbone plasmid that does not contain the gene encoding the TCR) using a virus. Effector cells treated with PMA were used as an additional control (star). The emission ratios are as defined for Figures 17A-17J. [Figure 18]Figure 18 is a graph showing the luminescence ratio obtained after co-culturing effector cells and target cells. COS7 cells (target cells) were transfected with HLA-DQA1*05:01 and HLA-DQB1*03:01 heterodimers, and then pulsed with the G13D 25-mer peptide from Example 1. Effector cells were independently Jurkat-NFAT-firefly luciferase CD4+ / CD8+ cell lines transduced with either 4400 TCR-C or 4400 TCR-20 via viral transfection. As a negative control, effector cells were co-culturified with untransfected COS7 cells loaded with the G13D 25-mer peptide. The luminescence ratio is the ratio of the experimental luminescence readout value to the luminescence readout value of the corresponding control. [Figures 19A-19B] Figures 19A–19B are graphs showing the percentage of CD8+ cells (Figures 19B and 19D) or CD4+ cells (Figures 19A and 19C) expressing one or both of 4-1BB and OX40, as measured by gated FACS, after co-culture of effector cells and target cells. Effector cells were PBLs independently transduced with 4400 TCR-C (Figures 19A–19B) or 4400 TCR-20 (Figures 19C–19D). Target cells were DCs pre-loaded with one of the various concentrations of G13D 25-mer peptide (G13D) or the corresponding WT 25-mer peptide (WT) shown. [Figures 19C-19D] Figures 19C–19D are graphs showing the percentage of cells expressing one or both of 4-1BB and OX40, as measured by gated FACS, in CD8+ cells (Figures 19B and 19D) or CD4+ cells (Figures 19A and 19C) after co-culture of effector cells and target cells. Effector cells were PBLs independently transduced with 4400 TCR-C (Figures 19A–19B) or 4400 TCR-20 (Figures 19C–19D). Target cells were DCs pre-loaded with one of the various concentrations of G13D 25-mer peptide (G13D) or the corresponding WT 25-mer peptide (WT) shown. [Modes for carrying out the invention]

[0016] The RAS family of proteins belongs to a large family of small GTPases. Although not bound by any specific theory or mechanism, when mutated, RAS proteins are thought to be involved in signal transduction in the early stages of carcinogenesis in many human cancers. A single amino acid substitution can activate the protein. Mutant RAS protein products can be constitutively activated. Mutant RAS proteins can be expressed in any of the following human cancers, for example, pancreatic cancer (e.g., pancreatic cancer), colorectal cancer, lung cancer (e.g., lung adenocarcinoma), endometrial cancer, ovarian cancer (e.g., epithelial ovarian cancer), and prostate cancer. Examples of human RAS family proteins include KRAS, HRAS, and NRAS.

[0017] KRAS is also known as GTPase KRAS, V-Ki-RAS2 Kirsten rat sarcoma virus oncogene, or KRAS2. KRAS has two transcript variants: KRAS variant A and KRAS variant B. Wild-type (WT) KRAS variant A has the amino acid sequence of SEQ ID NO: 51. WT KRAS variant B has the amino acid sequence of SEQ ID NO: 52. Hereafter, "KRAS" (mutant or non-mutant (WT)) refers to both variant A and variant B unless otherwise specified. When activated, mutant KRAS binds to guanosine-5'-triphosphate (GTP) and converts GTP to guanosine-5'-diphosphate (GDP).

[0018] HRAS is another member of the RAS protein family. HRAS is also known as Harvey rat sarcoma virus oncoprotein, V-Ha-RAS Harvey rat sarcoma virus oncogene homolog, or RAS family small GTP-binding protein H-RAS. WT HRAS has the amino acid sequence of SEQ ID NO: 53.

[0019] NRAS is yet another member of the RAS protein family. NRAS is also known as GTPase NRAS, V-RAS neuroblastoma RAS virus oncogene homolog, or NRAS1. WT NRAS has the amino acid sequence of SEQ ID NO: 54.

[0020] Embodiments of the present invention provide isolated or purified TCRs that have antigen specificity to the amino acid sequence of a mutant human RAS in which glycine at position 13 is substituted with aspartic acid, wherein the amino acid sequence of the mutant human RAS is the amino acid sequence of a mutant human KRAS, a mutant human HRAS, or a mutant human NRAS, and the TCR is defined by the 13th position referring to the protein of WT human KRAS, WT human HRAS, or WT human NRAS, respectively. Hereafter, references to "TCR" also refer to the functional portion and functional variants of the TCR unless otherwise specified.

[0021] The mutant human RAS amino acid sequence may be the mutant human KRAS amino acid sequence, the mutant human HRAS amino acid sequence, or the mutant human NRAS amino acid sequence. The amino acid sequences of the KRAS, NRAS, and HRAS proteins in wild-type (WT) humans have a length of 188 or 189 amino acid residues, respectively, and exhibit a high degree of identity with respect to each other. For example, the amino acid sequence of the WT human NRAS protein is 86.8% identical to that of the WT human KRAS protein. Amino acid residues 1-86 of the WT human NRAS protein and the WT human KRAS protein are 100% identical. The amino acid sequence of the WT human HRAS protein is 86.3% identical to that of the WT human KRAS protein. Amino acid residues 1-94 of the WT human HRAS protein and the WT human KRAS protein are 100% identical. Hereafter, unless otherwise specified, "RAS" (mutant or non-mutant (WT)) refers collectively to KRAS, HRAS, and NRAS.

[0022] In embodiments of the present invention, the mutant human RAS amino acid sequence includes a human RAS amino acid sequence in which glycine at position 13 is replaced with aspartic acid, and position 13 is defined by reference to the corresponding WT RAS protein. The WT RAS protein may be any one of the WT KRAS protein (SEQ ID NO: 51 or 52), WT HRAS protein (SEQ ID NO: 53), or WT NRAS protein (SEQ ID NO: 54), for the reason that, as explained above, amino acid residues 1-86 of the WT human NRAS protein and the WT human KRAS protein are 100% identical, and amino acid residues 1-94 of the WT human HRAS protein and the WT human KRAS protein are also 100% identical. Therefore, the amino acid residue at position 13 of the WT KRAS, WT HRAS, and WT NRAS proteins is the same, i.e., glycine.

[0023] The mutant human RAS amino acid sequence has a substitution of glycine at position 13 with aspartic acid. In this regard, embodiments of the present invention provide a TCR having antigen specificity for the amino acid sequence of any human RAS protein, polypeptide, or peptide having the G13D mutation.

[0024] Mutations and substitutions of the RAS are defined herein by reference to the amino acid sequence of the corresponding WT RAS protein. Accordingly, mutations and substitutions of the RAS are described herein by reference to the amino acid residue located at a specific position in the WT RAS protein (i.e., position 13), followed by the position number, followed by the amino acid residue that replaces that residue in the particular mutation or substitution under consideration. A RAS amino acid sequence (e.g., a RAS peptide) may contain fewer amino acid residues than the total amino acid residues of a full-length WT RAS protein. Accordingly, with the understanding that the actual position of the corresponding residue may differ in a particular example of a RAS amino acid sequence, position 13 is defined herein by reference to a WT full-length RAS protein (i.e., any one of sequence numbers 51-54). If the position is as defined by any one of sequence numbers 51-54, the term "G13" refers to the usual presence of glycine at position 13 in any one of sequence numbers 51-54, and "G13D" refers to the replacement of the glycine normally present at position 13 in any one of sequence numbers 51-54 with aspartic acid. For example, a specific example of the RAS amino acid sequence is, for example, TEYKLVVVGAG G In the case of VGKSALTIQLI (SEQ ID NO: 113) (an exemplary WT KRAS peptide corresponding to consecutive amino acid residues 2-24 of SEQ ID NO: 51), "G13D" refers to the substitution of the underlined glycine in SEQ ID NO: 113 with aspartic acid, even if the actual position of the underlined glycine in SEQ ID NO: 113 is 12. Hereinafter, human RAS amino acid sequences with the G13D mutation will be referred to as "G13D RAS".

[0025] Examples of full-length RAS proteins containing the G13D mutation are listed in Table 1 below.

[0026] [Table 1]

[0027] In embodiments of the present invention, the TCR has antigen specificity for the RAS peptide having the G13D mutation, and the G13D RAS peptide has any length. In embodiments of the present invention, the G13D RAS peptide has any length suitable for binding to any of the HLA class II molecules described herein. For example, the TCR may have antigen specificity for a RAS peptide having the G13D mutation, having a length of about 11 to about 30 amino acid residues, about 12 to about 24 amino acid residues, or about 18 to about 20 amino acid residues. The G13D RAS peptide may contain any sequence of amino acid residues of a mutant RAS protein containing the G13D mutation. In embodiments of the present invention, the TCR is a RAS peptide having the G13D mutation and may exhibit antigen specificity to mutant RAS peptides having lengths in the ranges of approximately 30 amino acid residues, approximately 29 amino acid residues, approximately 28 amino acid residues, approximately 27 amino acid residues, approximately 26 amino acid residues, approximately 25 amino acid residues, approximately 24 amino acid residues, approximately 23 amino acid residues, approximately 22 amino acid residues, approximately 21 amino acid residues, approximately 20 amino acid residues, approximately 19 amino acid residues, approximately 18 amino acid residues, approximately 17 amino acid residues, approximately 16 amino acid residues, approximately 15 amino acid residues, approximately 14 amino acid residues, approximately 13 amino acid residues, approximately 12 amino acid residues, approximately 11 amino acid residues, or any two of the above values. An example of a specific peptide having the G13D mutation that can be recognized by the TCR of the present invention is MTEYKLVVVGAG D GVGKSALTIQLI (SEQ ID NO: 106) is another example of a specific peptide having the G13D mutation that can be recognized by the TCR of the present invention. MTEYKLVVVGAG D This is VGKSALTIQLIQ (SEQ ID NO: 252). In embodiments of the present invention, the TCR has antigen specificity for the mutant human RAS amino acid sequence of SEQ ID NO: 106. In another embodiment of the present invention, the TCR has antigen specificity for the mutant human RAS amino acid sequence of SEQ ID NO: 252. In embodiments of the present invention, the TCR is MTEYKLVVVGAG G VGKSALTIQLI (SEQ ID NO: 107) does not have antigen specificity for the wild-type human RAS amino acid sequence. In another embodiment of the present invention, the TCR is MTEYKLVVVGAG GVGKSALTIQLIQ (SEQ ID NO: 253) does not exhibit antigen specificity for the wild-type human RAS amino acid sequence.

[0028] In embodiments of the present invention, the TCR of the present invention can recognize G13D RAS presented by HLA class II molecules. In this regard, the TCR can elicit an immune response when it binds to G13D RAS within the framework of an HLA class II molecule. The TCR of the present invention can recognize G13D RAS presented by an HLA class II molecule and can bind to HLA class II molecules in addition to G13D RAS.

[0029] In embodiments of the present invention, the HLA class II molecule is an HLA-DQ heterodimer. The HLA-DQ heterodimer is a cell surface receptor comprising an α chain and a β chain. The α chain of HLA-DQ is encoded by the HLA-DQA1 gene. Examples of HLA-DQA1 alleles include DQA1*01:01, DQA1*01:02, DQA1*01:03, DQA1*01:04, DQA1*02:01, DQA1*03:01, DQA1*03:02, DQA1*03:03, DQA1*04:01, DQA1*05:01, DQA1*05:05, and DQA1*06:01. The β chain of HLA-DQ is encoded by the HLA-DQB1 gene. HLA-DQB1 alleles include HLA-DQB1*02:01, HLA-DQB1*02:02, HLA-DQB1*02:03, HLA-DQB1*03:01, HLA- DQB1*03:02, HLA-DQB1*03:03, HLA-DQB1*03:04, HLA-DQB1*03:05, HLA-DQB1*04:01, HLA-DQB1*04: Examples include HLA-DQB1*05:01, HLA-DQB1*05:02, HLA-DQB1*05:03, HLA-DQB1*05:04, HLA-DQB1*06:01, HLA-DQB1*06:02, HLA-DQB1*06:03, HLA-DQB1*06:04, HLA-DQB1*06:05, and HLA-DQB1*06:09. In embodiments of the present invention, the HLA class II molecule is an HLA-DQA1:HLA-DQB1 heterodimer. In a particularly preferred embodiment, the HLA class II molecule is expressed by the HLA-DQA1*05:01:HLA-DQB1*03:01 allele (i.e., the HLA-DQA1*05:01:HLA-DQB1*03:01 heterodimer).

[0030] The TCR of the present invention may offer one or more of a variety of advantages, including when expressed by cells used for adoptive cell transfer. G13D RAS is expressed in cancer cells but not in normal non-cancerous cells. Although not bound by any particular theory or mechanism, the TCR of the present invention is advantageously thought to target the destruction of cancer cells while minimizing or eliminating the destruction of normal non-cancerous cells, for example, by minimizing or eliminating toxicity, thereby reducing the overall impact. Furthermore, since G13D mutations are likely to occur in the early stages of tumorigenesis, G13D RAS mutations may be expressed in substantially all cancer cells of a patient. The TCR of the present invention is advantageously capable of successfully treating or preventing G13D RAS-positive cancers that do not respond to other types of treatment, such as chemotherapy, surgery, or radiation therapy. Furthermore, the TCR of the present invention can provide highly avid recognition with high binding activity of G13D RAS, which may provide the ability to recognize unmanipulated tumor cells (e.g., tumor cells not treated with interferon (IFN)-γ, not transfected with a vector encoding either or both of the G13D RAS and the HLA-DR heterodimer described herein, not pulsed with the G13D RAS peptide, or a combination thereof). KRAS mutations are found in approximately 30% of all cancer patients. G13D RAS mutations are found in approximately 13% of cancer patients with KRAS mutations. In addition, the HLA-DQA1*05:01:HLA-DQB1*03:01 allele combination is expressed in approximately 35% of people of Caucasian ethnicity in the United States and is also commonly expressed in people of other ethnicities. Therefore, the TCR of the present invention can increase the number of immunotherapy-eligible cancer patients to include those expressing the HLA-DQA1*05:01:HLA-DQB1*03:01 allele combination, which may not be eligible for immunotherapy using a TCR that recognizes RAS presented by other MHC molecules.Furthermore, the TCRs, polypeptides, and proteins of the present invention include the amino acid sequences of the human CDR and variable region, thereby reducing the risk of rejection by the human immune system compared to, for example, TCRs, polypeptides, and proteins that include the amino acid sequences of the mouse CDR and variable region.

[0031] The term "antigen specificity," as used herein, means that the TCR specifically binds to G13D RAS with high binding activity and is immunologically recognizable. For example, when the TCR is co-cultured with (a) antigen-negative HLA class II molecule-positive target cells pulsed with a low concentration of G13D RAS peptide (e.g., approximately 0.05 ng / mL to approximately 10 ng / mL, 1 ng / mL, 2 ng / mL, 5 ng / mL, 8 ng / mL, 10 ng / mL, or any two of the above values), or (b) antigen-negative HLA class II molecule-positive target cells into which a nucleotide sequence encoding G13D RAS has been introduced so that the target cells express G13D RAS, approximately 1 × 10⁻¹⁶ cells express the TCR. 4 ~Approx. 1×10 5 If a T cell secretes at least approximately 200 pg / mL or more of IFN-γ (for example, 200 pg / mL or more, 300 pg / mL or more, 400 pg / mL or more, 500 pg / mL or more, 600 pg / mL or more, 700 pg / mL or more, 1000 pg / mL or more, 5,000 pg / mL or more, 7,000 pg / mL or more, 10,000 pg / mL or more, 20,000 pg / mL or more, or within a range defined by any two of the above values), it may be considered to have "antigen specificity" for G13D RAS. Cells expressing the TCR of the present invention can also secrete IFN-γ when co-cultured with antigen-negative HLA class II molecule-positive target cells pulsed with a higher concentration of G13D RAS peptide. The HLA class II molecule may be any of the HLA class II molecules described herein.

[0032] Alternatively, a TCR may be considered to have "antigen specificity" for G13D RAS if, when co-cultured with (a) antigen-negative HLA class II molecule-positive target cells pulsed with a low concentration of G13D RAS peptide or (b) antigen-negative HLA class II molecule-positive target cells into which a nucleotide sequence encoding G13D RAS has been introduced so that the target cells express G13D RAS, the T cells expressing the TCR secrete at least twice (e.g., five times) more IFN-γ compared to the amount of IFN-γ expressed by the negative control. The negative control may be, for example, (i)(a) antigen-negative HLA class II molecule-positive target cells pulsed with the same concentration of an unrelated peptide (e.g., several other peptides having a different sequence from the G13D RAS peptide), or (b) T cells expressing the TCR co-cultured with antigen-negative HLA class II molecule-positive target cells into which a nucleotide sequence encoding the unrelated peptide has been introduced so that the target cells express the unrelated peptide, or (ii)(a) antigen-negative HLA class II molecule-positive target cells pulsed with the same concentration of G13D RAS peptide, or (b) untransduced TCR cells (e.g., derived from PBMCs that do not express the TCR) co-cultured with antigen-negative HLA class II molecule-positive target cells into which a nucleotide sequence encoding G13D RAS has been introduced so that the target cells express G13D RAS. The HLA class II molecule expressed by the target cells of the negative control is the same HLA class II molecule expressed by the target cells co-cultured with the T cells under test. The HLA class II molecule may be any of the HLA class II molecules described herein. IFN-γ secretion can be measured by methods known in the art, such as enzyme-linked immunosorbent assay (ELISA).

[0033] Alternatively, a TCR may be considered to have "antigen specificity" for G13D RAS if, when co-cultured with (a) antigen-negative HLA class II molecule-positive target cells pulsed with a low concentration of G13D RAS peptide or (b) antigen-negative HLA class II molecule-positive target cells into which a nucleotide sequence encoding G13D RAS has been introduced so that the target cells express G13D RAS, at least twice (e.g., five times) more T cells expressing the TCR secrete IFN-γ compared to the number of negative control T cells secreting IFN-γ. The concentrations of HLA class II molecules, peptides, and negative controls may be as described herein in relation to other aspects of the present invention. The number of IFN-γ-secreting cells can be measured by methods known in the art, for example, by ELISPOT.

[0034] Alternatively, a TCR may be considered to have "antigen specificity" for G13D RAS if, after stimulation with target cells expressing G13D RAS, the T cells expressing the TCR upregulate the expression of one or more T cell activation markers, for example by flow cytometry. Examples of T cell activation markers include 4-1BB, OX40, CD107a, CD69, and cytokines that are upregulated upon antigen stimulation (e.g., tumor necrosis factor (TNF), interleukin (IL)-2, etc.).

[0035] Embodiments of the present invention provide a TCR comprising two polypeptides (i.e., polypeptide chains), such as an alpha (α) chain of TCR, a beta (β) chain of TCR, a gamma (γ) chain of TCR, a delta (δ) chain of TCR, or a combination thereof. The TCR polypeptide of the present invention may contain any amino acid sequence, as long as the TCR has antigen specificity for G13D RAS. In some embodiments, the TCR does not exist in nature.

[0036] In embodiments of the present invention, the TCR comprises two polypeptide chains, each containing a variable region comprising complementarity-determining regions (CDRs) 1, 2, and 3 of the TCR. In embodiments of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-A1) containing the amino acid sequence of SEQ ID NO: 1, CDR2 (CDR2 of the α-chain of 4400 TCR-A1) containing the amino acid sequence of SEQ ID NO: 2, and CDR3 (CDR3 of the α-chain of 4400 TCR-A1) containing the amino acid sequence of SEQ ID NO: 3, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-A1) containing the amino acid sequence of SEQ ID NO: 4, CDR2 (CDR2 of the β-chain of 4400 TCR-A1) containing the amino acid sequence of SEQ ID NO: 5, and CDR3 (CDR3 of the β-chain of 4400 TCR-A1) containing the amino acid sequence of SEQ ID NO: 6.

[0037] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-A2) containing the amino acid sequence of SEQ ID NO: 11, CDR2 (CDR2 of the α-chain of 4400 TCR-A2) containing the amino acid sequence of SEQ ID NO: 12, and CDR3 (CDR3 of the α-chain of 4400 TCR-A2) containing the amino acid sequence of SEQ ID NO: 13, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-A2) containing the amino acid sequence of SEQ ID NO: 14, CDR2 (CDR2 of the β-chain of 4400 TCR-A2) containing the amino acid sequence of SEQ ID NO: 15, and CDR3 (CDR3 of the β-chain of 4400 TCR-A2) containing the amino acid sequence of SEQ ID NO: 16.

[0038] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-E) containing the amino acid sequence of SEQ ID NO: 21, CDR2 (CDR2 of the α-chain of 4400 TCR-E) containing the amino acid sequence of SEQ ID NO: 22, and CDR3 (CDR3 of the α-chain of 4400 TCR-E) containing the amino acid sequence of SEQ ID NO: 23, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-E) containing the amino acid sequence of SEQ ID NO: 24, CDR2 (CDR2 of the β-chain of 4400 TCR-E) containing the amino acid sequence of SEQ ID NO: 25, and CDR3 (CDR3 of the β-chain of 4400 TCR-E) containing the amino acid sequence of SEQ ID NO: 26.

[0039] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-J) containing the amino acid sequence of SEQ ID NO: 31, CDR2 (CDR2 of the α-chain of 4400 TCR-J) containing the amino acid sequence of SEQ ID NO: 32, and CDR3 (CDR3 of the α-chain of 4400 TCR-J) containing the amino acid sequence of SEQ ID NO: 33, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-J) containing the amino acid sequence of SEQ ID NO: 34, CDR2 (CDR2 of the β-chain of 4400 TCR-J) containing the amino acid sequence of SEQ ID NO: 35, and CDR3 (CDR3 of the β-chain of 4400 TCR-J) containing the amino acid sequence of SEQ ID NO: 36.

[0040] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-N) containing the amino acid sequence of SEQ ID NO: 41, CDR2 (CDR2 of the α-chain of 4400 TCR-N) containing the amino acid sequence of SEQ ID NO: 42, and CDR3 (CDR3 of the α-chain of 4400 TCR-N) containing the amino acid sequence of SEQ ID NO: 43, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-N) containing the amino acid sequence of SEQ ID NO: 44, CDR2 (CDR2 of the β-chain of 4400 TCR-N) containing the amino acid sequence of SEQ ID NO: 45, and CDR3 (CDR3 of the β-chain of 4400 TCR-N) containing the amino acid sequence of SEQ ID NO: 46.

[0041] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-A3) containing the amino acid sequence of SEQ ID NO: 119, CDR2 (CDR2 of the α-chain of 4400 TCR-A3) containing the amino acid sequence of SEQ ID NO: 120, and CDR3 (CDR3 of the α-chain of 4400 TCR-A3) containing the amino acid sequence of SEQ ID NO: 121, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-A3) containing the amino acid sequence of SEQ ID NO: 122, CDR2 (CDR2 of the β-chain of 4400 TCR-A3) containing the amino acid sequence of SEQ ID NO: 123, and CDR3 (CDR3 of the β-chain of 4400 TCR-A3) containing the amino acid sequence of SEQ ID NO: 124.

[0042] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-J2) containing the amino acid sequence of SEQ ID NO: 129, CDR2 (CDR2 of the α-chain of 4400 TCR-J2) containing the amino acid sequence of SEQ ID NO: 130, and CDR3 (CDR3 of the α-chain of 4400 TCR-J2) containing the amino acid sequence of SEQ ID NO: 131, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-J2) containing the amino acid sequence of SEQ ID NO: 132, CDR2 (CDR2 of the β-chain of 4400 TCR-J2) containing the amino acid sequence of SEQ ID NO: 133, and CDR3 (CDR3 of the β-chain of 4400 TCR-J2) containing the amino acid sequence of SEQ ID NO: 134.

[0043] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-N4) containing the amino acid sequence of SEQ ID NO: 139, CDR2 (CDR2 of the α-chain of 4400 TCR-N4) containing the amino acid sequence of SEQ ID NO: 140, and CDR3 (CDR3 of the α-chain of 4400 TCR-N4) containing the amino acid sequence of SEQ ID NO: 141, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-N4) containing the amino acid sequence of SEQ ID NO: 142, CDR2 (CDR2 of the β-chain of 4400 TCR-N4) containing the amino acid sequence of SEQ ID NO: 143, and CDR3 (CDR3 of the β-chain of 4400 TCR-N4) containing the amino acid sequence of SEQ ID NO: 144.

[0044] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-N12) containing the amino acid sequence of SEQ ID NO: 149, CDR2 (CDR2 of the α-chain of 4400 TCR-N12) containing the amino acid sequence of SEQ ID NO: 150, and CDR3 (CDR3 of the α-chain of 4400 TCR-N12) containing the amino acid sequence of SEQ ID NO: 151, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-N12) containing the amino acid sequence of SEQ ID NO: 152, CDR2 (CDR2 of the β-chain of 4400 TCR-N12) containing the amino acid sequence of SEQ ID NO: 153, and CDR3 (CDR3 of the β-chain of 4400 TCR-N12) containing the amino acid sequence of SEQ ID NO: 154.

[0045] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-N13) containing the amino acid sequence of SEQ ID NO: 159, CDR2 (CDR2 of the α-chain of 4400 TCR-N13) containing the amino acid sequence of SEQ ID NO: 160, and CDR3 (CDR3 of the α-chain of 4400 TCR-N13) containing the amino acid sequence of SEQ ID NO: 161, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-N13) containing the amino acid sequence of SEQ ID NO: 162, CDR2 (CDR2 of the β-chain of 4400 TCR-N13) containing the amino acid sequence of SEQ ID NO: 163, and CDR3 (CDR3 of the β-chain of 4400 TCR-N13) containing the amino acid sequence of SEQ ID NO: 164.

[0046] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-C) containing the amino acid sequence of SEQ ID NO: 169, CDR2 (CDR2 of the α-chain of 4400 TCR-C) containing the amino acid sequence of SEQ ID NO: 170, and CDR3 (CDR3 of the α-chain of 4400 TCR-C) containing the amino acid sequence of SEQ ID NO: 171, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-C) containing the amino acid sequence of SEQ ID NO: 172, CDR2 (CDR2 of the β-chain of 4400 TCR-C) containing the amino acid sequence of SEQ ID NO: 173, and CDR3 (CDR3 of the β-chain of 4400 TCR-C) containing the amino acid sequence of SEQ ID NO: 174.

[0047] In another embodiment of the present invention, the TCR comprises a first polypeptide chain comprising CDR1 (CDR1 of the α-chain of 4400 TCR-20) containing the amino acid sequence of SEQ ID NO: 179, CDR2 (CDR2 of the α-chain of 4400 TCR-20) containing the amino acid sequence of SEQ ID NO: 180, and CDR3 (CDR3 of the α-chain of 4400 TCR-20) containing the amino acid sequence of SEQ ID NO: 181, and a second polypeptide chain comprising CDR1 (CDR1 of the β-chain of 4400 TCR-20) containing the amino acid sequence of SEQ ID NO: 182, CDR2 (CDR2 of the β-chain of 4400 TCR-20) containing the amino acid sequence of SEQ ID NO: 183, and CDR3 (CDR3 of the β-chain of 4400 TCR-20) containing the amino acid sequence of SEQ ID NO: 184.

[0048] In this regard, the TCR of the present invention may contain one or more amino acid sequences selected from the group consisting of SEQ ID NOs: 1-6, 11-16, 21-26, 31-36, and 41-46. In embodiments of the present invention, the TCR is (a) all of SEQ ID NOs 1-3, (b) all of SEQ ID NOs 4-6, (c) all of SEQ ID NOs 1-6, (d) all of SEQ ID NOs 11-13, (e) all of SEQ ID NOs 14-16, (f) all of SEQ ID NOs 11-16, (g) all of SEQ ID NOs 21-23, (h) all of SEQ ID NOs 24-26, (i) all of SEQ ID NOs 21-26, (j) all of SEQ ID NOs 31-33, (k) all of SEQ ID NOs 34-36, (l) all of SEQ ID NOs 31-36, (m) all of SEQ ID NOs 41-43, (n) all of SEQ ID NOs 44-46, (o) all of SEQ ID NOs 41-46, (p) all of SEQ ID NOs 119-121, (q) all of SEQ ID NOs 122-124, (r) all of SEQ ID NOs 119-124, (s) all of SEQ ID NOs 129-131, (t) (u) All of sequence numbers 129-134, (v) All of sequence numbers 139-141, (w) All of sequence numbers 142-144, (x) All of sequence numbers 139-144, (y) All of sequence numbers 149-151, (z) All of sequence numbers 152-154, (aa) All of sequence numbers 149-154, (bb) All of sequence numbers 159-161, (cc) All of sequence numbers 162-164, (dd) All of sequence numbers 159-164, (ee) All of sequence numbers 169-171, (ff) All of sequence numbers 172-174, (gg) All of sequence numbers 169-174, (hh) All of sequence numbers 179-181, (ii) All of sequence numbers 182-184, or (jj) All of sequence numbers 179-184. In a particularly preferred embodiment, the TCR includes all of the amino acid sequences of (a) SEQ ID NOs: 1-6, (b) SEQ ID NOs: 11-16, (c) SEQ ID NOs: 21-26, (d) SEQ ID NOs: 31-36, (e) SEQ ID NOs: 41-46, (f) SEQ ID NOs: 119-124, (g) SEQ ID NOs: 129-134, (h) SEQ ID NOs: 139-144, (i) SEQ ID NOs: 149-154, (j) SEQ ID NOs: 159-164, (k) SEQ ID NOs: 169-174, or (l) SEQ ID NOs: 179-184.

[0049] In embodiments of the present invention, the TCR includes the amino acid sequence of the variable region of the TCR, which includes the CDR. In this regard, TCRs include: (1) SEQ ID NO: 7 (predicted sequence of the variable region of the α chain of 4400 TCR-A1 without an N-terminal signal peptide); (2) SEQ ID NO: 8 (predicted sequence of the variable region of the β chain of 4400 TCR-A1 without an N-terminal signal peptide); (3) SEQ ID NO: 9 (variable region of the α chain of 4400 TCR-A1 with an N-terminal signal peptide); (4) SEQ ID NO: 10 (variable region of the β chain of 4400 TCR-A1 with an N-terminal signal peptide); (5) SEQ ID NO: 17 (predicted sequence of the variable region of the α chain of 4400 TCR-A2 without an N-terminal signal peptide); (6) SEQ ID NO: 18 (predicted sequence of the variable region of the β chain of 4400 TCR-A2 without an N-terminal signal peptide); (7) SEQ ID NO: 19 (variable region of the α chain of 4400 TCR-A2 with an N-terminal signal peptide); (8) SEQ ID NO: 20 (4400 TCR-A2 with an N-terminal signal peptide) (9)SEQ ID NO: 27 (Predicted sequence of the variable region of the α chain of 4400 TCR-E without an N-terminal signal peptide); (10)SEQ ID NO: 28 (Predicted sequence of the variable region of the β chain of 4400 TCR-E without an N-terminal signal peptide); (11)SEQ ID NO: 29 (Variable region of the α chain of 4400 TCR-E with an N-terminal signal peptide); (12)SEQ ID NO: 30 (Variable region of the β chain of 4400 TCR-E with an N-terminal signal peptide); (13)SEQ ID NO: 37 (Predicted sequence of the variable region of the α chain of 4400 TCR-J without an N-terminal signal peptide); (14)SEQ ID NO: 38 (Predicted sequence of the variable region of the β chain of 4400 TCR-J without an N-terminal signal peptide); (15)SEQ ID NO: 39 (Variable region of the α chain of 4400 TCR-J with an N-terminal signal peptide); (16)SEQ ID NO: 40 (4400 with an N-terminal signal peptide) (17) Variable region of the β chain of TCR-J; (18) SEQ ID NO: 48 (Predicted sequence of the variable region of the α chain of 4400 TCR-N without an N-terminal signal peptide); (19) SEQ ID NO: 49 (Variable region of the α chain of 4400 TCR-N with an N-terminal signal peptide);(20) SEQ ID NO: 50 (Variable region of the β-chain of 4400 TCR-N having an N-terminal signal peptide); (21) SEQ ID NO: 125 (Predicted sequence of the variable region of the α-chain of 4400 TCR-A3 without an N-terminal signal peptide); (22) SEQ ID NO: 126 (Predicted sequence of the variable region of the β-chain of 4400 TCR-A3 without an N-terminal signal peptide); (23) SEQ ID NO: 127 (Variable region of the α-chain of 4400 TCR-A3 having an N-terminal signal peptide); (24) SEQ ID NO: 128 (Variable region of the β-chain of 4400 TCR-A3 having an N-terminal signal peptide); (25) SEQ ID NO: 135 (Predicted sequence of the variable region of the α-chain of 4400 TCR-J2 without an N-terminal signal peptide); (26) SEQ ID NO: 136 (Predicted sequence of the variable region of the β-chain of 4400 TCR-J2 without an N-terminal signal peptide); (27) SEQ ID NO: 137 (4400 (28)SEQ ID NO: 138 (Variable region of the α chain of 4400 TCR-J2 with N-terminal signal peptide); (29)SEQ ID NO: 145 (Predicted sequence of the variable region of the α chain of 4400 TCR-N4 without N-terminal signal peptide); (30)SEQ ID NO: 146 (Predicted sequence of the variable region of the β chain of 4400 TCR-N4 without N-terminal signal peptide); (31)SEQ ID NO: 147 (Variable region of the α chain of 4400 TCR-N4 with N-terminal signal peptide); (32)SEQ ID NO: 148 (Variable region of the β chain of 4400 TCR-N4 with N-terminal signal peptide); (33)SEQ ID NO: 155 (Predicted sequence of the variable region of the α chain of 4400 TCR-N12 without N-terminal signal peptide); (34)SEQ ID NO: 156 (4400 without N-terminal signal peptide) (35) SEQ ID NO: 157 (Predicted sequence of the variable region of the β-chain of TCR-N12); (36) SEQ ID NO: 158 (Predicted sequence of the variable region of the α-chain of 4400 TCR-N12 having an N-terminal signal peptide); (37) SEQ ID NO: 165 (Predicted sequence of the variable region of the α-chain of 4400 TCR-N13 without an N-terminal signal peptide); (38) SEQ ID NO: 166 (Predicted sequence of the variable region of the β-chain of 4400 TCR-N13 without an N-terminal signal peptide);(39) SEQ ID NO: 167 (Variable region of the α chain of 4400 TCR-N13 having an N-terminal signal peptide); (40) SEQ ID NO: 168 (Variable region of the β chain of 4400 TCR-N13 having an N-terminal signal peptide); (41) SEQ ID NO: 175 (Predicted sequence of the variable region of the α chain of 4400 TCR-C without an N-terminal signal peptide); (42) SEQ ID NO: 176 (Predicted sequence of the variable region of the β chain of 4400 TCR-C without an N-terminal signal peptide); (43) SEQ ID NO: 177 (Variable region of the α chain of 4400 TCR-C having an N-terminal signal peptide); (44) SEQ ID NO: 178 (Variable region of the β chain of 4400 TCR-C having an N-terminal signal peptide); (45) SEQ ID NO: 185 (Predicted sequence of the variable region of the α chain of 4400 TCR-20 without an N-terminal signal peptide); (46) SEQ ID NO: 186 (4400 TCR-C without an N-terminal signal peptide) (47) SEQ ID NO: 187 (Variable region of the α-chain of 4400 TCR-20 with N-terminal signal peptide); (48) SEQ ID NO: 188 (Variable region of the β-chain of 4400 TCR-20 with N-terminal signal peptide); (49) Both SEQ ID NOs: 7 and 8; (50) Both SEQ ID NOs: 9 and 10; (51) Both SEQ ID NOs: 17 and 18; (52) Both SEQ ID NOs: 19 and 20; (53) Both SEQ ID NOs: 27 and 28; (54) Both SEQ ID NOs: 29 and 30; (55) Both SEQ ID NOs: 37 and 38; (56) Both SEQ ID NOs: 39 and 40; (57) Both SEQ ID NOs: 47 and 48; (58) Both SEQ ID NOs: 49 and 50; (59) Both SEQ ID NOs: 125 and 126; (60) SEQ ID NOs: 127 and Both 128; (61) Both sequence numbers 135 and 136; (62) Both sequence numbers 137 and 138; (63) Both sequence numbers 145 and 146; (64) Both sequence numbers 147 and 148; (65) Both sequence numbers 155 and 156; (66) Both sequence numbers 157 and 158; (67) Both sequence numbers 165 and 166; (68) Both sequence numbers 167 and 168; (69) Both sequence numbers 175 and 176; (70) Both sequence numbers 177 and 178; (71) Both sequence numbers 185 and 186;Or (72) may include both amino acid sequences of SEQ ID NOs. 187 and 188. Preferably, the TCR may include (i) both SEQ ID NOs. 7 and 8, (ii) both SEQ ID NOs. 9 and 10, (iii) both SEQ ID NOs. 17 and 18, (iv) both SEQ ID NOs. 19 and 20, (v) both SEQ ID NOs. 27 and 28, (vi) both SEQ ID NOs. 29 and 30, (vii) both SEQ ID NOs. 37 and 38, (viii) both SEQ ID NOs. 39 and 40, (ix) both SEQ ID NOs. 47 and 48, (x) both SEQ ID NOs. 49 and 50, (xi) both SEQ ID NOs. 125 and 126, (xii) both SEQ ID NOs. 127 and 128, (xiii) both SEQ ID NOs. 135 and 136 , may include the amino acid sequences of both (xiv) SEQ ID NOs. 137 and 138, both (xv) SEQ ID NOs. 145 and 146, both (xvi) SEQ ID NOs. 147 and 148, both (xvii) SEQ ID NOs. 155 and 156, both (xviii) SEQ ID NOs. 157 and 158, both (xix) SEQ ID NOs. 165 and 166, both (xx) SEQ ID NOs. 167 and 168, both (xxi) SEQ ID NOs. 175 and 176, both (xxii) SEQ ID NOs. 177 and 178, both (xxiii) SEQ ID NOs. 185 and 186, or both (xxiv) SEQ ID NOs. 187 and 188.

[0050] The TCR of the present invention may further comprise an α-chain constant region and a β-chain constant region. The constant regions may be derived from any suitable species, such as human or mouse. In embodiments of the present invention, the TCR further comprises mouse α and β chain constant regions or human α and β chain constant regions. As used herein, the terms “mouse” or “human” refer to the TCR or any component of the TCR described herein (e.g., CDR, variable region, constant region, α-chain, and / or β-chain), respectively, meaning a mouse or human-derived TCR (or its components), i.e., a TCR (or its components) originating from or formerly expressed by mouse T cells or human T cells, respectively.

[0051] Embodiments of the present invention provide a chimeric TCR comprising a human variable region and a mouse constant region, which has antigen specificity to a mutant human RAS amino acid sequence in which glycine at position 13 is substituted with aspartic acid. The mouse constant region may provide any one or more advantages. For example, the mouse constant region can reduce mispairing between the TCR of the present invention and the endogenous TCR of the host cell into which the TCR of the present invention is introduced. Alternatively, the mouse constant region may further increase the expression of the TCR of the present invention compared to the same TCR having a human constant region. The chimeric TCR may comprise the amino acid sequences of SEQ ID NO: 63 (WT mouse α-chain constant region), SEQ ID NO: 64 (WT mouse β-chain constant region), or both SEQ ID NOs. 63 and 64. Preferably, the TCR of the present invention comprises both SEQ ID NOs. 63 and 64. The chimeric TCR may comprise any of the mouse constant regions described herein in combination with any of the CDR regions described herein with respect to other embodiments of the present invention.In this regard, TCRs include (a) all of sequence numbers 1-3 and 63, (b) all of sequence numbers 4-6 and 64, (c) all of sequence numbers 1-6 and 63-64, (d) all of sequence numbers 11-13 and 63, (e) all of sequence numbers 14-16 and 64, (f) all of sequence numbers 11-16 and 63-64, (g) all of sequence numbers 21-23 and 63, (h) all of sequence numbers 24-26 and 64, (i) all of sequence numbers 21-26 and 63-64, and (j) sequence numbers 31-33. (k) All of sequence numbers 34-36 and 64, (l) All of sequence numbers 31-36 and 63-64, (m) All of sequence numbers 41-43 and 63, (n) All of sequence numbers 44-46 and 64, (o) All of sequence numbers 41-46 and 63-64, (p) All of sequence numbers 119-121 and 63, (q) All of sequence numbers 122-124 and 64, (r) All of sequence numbers 119-124 and 63-64, (s) All of sequence numbers 129-131 and 63, (t (u) All of sequence numbers 132-134 and 64, (v) All of sequence numbers 139-141 and 63, (w) All of sequence numbers 142-144 and 64, (x) All of sequence numbers 139-144 and 63-64, (y) All of sequence numbers 149-151 and 63, (z) All of sequence numbers 152-154 and 64, (aa) All of sequence numbers 149-154 and 63-64, (bb) All of sequence numbers 159-161 and 63, (cc) may contain all of sequence numbers 162-164 and 64, (dd) all of sequence numbers 159-164 and 63-64, (ee) all of sequence numbers 169-171 and 63, (ff) all of sequence numbers 172-174 and 64, (gg) all of sequence numbers 169-174 and 63-64, (hh) all of sequence numbers 179-181 and 63, (ii) all of sequence numbers 182-184 and 64, or (jj) all of the amino acid sequences of sequence numbers 179-184 and 63-64.

[0052] In another embodiment of the present invention, the chimeric TCR may include any of the mouse constant regions described herein in combination with any of the variable regions described herein in relation to other aspects of the present invention. In this regard, the TCR may include (1) both SEQ ID NOs: 7 and 63, (2) both SEQ ID NOs: 8 and 64, (3) both SEQ ID NOs: 9 and 63, (4) both SEQ ID NOs: 10 and 64, (5) both SEQ ID NOs: 17 and 63, (6) both SEQ ID NOs: 18 and 64, (7) both SEQ ID NOs: 19 and 63, (8) both SEQ ID NOs: 20 and 64, (9) both SEQ ID NOs: 27 and 63, (10) both SEQ ID NOs: 28 and 64, (11) both SEQ ID NOs: 29 and 63, (12) both SEQ ID NOs: 30 and 64, (13) SEQ ID NOs: 37 and Both of 63, (14) Both of sequence numbers 38 and 64, (15) Both of sequence numbers 39 and 63, (16) Both of sequence numbers 40 and 64, (17) Both of sequence numbers 47 and 63, (17) Both of sequence numbers 48 and 64, (19) Both of sequence numbers 49 and 63, (20) Both of sequence numbers 50 and 64, (21) Both of sequence numbers 125 and 63, (22) Both of sequence numbers 126 and 64, (23) Both of sequence numbers 127 and 63, (24) Both of sequence numbers 128 and 64, (25) Both of sequence numbers 135 and 63, (2 6) Both SEQ ID NOs: 136 and 64, (27) Both SEQ ID NOs: 137 and 63, (28) Both SEQ ID NOs: 138 and 64, (29) Both SEQ ID NOs: 145 and 63, (30) Both SEQ ID NOs: 146 and 64, (31) Both SEQ ID NOs: 147 and 63, (32) Both SEQ ID NOs: 148 and 64, (33) Both SEQ ID NOs: 155 and 63, (34) Both SEQ ID NOs: 156 and 64, (35) Both SEQ ID NOs: 157 and 63, (36) Both SEQ ID NOs: 158 and 64, (37) Both SEQ ID NOs: 165 and 63, (3 8) Both sequence numbers 166 and 64, (39) Both sequence numbers 167 and 63, (40) Both sequence numbers 168 and 64, (41) Both sequence numbers 175 and 63, (42) Both sequence numbers 176 and 64, (43) Both sequence numbers 177 and 63, (44) Both sequence numbers 178 and 64, (45) Both sequence numbers 185 and 63, (46) Both sequence numbers 186 and 64, (47) Both sequence numbers 187 and 63, (48) Both sequence numbers 188 and 64, (49) All sequence numbers 7-8 and 63-64,(50) All of sequence numbers 9-10 and 63-64, (51) All of sequence numbers 17-18 and 63-64, (52) All of sequence numbers 19-20 and 63-64, (53) All of sequence numbers 27-28 and 63-64, (54) All of sequence numbers 29-30 and 63-64, (55) All of sequence numbers 37-38 and 63-64, (56) All of sequence numbers 39-40 and 63-64, (57) All of sequence numbers 47-48 and 63-64, (58) All of sequence numbers 49-50 and 63-64, (59) All of sequence numbers 125-126 and 63-64, (60) All of sequence numbers 127-128 and 63-64, (61) All of sequence numbers 135-136 and 63-64, (62 (63) All of SEQ ID NOs: 137-138 and 63-64, (64) All of SEQ ID NOs: 147-148 and 63-64, (65) All of SEQ ID NOs: 155-156 and 63-64, (66) All of SEQ ID NOs: 157-158 and 63-64, (67) All of SEQ ID NOs: 165-166 and 63-64, (68) All of SEQ ID NOs: 167-168 and 63-64, (69) All of SEQ ID NOs: 175-176 and 63-64, (70) All of SEQ ID NOs: 177-178 and 63-64, (71) All of SEQ ID NOs: 185-186 and 63-64, or (72) All of SEQ ID NOs: 187-188 and 63-64.

[0053] In embodiments of the present invention, the TCR includes a substituted constant region. In this regard, the TCR may include any amino acid sequence of the TCR described herein, having one, two, three, or four amino acid substitutions in the constant regions of one or both of the α and β chains. Preferably, the TCR includes a mouse constant region having one, two, three, or four amino acid substitutions in the mouse constant region of one or both of the α and β chains. In a particularly preferred embodiment, the TCR includes a mouse constant region having one, two, three, or four amino acid substitutions in the mouse constant region of the α chain and one amino acid substitution in the mouse constant region of the β chain. In some embodiments, the TCR including the substituted constant region is advantageous compared to the parent TCR including the unsubstituted (wild-type) constant region, with respect to G13D RAS +The present invention provides one or more of the following: increased target recognition, increased expression by host cells, reduced mispairing with endogenous TCRs, and increased antitumor activity. Generally, the substituted amino acid sequences of the mouse constant regions of the α and β chains of the TCR, SEQ ID NOs. 59 and 60, respectively, correspond to all or part of the unsubstituted mouse constant region amino acid sequences, SEQ ID NOs. 63 and 64, respectively, with SEQ ID NOs. 59 having one, two, three, or four amino acid substitutions (multiple) compared to SEQ ID NOs. 63, and SEQ ID NOs. 60 having one amino acid substitution compared to SEQ ID NOs. 64. In this regard, embodiments of the present invention provide a TCR comprising (a)(i) X at position 48 is Thr or Cys; (ii) X at position 112 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 114 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 115 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp, such as SEQ ID NO: 59 (constant region of the α chain); (b) X at position 57 is Ser or Cys, such as SEQ ID NO: 60 (constant region of the β chain); or (c) the amino acid sequences of both SEQ ID NOs: 59 and 60. In embodiments of the present invention, a TCR comprising SEQ ID NO: 59 does not include SEQ ID NO: 63 (unsubstituted mouse constant region of the α chain). In embodiments of the present invention, the TCR containing SEQ ID NO: 60 does not contain SEQ ID NO: 64 (the non-substituted mouse constant region of the β chain).

[0054] In embodiments of the present invention, the TCR comprises an α chain including a variable region and a constant region, and a β chain including a variable region and a constant region. In this regard, TCR is (a)(i) the X at position 180 of SEQ ID NO: 65 is Thr or Cys; (ii) the X at position 244 of SEQ ID NO: 65 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) the X at position 246 of SEQ ID NO: 65 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) the X at position 247 of SEQ ID NO: 65 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp, the amino acid sequence of SEQ ID NO: 65 (α chain of 4400 TCR-A1 having an N-terminal signal peptide); (b) the amino acid sequence of SEQ ID NO: 66 (4400 having an N-terminal signal peptide) where the X at position 188 of SEQ ID NO: 66 is Ser or Cys (c) the β-chain of TCR-A1; (d) the amino acid sequences of both SEQ ID NOs. 65 and 66; (i) the X at position 158 of SEQ ID NOs. 67 is Thr or Cys; (ii) the X at position 222 of SEQ ID NOs. 67 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) the X at position 224 of SEQ ID NOs. 67 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) the X at position 225 of SEQ ID NOs. 67 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (predicted sequence of the α-chain of TCR-A1 without an N-terminal signal peptide); (e) the amino acid sequence of SEQ ID NOs. 68 where the X at position 169 of SEQ ID NOs. 67 is Ser or Cys (predicted sequence of the α-chain of TCR-A1 without an N-terminal signal peptide). (f) Predicted sequence of the β-chain of TCR-A1; (g) Amino acid sequences of both SEQ ID NOs. 67 and 68; (h) Amino acid sequence of SEQ ID NOs. 69 (α-chain of cysteine-substituted LVL modified 4400 TCR-A1 with N-terminal signal peptide); (i) Amino acid sequence of SEQ ID NOs. 70 (β-chain of cysteine-substituted LVL modified 4400 TCR-A1 with N-terminal signal peptide); (i) Amino acid sequence of SEQ ID NOs. 71 (Predicted sequence of the α-chain of cysteine-substituted LVL modified 4400 TCR-A1 without N-terminal signal peptide);(j) The amino acid sequence of SEQ ID NO: 72 (predicted sequence of the β-chain of cysteine-substituted LVL modified 4400 TCR-A1 without an N-terminal signal peptide); (k) The amino acid sequences of both SEQ ID NOs: 69 and 70; (l) The amino acid sequences of both SEQ ID NOs: 71 and 72; (m) The amino acid sequence of SEQ ID NO: 73 (i) X at position 180 of SEQ ID NO: 73 is Thr or Cys; (ii) X at position 244 of SEQ ID NO: 73 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of SEQ ID NO: 73 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 247 of SEQ ID NO: 73 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 TCR-A1 with an N-terminal signal peptide) (n) The α-chain of TCR-A2; (o) The amino acid sequence of SEQ ID NO: 74 (4400 TCR-A2 β-chain with N-terminal signal peptide), where X at position 188 of SEQ ID NO: 74 is Ser or Cys; (i) The amino acid sequences of both SEQ ID NO: 73 and 74; (ii) The X at position 222 of SEQ ID NO: 75 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 224 of SEQ ID NO: 75 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The X at position 225 of SEQ ID NO: 75 (4400 TCR-A2 β-chain without N-terminal signal peptide) (q) Amino acid sequence of the predicted α-chain of TCR-A2; (r) Amino acid sequence of SEQ ID NO: 76, where X at position 169 of SEQ ID NO: 76 is either Ser or Cys (predicted β-chain of 4400 TCR-A2 without an N-terminal signal peptide); (s) Amino acid sequences of both SEQ ID NOs: 75 and 76; (t) Amino acid sequence of SEQ ID NO: 77 (α-chain of 4400 TCR-A2 with N-terminal signal peptide and cysteine-substituted LVL modification); (t) Amino acid sequence of SEQ ID NO: 78 (β-chain of 4400 TCR-A2 with N-terminal signal peptide and cysteine-substituted LVL modification);(u) Amino acid sequence of SEQ ID NO: 79 (predicted sequence of the α chain of cysteine-substituted LVL modified 4400 TCR-A2 without an N-terminal signal peptide); (v) Amino acid sequence of SEQ ID NO: 80 (cysteine-substituted LVL modified 4400 without an N-terminal signal peptide) (w) Amino acid sequences of both SEQ ID NOs: 77 and 78; (x) Amino acid sequences of both SEQ ID NOs: 79 and 80; (y) Amino acid sequence of SEQ ID NOs: 81 (with N-terminal signal peptide 4400) such that (i) X at position 177 of SEQ ID NOs: 81 is Thr or Cys; (ii) X at position 241 of SEQ ID NOs: 81 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 243 of SEQ ID NOs: 81 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 244 of SEQ ID NOs: 81 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (z) The amino acid sequence of SEQ ID NO: 82 (4400 TCR-E β-chain having an N-terminal signal peptide), where X at position 189 of SEQ ID NO: 82 is Ser or Cys; (aa) The amino acid sequences of both SEQ ID NO: 81 and 82; (bb) (i) X at position 160 of SEQ ID NO: 83 is Thr or Cys; (ii) X at position 224 of SEQ ID NO: 83 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 226 of SEQ ID NO: 83 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 227 of SEQ ID NO: 83 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (cc) Predicted sequence of the α-chain of TCR-E; (cc) Amino acid sequence of SEQ ID NO: 84, where X at position 170 is either Ser or Cys (predicted sequence of the β-chain of 4400 TCR-E without an N-terminal signal peptide); (dd) Amino acid sequences of both SEQ ID NOs: 83 and 84; (ee) Amino acid sequence of SEQ ID NO: 85 (α-chain of cysteine-substituted LVL modified 4400 TCR-E with an N-terminal signal peptide);(ff) Amino acid sequence of SEQ ID NO: 86 (β chain of cysteine-substituted LVL modified 4400 TCR-E with N-terminal signal peptide); (gg) Amino acid sequence of SEQ ID NO: 87 (predicted sequence of α chain of cysteine-substituted LVL modified 4400 TCR-E without N-terminal signal peptide); (hh) Amino acid sequence of SEQ ID NO: 88 (cysteine-substituted LVL modified 4400 without N-terminal signal peptide) (ii) The predicted sequence of the β-chain of TCR-E; (ii) The amino acid sequences of both SEQ ID NOs: 85 and 86; (jj) The amino acid sequences of both SEQ ID NOs: 87 and 88; (kk) The amino acid sequence of SEQ ID NOs: 89 (with an N-terminal signal peptide) such that (i) X at position 183 of SEQ ID NOs: 89 is Thr or Cys; (ii) X at position 247 of SEQ ID NOs: 89 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 249 of SEQ ID NOs: 89 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 250 of SEQ ID NOs: 89 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (ii) The amino acid sequence of SEQ ID NO: 90 (4400 TCR-J β-chain) where X at position 188 of SEQ ID NO: 90 is Ser or Cys; (mm) The amino acid sequences of both SEQ ID NO: 89 and 90; (nn) (i) X at position 161 of SEQ ID NO: 91 is Thr or Cys; (ii) X at position 225 of SEQ ID NO: 91 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of SEQ ID NO: 91 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of SEQ ID NO: 91 (4400 TCR-J β-chain) where X at position 228 of SEQ ID NO: 91 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (oo) Predicted sequence of the α-chain of TCR-J; (oo) Amino acid sequence of SEQ ID NO: 92, where X at position 169 of SEQ ID NO: 92 is either Ser or Cys (predicted sequence of the β-chain of TCR-J without an N-terminal signal peptide); (pp) Amino acid sequences of both SEQ ID NOs: 91 and 92;(qq) Amino acid sequence of SEQ ID NO: 93 (α chain of cysteine-substituted LVL modified 4400 TCR-J with N-terminal signal peptide); (rr) Amino acid sequence of SEQ ID NO: 94 (β chain of cysteine-substituted LVL modified 4400 TCR-J with N-terminal signal peptide); (ss) Amino acid sequence of SEQ ID NO: 95 (predicted sequence of α chain of cysteine-substituted LVL modified 4400 TCR-J without N-terminal signal peptide); (tt) Amino acid sequence of SEQ ID NO: 96 (cysteine-substituted LVL modified 4400 without N-terminal signal peptide) (uu) Amino acid sequences of both SEQ ID NOs: 93 and 94; (vv) Amino acid sequences of both SEQ ID NOs: 95 and 96; (ww) Amino acid sequence of SEQ ID NOs: 97 (with N-terminal signal peptide 4400) where (i) X at position 178 of SEQ ID NOs: 97 is Thr or Cys; (ii) X at position 242 of SEQ ID NOs: 97 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 244 of SEQ ID NOs: 97 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 245 of SEQ ID NOs: 97 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (xx) The amino acid sequence of SEQ ID NO: 98 (4400 TCR-N β-chain with N-terminal signal peptide), where X at position 188 of SEQ ID NO: 98 is Ser or Cys; (yy) The amino acid sequences of both SEQ ID NO: 97 and 98; (zz) (i) X at position 157 of SEQ ID NO: 99 is Thr or Cys; (ii) X at position 221 of SEQ ID NO: 99 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 223 of SEQ ID NO: 99 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 224 of SEQ ID NO: 99 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp Predicted sequence of the α-chain of TCR-N);(aaa) The amino acid sequence of SEQ ID NO: 100, where X at position 169 of SEQ ID NO: 100 is either Ser or Cys (predicted sequence of the β-chain of 4400 TCR-N without an N-terminal signal peptide); (bbb) The amino acid sequences of both SEQ ID NO: 99 and 100; (ccc) The amino acid sequence of SEQ ID NO: 101 (α-chain of cysteine-substituted LVL-modified 4400 TCR-N with an N-terminal signal peptide); (ddd) The amino acid sequence of SEQ ID NO: 102; (β-chain of cysteine-substituted LVL modified 4400 TCR-N with N-terminal signal peptide); (eee) Amino acid sequence of SEQ ID NO: 103 (predicted sequence of α-chain of cysteine-substituted LVL modified 4400 TCR-N without N-terminal signal peptide); (fff) Amino acid sequence of SEQ ID NO: 104 (cysteine-substituted LVL modified 4400 without N-terminal signal peptide) (iii)(i) The amino acid sequence of the β-chain of TCR-N; (ggg) The amino acid sequences of both SEQ ID NOs: 101 and 102; (hhh) The amino acid sequences of both SEQ ID NOs: 103 and 104; (iii) The amino acid sequence of SEQ ID NOs: 189 (with N-terminal signal peptide 4400) where (i) X at position 176 of SEQ ID NOs: 189 is Thr or Cys; (ii) X at position 240 of SEQ ID NOs: 189 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 242 of SEQ ID NOs: 189 is Met, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; and (iv) X at position 243 of SEQ ID NOs: 189 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp TCR-A3 α-chain); (jjj) The amino acid sequence of SEQ ID NO: 190 (4400 having an N-terminal signal peptide) where X at position 188 of SEQ ID NO: 190 is either Ser or Cys. (kkk) Amino acid sequences of both SEQ ID NOs: 189 and 190; (lll) (i) X at position 157 of SEQ ID NO: 191 is Thr or Cys; (ii) X at position 221 of SEQ ID NO: 191 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 223 of SEQ ID NO: 191 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 224 of SEQ ID NO: 191 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 without an N-terminal signal peptide) Predicted sequence of the α-chain of TCR-A3; (mmm) Amino acid sequence of SEQ ID NO: 192 where X at position 169 is Ser or Cys (4400 predicted sequence of the β-chain of TCR-A3 without an N-terminal signal peptide);(nnn) Amino acid sequences of both SEQ ID NOs: 191 and 192; (ooo) Amino acid sequence of SEQ ID NO: 193 (α-chain of cysteine-substituted LVL modified 4400 TCR-A3 with N-terminal signal peptide); (ppp) Amino acid sequence of SEQ ID NO: 194 (β-chain of cysteine-substituted LVL modified 4400 TCR-A3 with N-terminal signal peptide); (qqq) Amino acid sequence of SEQ ID NO: 195 (predicted sequence of α-chain of cysteine-substituted LVL modified 4400 TCR-A3 without N-terminal signal peptide); (rrr) Amino acid sequence of SEQ ID NO: 196 (cysteine-substituted LVL modified 4400 without N-terminal signal peptide) (sss) Amino acid sequences of both SEQ ID NOs: 193 and 194; (ttt) Amino acid sequences of both SEQ ID NOs: 195 and 196; (uuu) Amino acid sequence of SEQ ID NOs: 197 (i) X at position 181 of SEQ ID NOs: 197 is Thr or Cys; (ii) X at position 245 of SEQ ID NOs: 197 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 247 of SEQ ID NOs: 197 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 248 of SEQ ID NOs: 197 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 having an N-terminal signal peptide) (vvv) The α-chain of TCR-J2; (vvv) The amino acid sequence of SEQ ID NO: 198, where X at position 188 of SEQ ID NO: 198 is Ser or Cys (β-chain of 4400 TCR-J2 with N-terminal signal peptide); (www) The amino acid sequences of both SEQ ID NO: 197 and 198; (xxx) (i) X at position 161 of SEQ ID NO: 199 is Thr or Cys; (ii) X at position 225 of SEQ ID NO: 199 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of SEQ ID NO: 199 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp;(iv) The amino acid sequence of SEQ ID NO: 199 (predicted sequence of the α chain of 4400 TCR-J2 without an N-terminal signal peptide) where X at position 228 of SEQ ID NO: 199 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (yyy) The amino acid sequence of SEQ ID NO: 200 (predicted sequence of the β chain of 4400 TCR-J2 without an N-terminal signal peptide) where X at position 169 of SEQ ID NO: 200 is Ser or Cys; (zzz) The amino acid sequences of both SEQ ID NO: 199 and 200; (aaaa) The amino acid sequence of SEQ ID NO: 201 (α chain of cysteine-substituted LVL modified 4400 TCR-J2 with an N-terminal signal peptide); (bbbb) The amino acid sequence of SEQ ID NO: 202 (cysteine-substituted LVL modified 4400 with an N-terminal signal peptide) TCR-J2 β-chain); (cccc) Amino acid sequence of SEQ ID NO: 203 (Cysteine-substituted LVL modification without N-terminal signal peptide 4400 Predicted sequence of TCR-J2 α-chain); (dddd) Amino acid sequence of SEQ ID NO: 204 (Cysteine-substituted LVL modification without N-terminal signal peptide 4400) (eeee) Amino acid sequences of both SEQ ID NOs. 201 and 202; (ffff) Amino acid sequences of both SEQ ID NOs. 203 and 204; (gggg) Amino acid sequence of SEQ ID NOs. 205 (4400 with N-terminal signal peptide) where (i) X at position 184 of SEQ ID NOs. 205 is Thr or Cys; (ii) X at position 248 of SEQ ID NOs. 205 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 250 of SEQ ID NOs. 205 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 251 of SEQ ID NOs. 205 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (TCR-N4 α chain); (hhhh) The amino acid sequence of SEQ ID NO: 206, where X at position 190 of SEQ ID NO: 206 is Ser or Cys (β chain of 4400 TCR-N4 with N-terminal signal peptide); (iiii) The amino acid sequences of both SEQ ID NO: 205 and 206; (jjjj) (i) The X at position 163 of SEQ ID NO: 207 is Thr or Cys;(ii) The amino acid sequence of SEQ ID NO: 207 (predicted sequence of the α chain of 4400 TCR-N4 without an N-terminal signal peptide) is such that (ii) X at position 227 of SEQ ID NO: 207 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; and (iv) X at position 230 of SEQ ID NO: 207 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (kkkk) The amino acid sequence of SEQ ID NO: 208 (predicted sequence of the α chain of 4400 TCR-N4 without an N-terminal signal peptide) is such that (ii) X at position 227 of SEQ ID NO: 207 is Ser or Cys Predicted sequence of the β-chain of TCR-N4); (llll) Amino acid sequences of both SEQ ID NOs. 207 and 208; (mmmm) Amino acid sequence of SEQ ID NOs. 209 (α-chain of 4400 TCR-N4 with N-terminal signal peptide and cysteine-substituted LVL modification); (nnnn) Amino acid sequence of SEQ ID NOs. 210 (β-chain of 4400 TCR-N4 with N-terminal signal peptide and cysteine-substituted LVL modification); (oooo) Amino acid sequence of SEQ ID NOs. 211 (predicted sequence of the α-chain of 4400 TCR-N4 with N-terminal signal peptide and cysteine-substituted LVL modification); (pppp) Amino acid sequence of SEQ ID NOs. 212 (4400 TCR-N4 with N-terminal signal peptide and cysteine-substituted LVL modification); (i) The amino acid sequence of the β-chain of TCR-N4 (α-chain of 4400 TCR-N12 having an N-terminal signal peptide), (qqqq) The amino acid sequences of both SEQ ID NOs. 209 and 210; (rrrr) The amino acid sequences of both SEQ ID NOs. 211 and 212; (ssss) The amino acid sequence of SEQ ID NOs. 213 (α-chain of 4400 TCR-N12 having an N-terminal signal peptide), where (i) X at position 183 of SEQ ID NOs. 213 is Thr or Cys; (ii) X at position 247 of SEQ ID NOs. 213 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; and (iv) X at position 250 of SEQ ID NOs. 213 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp;(tttt) The amino acid sequence of SEQ ID NO: 214 (4400 having an N-terminal signal peptide) is such that the X at position 188 of SEQ ID NO: 214 is either Ser or Cys. The β-chain of TCR-N12; (uuuu) The amino acid sequences of both SEQ ID NOs. 213 and 214; (vvvv) (i) X at position 161 of SEQ ID NOs. 215 is Thr or Cys; (ii) X at position 225 of SEQ ID NOs. 215 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of SEQ ID NOs. 215 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 228 of SEQ ID NOs. 215 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 without an N-terminal signal peptide) Predicted sequence of the α-chain of TCR-N12); (wwww) Amino acid sequence of SEQ ID NO: 216 where X at position 169 of SEQ ID NO: 216 is Ser or Cys (predicted sequence of the β-chain of 4400 TCR-N12 without an N-terminal signal peptide); (xxxx) Amino acid sequences of both SEQ ID NO: 215 and 216; (yyyy) Amino acid sequence of SEQ ID NO: 217 (α-chain of 4400 TCR-N12 with N-terminal signal peptide and cysteine-substituted LVL modification); (zzzz) Amino acid sequence of SEQ ID NO: 218 (β-chain of 4400 TCR-N12 with N-terminal signal peptide and cysteine-substituted LVL modification); (aaaaa) Amino acid sequence of SEQ ID NO: 219 (predicted sequence of the α-chain of 4400 TCR-N12 with N-terminal signal peptide and cysteine-substituted LVL modification); (bbbbb) Amino acid sequence of SEQ ID NO: 220 (4400 TCR-N12 with N-terminal signal peptide and cysteine-substituted LVL modification); (ccccc) Predicted sequence of the β-chain of TCR-N12; (ddddd) Amino acid sequences of both SEQ ID NOs: 217 and 218; (eeeee) (i) X at position 180 of SEQ ID NO: 221 is either Thr or Cys; (ii) X at position 244 of SEQ ID NO: 221 is either Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp;(iii) The amino acid sequence of SEQ ID NO: 221 (α chain of 4400 TCR-N13 with an N-terminal signal peptide) where X at position 246 of SEQ ID NO: 221 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of SEQ ID NO: 221 (α chain of 4400 TCR-N13 with an N-terminal signal peptide) where X at position 188 of SEQ ID NO: 222 is Ser or Cys; The β-chain of TCR-N13; (ggggg) Amino acid sequences of both SEQ ID NOs. 221 and 222; (hhhhh) (i) X at position 158 of SEQ ID NOs. 223 is Thr or Cys; (ii) X at position 222 of SEQ ID NOs. 223 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 224 of SEQ ID NOs. 223 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 225 of SEQ ID NOs. 223 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 without an N-terminal signal peptide) (iiiii) Amino acid sequence of SEQ ID NO: 224 where X at position 169 of SEQ ID NO: 224 is Ser or Cys (predicted sequence of the β chain of 4400 TCR-N13 without an N-terminal signal peptide); (jjjjj) Amino acid sequences of both SEQ ID NO: 223 and 224; (kkkkk) Amino acid sequence of SEQ ID NO: 225 (α chain of 4400 TCR-N13 with N-terminal signal peptide and cysteine-substituted LVL modification); (lllll) Amino acid sequence of SEQ ID NO: 226 (β chain of 4400 TCR-N13 with N-terminal signal peptide and cysteine-substituted LVL modification); (mmmmm) Amino acid sequence of SEQ ID NO: 227 (predicted sequence of the α chain of 4400 TCR-N13 with N-terminal signal peptide and cysteine-substituted LVL modification); (nnnnn) Amino acid sequence of SEQ ID NO: 228 (4400 TCR-N13 with N-terminal signal peptide and cysteine-substituted LVL modification); Predicted sequence of the β-chain of TCR-N13; (ooooo) Amino acid sequences of both SEQ ID NOs. 225 and 226; (ppppp) Amino acid sequences of both SEQ ID NOs. 227 and 228; (qqqqq) (i) X at position 184 of SEQ ID NOs. 229 is either Thr or Cys; (ii) X at position 248 of SEQ ID NOs. 229 is either Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 250 of SEQ ID NOs. 229 is either Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp;(iv) The amino acid sequence of SEQ ID NO: 229 (α chain of 4400 TCR-C having an N-terminal signal peptide) where X at position 251 of SEQ ID NO: 229 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (rrrrr) The amino acid sequence of SEQ ID NO: 230 (α chain of 4400 TCR-C having an N-terminal signal peptide) where X at position 189 of SEQ ID NO: 230 is Ser or Cys (ssss) Amino acid sequences of both SEQ ID NOs: 229 and 230; (ttttt) (i) X at position 163 of SEQ ID NOs: 231 is Thr or Cys; (ii) X at position 227 of SEQ ID NOs: 231 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of SEQ ID NOs: 231 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 230 of SEQ ID NOs: 231 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 without an N-terminal signal peptide) Predicted sequence of the α-chain of TCR-C); (uuuuu) Amino acid sequence of SEQ ID NO: 232, where X at position 170 of SEQ ID NO: 232 is Ser or Cys (predicted sequence of the β-chain of 4400 TCR-C without an N-terminal signal peptide); (vvvvv) Amino acid sequences of both SEQ ID NO: 231 and 232; (wwwww) Amino acid sequence of SEQ ID NO: 233 (α-chain of cysteine-substituted LVL modified 4400 TCR-C with an N-terminal signal peptide); (xxxxx) Amino acid sequence of SEQ ID NO: 234 (β-chain of cysteine-substituted LVL modified 4400 TCR-C with an N-terminal signal peptide); (yyyyy) Amino acid sequence of SEQ ID NO: 235 (predicted sequence of the α-chain of cysteine-substituted LVL modified 4400 TCR-C without an N-terminal signal peptide); (zzzzz) Amino acid sequence of SEQ ID NO: 236 (cysteine-substituted LVL modified 4400 without an N-terminal signal peptide) Predicted sequence of the β-chain of TCR-C; (aaaaaa) Amino acid sequences of both SEQ ID NOs. 233 and 234; (bbbbbb) Amino acid sequences of both SEQ ID NOs. 235 and 236; (cccccc) (i) The X at position 184 of SEQ ID NOs. 237 is either Thr or Cys;(ii) The X at position 248 of SEQ ID NO: 237 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of SEQ ID NO: 237 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The X at position 251 of SEQ ID NO: 237 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp, the amino acid sequence of SEQ ID NO: 237 (α chain of 4400 TCR-20 having an N-terminal signal peptide); (dddddd) The X at position 189 of SEQ ID NO: 238 is Ser or Cys, the amino acid sequence of SEQ ID NO: 238 (α chain of 4400 TCR-20 having an N-terminal signal peptide) The β-chain of TCR-20; (eeeeee) The amino acid sequences of both SEQ ID NOs. 237 and 238; (ffffff) (i) X at position 163 of SEQ ID NOs. 239 is Thr or Cys; (ii) X at position 227 of SEQ ID NOs. 239 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of SEQ ID NOs. 239 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 230 of SEQ ID NOs. 239 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 amino acid sequences without an N-terminal signal peptide) Predicted sequence of the α-chain of TCR-20); (gggggg) Amino acid sequence of SEQ ID NO: 240, where X at position 170 of SEQ ID NO: 240 is either Ser or Cys (predicted sequence of the β-chain of 4400 TCR-20 without an N-terminal signal peptide); (hhhhhh) Amino acid sequences of both SEQ ID NO: 239 and 240; (iiiiii) Amino acid sequence of SEQ ID NO: 241 (α-chain of 4400 TCR-20 with N-terminal signal peptide and cysteine-substituted LVL modification); (jjjjjj) Amino acid sequence of SEQ ID NO: 242 (β-chain of 4400 TCR-20 with N-terminal signal peptide and cysteine-substituted LVL modification); (kkkkkk) Amino acid sequence of SEQ ID NO: 243 (predicted sequence of the α-chain of 4400 TCR-20 with N-terminal signal peptide and cysteine-substituted LVL modification);(llllll) The amino acid sequence of SEQ ID NO: 244 (predicted sequence of the β-chain of cysteine-substituted LVL modified 4400 TCR-20 without an N-terminal signal peptide); (mmmmmm) The amino acid sequences of both SEQ ID NOs: 241 and 242; or (nnnnnn) The amino acid sequences of both SEQ ID NOs: 243 and 244 may be included.

[0055] In embodiments of the present invention, the substituted constant region includes a cysteine ​​substitution in the constant region of one or both of the α-chain and β-chain to provide a cysteine-substituted TCR. Opposing cysteines in the α-chain and β-chain link the constant regions of the α-chain and β-chain of the substituted TCR together, providing a disulfide bond that is not present in TCRs containing the unsubstituted mouse constant region. In this regard, the TCR may be a cysteine-substituted TCR in which one or both of the native Thr at position 48 of SEQ ID NO: 63 (Thr48) and the native Ser at position 57 of SEQ ID NO: 64 (Ser57) may be substituted with Cys. Preferably, both the native Thr48 of SEQ ID NO: 63 and the native Ser57 of SEQ ID NO: 64 are substituted with Cys. Examples of constant region sequences of cysteine-substituted TCRs are shown in Table 2. In embodiments of the present invention, the cysteine-substituted TCR comprises (i) SEQ ID NO: 59, (ii) SEQ ID NO: 60, or (iii) both SEQ ID NOs: 59 and 60, both of which are defined in Table 2. The cysteine-substituted TCR of the present invention may include a substituted steady-state region in addition to either the CDR or variable region described herein.

[0056] In embodiments of the present invention, the cysteine-substituted chimeric TCR includes a full-length α chain and a full-length β chain. Examples of the sequences of the α and β chains of the cysteine-substituted chimeric TCR are shown in Table 2. In embodiments of the present invention, the TCR is (1) SEQ ID NO: 59, (2) SEQ ID NO: 60, (3) SEQ ID NO: 65, (4) SEQ ID NO: 66, (5) SEQ ID NO: 67, (6) SEQ ID NO: 68, (7) SEQ ID NO: 73, (8) SEQ ID NO: 74, (9) SEQ ID NO: 75, (10) SEQ ID NO: 76, (11) SEQ ID NO: 81, (12) SEQ ID NO: 82, (13) SEQ ID NO: 83, (14) SEQ ID NO: 84, (15) SEQ ID NO: 89, (16) SEQ ID NO: 90, (17) SEQ ID NO: 91, (18) SEQ ID NO: 92, (19) SEQ ID NO: 97, (20) SEQ ID NO: 98, (21) Sequence ID 99, (22) Sequence ID 100, (23) Sequence ID 189, (24) Sequence ID 190, (25) Sequence ID 191, (26) Sequence ID 192, (27) Sequence ID 197, (28) Sequence ID 198, (29) Sequence ID 199, (30) Sequence ID 200, (31) Sequence ID 205, (32) Sequence ID 206, (33) Sequence ID 207, (34) Sequence ID 208, (35) Sequence ID 213, (36) Sequence ID 214, (37) Sequence ID 215, (38) Sequence ID 216, (39) Sequence ID 221, (40) Sequence ID 222, (41) Sequence ID 223, (42) Sequence ID 224, (43) Sequence ID 229, (44) Sequence ID 230, (45) Sequence ID 231, (46) Sequence ID 232, (47) Sequence ID 237, (48) Sequence ID 238, (49) Sequence ID 239, (50) Sequence ID 240, (51) Both Sequence IDs 59 and 60, (52) Both Sequence IDs 65 and 66, (53) Both Sequence IDs 67 and 68, (54) Both Sequence IDs 73 and 74, (55) Both Sequence IDs 75 and 76, (56) Both Sequence IDs 81 and 82 , (57) both sequence numbers 83 and 84, (58) both sequence numbers 89 and 90, (59) both sequence numbers 91 and 92, (60) both sequence numbers 97 and 98, (61) both sequence numbers 99 and 100, (62) both sequence numbers 189 and 190, (63) both sequence numbers 191 and 192, (64) both sequence numbers 197 and 198, (65) both sequence numbers 199 and 200, (66) both sequence numbers 205 and 206, (67) both sequence numbers 207 and 208, (68) both sequence numbers 213 and 214,(69) Both sequence numbers 215 and 216, (70) Both sequence numbers 221 and 222, (71) Both sequence numbers 223 and 224, (72) Both sequence numbers 229 and 230, (73) Both sequence numbers 231 and 232, (74) Both sequence numbers 237 and 238, or (75) Both sequence numbers 239 and 240, and sequence numbers 59-60, 65-68, 73-76, 81-84, 89-92, 97-100, 189-192, 197-200, 205-208, 213-216, 221-224, 229-232, and 237-240 are all as defined in Table 2.

[0057] [Table 2-1]

[0058] [Table 2-2]

[0059] [Table 2-3]

[0060] [Table 2-4]

[0061] In embodiments of the present invention, the substituted amino acid sequence includes the substitution of one, two, or three amino acids with hydrophobic amino acids in the transmembrane (TM) domain of the constant region of the α chain to provide a TCR substituted with hydrophobic amino acids (also referred herein as an "LVL-modified TCR"). Hydrophobic amino acid substitutions(s) in the TM domain of the TCR can increase the hydrophobicity of the TM domain of the TCR compared to a TCR that does not have hydrophobic amino acid substitutions(s) in the TM domain. In this regard, the TCR is an LVL-modified TCR in which one, two, or three of the native Ser112, Met114, and Gly115 of SEQ ID NO: 63 may be independently substituted with Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; preferably Leu, Ile, or Val. Preferably, all three native Ser112, Met114, and Gly115 of SEQ ID NO: 63 may be independently substituted with Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; preferably Leu, Ile, or Val. In embodiments of the present invention, the LVL-modified TCR comprises (i) SEQ ID NO: 59, (ii) SEQ ID NO: 60, or (iii) both SEQ ID NOs: 59 and 60, both of which are defined in Table 3. The LVL-modified TCR of the present invention may include a substitution steady-state region in addition to either the CDR or variable region described herein.

[0062] In embodiments of the present invention, the LVL-modified TCR includes a full-length α chain and a full-length β chain. Examples of the sequences of the α and β chains of the LVL-modified TCR are shown in Table 3. In embodiments of the present invention, the TCR is (1) SEQ ID NO: 59, (2) SEQ ID NO: 60, (3) SEQ ID NO: 65, (4) SEQ ID NO: 66, (5) SEQ ID NO: 67, (6) SEQ ID NO: 68, (7) SEQ ID NO: 73, (8) SEQ ID NO: 74, (9) SEQ ID NO: 75, (10) SEQ ID NO: 76, (11) SEQ ID NO: 81, (12) SEQ ID NO: 82, (13) SEQ ID NO: 83, (14) SEQ ID NO: 84, (15) SEQ ID NO: 89, (16) SEQ ID NO: 90, (17) SEQ ID NO: 91, (18) SEQ ID NO: 92, (19) SEQ ID NO: 97, (20) SEQ ID NO: 98, (21) Sequence ID 99, (22) Sequence ID 100, (23) Sequence ID 189, (24) Sequence ID 190, (25) Sequence ID 191, (26) Sequence ID 192, (27) Sequence ID 197, (28) Sequence ID 198, (29) Sequence ID 199, (30) Sequence ID 200, (31) Sequence ID 205, (32) Sequence ID 206, (33) Sequence ID 207, (34) Sequence ID 208, (35) Sequence ID 213, (36) Sequence ID 214, (37) Sequence ID 215, (38) Sequence ID 216, (39) Sequence ID 221, (40) Sequence ID 222, (41) Sequence ID 223, (42) Sequence ID 224, (43) Sequence ID 229, (44) Sequence ID 230, (45) Sequence ID 231, (46) Sequence ID 232, (47) Sequence ID 237, (48) Sequence ID 238, (49) Sequence ID 239, (50) Sequence ID 240, (51) Both Sequence IDs 59 and 60, (52) Both Sequence IDs 65 and 66, (53) Both Sequence IDs 67 and 68, (54) Both Sequence IDs 73 and 74, (55) Both Sequence IDs 75 and 76, (56) Both Sequence IDs 81 and 82 , (57) both sequence numbers 83 and 84, (58) both sequence numbers 89 and 90, (59) both sequence numbers 91 and 92, (60) both sequence numbers 97 and 98, (61) both sequence numbers 99 and 100, (62) both sequence numbers 189 and 190, (63) both sequence numbers 191 and 192, (64) both sequence numbers 197 and 198, (65) both sequence numbers 199 and 200, (66) both sequence numbers 205 and 206, (67) both sequence numbers 207 and 208, (68) both sequence numbers 213 and 214,(69) Both sequence numbers 215 and 216, (70) Both sequence numbers 221 and 222, (71) Both sequence numbers 223 and 224, (72) Both sequence numbers 229 and 230, (73) Both sequence numbers 231 and 232, (74) Both sequence numbers 237 and 238, or (75) Both sequence numbers 239 and 240, and sequence numbers 59-60, 65-68, 73-76, 81-84, 89-92, 97-100, 189-192, 197-200, 205-208, 213-216, 221-224, 229-232, and 237-240 are all as defined in Table 3.

[0063] [Table 3-1]

[0064] [Table 3-2]

[0065] [Table 3-3]

[0066] [Table 3-4]

[0067] [Table 3-5]

[0068] [Table 3-6]

[0069] [Table 3-7]

[0070] [Table 3-8]

[0071] In embodiments of the present invention, the substituted amino acid sequence includes a cysteine ​​substitution in the constant regions of one or both the α and β chains, in combination with the substitution of one, two, or three amino acids by hydrophobic amino acids in the transmembrane (TM) domain of the constant region of the α chain (also referred to herein as a "cysteine-substituted LVL-modified TCR"). In this regard, the TCR is a cysteine-substituted LVL-modified chimeric TCR in which the native Thr48 of SEQ ID NO: 53 is substituted with Cys; one, two, or three of the native Ser112, Met114, and Gly115 of SEQ ID NO: 63 are independently substituted with Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; preferably Leu, Ile, or Val; and the native Ser57 of SEQ ID NO: 64 is substituted with Cys. Preferably, all three native Ser112, Met114, and Gly115 of SEQ ID NO: 63 may be independently substituted with Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; preferably Leu, Ile, or Val. In embodiments of the present invention, the cysteine-substituted LVL-modified TCR includes (i) SEQ ID NO: 59, (ii) SEQ ID NO: 60, or (iii) both SEQ ID NOs: 59 and 60, both of which are defined in Table 4. The cysteine-substituted LVL-modified TCR of the present invention may include a substituted constant region in addition to either the CDR or variable region described herein.

[0072] In embodiments, the cysteine-substituted LVL-modified TCR includes a full-length α chain and a full-length β chain. Examples of the sequences of the α and β chains of the cysteine-substituted LVL-modified TCR are shown in Tables 4 and 7. In embodiments of the present invention, the TCR is (1) SEQ ID NO: 59, (2) SEQ ID NO: 60, (3) SEQ ID NO: 65, (4) SEQ ID NO: 66, (5) SEQ ID NO: 67, (6) SEQ ID NO: 68, (7) SEQ ID NO: 69, (8) SEQ ID NO: 70, (9) SEQ ID NO: 71, (10) SEQ ID NO: 72, (11) SEQ ID NO: 73, (12) SEQ ID NO: 74, (13) SEQ ID NO: 75, (14) SEQ ID NO: 76, (15) SEQ ID NO: 77, (16) SEQ ID NO: 78, (17) SEQ ID NO: 79, (18) SEQ ID NO: 80, (19) SEQ ID NO: 81, (20) SEQ ID NO: 82, (2 1) SEQ ID NO: 83, (22) SEQ ID NO: 84, (23) SEQ ID NO: 85, (24) SEQ ID NO: 86, (25) SEQ ID NO: 87, (26) SEQ ID NO: 88, (27) SEQ ID NO: 89, (28) SEQ ID NO: 90, (29) SEQ ID NO: 91, (30) SEQ ID NO: 92, (31) SEQ ID NO: 93, (32) SEQ ID NO: 94, (33) SEQ ID NO: 95, (34) SEQ ID NO: 96, (35) SEQ ID NO: 97, (36) SEQ ID NO: 98, (37) SEQ ID NO: 99, (38) SEQ ID NO: 100, (39) SEQ ID NO: 101, (40) SEQ ID NO: 102, (41) SEQ ID NO: 1 03, (42) SEQ ID NO: 104, (43) SEQ ID NO: 189, (44) SEQ ID NO: 190, (45) SEQ ID NO: 191, (46) SEQ ID NO: 192, (47) SEQ ID NO: 193, (48) SEQ ID NO: 194, (49) SEQ ID NO: 195, (50) SEQ ID NO: 196, (51) SEQ ID NO: 197, (52) SEQ ID NO: 198, (53) SEQ ID NO: 199, (54) SEQ ID NO: 200, (55) SEQ ID NO: 201, (56) SEQ ID NO: 202, (57) SEQ ID NO: 203, (58) SEQ ID NO: 204, (59) SEQ ID NO: 205, (60) SEQ ID NO: 20 6, (61) Sequence ID 207, (62) Sequence ID 208, (63) Sequence ID 209, (64) Sequence ID 210, (65) Sequence ID 211, (66) Sequence ID 212, (67) Sequence ID 213, (68) Sequence ID 214, (69) Sequence ID 215, (70) Sequence ID 216, (71) Sequence ID 217, (72) Sequence ID 218, (73) Sequence ID 219, (74) Sequence ID 220, (75) Sequence ID 221, (76) Sequence ID 222, (77) Sequence ID 223, (78) Sequence ID 224, (79) Sequence ID 225,(80) Sequence ID 226, (81) Sequence ID 227, (82) Sequence ID 228, (83) Sequence ID 229, (84) Sequence ID 230, (85) Sequence ID 231, (86) Sequence ID 232, (87) Sequence ID 233, (88) Sequence ID 234, (89) Sequence ID 235, (90) Sequence ID 236, (91) Sequence ID 237, (92) Sequence ID 238, (93) Sequence ID 239, (94) Sequence ID 240, (95) Sequence ID 241, (96) Sequence ID 242, (97) Sequence ID 243, (98) Sequence ID 244, (99) Both Sequence IDs 59 and 60, ( 100) Both sequence numbers 65 and 66, (101) Both sequence numbers 67 and 68, (102) Both sequence numbers 69 and 70; (103) Both sequence numbers 71 and 72, (104) Both sequence numbers 73 and 74, (105) Both sequence numbers 75 and 76, (106) Both sequence numbers 77 and 78, (107) Both sequence numbers 79 and 80, (108) Both sequence numbers 81 and 82, (109) Both sequence numbers 83 and 84, (110) Both sequence numbers 85 and 86, (111) Both sequence numbers 87 and 88, (112) Both sequence numbers 89 and 90, ( 113) Both sequence numbers 91 and 92, (114) Both sequence numbers 93 and 94, (115) Both sequence numbers 95 and 96, (116) Both sequence numbers 97 and 98, (117) Both sequence numbers 99 and 100, (118) Both sequence numbers 101 and 102, (119) Both sequence numbers 103 and 104, (120) Both sequence numbers 189 and 190, (121) Both sequence numbers 191 and 192, (122) Both sequence numbers 193 and 194, (123) Both sequence numbers 195 and 196, (124) Both sequence numbers 197 and 198, (125) Both sequence numbers 199 and 200, (126) both sequence numbers 201 and 202, (127) both sequence numbers 203 and 204, (128) both sequence numbers 205 and 206, (129) both sequence numbers 207 and 208, (130) both sequence numbers 209 and 210, (131) both sequence numbers 211 and 212, (132) both sequence numbers 213 and 214, (133) both sequence numbers 215 and 216, (134) both sequence numbers 217 and 218, (135) both sequence numbers 219 and 220, (136) both sequence numbers 221 and 222,(137) Both sequence numbers 223 and 224, (138) Both sequence numbers 225 and 226, (139) Both sequence numbers 227 and 228, (140) Both sequence numbers 229 and 230, (141) Both sequence numbers 231 and 232, (142) Both sequence numbers 233 and 234, (143) Both sequence numbers 235 and 236, (144) Both sequence numbers 237 and 238, (145) Sequence number This includes both sequence numbers 239 and 240, both sequence numbers 241 and 242 (146), or both sequence numbers 243 and 244 (147), and sequence numbers 59-60, 65-68, 73-76, 81-84, 89-92, 97-100, 189-192, 197-200, 205-208, 213-216, 221-224, 229-232, and 237-240 are all as defined in Table 4.

[0073] [Table 4-1]

[0074] [Table 4-2]

[0075] [Table 4-3]

[0076] [Table 4-4]

[0077] [Table 4-5]

[0078] [Table 4-6]

[0079] [Table 4-7]

[0080] [Table 4-8]

[0081] [Table 4-9]

[0082] In embodiments of the present invention, the cysteine-substituted LVL-modified TCR includes (a) SEQ ID NO: 61 (α-chain constant region of the cysteine-substituted LVL-modified TCR); (b) SEQ ID NO: 62 (β-chain constant region of the cysteine-substituted LVL-modified TCR); or (c) both (a) and (b).

[0083] Furthermore, the present invention provides polypeptides comprising any of the functional portions of the TCRs described herein. The term "polypeptide," as used herein, refers to a single chain of amino acids comprising an oligopeptide and linked by one or more peptide bonds.

[0084] With respect to the polypeptide of the present invention, the functional portion may be any portion of the TCR comprising a sequence of amino acids, insofar as it specifically binds to the G13D RAS. When the term “functional portion” is used in relation to the TCR, it refers to any portion or fragment of the TCR of the present invention that retains the biological activity of the TCR (parent TCR) to which the portion or fragment is a part. The functional portion includes, for example, a portion of the TCR that specifically binds to the G13D RAS or retains the ability to detect, treat, or prevent cancer to the same degree, the same degree, or a higher degree as the parent TCR (for example, within the framework of any of the HLA class II molecules described herein). With respect to the parent TCR, the functional portion may constitute, for example, about 10%, about 25%, about 30%, about 50%, about 70%, about 80%, about 90%, about 95%, or more of the parent TCR.

[0085] The functional portion may contain additional amino acids at its amino or carboxyl terminus, or both, that are not present in the amino acid sequence of the parent TCR. Preferably, the additional amino acids do not interfere with the biological function of the functional portion, such as having the ability to specifically bind to G13D RAS and / or detect cancer, or to treat or prevent cancer. More preferably, the additional amino acids enhance the biological activity compared to the biological activity of the parent TCR.

[0086] The polypeptide may include functional portions of either or both of the α-chain and β-chain of the TCR of the present invention, for example, a functional portion comprising one or more of the variable regions CDR1, CDR2, and CDR3 of the α-chain and / or β-chain of the TCR of the present invention. In embodiments of the present invention, the polypeptide is sequence number 1 (CDR1 of the α chain of 4400 TCR-A1), sequence number 2 (CDR2 of the α chain of 4400 TCR-A1), sequence number 3 (CDR3 of the α chain of 4400 TCR-A1), sequence number 4 (CDR1 of the β chain of 4400 TCR-A1), sequence number 5 (CDR2 of the β chain of 4400 TCR-A1), sequence number 6 (CDR3 of the β chain of 4400 TCR-A1), sequence number 11 (CDR1 of the α chain of 4400 TCR-A2), sequence number 12 (CDR2 of the α chain of 4400 TCR-A2), sequence number 13 (CDR3 of the α chain of 4400 TCR-A2), sequence number 14 (CDR1 of the β chain of 4400 TCR-A2), sequence number 15 (4400 TCR-A2 β-chain CDR2), SEQ ID NO: 16 (4400 TCR-A2 β-chain CDR3), SEQ ID NO: 21 (4400 TCR-E α-chain CDR1), SEQ ID NO: 22 (4400 TCR-E α-chain CDR2), SEQ ID NO: 23 (4400 TCR-E α-chain CDR3), SEQ ID NO: 24 (4400 TCR-E β-chain CDR1), SEQ ID NO: 25 (4400 TCR-E β-chain CDR2), SEQ ID NO: 26 (4400 TCR-E β-chain CDR3), SEQ ID NO: 31 (4400 TCR-J α-chain CDR1), SEQ ID NO: 32 (4400 TCR-J α-chain CDR2), SEQ ID NO: 33 (4400 TCR-J α-chain CDR3), SEQ ID NO: 34 (4400 CDR1 of the β-chain of TCR-J), SEQ ID NO: 35 (CDR2 of the β-chain of 4400 TCR-J), SEQ ID NO: 36 (CDR3 of the β-chain of 4400 TCR-J), SEQ ID NO: 41 (CDR1 of the α-chain of 4400 TCR-N), SEQ ID NO: 42 (CDR2 of the α-chain of 4400 TCR-N), SEQ ID NO: 43 (CDR3 of the α-chain of 4400 TCR-N), SEQ ID NO: 44 (CDR1 of the β-chain of 4400 TCR-N), SEQ ID NO: 45 (CDR2 of the β-chain of 4400 TCR-N), SEQ ID NO: 46 (CDR3 of the β-chain of 4400 TCR-N), SEQ ID NO: 119 (CDR1 of the α-chain of 4400 TCR-A3), SEQ ID NO: 120 (CDR2 of the α-chain of 4400 TCR-A3),SEQ ID NO: 121 (CDR3 of the α chain of 4400 TCR-A3), SEQ ID NO: 122 (CDR1 of the β chain of 4400 TCR-A3), SEQ ID NO: 123 (CDR2 of the β chain of 4400 TCR-A3), SEQ ID NO: 124 (CDR3 of the β chain of 4400 TCR-A3), SEQ ID NO: 129 (CDR1 of the α chain of 4400 TCR-J2), SEQ ID NO: 130 (CDR2 of the α chain of 4400 TCR-J2), SEQ ID NO: 131 (CDR3 of the α chain of 4400 TCR-J2), SEQ ID NO: 132 (CDR1 of the β chain of 4400 TCR-J2), SEQ ID NO: 133 (CDR2 of the β chain of 4400 TCR-J2), SEQ ID NO: 134 (CDR3 of the β chain of 4400 TCR-J2), SEQ ID NO: 139 (4400 TCR-N4 α-chain CDR1), SEQ ID NO: 140 (4400 TCR-N4 α-chain CDR2), SEQ ID NO: 141 (4400 TCR-N4 α-chain CDR3), SEQ ID NO: 142 (4400 TCR-N4 β-chain CDR1), SEQ ID NO: 143 (4400 TCR-N4 β-chain CDR2), SEQ ID NO: 144 (4400 TCR-N4 β-chain CDR3), SEQ ID NO: 149 (4400 TCR-N12 α-chain CDR1), SEQ ID NO: 150 (4400 TCR-N12 α-chain CDR2), SEQ ID NO: 151 (4400 TCR-N12 α-chain CDR3), SEQ ID NO: 152 (4400 TCR-N12 β-chain CDR1), SEQ ID NO: 153 (4400 TCR-N12 β-chain CDR2), SEQ ID NO: 154 (4400 TCR-N12 β-chain CDR3), SEQ ID NO: 159 (4400 TCR-N13 α-chain CDR1), SEQ ID NO: 160 (4400 TCR-N13 α-chain CDR2), SEQ ID NO: 161 (4400 TCR-N13 α-chain CDR3), SEQ ID NO: 162 (4400 TCR-N13 β-chain CDR1), SEQ ID NO: 163 (4400 TCR-N13 β-chain CDR2), SEQ ID NO: 164 (4400 TCR-N13 β-chain CDR3), SEQ ID NO: 169 (4400 TCR-C α-chain CDR1), SEQ ID NO: 170 (4400 TCR-C α-chain CDR2), SEQ ID NO: 171 (4400 CDR3 of the α chain of TCR-C), SEQ ID NO: 172 (CDR1 of the β chain of 4400 TCR-C), SEQ ID NO: 173 (CDR2 of the β chain of 4400 TCR-C), SEQ ID NO: 174 (CDR3 of the β chain of 4400 TCR-C),The amino acid sequences may include SEQ ID NO: 179 (CDR1 of the α-chain of 4400 TCR-20), SEQ ID NO: 180 (CDR2 of the α-chain of 4400 TCR-20), SEQ ID NO: 181 (CDR3 of the α-chain of 4400 TCR-20), SEQ ID NO: 182 (CDR1 of the β-chain of 4400 TCR-20), SEQ ID NO: 183 (CDR2 of the β-chain of 4400 TCR-20), SEQ ID NO: 184 (CDR3 of the β-chain of 4400 TCR-20), or combinations thereof. In this regard, the polypeptide of the present invention may contain one or more amino acid sequences selected from the group consisting of SEQ ID NOs: 1-6, 11-16, 21-26, 31-36, 41-46, 119-124, 129-134, 139-144, 149-154, 159-164, 169-174, or 179-184. In embodiments of the present invention, the polypeptide is (a) all of SEQ ID NOs: 1-3, (b) all of SEQ ID NOs: 4-6, (c) all of SEQ ID NOs: 1-6, (d) all of SEQ ID NOs: 11-13, (e) all of SEQ ID NOs: 14-16, (f) all of SEQ ID NOs: 11-16, (g) all of SEQ ID NOs: 21-23, (h) all of SEQ ID NOs: 24-26, (i) all of SEQ ID NOs: 21-26, (j) all of SEQ ID NOs: 31-33, (k) all of SEQ ID NOs: 34-36, (l) all of SEQ ID NOs: 31-36, (m) all of SEQ ID NOs: 41-43, (n) all of SEQ ID NOs: 44-46, (o) all of SEQ ID NOs: 41-46, (p) all of SEQ ID NOs: 119-121, (q) all of SEQ ID NOs: 122-124, (r) all of SEQ ID NOs: 119-124, (s) All of sequence numbers 129-131, (t) all of sequence numbers 132-134, (u) all of sequence numbers 129-134, (v) all of sequence numbers 139-141, (w) all of sequence numbers 142-144, (x) all of sequence numbers 139-144, (y) all of sequence numbers 149-151, (z) all of sequence numbers 152-154, (aa) all of sequence numbers 149-154, (bb) all of sequence numbers 159-161, (cc) all of sequence numbers 162-164, (dd) all of sequence numbers 159-164, (ee) all of sequence numbers 169-171, (ff) all of sequence numbers 172-174, (gg) all of sequence numbers 169-174, (hh) all of sequence numbers 179-181, (ii) all of sequence numbers 182-184,Or (jj) containing all amino acid sequences of SEQ ID NOs. 179-184. In preferred embodiments, the polypeptide contains all amino acid sequences of (i) SEQ ID NOs. 1-6, (ii) SEQ ID NOs. 11-16, (iii) SEQ ID NOs. 21-26, (iv) SEQ ID NOs. 31-36, (v) SEQ ID NOs. 41-46, (vi) all of SEQ ID NOs. 119-124, (vii) all of SEQ ID NOs. 129-134, (viii) all of SEQ ID NOs. 139-144, (ix) all of SEQ ID NOs. 149-154, (x) all of SEQ ID NOs. 159-164, (xi) all of SEQ ID NOs. 169-174, or (xii) all of SEQ ID NOs. 179-184.

[0087] In embodiments of the present invention, the polypeptide of the present invention may include, for example, a variable region of the TCR of the present invention that includes a combination of the above-mentioned CDR regions. In this regard, the polypeptide is (1) SEQ ID NO: 7, (2) SEQ ID NO: 8, (3) SEQ ID NO: 9, (4) SEQ ID NO: 10, (5) SEQ ID NO: 17, (6) SEQ ID NO: 18, (7) SEQ ID NO: 19, (8) SEQ ID NO: 20, (9) SEQ ID NO: 27, (10) SEQ ID NO: 28, (11) SEQ ID NO: 29, (12) SEQ ID NO: 30, (13) SEQ ID NO: 37, (14) SEQ ID NO: 38, (15) SEQ ID NO: 39, (16) SEQ ID NO: 40, (17) SEQ ID NO: 47, (18) SEQ ID NO: 48, (19) SEQ ID NO: 49, (20) SEQ ID NO: 50, (21) SEQ ID NO: 125 , (22) SEQ ID NO: 126, (23) SEQ ID NO: 127, (24) SEQ ID NO: 128, (25) SEQ ID NO: 135, (26) SEQ ID NO: 136, (27) SEQ ID NO: 137, (28) SEQ ID NO: 138, (29) SEQ ID NO: 145, (30) SEQ ID NO: 146, (31) SEQ ID NO: 147, (32) SEQ ID NO: 148, (33) SEQ ID NO: 155, (34) SEQ ID NO: 156, (35) SEQ ID NO: 157, (36) SEQ ID NO: 158, (37) SEQ ID NO: 165, (38) SEQ ID NO: 166, (39) SEQ ID NO: 167, (40) SEQ ID NO: 168, (41) Column number 175, (42) Sequence number 176, (43) Sequence number 177, (44) Sequence number 178, (45) Sequence number 185, (46) Sequence number 186, (47) Sequence number 187, (48) Sequence number 188, (49) Both Sequence numbers 7 and 8, (50) Both Sequence numbers 9 and 10, (51) Both Sequence numbers 17 and 18, (52) Both Sequence numbers 19 and 20, (53) Both Sequence numbers 27 and 28, (54) Both Sequence numbers 29 and 30, (55) Both Sequence numbers 37 and 38, (56) Both Sequence numbers 39 and 40, (5 7) Both SEQ ID NOs. 47 and 48, (58) Both SEQ ID NOs. 49 and 50, (59) Both SEQ ID NOs. 125 and 126, (60) Both SEQ ID NOs. 127 and 128, (61) Both SEQ ID NOs. 135 and 136, (62) Both SEQ ID NOs. 137 and 138, (63) Both SEQ ID NOs. 145 and 146, (64) Both SEQ ID NOs. 147 and 148, (65) Both SEQ ID NOs. 155 and 156, (66) Both SEQ ID NOs. 157 and 158, (67) Both SEQ ID NOs. 165 and 166, (68) Both SEQ ID NOs. 167 and 168(69) Both of SEQ ID NOs: 175 and 176, (70) Both of SEQ ID NOs: 177 and 178, (71) Both of SEQ ID NOs: 185 and 186, or (72) Both of SEQ ID NOs: 187 and 188 may comprise the amino acid sequence(s). In a preferred embodiment, the polypeptide may comprise (a) both of SEQ ID NOs: 7 and 8, (b) both of SEQ ID NOs: 9 and 10, (c) both of SEQ ID NOs: 17 and 18, (d) both of SEQ ID NOs: 19 and 20, (e) both of SEQ ID NOs: 27 and 28, (f) both of SEQ ID NOs: 29 and 30, (g) both of SEQ ID NOs: 37 and 38, (h) both of SEQ ID NOs: 39 and 40, (i) both of SEQ ID NOs: 47 and 48, (j) both of SEQ ID NOs: 49 and 50, (k) both of SEQ ID NOs: 125 and 126, (l) both of SEQ ID NOs: 127 and 128, (m) SEQ ID NOs: 1 (n) Both SEQ ID NOs: 137 and 138, (o) Both SEQ ID NOs: 145 and 146, (p) Both SEQ ID NOs: 147 and 148, (q) Both SEQ ID NOs: 155 and 156, (r) Both SEQ ID NOs: 157 and 158, (s) Both SEQ ID NOs: 165 and 166, (t) Both SEQ ID NOs: 167 and 168, (u) Both SEQ ID NOs: 175 and 176, (v) Both SEQ ID NOs: 177 and 178, (w) Both SEQ ID NOs: 185 and 186; or (x) Both SEQ ID NOs: 187 and 188;

[0088] In embodiments of the present invention, the polypeptide of the present invention may further comprise the constant region of the TCR of the present invention described above. In this regard, the polypeptide may further comprise the amino acid sequences of SEQ ID NO: 63 (WT mouse constant region of the α chain), SEQ ID NO: 64 (WT mouse constant region of the β chain), SEQ ID NO: 59 (substituted mouse constant region of the α chain), SEQ ID NO: 60 (substituted mouse constant region of the β chain), SEQ ID NO: 61 (α chain constant region of cysteine-substituted LVL-modified TCR), SEQ ID NO: 62 (β chain constant region of cysteine-substituted LVL-modified TCR), both SEQ ID NOs. 59 and 60, both SEQ ID NOs. 61 and 62, or both SEQ ID NOs. 63 and 64. Preferably, the polypeptide further comprises the amino acid sequences of both SEQ ID NOs. 59 and 60, both SEQ ID NOs. 61 and 62, or both SEQ ID NOs. 63 and 64 in combination with any of the CDR regions or variable regions described herein in relation to other embodiments of the present invention. In embodiments of the present invention, one or both SEQ ID NOs. 59 and 60 of the polypeptide are as defined in any one of Tables 2 to 4.

[0089] In embodiments of the present invention, the polypeptide of the present invention may include the full-length α-chain or β-chain of the TCR described herein. In this regard, the polypeptide of the present invention includes SEQ ID NOs. 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198 , may include the amino acid sequence of SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 202, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 213, SEQ ID NO: 214, SEQ ID NO: 215, SEQ ID NO: 216, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 222, SEQ ID NO: 223, SEQ ID NO: 224, SEQ ID NO: 225, SEQ ID NO: 226, SEQ ID NO: 227, SEQ ID NO: 228, SEQ ID NO: 229, SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, SEQ ID NO: 237, SEQ ID NO: 238, SEQ ID NO: 239, SEQ ID NO: 240, SEQ ID NO: 241, SEQ ID NO: 242, SEQ ID NO: 243, or SEQ ID NO: 244.

[0090] Alternatively, the polypeptide of the present invention may contain both chains of the TCR described herein. For example, the polypeptide may contain both of SEQ ID NOs. 65-66, both of SEQ ID NOs. 67-68, both of SEQ ID NOs. 69-70, both of SEQ ID NOs. 71-72, both of SEQ ID NOs. 73-74, both of SEQ ID NOs. 75-76, both of SEQ ID NOs. 77-78, both of SEQ ID NOs. 79-80, both of SEQ ID NOs. 81-82, both of SEQ ID NOs. 83-84, both of SEQ ID NOs. 85-86, both of SEQ ID NOs. 87-88, both of SEQ ID NOs. 89-90, both of SEQ ID NOs. 91-92, both of SEQ ID NOs. 93-94, both of SEQ ID NOs. 95-96, both of SEQ ID NOs. 97-98, both of SEQ ID NOs. 99-100, both of SEQ ID NOs. 101-102, both of SEQ ID NOs. 103-104, both of SEQ ID NOs. 189 and 190, both of SEQ ID NOs. 191 and 192, both of SEQ ID NOs. 193 and 194, both of SEQ ID NOs. 195 and 196, both of SEQ ID NOs. 197 and 198, both of SEQ ID NOs. 199 and 200 The amino acid sequences may include both of the following: both of sequence numbers 201 and 202, both of sequence numbers 203 and 204, both of sequence numbers 205 and 206, both of sequence numbers 207 and 208, both of sequence numbers 209 and 210, both of sequence numbers 211 and 212, both of sequence numbers 213 and 214, both of sequence numbers 215 and 216, both of sequence numbers 217 and 218, both of sequence numbers 219 and 220, both of sequence numbers 221 and 222, both of sequence numbers 223 and 224, both of sequence numbers 225 and 226, both of sequence numbers 227 and 228, both of sequence numbers 229 and 230, both of sequence numbers 231 and 232, both of sequence numbers 233 and 234, both of sequence numbers 235 and 236, both of sequence numbers 237 and 238, both of sequence numbers 239 and 240, both of sequence numbers 241 and 242, or both of sequence numbers 243 and 244.

[0091] For example, the polypeptide of the present invention is (a) (i) X at position 180 of SEQ ID NO: 65 is Thr or Cys; (ii) X at position 244 of SEQ ID NO: 65 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of SEQ ID NO: 65 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 247 of SEQ ID NO: 65 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp, the amino acid sequence of SEQ ID NO: 65 (α chain of 4400 TCR-A1 having an N-terminal signal peptide); (b) the amino acid sequence of SEQ ID NO: 66 (4400 having an N-terminal signal peptide) where X at position 188 of SEQ ID NO: 66 is Ser or Cys (c) the β-chain of TCR-A1; (d) the amino acid sequences of both SEQ ID NOs. 65 and 66; (i) the X at position 158 of SEQ ID NOs. 67 is Thr or Cys; (ii) the X at position 222 of SEQ ID NOs. 67 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) the X at position 224 of SEQ ID NOs. 67 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) the X at position 225 of SEQ ID NOs. 67 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp, the amino acid sequence of SEQ ID NOs. 67 (predicted sequence of the α-chain of 4400 TCR-A1 without an N-terminal signal peptide); (e) the amino acid sequence of SEQ ID NOs. 68 (predicted sequence of the α-chain of 4400 TCR-A1 without an N-terminal signal peptide) where the X at position 169 of SEQ ID NOs. 68 is Ser or Cys; (f) Predicted sequence of the β-chain of TCR-A1; (g) Amino acid sequences of both SEQ ID NOs. 67 and 68; (h) Amino acid sequence of SEQ ID NOs. 69 (α-chain of cysteine-substituted LVL modified 4400 TCR-A1 with N-terminal signal peptide); (i) Amino acid sequence of SEQ ID NOs. 70 (β-chain of cysteine-substituted LVL modified 4400 TCR-A1 with N-terminal signal peptide); (i) Amino acid sequence of SEQ ID NOs. 71 (Predicted sequence of the α-chain of cysteine-substituted LVL modified 4400 TCR-A1 without N-terminal signal peptide);(j) The amino acid sequence of SEQ ID NO: 72 (predicted sequence of the β-chain of cysteine-substituted LVL modified 4400 TCR-A1 without an N-terminal signal peptide); (k) The amino acid sequences of both SEQ ID NOs: 69 and 70; (l) The amino acid sequences of both SEQ ID NOs: 71 and 72; (m) The amino acid sequence of SEQ ID NO: 73 (i) X at position 180 of SEQ ID NO: 73 is Thr or Cys; (ii) X at position 244 of SEQ ID NO: 73 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of SEQ ID NO: 73 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 247 of SEQ ID NO: 73 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 TCR-A1 with an N-terminal signal peptide) (n) The amino acid sequence of SEQ ID NO: 74 (4400 TCR-A2 β-chain having an N-terminal signal peptide), where X at position 188 of SEQ ID NO: 74 is Ser or Cys; (o) The amino acid sequences of both SEQ ID NO: 73 and 74; (p) (i) X at position 158 of SEQ ID NO: 75 is Thr or Cys; (ii) X at position 222 of SEQ ID NO: 75 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 224 of SEQ ID NO: 75 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 225 of SEQ ID NO: 75 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (q) Predicted sequence of the α-chain of TCR-A2; (q) Amino acid sequence of SEQ ID NO: 76, where X at position 169 of SEQ ID NO: 76 is either Ser or Cys (predicted sequence of the β-chain of 4400 TCR-A2 without an N-terminal signal peptide); (r) Amino acid sequences of both SEQ ID NOs: 75 and 76; (s) Amino acid sequence of SEQ ID NO: 77 (α-chain of cysteine-substituted LVL modified 4400 TCR-A2 with an N-terminal signal peptide); (t) Amino acid sequence of SEQ ID NO: 78 (β-chain of cysteine-substituted LVL modified 4400 TCR-A2 with an N-terminal signal peptide);(u) Amino acid sequence of SEQ ID NO: 79 (predicted sequence of the α chain of cysteine-substituted LVL modified 4400 TCR-A2 without an N-terminal signal peptide); (v) Amino acid sequence of SEQ ID NO: 80 (cysteine-substituted LVL modified 4400 without an N-terminal signal peptide) (w) Amino acid sequences of both SEQ ID NOs: 77 and 78; (x) Amino acid sequences of both SEQ ID NOs: 79 and 80; (y) Amino acid sequence of SEQ ID NOs: 81 (with N-terminal signal peptide 4400) such that (i) X at position 177 of SEQ ID NOs: 81 is Thr or Cys; (ii) X at position 241 of SEQ ID NOs: 81 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 243 of SEQ ID NOs: 81 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 244 of SEQ ID NOs: 81 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (z) The amino acid sequence of SEQ ID NO: 82 (4400 TCR-E β-chain having an N-terminal signal peptide), where X at position 189 of SEQ ID NO: 82 is Ser or Cys; (aa) The amino acid sequences of both SEQ ID NO: 81 and 82; (bb) (i) X at position 160 of SEQ ID NO: 83 is Thr or Cys; (ii) X at position 224 of SEQ ID NO: 83 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 226 of SEQ ID NO: 83 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 227 of SEQ ID NO: 83 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (cc) Predicted sequence of the α-chain of TCR-E; (cc) Amino acid sequence of SEQ ID NO: 84, where X at position 170 is either Ser or Cys (predicted sequence of the β-chain of 4400 TCR-E without an N-terminal signal peptide); (dd) Amino acid sequences of both SEQ ID NOs: 83 and 84; (ee) Amino acid sequence of SEQ ID NO: 85 (α-chain of cysteine-substituted LVL modified 4400 TCR-E with an N-terminal signal peptide);(ff) Amino acid sequence of SEQ ID NO: 86 (β chain of cysteine-substituted LVL modified 4400 TCR-E with N-terminal signal peptide); (gg) Amino acid sequence of SEQ ID NO: 87 (predicted sequence of α chain of cysteine-substituted LVL modified 4400 TCR-E without N-terminal signal peptide); (hh) Amino acid sequence of SEQ ID NO: 88 (cysteine-substituted LVL modified 4400 without N-terminal signal peptide) (ii) The predicted sequence of the β-chain of TCR-E; (ii) The amino acid sequences of both SEQ ID NOs: 85 and 86; (jj) The amino acid sequences of both SEQ ID NOs: 87 and 88; (kk) The amino acid sequence of SEQ ID NOs: 89 (with an N-terminal signal peptide) such that (i) X at position 183 of SEQ ID NOs: 89 is Thr or Cys; (ii) X at position 247 of SEQ ID NOs: 89 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 249 of SEQ ID NOs: 89 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 250 of SEQ ID NOs: 89 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (ii) The amino acid sequence of SEQ ID NO: 90 (4400 TCR-J β-chain) where X at position 188 of SEQ ID NO: 90 is Ser or Cys; (mm) The amino acid sequences of both SEQ ID NO: 89 and 90; (nn) (i) X at position 161 of SEQ ID NO: 91 is Thr or Cys; (ii) X at position 225 of SEQ ID NO: 91 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of SEQ ID NO: 91 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of SEQ ID NO: 91 (4400 TCR-J β-chain) where X at position 228 of SEQ ID NO: 91 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (oo) Predicted sequence of the α-chain of TCR-J; (oo) Amino acid sequence of SEQ ID NO: 92, where X at position 169 of SEQ ID NO: 92 is either Ser or Cys (predicted sequence of the β-chain of TCR-J without an N-terminal signal peptide); (pp) Amino acid sequences of both SEQ ID NOs: 91 and 92;(qq) Amino acid sequence of SEQ ID NO: 93 (α chain of cysteine-substituted LVL modified 4400 TCR-J with N-terminal signal peptide); (rr) Amino acid sequence of SEQ ID NO: 94 (β chain of cysteine-substituted LVL modified 4400 TCR-J with N-terminal signal peptide); (ss) Amino acid sequence of SEQ ID NO: 95 (predicted sequence of α chain of cysteine-substituted LVL modified 4400 TCR-J without N-terminal signal peptide); (tt) Amino acid sequence of SEQ ID NO: 96 (cysteine-substituted LVL modified 4400 without N-terminal signal peptide) (uu) Amino acid sequences of both SEQ ID NOs: 93 and 94; (vv) Amino acid sequences of both SEQ ID NOs: 95 and 96; (ww) Amino acid sequence of SEQ ID NOs: 97 (with N-terminal signal peptide 4400) where (i) X at position 178 of SEQ ID NOs: 97 is Thr or Cys; (ii) X at position 242 of SEQ ID NOs: 97 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 244 of SEQ ID NOs: 97 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 245 of SEQ ID NOs: 97 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (xx) The amino acid sequence of SEQ ID NO: 98 (4400 TCR-N β-chain with N-terminal signal peptide), where X at position 188 of SEQ ID NO: 98 is Ser or Cys; (yy) The amino acid sequences of both SEQ ID NO: 97 and 98; (zz) (i) X at position 157 of SEQ ID NO: 99 is Thr or Cys; (ii) X at position 221 of SEQ ID NO: 99 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 223 of SEQ ID NO: 99 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 224 of SEQ ID NO: 99 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp Predicted sequence of the α-chain of TCR-N);(aaa) The amino acid sequence of SEQ ID NO: 100, where X at position 169 of SEQ ID NO: 100 is either Ser or Cys (predicted sequence of the β-chain of 4400 TCR-N without an N-terminal signal peptide); (bbb) The amino acid sequences of both SEQ ID NO: 99 and 100; (ccc) The amino acid sequence of SEQ ID NO: 101 (α-chain of cysteine-substituted LVL modified 4400 TCR-N with an N-terminal signal peptide); (ddd) The amino acid sequence of SEQ ID NO: 102 (β-chain of cysteine-substituted LVL modified 4400 TCR-N with an N-terminal signal peptide); (eee) The amino acid sequence of SEQ ID NO: 103 (cysteine-substituted LVL without an N-terminal signal peptide; Modified 4400 TCR-N α-chain predicted sequence); (fff) Amino acid sequence of SEQ ID NO: 104 (Cysteine-substituted LVL modification 4400 without N-terminal signal peptide) (iii)(i) The amino acid sequence of the β-chain of TCR-N; (ggg) The amino acid sequences of both SEQ ID NOs: 101 and 102; (hhh) The amino acid sequences of both SEQ ID NOs: 103 and 104; (iii) The amino acid sequence of SEQ ID NOs: 189 (with N-terminal signal peptide 4400) where (i) X at position 176 of SEQ ID NOs: 189 is Thr or Cys; (ii) X at position 240 of SEQ ID NOs: 189 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 242 of SEQ ID NOs: 189 is Met, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; and (iv) X at position 243 of SEQ ID NOs: 189 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp TCR-A3 α-chain); (jjj) The amino acid sequence of SEQ ID NO: 190 (4400 having an N-terminal signal peptide) where X at position 188 of SEQ ID NO: 190 is either Ser or Cys. (kkk) Amino acid sequences of both SEQ ID NOs: 189 and 190; (lll) (i) X at position 157 of SEQ ID NO: 191 is Thr or Cys; (ii) X at position 221 of SEQ ID NO: 191 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 223 of SEQ ID NO: 191 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 224 of SEQ ID NO: 191 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 without an N-terminal signal peptide) Predicted sequence of the α-chain of TCR-A3; (mmm) Amino acid sequence of SEQ ID NO: 192, where X at position 169 is Ser or Cys (predicted sequence of the β-chain of 4400 TCR-A3 without an N-terminal signal peptide); (nnn) Amino acid sequences of both SEQ ID NOs: 191 and 192; (ooo) Amino acid sequence of SEQ ID NO: 193 (α-chain of 4400 TCR-A3 with N-terminal signal peptide and cysteine-substituted LVL modification);(ppp) Amino acid sequence of SEQ ID NO: 194 (β-chain of cysteine-substituted LVL modified 4400 TCR-A3 with N-terminal signal peptide); (qqq) Amino acid sequence of SEQ ID NO: 195 (predicted sequence of α-chain of cysteine-substituted LVL modified 4400 TCR-A3 without N-terminal signal peptide); (rrr) Amino acid sequence of SEQ ID NO: 196 (cysteine-substituted LVL modified 4400 without N-terminal signal peptide) (sss) Amino acid sequences of both SEQ ID NOs: 193 and 194; (ttt) Amino acid sequences of both SEQ ID NOs: 195 and 196; (uuu) Amino acid sequence of SEQ ID NOs: 197 (i) X at position 181 of SEQ ID NOs: 197 is Thr or Cys; (ii) X at position 245 of SEQ ID NOs: 197 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 247 of SEQ ID NOs: 197 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 248 of SEQ ID NOs: 197 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 having an N-terminal signal peptide) TCR-J2 α-chain); (vvv) The amino acid sequence of SEQ ID NO: 198 (4400 having an N-terminal signal peptide) where X at position 188 of SEQ ID NO: 198 is either Ser or Cys (www) Amino acid sequences of both SEQ ID NOs: 197 and 198; (xxx) Amino acid sequence of SEQ ID NOs: 199 (predicted sequence of the α-chain of 4400 TCR-J2 without an N-terminal signal peptide), where (i) X at position 161 of SEQ ID NOs: 199 is Thr or Cys; (ii) X at position 225 of SEQ ID NOs: 199 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of SEQ ID NOs: 199 is Met, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; and (iv) X at position 228 of SEQ ID NOs: 199 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp;(yyy) The amino acid sequence of SEQ ID NO: 200, where X at position 169 of SEQ ID NO: 200 is either Ser or Cys (predicted sequence of the β-chain of 4400 TCR-J2 without an N-terminal signal peptide); (zzz) The amino acid sequences of both SEQ ID NO: 199 and 200; (aaaa) The amino acid sequence of SEQ ID NO: 201 (α-chain of cysteine-substituted LVL modified 4400 TCR-J2 with an N-terminal signal peptide); (bbbb) The amino acid sequence of SEQ ID NO: 202 (β-chain of cysteine-substituted LVL modified 4400 TCR-J2 with an N-terminal signal peptide); (cccc) The amino acid sequence of SEQ ID NO: 203 (predicted sequence of the α-chain of cysteine-substituted LVL modified 4400 TCR-J2 without an N-terminal signal peptide); (dddd) The amino acid sequence of SEQ ID NO: 204 (cysteine-substituted LVL modified 4400 without an N-terminal signal peptide) (eeee) Amino acid sequences of both SEQ ID NOs. 201 and 202; (ffff) Amino acid sequences of both SEQ ID NOs. 203 and 204; (gggg) Amino acid sequence of SEQ ID NOs. 205 (4400 with N-terminal signal peptide) where (i) X at position 184 of SEQ ID NOs. 205 is Thr or Cys; (ii) X at position 248 of SEQ ID NOs. 205 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 250 of SEQ ID NOs. 205 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 251 of SEQ ID NOs. 205 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (TCR-N4 α chain); (hhhh) The amino acid sequence of SEQ ID NO: 206 (β chain of 4400 TCR-N4 with N-terminal signal peptide) where X at position 190 of SEQ ID NO: 206 is Ser or Cys; (iiii) The amino acid sequences of both SEQ ID NO: 205 and 206; (jjjj) (i) X at position 163 of SEQ ID NO: 207 is Thr or Cys; (ii) X at position 227 of SEQ ID NO: 207 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of SEQ ID NO: 207 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp;(iv) The amino acid sequence of SEQ ID NO: 207 (predicted sequence of the α chain of 4400 TCR-N4 without an N-terminal signal peptide) where X at position 230 of SEQ ID NO: 207 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (kkkk) The amino acid sequence of SEQ ID NO: 208 (predicted sequence of the β chain of 4400 TCR-N4 without an N-terminal signal peptide) where X at position 164 of SEQ ID NO: 208 is Ser or Cys; (llll) The amino acid sequences of both SEQ ID NOs: 207 and 208; (mmmm) The amino acid sequence of SEQ ID NO: 209 (α chain of cysteine-substituted LVL modified 4400 TCR-N4 with an N-terminal signal peptide); (nnnn) The amino acid sequence of SEQ ID NO: 210 (cysteine-substituted LVL modified 4400 with an N-terminal signal peptide) TCR-N4 β-chain); (oooo) Amino acid sequence of SEQ ID NO: 211 (Cysteine-substituted LVL modification without N-terminal signal peptide 4400 Predicted sequence of TCR-N4 α-chain); (pppp) Amino acid sequence of SEQ ID NO: 212 (Cysteine-substituted LVL modification without N-terminal signal peptide 4400 (i) The amino acid sequence of the β-chain of TCR-N4 (4400 with an N-terminal signal peptide) is such that (i) X at position 183 of SEQ ID NO: 213 is either Thr or Cys; (ii) X at position 247 of SEQ ID NO: 213 is either Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 249 of SEQ ID NO: 213 is either Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 250 of SEQ ID NO: 213 is either Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp The α-chain of TCR-N12; (tttt) The amino acid sequence of SEQ ID NO: 214, where X at position 188 of SEQ ID NO: 214 is Ser or Cys (4400 TCR-N12 β-chain with N-terminal signal peptide); (uuuu) The amino acid sequences of both SEQ ID NO: 213 and 214; (vvvv) (i) The X at position 161 of SEQ ID NO: 215 is Thr or Cys;(ii) The amino acid sequence of SEQ ID NO: 215 (predicted sequence of the α chain of 4400 TCR-N12 without an N-terminal signal peptide) is such that (ii) X at position 225 of SEQ ID NO: 215 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; and (iv) X at position 228 of SEQ ID NO: 215 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (www) The amino acid sequence of SEQ ID NO: 216 (predicted sequence of the α chain of 4400 TCR-N12 without an N-terminal signal peptide) is such that (ii) X at position 225 of SEQ ID NO: 215 is Ser or Cys; Predicted sequence of the β-chain of TCR-N12); (xxxx) Amino acid sequences of both SEQ ID NOs. 215 and 216; (yyyy) Amino acid sequence of SEQ ID NOs. 217 (α-chain of TCR-N12 with N-terminal signal peptide and cysteine-substituted LVL modification 4400); (zzzz) Amino acid sequence of SEQ ID NOs. 218 (β-chain of TCR-N12 with N-terminal signal peptide and cysteine-substituted LVL modification 4400); (aaaaa) Amino acid sequence of SEQ ID NOs. 219 (predicted sequence of the α-chain of TCR-N12 with N-terminal signal peptide and cysteine-substituted LVL modification 4400); (bbbbb) Amino acid sequence of SEQ ID NOs. 220 (4400 with N-terminal signal peptide and cysteine-substituted LVL modification (cccc) Amino acid sequences of both SEQ ID NOs: 217 and 218; (ddddd) Amino acid sequences of both SEQ ID NOs: 219 and 220; (eeeee) Amino acid sequence of SEQ ID NOs: 221 (α-chain of 4400 TCR-N13 having an N-terminal signal peptide), where (i) X at position 180 of SEQ ID NOs: 221 is Thr or Cys; (ii) X at position 244 of SEQ ID NOs: 221 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of SEQ ID NOs: 221 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 247 of SEQ ID NOs: 221 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp;(fffff) The amino acid sequence of SEQ ID NO: 222 (β-chain of 4400 TCR-N13 with N-terminal signal peptide) where X at position 188 of SEQ ID NO: 222 is Ser or Cys; (ggggg) The amino acid sequences of both SEQ ID NO: 221 and 222; (hhhhh) (i) X at position 158 of SEQ ID NO: 223 is Thr or Cys; (ii) X at position 222 of SEQ ID NO: 223 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 224 of SEQ ID NO: 223 is Met; , Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) the amino acid sequence of SEQ ID NO: 223 (predicted sequence of the α chain of 4400 TCR-N13 without an N-terminal signal peptide) where X at position 225 of SEQ ID NO: 223 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iiiii) the amino acid sequence of SEQ ID NO: 224 (predicted sequence of the β chain of 4400 TCR-N13 without an N-terminal signal peptide) where X at position 169 of SEQ ID NO: 224 is Ser or Cys; (jjjjj) the amino acid sequences of both SEQ ID NO: 223 and 224; (kkkkk) the amino acid sequence of SEQ ID NO: 225 (α chain of cysteine-substituted LVL modified 4400 TCR-N13 with an N-terminal signal peptide); (lllll) the amino acid sequence of SEQ ID NO: 226 (cysteine-substituted LVL modified 4400 with an N-terminal signal peptide) TCR-N13 β-chain; (mmmmm) Amino acid sequence of SEQ ID NO: 227 (Cysteine-substituted LVL modification without N-terminal signal peptide 4400 Predicted sequence of TCR-N13 α-chain; (nnnnn) Amino acid sequence of SEQ ID NO: 228 (Cysteine-substituted LVL modification without N-terminal signal peptide 4400) (4400) Amino acid sequences of SEQ ID NO: 229 (with N-terminal signal peptide) where (i) X at position 184 of SEQ ID NO: 229 is Thr or Cys; (ii) X at position 248 of SEQ ID NO: 229 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 250 of SEQ ID NO: 229 is Met, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; and (iv) X at position 251 of SEQ ID NO: 229 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp The α-chain of TCR-C; (rrrrr) The amino acid sequence of SEQ ID NO: 230, where X at position 189 of SEQ ID NO: 230 is either Ser or Cys (β-chain of 4400 TCR-C with N-terminal signal peptide); (sssss) The amino acid sequences of both SEQ ID NOs: 229 and 230;(ttttt)(i) X at position 163 of SEQ ID NO: 231 is Thr or Cys; (ii) X at position 227 of SEQ ID NO: 231 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of SEQ ID NO: 231 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 230 of SEQ ID NO: 231 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp, the amino acid sequence of SEQ ID NO: 231 (predicted sequence of the α chain of 4400 TCR-C without an N-terminal signal peptide); (uuuuu) X at position 170 of SEQ ID NO: 232 is Ser or Cys, the amino acid sequence of SEQ ID NO: 232 (4400 without an N-terminal signal peptide) Predicted sequence of the β-chain of TCR-C); (vvvvv) Amino acid sequences of both SEQ ID NOs. 231 and 232; (wwwww) Amino acid sequence of SEQ ID NOs. 233 (α-chain of 4400 TCR-C with N-terminal signal peptide and cysteine-substituted LVL modification); (xxxxx) Amino acid sequence of SEQ ID NOs. 234 (β-chain of 4400 TCR-C with N-terminal signal peptide and cysteine-substituted LVL modification); (yyyyy) Amino acid sequence of SEQ ID NOs. 235 (Predicted sequence of the α-chain of 4400 TCR-C with N-terminal signal peptide and cysteine-substituted LVL modification); (zzzzz) Amino acid sequence of SEQ ID NOs. 236 (4400 TCR-C with N-terminal signal peptide and cysteine-substituted LVL modification) Predicted sequence of the β-chain of TCR-C; (aaaaaa) Amino acid sequences of both SEQ ID NOs. 233 and 234; (bbbbbb) Amino acid sequences of both SEQ ID NOs. 235 and 236; (cccccc) (i) X at position 184 of SEQ ID NOs. 237 is either Thr or Cys; (ii) X at position 248 of SEQ ID NOs. 237 is either Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 250 of SEQ ID NOs. 237 is either Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp;(iv) The amino acid sequence of SEQ ID NO: 237 (α chain of 4400 TCR-20 with N-terminal signal peptide) where X at position 251 of SEQ ID NO: 237 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (dddddd) The amino acid sequence of SEQ ID NO: 238 (α chain of 4400 TCR-20 with N-terminal signal peptide) where X at position 189 of SEQ ID NO: 238 is Ser or Cys The β-chain of TCR-20; (eeeeee) The amino acid sequences of both SEQ ID NOs. 237 and 238; (ffffff) (i) X at position 163 of SEQ ID NOs. 239 is Thr or Cys; (ii) X at position 227 of SEQ ID NOs. 239 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of SEQ ID NOs. 239 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 230 of SEQ ID NOs. 239 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp (4400 amino acid sequences without an N-terminal signal peptide) Predicted sequence of the α-chain of TCR-20); (gggggg) Amino acid sequence of SEQ ID NO: 240, where X at position 170 of SEQ ID NO: 240 is Ser or Cys (predicted sequence of the β-chain of 4400 TCR-20 without an N-terminal signal peptide); (hhhhhh) Amino acid sequences of both SEQ ID NO: 239 and 240; (iiiiii) Amino acid sequence of SEQ ID NO: 241 (α-chain of 4400 TCR-20 with N-terminal signal peptide and cysteine-substituted LVL modification); (jjjjjj) Amino acid sequence of SEQ ID NO: 242 (β-chain of 4400 TCR-20 with N-terminal signal peptide and cysteine-substituted LVL modification); (kkkkkk) Amino acid sequence of SEQ ID NO: 243 (predicted sequence of the α-chain of 4400 TCR-20 with N-terminal signal peptide and cysteine-substituted LVL modification); (llllll) Amino acid sequence of SEQ ID NO: 244 (4400 with N-terminal signal peptide and cysteine-substituted LVL modification); Predicted sequence of the β-chain of TCR-20; (mmmmmm) Amino acid sequences of both SEQ ID NOs. 241 and 242;Alternatively, (nnnnnn) may contain both amino acid sequences of SEQ ID NOs. 243 and 244. In embodiments of the present invention, one or more of the SEQ ID NOs. 65-68, 73-76, 81-84, 89-92, 97-100, 189-192, 197-200, 205-208, 213-216, 221-224, 229-232, and 237-240 of the polypeptide are as defined in any one of Tables 2-4.

[0092] Embodiments of the present invention provide proteins comprising at least one polypeptide described herein. “Protein” means a molecule comprising one or more polypeptide chains.

[0093] In embodiments of the present invention, the protein of the present invention comprises: (a) a first polypeptide chain containing the amino acid sequences of SEQ ID NOs. 1-3 and a second polypeptide chain containing the amino acid sequences of SEQ ID NOs. 4-6; (b) a first polypeptide chain containing the amino acid sequences of SEQ ID NOs. 11-13 and a second polypeptide chain containing the amino acid sequences of SEQ ID NOs. 14-16; (c) a first polypeptide chain containing the amino acid sequences of SEQ ID NOs. 21-23 and a second polypeptide chain containing the amino acid sequences of SEQ ID NOs. 24-26; (d) a first polypeptide chain containing the amino acid sequences of SEQ ID NOs. 31-33 and a second polypeptide chain containing the amino acid sequences of SEQ ID NOs. 34-36; (e) a first polypeptide chain containing the amino acid sequences of SEQ ID NOs. 41-43 and a second polypeptide chain containing the amino acid sequences of SEQ ID NOs. 44-46; (f) a first polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 119-121 and a second polypeptide chain containing all the amino acid sequences of SEQ ID NOs. 122-124; (g) all the amino acid sequences of SEQ ID NOs. 129-131 (h) A first polypeptide chain containing amino acid sequences and a second polypeptide chain containing all amino acid sequences of SEQ ID NOs. 132-134; (i) A first polypeptide chain containing all amino acid sequences of SEQ ID NOs. 149-151 and a second polypeptide chain containing all amino acid sequences of SEQ ID NOs. 152-154; (j) A first polypeptide chain containing all amino acid sequences of SEQ ID NOs. 159-161 and a second polypeptide chain containing all amino acid sequences of SEQ ID NOs. 162-164; (k) A first polypeptide chain containing all amino acid sequences of SEQ ID NOs. 169-171 and a second polypeptide chain containing all amino acid sequences of SEQ ID NOs. 172-174; or (l) A first polypeptide chain containing all amino acid sequences of SEQ ID NOs. 179-181 and a second polypeptide chain containing all amino acid sequences of SEQ ID NOs. 182-184.

[0094] In another embodiment of the present invention, (i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 7 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 8; (ii) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10; (iii) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18; (iv) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 19 and the second polypeptide chain (v) The chain contains the amino acid sequence of SEQ ID NO: 20; (vi) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 27, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 28; (vi) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 29, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 30; (vii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 37, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 38; (viii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 39 (ix) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 47, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 48; (x) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 49, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 50; (xi) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 125, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 126; (xii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: (xiii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 127, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 128; (xiv) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 137, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 138; (xv) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 145, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 146;(xvi) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 147, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 148; (xvii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 155, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 156; (xviii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 157, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 158; (xix) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 165, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 166; (xx) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 167 (xxii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 168; (xxiii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 175, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 176; (xxiv) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 177, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 178; (xxiii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 185, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 186; or (xxiv) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 187, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 188.

[0095] The protein of the present invention may further comprise any of the constant regions described herein in relation to other aspects of the present invention. In this regard, in embodiments of the present invention, (i) the first polypeptide chain may further comprise the amino acid sequence of SEQ ID NO: 59 and the second polypeptide chain may further comprise the amino acid sequence of SEQ ID NO: 60; (ii) the first polypeptide chain may further comprise the amino acid sequence of SEQ ID NO: 61 and the second polypeptide chain may further comprise the amino acid sequence of SEQ ID NO: 62; or (ii) the first polypeptide chain may comprise the amino acid sequence of SEQ ID NO: 63 and the second polypeptide chain may comprise the amino acid sequence of SEQ ID NO: 64. In embodiments of the present invention, one or both of SEQ ID NOs. 59 and 60 of the protein are as defined in any one of Tables 2 to 4.

[0096] The protein of the present invention may include a full-length α-chain or β-chain as described herein in relation to other embodiments of the present invention. In this regard, in embodiments of the present invention, (a) the first polypeptide chain is (i) X at position 180 of SEQ ID NO: 65 is Thr or Cys; (ii) X at position 244 of SEQ ID NO: 65 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of SEQ ID NO: 65 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 247 of SEQ ID NO: 65 is Gly, Ala, Val, Leu, Ile, Pro, Phe, M (b) The amino acid sequence of SEQ ID NO: 65 is et or Trp; (c) The second polypeptide chain is the amino acid sequence of SEQ ID NO: 66, wherein the X at position 188 of SEQ ID NO: 66 is Ser or Cys; (d) The first polypeptide chain is (i) the X at position 158 of SEQ ID NO: 67 is Thr or Cys; (ii) the X at position 222 of SEQ ID NO: 67 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) the X at position 224 of SEQ ID NO: 67 (i) the first polypeptide chain is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) the amino acid sequence of SEQ ID NO: 67 is included, wherein X at position 225 of SEQ ID NO: 67 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (e) the second polypeptide chain is included, wherein X at position 169 of SEQ ID NO: 68 is Ser or Cys; (f) both (d) and (e); (g) the first polypeptide chain is included, wherein X at position 69 is Ser or Cys; (h) the The polypeptide chain of 2 contains the amino acid sequence of SEQ ID NO: 70; (i) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 71; (j) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 72; (k) Both (g) and (h); (l) Both (i) and (j); (m) The first polypeptide chain is (i) X at position 180 of SEQ ID NO: 73 is Thr or Cys; (ii) X at position 244 of SEQ ID NO: 73 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp;(iii) The amino acid sequence of SEQ ID NO: 73 is such that X at position 246 of SEQ ID NO: 73 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of SEQ ID NO: 73 is such that X at position 247 of SEQ ID NO: 73 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (n) The second polypeptide chain is such that X at position 188 of SEQ ID NO: 74 is Ser or Cys; (o) Both (m) and (n); (p) The first polypeptide chain is such that (i) the sequence number (i) the amino acid sequence of Sequence ID No. 75, wherein X at position 158 of Sequence ID No. 75 is Thr or Cys; (ii) X at position 222 of Sequence ID No. 75 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 224 of Sequence ID No. 75 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 225 of Sequence ID No. 75 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (q) a second polypeptide The chain contains the amino acid sequence of SEQ ID NO: 76, where X at position 169 of SEQ ID NO: 76 is either Ser or Cys; (r) is both (p) and (q); (s) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 77; (t) the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 78; (u) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 79; (v) the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 80; (w) is both (s) and (t); (x) is both (u) and (v); (y) the first polypeptide The ptide chain contains the amino acid sequence of SEQ ID NO: 81, wherein (i) X at position 177 of SEQ ID NO: 81 is Thr or Cys; (ii) X at position 241 of SEQ ID NO: 81 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 243 of SEQ ID NO: 81 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 244 of SEQ ID NO: 81 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp.(z) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 82, wherein X at position 189 of SEQ ID NO: 82 is Ser or Cys; (aa)(y) and (z); (bb) The first polypeptide chain is (i) X at position 160 of SEQ ID NO: 83 is Thr or Cys; (ii) X at position 224 of SEQ ID NO: 83 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 226 of SEQ ID NO: 83 is Met, Ala, Val, Leu, Ile, Pro, Phe, or (iv) The amino acid sequence of SEQ ID NO: 83 is Trp; and (cc) the second polypeptide chain is the amino acid sequence of SEQ ID NO: 84, where X at position 227 of SEQ ID NO: 83 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (cc) the second polypeptide chain is the amino acid sequence of SEQ ID NO: 84, where X at position 170 of SEQ ID NO: 84 is Ser or Cys; (dd) (bb) and (cc) are both; (ee) the first polypeptide chain is the amino acid sequence of SEQ ID NO: 85; (ff) the second polypeptide chain is the amino acid sequence of SEQ ID NO: 86; (gg) the Polypeptide chain 1 contains the amino acid sequence of SEQ ID NO: 87; (hh) Polypeptide chain 2 contains the amino acid sequence of SEQ ID NO: 88; (ii) Both (ee) and (ff); (jj) Both (gg) and (hh); (kk) Polypeptide chain 1 contains (i) X at position 183 of SEQ ID NO: 89 is Thr or Cys; (ii) X at position 247 of SEQ ID NO: 89 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 249 of SEQ ID NO: 89 is Met, Ala, V (i) The first polypeptide chain is al, Leu, Ile, Pro, Phe, or Trp; and (iv) the amino acid sequence of SEQ ID NO: 89 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (ll) the second polypeptide chain is the amino acid sequence of SEQ ID NO: 90 is Ser or Cys at position 188 of SEQ ID NO: 90; (mm) (kk) and (ll) are both; (nn) the first polypeptide chain is (i) the X at position 161 of SEQ ID NO: 91 is Thr or Cys;(ii) X at position 225 of SEQ ID NO: 91 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of SEQ ID NO: 91 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 228 of SEQ ID NO: 91 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp, comprising the amino acid sequence of SEQ ID NO: 91; (oo) The second polypeptide chain is such that X at position 169 of SEQ ID NO: 92 is Ser or Cys, containing the amino acid sequence of SEQ ID NO: 92; both (pp)(nn) and (oo); (qq) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 93; (rr) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 94; (ss) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 95; (tt) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 96; both (uu)(qq) and (rr); both (vv)(ss) and (tt); (ww) The first polypeptide chain contains the (i) sequence (ii) the X at position 178 of sequence number 97 is Thr or Cys; (ii) the X at position 242 of sequence number 97 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) the X at position 244 of sequence number 97 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) the X at position 245 of sequence number 97 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp, and the amino acid sequence of sequence number 97 is included; (xx) the second polyp The cytoside chain contains the amino acid sequence of SEQ ID NO: 98, wherein the X at position 188 of SEQ ID NO: 98 is either Ser or Cys; it is both (yy)(ww) and (xx); (zz) The first polypeptide chain is (i) the X at position 157 of SEQ ID NO: 99 is either Thr or Cys; (ii) the X at position 221 of SEQ ID NO: 99 is either Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) the X at position 223 of SEQ ID NO: 99 is either Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp;(iv) The amino acid sequence of SEQ ID NO: 99 is included, wherein X at position 224 of SEQ ID NO: 99 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (aaa) The second polypeptide chain is included, wherein X at position 169 of SEQ ID NO: 100 is Ser or Cys; (bbb)(zz) and (aaa) are both; (ccc) The first polypeptide chain is included, wherein the amino acid sequence of SEQ ID NO: 101 is included; (ddd) The second polypeptide chain is included, wherein the amino acid sequence of SEQ ID NO: 102 is included; (eee) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 103; (fff) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 104; (ggg)(ccc) and (ddd) are both; (hhh)(eee) and (fff) are both; (iii) The first polypeptide chain is (i) the X at position 176 of SEQ ID NO: 189 is Thr or Cys; (ii) the X at position 240 of SEQ ID NO: 189 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) SEQ ID NO: The first polypeptide chain is: (iv) The amino acid sequence of SEQ ID NO: 189 is included, wherein X at position 242 of SEQ ID NO: 189 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; (jjj) The second polypeptide chain is included, wherein X at position 188 of SEQ ID NO: 190 is Ser or Cys; (kkk) Both (iii) and (jjj); (lll) The first polypeptide chain is , comprising the amino acid sequence of Sequence ID No. 191, wherein (i) X at position 157 of Sequence ID No. 191 is Thr or Cys; (ii) X at position 221 of Sequence ID No. 191 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 223 of Sequence ID No. 191 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 224 of Sequence ID No. 191 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp;(mmm) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 192, where X at position 169 of SEQ ID NO: 192 is either Ser or Cys; it is both (nnn)(lll) and (mmm); (ooo) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 193; (ppp) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 194; (qqq) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 195; (rrr) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 196; it is both (sss)(ooo) and (ppp); it is both (ttt)(qqq) and (rrr); (uuu) The first polypeptide chain is (i) X at position 181 of SEQ ID NO: 197 is Thr or Cys; (ii) X at position 245 of SEQ ID NO: 197 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 247 of SEQ ID NO: 197 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 248 of SEQ ID NO: 197 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp The first polypeptide chain is (i) the amino acid sequence of SEQ ID NO: 197 is Thr or Cys; (ii) the X at position 225 of SEQ ID NO: 199 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) SEQ ID NO: 19 The amino acid sequence of SEQ ID NO: 199 is included, wherein the X at position 227 of 9 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) the amino acid sequence of SEQ ID NO: 199 is included, wherein the X at position 228 of SEQ ID NO: 199 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (yyy) The second polypeptide chain is included, wherein the X at position 169 of SEQ ID NO: 200 is Ser or Cys; (zzz) Both (xxx) and (yyy); (aaaa) The first polypeptide chain The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 201; (bbbb) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 202; (cccc) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 203; (dddd) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 204; (eeee) (aaaa) and (bbbb) are both; (ffff) (cccc) and (dddd) are both; (gggg) The first polypeptide chain (i) has X at position 184 of SEQ ID NO: 205 as either Thr or Cys;(ii) The X at position 248 of SEQ ID NO: 205 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of SEQ ID NO: 205 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The X at position 251 of SEQ ID NO: 205 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp, and the amino acid sequence of SEQ ID NO: 205 is included; (hhhh) The second polypeptide chain has X at position 190 of SEQ ID NO: 206, The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 206, which is either Ser or Cys; (iii) is both (gggg) and (hhhh); (jjjj) the first polypeptide chain is (i) X at position 163 of SEQ ID NO: 207 is either Thr or Cys; (ii) X at position 227 of SEQ ID NO: 207 is either Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of SEQ ID NO: 207 is either Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The first polypeptide chain contains the amino acid sequence of Sequence ID No. 207, where X at position 230 of sequence number 207 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (kkkk) The second polypeptide chain contains the amino acid sequence of Sequence ID No. 208, where X at position 164 of Sequence ID No. 208 is Ser or Cys; (llll) (jjjj) and (kkkk) are both; (mmmm) The first polypeptide chain contains the amino acid sequence of Sequence ID No. 209; (nnnn) The second polypeptide chain contains the amino acid sequence of Sequence ID No. 210 ;(oooo) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 211;(pppp) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 212;(qqqq) is both (mmmm) and (nnnn);(rrrr) is both (oooo) and (pppp);(ssss) The first polypeptide chain is (i) X at position 183 of SEQ ID NO: 213 is Thr or Cys;(ii) X at position 247 of SEQ ID NO: 213 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp;(iii) The amino acid sequence of SEQ ID NO: 213 is such that X at position 249 of SEQ ID NO: 213 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of SEQ ID NO: 213 is such that X at position 250 of SEQ ID NO: 213 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (tttt) The second polypeptide chain is such that X at position 188 of SEQ ID NO: 214 is Ser or Cys; (uuuu)(ssss) and (tttt) are both; (vvvv ) The first polypeptide chain is (i) X at position 161 of SEQ ID NO: 215 is Thr or Cys; (ii) X at position 225 of SEQ ID NO: 215 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of SEQ ID NO: 215 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 228 of SEQ ID NO: 215 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp, SEQ ID NO: 215 The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 216; (wwww) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 216, where X at position 169 of SEQ ID NO: 216 is either Ser or Cys; (xxxx) (vvvv) and (wwww); (yyyy) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 217; (zzzz) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 218; (aaaaa) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 219; (bbbbb) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 220 Contains a mino acid sequence; is both (ccccc)(yyyy) and (zzzz); is both (ddddd)(aaaaa) and (bbbbb); (eeeee) The first polypeptide chain is (i) X at position 180 of SEQ ID NO: 221 is Thr or Cys; (ii) X at position 244 of SEQ ID NO: 221 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of SEQ ID NO: 221 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp;(iv) The amino acid sequence of SEQ ID NO: 221 is included, wherein the X at position 247 of SEQ ID NO: 221 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (fffff) The second polypeptide chain is included, wherein the X at position 188 of SEQ ID NO: 222 is Ser or Cys; (ggggg)(eeeee) and (fffff) are both; (hhhhh) The first polypeptide chain is (i) the X at position 158 of SEQ ID NO: 223 is Thr or Cys; (ii) the X at position 222 of SEQ ID NO: 223 (iii) the amino acid sequence of SEQ ID NO: 223, wherein X at position 224 of SEQ ID NO: 223 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) the amino acid sequence of SEQ ID NO: 223, wherein X at position 225 of SEQ ID NO: 223 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iiiii) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 224, wherein X at position 169 of SEQ ID NO: 224 is Ser or Cys Includes a column; (jjjjj)(hhhhh) and (iiiii); (kkkkk) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 225; (lllll) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 226; (mmmmm) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 227; (nnnnn) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 228; (ooooo)(kkkkk) and (lllll); (ppppp)(mmmmm) and (nnnnn); (qqqqq) The first polypeptide chain contains the amino acid sequence of Sequence ID No. 229, wherein (i) X at position 184 of Sequence ID No. 229 is Thr or Cys; (ii) X at position 248 of Sequence ID No. 229 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 250 of Sequence ID No. 229 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 251 of Sequence ID No. 229 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp.(rrrrr) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 230, wherein the X at position 189 of SEQ ID NO: 230 is either Ser or Cys; it is both (sssss)(qqqqq) and (rrrrr); (ttttt) The first polypeptide chain is (i) the X at position 163 of SEQ ID NO: 231 is either Thr or Cys; (ii) the X at position 227 of SEQ ID NO: 231 is either Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) the X at position 229 of SEQ ID NO: 231 is either Met, Ala, Val, Le (iv) The amino acid sequence of SEQ ID NO: 231 is u, Ile, Pro, Phe, or Trp; and (iv) the amino acid sequence of SEQ ID NO: 231 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (uuuuu) The second polypeptide chain is the amino acid sequence of SEQ ID NO: 232, where the X at position 170 is Ser or Cys; (vvvvv) Both (ttttt) and (uuuuu); (wwwww) The first polypeptide chain is the amino acid sequence of SEQ ID NO: 233; (xxxx x) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 234; (yyyyy) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 235; (zzzzz) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 236; (aaaaaa) (wwwww) and (xxxxx) are both; (bbbbbb) (yyyyy) and (zzzzz) are both; (cccccc) The first polypeptide chain is (i) the X at position 184 of SEQ ID NO: 237 is Thr or Cys; (ii) the X at position 248 of SEQ ID NO: 237 is Ser or Al (iii) the amino acid sequence of SEQ ID NO: 237 is a, Val, Leu, Ile, Pro, Phe, Met, or Trp; and (iv) the amino acid sequence of SEQ ID NO: 237 is Gly, Ala, Val, Leu, Ile, Pro, Phe, or Trp, and (iv) the amino acid sequence of SEQ ID NO: 237 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (dddddd) the second polypeptide chain is the amino acid sequence of SEQ ID NO: 238 is Ser or Cys, and the X at position 189 of SEQ ID NO: 238 is Ser or Cys;(eeeeee)(cccccc) and (dddddd); (ffffff) The first polypeptide chain is (i) X at position 163 of SEQ ID NO: 239 is Thr or Cys; (ii) X at position 227 of SEQ ID NO: 239 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of SEQ ID NO: 239 is Met, Ala, Val, or Leu; , Ile, Pro, Phe, or Trp; and (iv) the amino acid sequence of SEQ ID NO: 239, wherein X at position 230 of SEQ ID NO: 239 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (gggggg) the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 240, wherein X at position 170 of SEQ ID NO: 240 is Ser or Cys; (hhhhhh) (ffffff) and (gggggg); (iii) iii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 241; (jjjjjj) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 242; (kkkkkk) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 243; (llllll) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 244; (mmmmmm)(iiiiii) and (jjjjjj) or (nnnnnn)(kkkkkk) and (llllll). In embodiments of the present invention, one or more of the protein SEQ ID NOs: 65-68, 73-76, 81-84, 89-92, 97-100, 189-192, 197-200, 205-208, 213-216, 221-224, 229-232, and 237-240 are as defined in any one of Tables 2-4.

[0097] The protein of the present invention may be a TCR. Alternatively, the protein of the present invention may be a fusion protein if, for example, the protein comprises a single polypeptide chain containing the amino acid sequences of both the α and β chains of a TCR, or if the first and / or second polypeptide chain(s) of the protein further comprises an amino acid sequence encoding another amino acid sequence, such as an immunoglobulin or a portion thereof. In this regard, the present invention also provides a fusion protein comprising at least one of the polypeptides of the present invention described herein, together with at least one other polypeptide. The other polypeptide may exist as a separate polypeptide of the fusion protein, or as a polypeptide expressed in frame (tandem) with one of the polypeptides of the present invention described herein. The other polypeptide may encode any peptide or protein molecule or a portion thereof, including but not limited to immunoglobulins, CD3, CD4, CD8, MHC molecules, CD1 molecules, e.g., CD1a, CD1b, CD1c, CD1d, etc.

[0098] The fusion protein may comprise one or more copies of the polypeptide of the present invention and / or one or more copies of other polypeptides. For example, the fusion protein may comprise one, two, three, four, five, or more copies of the polypeptide of the present invention and / or other polypeptides. Preferred methods for producing the fusion protein are known in the art and include, for example, recombinant methods.

[0099] In some embodiments of the present invention, the TCR, polypeptide, and protein of the present invention may be expressed as a single protein comprising a linker peptide linking the α and β chains. In this regard, the TCR, polypeptide, and protein of the present invention may further comprise a linker peptide. The linker peptide may advantageously promote the expression of recombinant TCR, polypeptide, and / or protein in host cells. The linker peptide may comprise any suitable amino acid sequence. The linker peptide may be a cleavable linker peptide. For example, the linker peptide may be a furin-SGSG-P2A linker peptide comprising the amino acid sequence RAKRSGSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 105). Once a construct comprising the linker peptide is expressed by a host cell, the linker peptide may be cleaved to obtain separated α and β chains. In embodiments of the present invention, the TCR, polypeptide, or protein may comprise an amino acid sequence comprising a full-length α chain, a full-length β chain, and a linker peptide located between the α and β chains.

[0100] The protein of the present invention may be a recombinant antibody or its antigen-binding portion, comprising at least one of the polypeptides of the present invention described herein. As used herein, “recombinant antibody” means a recombinant (e.g., genetically engineered) protein comprising at least one of the polypeptides of the present invention and the polypeptide chain of the antibody or its antigen-binding portion. The polypeptide of the antibody or its antigen-binding portion may be the heavy chain, light chain, variable or constant region of the heavy or light chain, single-chain variable region (scFv), or fragments of Fc, Fab, or F(ab)2' of the antibody. The polypeptide chain of the antibody or its antigen-binding portion may exist as separate polypeptides of the recombinant antibody. Alternatively, the polypeptide chain of the antibody or its antigen-binding portion may exist as a polypeptide expressed in frame (tandem) with the polypeptide of the present invention. The polypeptide of the antibody or its antigen-binding portion may be a polypeptide of any antibody or any antibody fragment, comprising any of the antibodies and antibody fragments described herein.

[0101] Functional variants of the TCR, polypeptide, or protein described herein are included within the scope of the present invention. The term “functional variant” as used herein means a TCR, polypeptide, or protein having substantial or significant sequence identity or similarity to the parent TCR, polypeptide, or protein, wherein the functional variant retains the biological activity of the TCR, polypeptide, or protein to which the functional variant is the variant. Functional variants include, for example, variants of the TCR, polypeptide, or protein (parent TCR, polypeptide, or protein) described herein, which retain, to the same degree, or to a greater degree, the ability of the parent TCR to have antigen specificity or to specifically bind to the G13D RAS to which the parent polypeptide or protein specifically binds. With respect to the parental TCR, polypeptide, or protein, the functional variant may be identical in amino acid sequence to, for example, the parental TCR, polypeptide, or protein by at least about 30%, about 50%, about 75%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or more.

[0102] A functional variant may include, for example, the amino acid sequence of a parent TCR, polypeptide, or protein having at least one conserved amino acid substitution. Conserved amino acid substitutions are known in the art and include amino acid substitutions in which one amino acid having certain physical and / or chemical properties is replaced by another amino acid having the same chemical or physical properties. For example, a conserved amino acid substitution may be the substitution of an acidic amino acid with another acidic amino acid (e.g., Asp or Glu), the substitution of an amino acid having a nonpolar side chain with another amino acid having a nonpolar side chain (e.g., Ala, Gly, Val, Ile, Leu, Met, Phe, Pro, Trp, Val, etc.), the substitution of a basic amino acid with another basic amino acid (Lys, Arg, etc.), the substitution of an amino acid having a polar side chain with another amino acid having a polar side chain (Asn, Cys, Gln, Ser, Thr, Tyr, etc.).

[0103] Alternatively, the functional variant may further include an amino acid sequence of a parent TCR, polypeptide, or protein having at least one non-conservative amino acid substitution. In this case, it is preferable that the non-conservative amino acid substitution does not interfere with or inhibit the biological activity of the functional variant. Preferably, the non-conservative amino acid substitution enhances the biological activity of the functional variant, resulting in increased biological activity compared to the parent TCR, polypeptide, or protein.

[0104] A TCR, polypeptide, or protein may essentially consist of one of the specified amino acid sequences described herein, and as a result, other components of the TCR, polypeptide, or protein, such as other amino acids, will not substantially alter the biological activity of the TCR, polypeptide, or protein. In this regard, the TCR, polypeptide, or protein of the present invention may be, for example, SEQ ID NOs. 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 9 0, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 189, SEQ ID NO: 190, SEQ ID NO: 191, SEQ ID NO: 192, SEQ ID NO: 193, SEQ ID NO: 194, SEQ ID NO: 195, SEQ ID NO: 196, SEQ ID NO: 197, SEQ ID NO: 198, SEQ ID NO: 199, SEQ ID NO: 200, SEQ ID NO: 201, SEQ ID NO: 20 2, SEQ ID NO: 203, SEQ ID NO: 204, SEQ ID NO: 205, SEQ ID NO: 206, SEQ ID NO: 207, SEQ ID NO: 208, SEQ ID NO: 209, SEQ ID NO: 210, SEQ ID NO: 211, SEQ ID NO: 212, SEQ ID NO: 213, SEQ ID NO: 214, SEQ ID NO: 215, SEQ ID NO: 216, SEQ ID NO: 217, SEQ ID NO: 218, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 222, SEQ ID NO: 223, SEQ ID NO: 224, SEQ ID NO: 225, SEQ ID NO: 226, SEQ ID NO: 227, SEQ ID NO: 228, SEQ ID NO: 2 29, SEQ ID NOs. 230, SEQ ID NOs. 231, SEQ ID NOs. 232, SEQ ID NOs. 233, SEQ ID NOs. 234, SEQ ID NOs. 235, SEQ ID NOs. 236, SEQ ID NOs. 237, SEQ ID NOs. 238, SEQ ID NOs. 239, SEQ ID NOs. 240, SEQ ID NOs. 241, SEQ ID NOs. 242, SEQ ID NOs. 243, or SEQ ID NOs. 244, both SEQ ID NOs. 65-66, both SEQ ID NOs. 67-68, both SEQ ID NOs. 69-70, both SEQ ID NOs. 71-72, both SEQ ID NOs. 73-74, both SEQ ID NOs. 75-76, both SEQ ID NOs. 77-78,Both of sequence numbers 79-80, both of sequence numbers 81-82, both of sequence numbers 83-84, both of sequence numbers 85-86, both of sequence numbers 87-88, both of sequence numbers 89-90, both of sequence numbers 91-92, both of sequence numbers 93-94, both of sequence numbers 95-96, both of sequence numbers 97-98, both of sequence numbers 99-100, both of sequence numbers 101-102, both of sequence numbers 103-104, both of sequence numbers 189 and 190, both of sequence numbers 191 and 192, both of sequence numbers 193 and 194, both of sequence numbers 195 and 196, both of sequence numbers 197 and 198, both of sequence numbers 199 and 200, both of sequence numbers 201 and 202, both of sequence numbers 203 and 204, both of sequence numbers 205 and 206, sequence numbers It may essentially consist of the amino acid sequences of both 207 and 208, both 209 and 210, both 211 and 212, both 213 and 214, both 215 and 216, both 217 and 218, both 219 and 220, both 221 and 222, both 223 and 224, both 225 and 226, both 227 and 228, both 229 and 230, both 231 and 232, both 233 and 234, both 235 and 236, both 237 and 238, both 239 and 240, both 241 and 242, or both 243 and 244.

[0105] Furthermore, for example, the TCR, polypeptide, or protein of the present invention may include (1) SEQ ID NO: 7, (2) SEQ ID NO: 8, (3) SEQ ID NO: 9, (4) SEQ ID NO: 10, (5) SEQ ID NO: 17, (6) SEQ ID NO: 18, (7) SEQ ID NO: 19, (8) SEQ ID NO: 20, (9) SEQ ID NO: 27, (10) SEQ ID NO: 28, (11) SEQ ID NO: 29, (12) SEQ ID NO: 30, (13) SEQ ID NO: 37, (14) SEQ ID NO: 38, (15) SEQ ID NO: 39, (16) SEQ ID NO: 40, (17) SEQ ID NO: 47, (18) SEQ ID NO: 48, (19) SEQ ID NO: 49, (20) SEQ ID NO: 50, (21) SEQ ID NO: 1 25, (22) SEQ ID NO: 126, (23) SEQ ID NO: 127, (24) SEQ ID NO: 128, (25) SEQ ID NO: 135, (26) SEQ ID NO: 136, (27) SEQ ID NO: 137, (28) SEQ ID NO: 138, (29) SEQ ID NO: 145, (30) SEQ ID NO: 146, (31) SEQ ID NO: 147, (32) SEQ ID NO: 148, (33) SEQ ID NO: 155, (34) SEQ ID NO: 156, (35) SEQ ID NO: 157, (36) SEQ ID NO: 158, (37) SEQ ID NO: 165, (38) SEQ ID NO: 166, (39) SEQ ID NO: 167, (40) SEQ ID NO: 168, (41) SEQ ID NO: 175, (42) SEQ ID NO: Column number 176, (43) Sequence number 177, (44) Sequence number 178, (45) Sequence number 185, (46) Sequence number 186, (47) Sequence number 187, (48) Sequence number 188, (49) Both Sequence numbers 7 and 8, (50) Both Sequence numbers 9 and 10, (51) Both Sequence numbers 17 and 18, (52) Both Sequence numbers 19 and 20, (53) Both Sequence numbers 27 and 28, (54) Both Sequence numbers 29 and 30, (55) Both Sequence numbers 37 and 38, (56) Both Sequence numbers 39 and 40, (57) Both Sequence numbers 47 and 48, (58) Sequence number 49 (59) Both of sequence numbers 125 and 126, (60) Both of sequence numbers 127 and 128, (61) Both of sequence numbers 135 and 136, (62) Both of sequence numbers 137 and 138, (63) Both of sequence numbers 145 and 146, (64) Both of sequence numbers 147 and 148, (65) Both of sequence numbers 155 and 156, (66) Both of sequence numbers 157 and 158, (67) Both of sequence numbers 165 and 166, (68) Both of sequence numbers 167 and 168, (69) Both of sequence numbers 175 and 176, (70) Both of sequence numbers 177 and 178,(71) It may essentially consist of both of sequence numbers 185 and 186, or (72) both of sequence numbers 187 and 188. Furthermore, the TCR, polypeptide, or protein of the present invention includes (a) all of SEQ ID NOs: 1-3, (b) all of SEQ ID NOs: 4-6, (c) all of SEQ ID NOs: 1-6, (d) all of SEQ ID NOs: 11-13, (e) all of SEQ ID NOs: 14-16, (f) all of SEQ ID NOs: 11-16, (g) all of SEQ ID NOs: 21-23, (h) all of SEQ ID NOs: 24-26, (i) all of SEQ ID NOs: 21-26, (j) all of SEQ ID NOs: 31-33, (k) all of SEQ ID NOs: 34-36, (l) all of SEQ ID NOs: 31-36, (m) all of SEQ ID NOs: 41-43, (n) all of SEQ ID NOs: 44-46, (o) all of SEQ ID NOs: 41-46, (p) all of SEQ ID NOs: 119-121, (q) all of SEQ ID NOs: 122-124, (r) all of SEQ ID NOs: 119-124, (s) all of SEQ ID NOs: 129-131, (t) (u) All of sequence numbers 132-134, (v) All of sequence numbers 139-141, (w) All of sequence numbers 142-144, (x) All of sequence numbers 139-144, (y) All of sequence numbers 149-151, (z) All of sequence numbers 152-154, (aa) All of sequence numbers 149-154, (bb) All of sequence numbers 159-161, (cc) sequence The TCRs, polypeptides, and proteins of the present invention may essentially consist of all of sequence numbers 162-164, (dd) all of sequence numbers 159-164, (ee) all of sequence numbers 169-171, (ff) all of sequence numbers 172-174, (gg) all of sequence numbers 169-174, (hh) all of sequence numbers 179-181, (ii) all of sequence numbers 182-184, or (jj) all of the amino acid sequences of sequence numbers 179-184. The TCRs, polypeptides, and proteins of the present invention may be of any length, that is, they may contain any number of amino acids as long as they retain their biological activity, such as the ability to specifically bind to G13D RAS; to detect cancer in mammals; or to treat or prevent cancer in mammals. For example, polypeptides range in length from approximately 50 to approximately 5000 amino acids, for example, approximately 50, 70, 75, 100, 125, 150, 175, 200, 300, 400, 500, 600, 700, 800,The amino acid length may be approximately 900, approximately 1000, or more. In this regard, the polypeptide of the present invention also includes oligopeptides.

[0106] The TCRs, polypeptides, and proteins of the present invention may contain synthetic amino acids instead of one or more naturally occurring amino acids. Such synthetic amino acids are known in the art and include, for example, aminocyclohexanecarboxylic acid, norleucine, α-amino-n-decanoic acid, homoserine, S-acetylaminomethylcysteine, trans-3- and trans-4-hydroxyproline, 4-aminophenylalanine, 4-nitrophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine, β-phenylserine, β-hydroxyphenylalanine, phenylglycine, α-naphthylalanine, cyclohexylalanine, cyclohexylglycine, and indoline. Examples include -2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomalonic acid, aminomalonic acid monoamide, N'-benzyl-N'-methyllysine, N',N'-dibenzyl-lysine, 6-hydroxylysine, ornithine, α-aminocyclopentanecarboxylic acid, α-aminocyclohexanecarboxylic acid, α-aminocycloheptanecarboxylic acid, α-(2-amino-2-norbornane)-carboxylic acid, α,γ-diaminobutyric acid, α,β-diaminopropionic acid, homophenylalanine, and α-tert-butylglycine.

[0107] The TCR, polypeptide, and protein of the present invention may be glycosylated, amidated, carboxylated, phosphorylated, esterified, N-acylated, cyclized via disulfide crosslinks, etc., or converted to an acid addition salt, and / or optionally dimerized, polymerized, or conjugated.

[0108] The TCRs, polypeptides, and / or proteins of the present invention can be obtained by methods known in the art, for example, by de novo synthesis. Alternatively, the polypeptides and proteins can be recombinantly produced using standard recombinant methods and nucleic acids described herein. See, for example, Green and Sambrook, Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Press, Cold Spring Harbor, NY (2012). Alternatively, the TCRs, polypeptides, and / or proteins described herein may be synthesized by any of the various commercial entities. In this regard, the TCRs, polypeptides, and proteins of the present invention may be synthesized, recombinant, isolated, and / or purified. Embodiments of the present invention provide isolated or purified TCRs, polypeptides, or proteins encoded by any of the nucleic acids or vectors described herein in relation to other aspects of the present invention. Another embodiment of the present invention provides isolated or purified TCRs, polypeptides, or proteins obtained as a result of intracellular expression of any of the nucleic acids or vectors described herein. A further embodiment of the present invention provides a method for producing any of the TCRs, polypeptides, or proteins described herein, comprising culturing any of the host cells or populations of host cells described herein so as to produce the TCRs, polypeptides, or proteins.

[0109] The scope of the present invention also includes conjugates, such as bioconjugates, that contain any of the TCRs, polypeptides, or proteins (including any functional portion or variant thereof), nucleic acids, recombinant expression vectors, host cells, populations of host cells, or antibodies or their antigen-binding portions. Conjugates and methods for synthesizing conjugates in general are known in the art.

[0110] Embodiments of the present invention provide nucleic acids comprising nucleotide sequences encoding any of the TCRs, polypeptides, or proteins described herein. “Nucleic acid,” as used herein, includes “polynucleotide,” “oligonucleotide,” and “nucleic acid molecule,” and generally means polymers of DNA or RNA, which may be single-stranded or double-stranded, may contain natural, unnatural, or modified nucleotides, and may contain natural, unnatural, or modified internucleotide bonds, such as phosphoramidate bonds or phosphorothioate bonds, instead of phosphodiesters found between nucleotides in unmodified oligonucleotides. In one embodiment, the nucleic acid comprises complementary DNA (cDNA). Generally, it is preferable that the nucleic acid does not contain any insertions, deletions, inversions, and / or substitutions. However, in some examples, as discussed herein, it may be preferable for the nucleic acid to contain one or more insertions, deletions, inversions, and / or substitutions.

[0111] Preferably, the nucleic acids of the present invention are recombinants. As used herein, the term “recombinant” means (i) a molecule constructed outside of a living cell by linking a natural or synthetic nucleic acid segment to a nucleic acid molecule that can be replicated in a living cell, or (ii) a molecule obtained by replication of the one described in (i) above. For the purposes of this specification, replication may be in vitro or in vivo.

[0112] In embodiments of the present invention, the nucleic acid includes the nucleotide sequence of SEQ ID NO: 114 (4400 TCR-E), SEQ ID NO: 115 (4400 TCR-J), SEQ ID NO: 116 (4400 TCR-N), SEQ ID NO: 117 (4400 TCR-A1), or SEQ ID NO: 118 (4400 TCR-A2).

[0113] Nucleic acids can be constructed based on chemical synthesis and / or enzymatic ligation reactions using procedures known in the art. See, for example, Green and Sambrook et al., cited above. For example, nucleic acids can be chemically synthesized using naturally occurring nucleotides or various modified nucleotides (e.g., phosphorothioate derivatives and acridine-substituted nucleotides) designed to increase the biological stability of the molecule or the physical stability of the double strands formed during hybridization. Examples of modified nucleotides that can be used to make nucleic acids include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, β-D-galactosylqueosin, inosine, N 6 -Isopentenyl adenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N 6 - Substituted adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, β-D-mannosylqueosin, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N 6 Examples include, but are not limited to, isopentenyl adenine, uracil-5-oxyacetic acid(v), weybutoxosin, pseudouracil, queosin, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methyl ester, 3-(3-amino-3-N-2-carboxypropyl)uracil, and 2,6-diaminopurine. Alternatively, one or more of the nucleic acids of the present invention may be purchased from any of the various commercial entities.

[0114] Nucleic acids may comprise any nucleotide sequence encoding any of the TCRs, polypeptides, or proteins described herein. In embodiments of the present invention, the nucleic acid comprises a codon-optimized nucleotide sequence encoding any of the TCRs, polypeptides, or proteins described herein. While not bound by any particular theory or mechanism, codon optimization of nucleotide sequences is thought to increase the translation efficiency of mRNA transcripts. Codon optimization of nucleotide sequences may involve replacing native codons with other codons that encode the same amino acids but can be translated by tRNAs that are more readily available in the cell, thereby increasing translation efficiency. Alternatively, nucleotide sequence optimization may also increase translation efficiency by reducing the secondary structure of mRNA that interferes with translation.

[0115] Furthermore, the present invention provides nucleic acids comprising a nucleotide sequence complementary to any of the nucleotide sequences of the nucleic acids described herein, or a nucleotide sequence that hybridizes to any of the nucleotide sequences of the nucleic acids described herein under stringent conditions.

[0116] Nucleotide sequences that hybridize under stringent conditions preferably hybridize under high-stringent conditions. “High-stringent conditions” means that the nucleotide sequence specifically hybridizes to the target sequence (any nucleotide sequence of the nucleic acids described herein) in a detectably greater amount than in non-specific hybridization. High-stringent conditions include conditions that distinguish polynucleotides having precisely complementary sequences or containing only a few scattered mismatches from random sequences that coincidentally have several small regions (e.g., 3-10 bases) that match the nucleotide sequence. Such complementary small regions melt more readily than full-length complements of 14-17 bases or more, and are therefore readily distinguishable by high-stringent hybridization. Relatively high-stringent conditions include low-salt and / or high-temperature conditions, such as those provided by about 0.02-0.1 M NaCl or equivalent, at a temperature of about 50-70°C. Such highly stringent conditions tolerate only slight mismatches (if any) between the nucleotide sequence and the template or target chain, making them particularly suitable for detecting the expression of any of the TCRs of the present invention. Generally, it is understood that conditions can be made more stringent by adding gradually increasing amounts of formamide.

[0117] Embodiments of the present invention provide nucleic acids comprising nucleotide sequences that are at least about 70% identical, for example, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to any of the nucleic acids described herein. In this regard, the nucleic acid may essentially consist of any of the nucleotide sequences described herein.

[0118] Embodiments of the present invention provide an isolated or purified nucleic acid comprising a first nucleic acid sequence and a second nucleotide sequence from 5' to 3', wherein the first and second nucleotide sequences are, respectively, sequence numbers 7 and 8; 8 and 7; 9 and 10; 10 and 9; 17 and 18; 18 and 17; 19 and 20; 20 and 19; 27 and 28; 28 and 27; 29 and 30; 30 and 29; 37 and 38; 38 and 37; 39 and 40; 40 and 39; 47 and 48; 48 and 47; 49 and 50; 50 and 49; 125 and 126; 126 and 125; 127 and 128; 128 and 127; 135 and 136; 136 and 135; 137 and 138; 138 and 137; 145 and 146; 146 and 145; 147 and 148; 148 and 147; 155 and 156; 156 and 155; 157 and 158; 158 and 157; 165 and 166; 166 and 165; 167 and 168; 168 and 167; 175 and 176; 176 and 175; 177 and 178; 178 and 177; 185 and 186; 186 and 185; 187 and 188; 188 and 187; 65 and 66; 66 and 65; 67 and 68; 68 and 67; 69 and 70; 70 and 69; 71 and 72; 72 and 71; 73 and 74; 74 and 73; 75 and 76; 76 and 75; 77 and 78; 78 and 77; 79 and 80; 80 and 79; 81 and 82; 82 and 81; 83 and 84; 84 and 83; 85 and 86; 86 and 85; 87 and 88; 88 and 87; 89 and 90; 90 and 89; 91 and 92; 92 and 91; 93 and 94; 94 and 93; 95 and 96; 96 and 95; 97 and 98; 98 and 97; 99 and 100; 100 and 99; 101 and 102; 102 and 101; 10 3 and 104; 104 and 103; 189 and 190; 190 and 189; 191 and 192; 192 and 191; 193 and 194; 194 and 193; 195 and 196; 196 and 195; 197 and 198; 198 and 197; 199 and 200; 200 and 199; 201 and 202; 202 and 201; 203 and 204; 204 and 203; 205 and 206; 206 and 205; 207 and 208; 208 and 207; 209 and 210; 210 and 209; 211 and 212; 212 and 211; 213 and 214; 214 and 213;215 and 216; 216 and 215; 217 and 218; 218 and 217; 219 and 220; 220 and 219; 221 and 222; 222 and 221; 223 and 224; 224 and 223; 225 and 226; 226 and 225; 227 and 228; 228 and 227; 229 and 230; 230 and 229; 23 The present invention provides nucleic acids encoding the amino sequences 1 and 232; 232 and 231; 233 and 234; 234 and 233; 235 and 236; 236 and 235; 237 and 238; 238 and 237; 239 and 240; 240 and 239; 241 and 242; 242 and 241; 243 and 244; or 244 and 243.

[0119] In embodiments of the present invention, the isolated or purified nucleic acid further comprises a third nucleotide sequence interposed between a first nucleotide sequence and a second nucleotide sequence, the third nucleotide sequence encoding a cleavable linker peptide. In embodiments of the present invention, the cleavable linker peptide comprises the amino acid sequence RAKRSGSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 105).

[0120] The nucleic acids of the present invention can be incorporated into recombinant expression vectors. In this regard, the present invention provides recombinant expression vectors comprising any of the nucleic acids of the present invention. In embodiments of the present invention, the recombinant expression vector comprises nucleotide sequences encoding an α chain, a β chain, and a linker peptide.

[0121] For the purposes of this specification, the term “recombinant expression vector” means a genetically modified oligonucleotide or polynucleotide construct comprising a nucleotide sequence encoding mRNA, protein, polypeptide, or peptide, such that when the vector is brought into contact with a host cell under conditions sufficient to express the mRNA, protein, polypeptide, or peptide in the host cell, the cell will be able to express the mRNA, protein, polypeptide, or peptide. The vectors of the present invention do not exist in nature as a whole. However, parts of the vectors may exist in nature. The recombinant expression vectors of the present invention may contain any type of nucleotide, including but not limited to DNA and RNA, which may be single-stranded or double-stranded, may be synthesized or partially obtained from natural sources, and may contain natural, non-natural, or modified nucleotides. The recombinant expression vectors may contain naturally occurring nucleotide-nucleotide bonds, non-natural nucleotide-nucleotide bonds, or both types of bonds. Preferably, non-natural or modified nucleotides or nucleotide-nucleotide bonds do not interfere with the transcription or replication of the vector.

[0122] The recombinant expression vector of the present invention may be any suitable recombinant expression vector and can be used to transform or transfect any suitable host cell. Suitable vectors include plasmids and viruses, etc., designed for propagation and proliferation, or for expression, or both. Vectors may be selected from the group consisting of the pUC series (Fermentas Life Sciences), pBluescript series (Stratagene, LaJolla, CA), pET series (Novagen, Madison, WI), pGEX series (Pharmacia Biotech, Uppsala, Sweden), and pEX series (Clontech, Palo Alto, CA). Bacteriophage vectors such as λGT10, λGT11, λZapII (Stratagene), λEMBL4, and λNM1149 may also be used. Examples of plant expression vectors include pBI01, pBI101.2, pBI101.3, pBI121, and pBIN19 (Clontech). Examples of animal expression vectors include pEUK-Cl, pMAM, and pMAMneo(Clontech). Preferably, the recombinant expression vector is a viral vector, such as a retroviral vector. In a particularly preferred embodiment, the recombinant expression vector is an MSGV1 vector. In embodiments of the present invention, the recombinant expression vector is a transposon or a lentiviral vector.

[0123] The recombinant expression vectors of the present invention can be prepared, for example, using the standard recombinant DNA techniques described above by Green and Sambrook et al. The circular or linear expression vector constructs can be prepared to contain a replication system that functions in prokaryotic or eukaryotic host cells. The replication system may be derived from, for example, ColEl, 2μ plasmid, λ, SV40, bovine papillomavirus, etc.

[0124] Preferably, the recombinant expression vector includes regulatory sequences, for example, start and stop codons for transcription and translation specific to the type of host cell into which the vector is introduced (e.g., bacteria, fungi, plants, or animals), as needed, and taking into consideration whether the vector is DNA-based or RNA-based.

[0125] Recombinant expression vectors may contain one or more marker genes that enable the selection of transformed or transfected host cells. Marker genes include those for biocide resistance, such as resistance to antibiotics and heavy metals, and nutritional complementation in the host to provide protrophotrophy. Suitable marker genes for the expression vectors of the present invention include, for example, neomycin / G418 resistance genes, hygromycin resistance genes, histidinol resistance genes, tetracycline resistance genes, and ampicillin resistance genes.

[0126] Recombinant expression vectors may include native or non-native promoters operably ligated to nucleotide sequences encoding TCRs, polypeptides, or proteins, or to nucleotide sequences complementary to or hybridizing with TCRs, polypeptides, or protein-encoding nucleotide sequences. For example, the selection of strong, weak, inducible, tissue-specific, and developmental stage-specific promoters is within the scope of the skills of those skilled in the art. Similarly, the combination of nucleotide sequences and promoters is also within the scope of the skills of those skilled in the art. Promoters may be non-viral promoters, or they may be viral promoters, such as cytomegalovirus (CMV) promoters, SV40 promoters, RSV promoters, and promoters found in the terminal repeat sequences of mouse stem cell viruses.

[0127] The recombinant expression vectors of the present invention can be designed for transient expression, stable expression, or both. Furthermore, the recombinant expression vectors can be prepared for constitutive or inducible expression.

[0128] Furthermore, recombinant expression vectors may be constructed to include suicide genes. As used herein, the term “suicide gene” means a gene that causes cells expressing a suicide gene to die. A suicide gene may be a gene that confers sensitivity to an agent, such as a drug, to cells expressing the gene, and causes the cells to die when they come into contact with or are exposed to the agent. Suicide genes are known in the art and include, for example, the herpes simplex virus (HSV) thymidine kinase (TK) gene, cytosine deaminase, purine nucleoside phosphorylase, nitroreductase, and the inducible caspase 9 gene system.

[0129] Another embodiment of the present invention further provides a host cell containing either the nucleic acid or recombinant expression vector described herein. As used herein, the term “host cell” means any type of cell that may contain the recombinant expression vector of the present invention. The host cell may be a eukaryotic cell, e.g., a plant, animal, fungus, or algae, or a prokaryotic cell, e.g., a bacterium or protist. The host cell may be a cultured cell, or a primary cell, i.e., a cell directly isolated from an organism, e.g., a human. The host cell may be an adherent cell, or a suspension cell, i.e., a cell growing in a suspension. Suitable host cells are known in the art and include, for example, DH5α Escherichia coli cells, Chinese hamster ovary cells, monkey VERO cells, COS cells, HEK293 cells, etc. For the purpose of amplifying or replicating the recombinant expression vector, the host cell is preferably a prokaryotic cell, e.g., a DH5α cell. For the purpose of producing recombinant TCRs, polypeptides, or proteins, the host cell is preferably a mammalian cell. Most preferably, the host cell is a human cell. The host cell may be any cell type, may originate from any type of tissue, and may be at any developmental stage, but the host cell is preferably a peripheral blood lymphocyte (PBL) or peripheral blood mononuclear cell (PBMC). More preferably, the host cell is a T cell. In embodiments of the present invention, the host cell is a human lymphocyte. In another embodiment of the present invention, the host cell is selected from the group consisting of T cells, natural killer T (NKT) cells, invariant natural killer T (iNKT) cells, and natural killer (NK) cells. Yet another embodiment of the present invention is MTEYKLVVVGAG D A method is provided for producing host cells that express a TCR having antigen specificity for the peptide VGKSALTIQLIQ (SEQ ID NO: 252), comprising contacting the cells with one of the vectors described herein under conditions that allow for the introduction of the vector into the cells.

[0130] For the purposes of this specification, the T cells can be any T cells, such as cultured T cells, e.g., primary T cells, or T cells derived from cultured T cell lines, e.g., Jurkat, SupT1, etc., or T cells obtained from mammals, etc. When obtained from mammals, the T cells can be obtained from a number of sources including, but not limited to, blood, bone marrow, lymph nodes, thymus, or other tissues or body fluids. Also, the T cells may be concentrated or purified. Preferably, the T cells are human T cells. The T cells can be any type of T cells and can be at any stage of development, CD4 + / CD8 + double positive T cells, CD4 + helper T cells, e.g., Th1 and Th2 cells, CD4 + T cells, CD8 + T cells (e.g., cytotoxic T cells), tumor infiltrating lymphocytes (TIL), memory T cells (e.g., central memory T cells and effector memory T cells), naive T cells, etc., but are not limited thereto.

[0131] Also provided by the present invention is a population of cells comprising at least one host cell described herein. The population of cells can be a heterogeneous population comprising at least one other cell that does not contain any of the recombinant expression vectors, e.g., a host cell (e.g., a T cell), or a cell other than a T cell, e.g., a B cell, macrophage, neutrophil, erythrocyte, hepatocyte, endothelial cell, epithelial cell, muscle cell, brain cell, etc., in addition to a host cell containing any of the described recombinant expression vectors. Alternatively, the population of cells can be a substantially homogeneous population mainly comprising host cells containing (e.g., consisting essentially of) a recombinant expression vector. Also, the population can be a clonal population of cells where all cells of the population are clones of one host cell containing a recombinant expression vector, and as a result, all cells of the population contain the recombinant expression vector. In one embodiment of the present invention, the population of cells is a clonal population comprising host cells containing the recombinant expression vector described herein.

[0132] In embodiments of the present invention, the number of cells in a population can be rapidly increased. The increase in T cell numbers can be achieved by any of numerous methods known in the art, as described, for example, in U.S. Patent Nos. 8,034,334 and 8,383,099, U.S. Patent Application Publication No. 2012 / 0244133, Dudley et al., J. Immunother., 26:332-42 (2003), and Riddell et al., J. Immunol. Methods, 128:189-201 (1990). In one embodiment, the increase in T cell numbers is carried out by culturing the T cells with an OKT3 antibody, IL-2, and feeder PBMCs (e.g., irradiated allogeneic PBMCs).

[0133] The TCRs, polypeptides, proteins, nucleic acids, recombinant expression vectors, and host cells (including populations thereof) of the present invention may be isolated and / or purified. The term “isolated” as used herein means removed from its natural environment. The term “purified” as used herein means increased purity, and “purity” is a relative term and is not necessarily to be interpreted as absolute purity. For example, purity may be at least about 50%, and may be greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 95%, and may be about 100%.

[0134] The TCRs, polypeptides, proteins, nucleic acids, recombinant expression vectors, and host cells (including populations thereof) of the present invention (hereinafter collectively referred to as "the TCR materials of the present invention") may be formulated into compositions such as pharmaceutical compositions. In this regard, the present invention provides a pharmaceutical composition comprising any of the TCRs, polypeptides, proteins, nucleic acids, expression vectors, and host cells (including populations thereof) described herein, and a pharmaceutically acceptable carrier. A pharmaceutical composition of the present invention containing any of the TCR materials of the present invention may contain one or more TCR materials of the present invention, for example, polypeptides and nucleic acids, or two or more different TCRs. Alternatively, the pharmaceutical composition may contain the TCR materials of the present invention in combination with another pharmaceutically active agent(s) or drug(s), for example, chemotherapeutic agents, for example, asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.

[0135] Preferably, the carrier is a pharmaceutically acceptable carrier. With respect to the pharmaceutical composition, the carrier may be any of those conventionally used with the specific TCR material of the present invention under consideration. Methods for preparing the administerable composition are known or obvious to those skilled in the art, e.g., Remington: The Science and Practice of Pharmacy, 22 nd This is described in detail in Ed., Pharmaceutical Press (2012). A pharmaceutically acceptable carrier is preferably one that does not have harmful side effects or toxicity under the conditions of use.

[0136] The choice of carrier is determined in part by the specific TCR material of the present invention and the specific method used to administer the TCR material of the present invention. Accordingly, a variety of suitable formulations of the pharmaceutical composition of the present invention exist. Suitable formulations may include those administered parenterally, subcutaneously, intravenously, intramuscularly, intra-arterially, subarachnoidally, intratumorally, or intraperitoneally. The TCR material of the present invention may be administered using more than one route, and in certain cases, a particular route may provide a more immediate and effective response than another route.

[0137] Preferably, the TCR material of the present invention is administered, for example, by intravenous injection. When the TCR material of the present invention is host cells (or a population thereof) expressing the TCR of the present invention, a pharmaceutically acceptable carrier for the cells for injection may contain any isotonic carrier, for example, normal saline (about 0.90% w / v NaCl in water, about 300 mOsm / L NaCl in water, or about 9.0 g NaCl per liter of water), NORMOSOL R electrolyte solution (Abbott, Chicago, IL), PLASMA-LYTE A (Baxter, Deerfield, IL), about 5% dextrose in water, or Ringer's lactate solution. In one embodiment, the pharmaceutically acceptable carrier is supplemented with human serum albumen.

[0138] For the purposes of the present invention, the amount or dose of the TCR material of the present invention administered (for example, the number of cells if the TCR material of the present invention is one or more cells) must be sufficient to produce an effect, such as a therapeutic or prophylactic response, in the subject or animal over an appropriate time frame. For example, the dose of the TCR material of the present invention must be sufficient to bind to a cancer antigen (e.g., G13D RAS) or to detect, treat, or prevent cancer for about two hours or more from the time of administration, for example, 12 to 24 hours or longer. In certain embodiments, the period may be longer. The dose is determined by the efficacy of the specific TCR material of the present invention and the condition of the animal (e.g., human), as well as the body weight of the animal being treated (e.g., human).

[0139] Many assays for determining the dose to be administered are known in the art. For the purposes of the present invention, the starting dose to be administered to mammals can be determined by using an assay that includes comparing the extent to which target cells are lysed or IFN-γ is secreted by T cells expressing a given dose of the TCR, polypeptide, or protein of the present invention in a set of mammals given different doses of T cells. The extent to which target cells are lysed or IFN-γ is secreted upon administration of a particular dose can be assayed by methods known in the art.

[0140] The dosage of the TCR material of the present invention is also determined by the presence, nature, and extent of any adverse side effects that may accompany the administration of the specific TCR material of the present invention. Typically, the attending physician determines the dosage of the TCR material of the present invention for treating each individual patient by considering various factors, such as age, weight, overall health, diet, sex, the TCR material of the present invention administered, the route of administration, and the severity of the cancer being treated. In embodiments in which the TCR material of the present invention is a population of cells, the number of cells administered per injection is, for example, about 1 × 10⁶ 6 ~Approx. 1×10 12 It can vary at the level of a single cell or more. In a particular embodiment, 1 × 10 6 It is acceptable to administer fewer than one cell.

[0141] Those skilled in the art will readily understand that the TCR material of the present invention may be modified in any number of ways, and that the therapeutic or prophylactic efficacy of the TCR material of the present invention may be increased through such modification. For example, the TCR material of the present invention may be conjugated with a chemotherapeutic agent directly or indirectly via crosslinking. The practice of conjugating compounds with chemotherapeutic agents is known in the art. Those skilled in the art will recognize that sites of the TCR material of the present invention that are not essential to the function of the TCR material of the present invention are suitable sites for conjugating crosslinks and / or chemotherapeutic agents, as long as the binding of the crosslinks and / or chemotherapeutic agents to the TCR material of the present invention does not interfere with the function of the TCR material of the present invention, i.e., its ability to bind to G13D RAS or its ability to detect, treat, or prevent cancer.

[0142] The pharmaceutical compositions, TCRs, polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, and populations of cells of the present invention are intended to be used in methods for treating or preventing cancer. Although not bound by any particular theory, it is believed that the TCRs of the present invention specifically bind to G13D RAS, and as a result, when expressed by cells, the TCRs (or related polypeptides or proteins of the present invention) can mediate an immune response against target cells expressing G13D RAS. In this regard, embodiments of the present invention provide a method for treating or preventing cancer in a mammal, comprising administering to a mammal an effective amount for treating or preventing cancer in the mammal any of the pharmaceutical compositions, TCRs, polypeptides, or proteins described herein, any nucleic acid or recombinant expression vector containing a nucleotide sequence encoding any of the TCRs, polypeptides, or proteins described herein, or any host cell or population of cells containing a recombinant vector encoding any of the TCRs, polypeptides, or proteins described herein.

[0143] Embodiments of the present invention provide a method for inducing an immune response against cancer in a mammal, comprising administering to the mammal in an amount effective for inducing an immune response against cancer, any of the following: a pharmaceutical composition described herein, a TCR, polypeptide, or protein, any nucleic acid comprising a nucleotide sequence encoding any of the TCR, polypeptide, or protein described herein, or a recombinant expression vector, or any host cell or population of cells comprising a recombinant vector encoding any of the TCR, polypeptide, or protein described herein.

[0144] Embodiments of the present invention provide any of the following for use in the treatment or prevention of cancer in mammals: a pharmaceutical composition described herein, a TCR, polypeptide, or protein, any nucleic acid or recombinant expression vector comprising a nucleotide sequence encoding any of the TCR, polypeptide, or protein described herein, or any host cell or population of cells comprising a recombinant vector encoding any of the TCR, polypeptide, or protein described herein.

[0145] Embodiments of the present invention provide any of the following for use in inducing an immune response against cancer in mammals: a pharmaceutical composition described herein, a TCR, polypeptide, or protein, any nucleic acid or recombinant expression vector comprising a nucleotide sequence encoding any of the TCR, polypeptide, or protein described herein, or any host cell or population of cells comprising a recombinant vector encoding any of the TCR, polypeptide, or protein described herein.

[0146] The terms “to treat” and “to prevent,” and any terms derived therefrom, as used herein, do not necessarily imply 100%, i.e., complete treatment or prevention. Rather, there are varying degrees of treatment or prevention that a person skilled in the art would recognize as having potential benefits or therapeutic effects. In this regard, the methods of the present invention can provide any level of treatment or prevention of any amount of cancer in mammals. Furthermore, the treatment or prevention provided by the methods of the present invention may include the treatment or prevention of one or more conditions or symptoms of the cancer being treated or prevented. For example, treatment or prevention may include promoting tumor regression. Also, for the purposes of this specification, “prevention” may include delaying the onset of cancer or its symptoms or conditions. Or, further, “prevention” may include preventing or delaying the recurrence of cancer or its symptoms or conditions.

[0147] Furthermore, a method for detecting the presence of cancer in mammals is also provided. The method comprises (i) contacting one of the TCRs, polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, cell populations, or pharmaceutical compositions of the present invention as described herein with a sample containing one or more cells of mammalian origin to form a complex, and (ii) detecting the complex, wherein the detection of the complex indicates the presence of cancer in the mammal.

[0148] With respect to the method of the present invention for detecting cancer in mammals, the cell sample may be a sample containing whole cells, their lysates, or fractions of whole cell lysates, such as a nuclear or cytoplasmic fraction, a total protein fraction, or a nucleic acid fraction.

[0149] For the purposes of the present invention's method for detecting cancer, contact may be performed in vitro or in vivo on a mammal. Preferably, contact is performed in vitro.

[0150] Furthermore, the complex can be detected by any number of methods known in the art. For example, the TCR, polypeptide, protein, nucleic acid, recombinant expression vector, host cell, or population of cells described herein may be labeled with a detectable label, such as a radioisotope, fluorophore (e.g., fluorescein isothiocyanate (FITC), phycoerythrin (PE)), enzyme (e.g., alkaline phosphatase, horseradish peroxidase), and elemental particles (e.g., gold particles).

[0151] For the purposes of the method of the present invention, in which host cells or a population of cells are administered, the cells may be homogeneous or self-cells to the mammal. Preferably, the cells are self-cells to the mammal.

[0152] Regarding the method of the present invention, cancers include acute lymphoblastic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vagina, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumors, The cancer may be any cancer, including any of the following: glioma, Hodgkin lymphoma, hypopharyngeal cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharyngeal cancer, non-Hodgkin lymphoma, oropharyngeal cancer, ovarian cancer, penile cancer, pancreatic cancer, peritoneal, retinal, and mesentery cancer, pharyngeal cancer, prostate cancer, rectal cancer, kidney cancer, skin cancer, small intestine cancer, soft tissue cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, ureteral cancer, and bladder cancer. Preferred cancers are pancreatic, colorectal, lung, endometrial, ovarian, or prostate cancer. Preferably, lung cancer is lung adenocarcinoma, ovarian cancer is epithelial ovarian cancer, and pancreatic cancer is pancreatic adenocarcinoma. In embodiments of the present invention, cancer expresses a mutant human RAS amino acid sequence in which glycine at position 13 is substituted with aspartic acid, wherein the mutant human RAS amino acid sequence is the amino acid sequence of mutant human KRAS, mutant human HRAS, or mutant human NRAS, and position 13 is defined by referring to the WT human KRAS, WT human HRAS, or WT human NRAS protein, respectively. The mutant human KRAS, mutant human HRAS, and mutant human NRAS expressed by cancer may be as described herein in relation to other embodiments of the present invention.

[0153] The mammals referred to in the methods of the present invention may be any mammal. As used herein, the term “mammal” means any mammal, including but not limited to rodents such as mice and hamsters, and mammals of the order Lagomorpha such as rabbits. Preferably, the mammals are carnivores, including cats and dogs. More preferably, the mammals are even-toed ungulates, including cats and pigs, or odd-toed ungulates, including horses. Most preferably, the mammals are mammals of the order Primates, Ceboids or Simoids (monkeys), or Haplorhini (humans and apes). A particularly preferred mammal is humans. [Examples]

[0154] The following embodiments further illustrate the present invention, but of course, they should not be interpreted as limiting its scope in any way.

[0155] Example 1 This example demonstrates the isolation of anti-G13D RAS TCRs from TILs in 4400 colorectal cancer patients.

[0156] TILs from tumor fragments of 4400 colorectal cancer patients were independently screened for responsiveness to RAS G13D. TILs (effector cells) from tumor fragments of 4400 patients (numbered F1-F8, F10-F16, and F18-F22) were co-cultured with DCs (target cells). DCs were transfected with (i) mRNA encoding full-length (FL) G13D KRAS (variant B) or the corresponding FL wild-type (WT) KRAS (variant B); or (ii) G13D 25-mer peptide MTEYKLVVVGAGDVGKSALTIQLIQ (SEQ ID NO: 252) or the corresponding WT 25-mer peptide MTEYKLVVVGAG GEffector cells were pulsed with VGKSALTIQLIQ (SEQ ID NO: 253) or cultured with (iii) G13D ME "Mix" (containing a combination of three predicted minimum epitopes from the mutant peptide). Effector cells were used as negative controls by (i) co-culturing with DMSO-treated DCs or (ii) culturing alone (T cells only). Effector cells treated with anti-CD3 / anti-CD28 antibody were used as positive controls.

[0157] Reactivity was tested by measuring IFNγ secretion using the ELISpot assay (Figure 1), and by measuring the expression of one or both of 4-1BB and OX40 by a gated flow cytometry assay of (i) CD3+ / CD4+ cells (Figure 2A) or (ii) CD3+ / CD8+ cells (Figure 2B). TILs from tumor fragments F15, F16, F21, and F22 were co-cultured with DCs pulsed with G13D 25-mer peptide or transduced with full-length G13D KRAS protein, and then reactive cells were observed.

[0158] The enriched populations of TILs from tumor fragments F15, F16, F21, and F22 were screened for reactivity as follows: TILs from tumor fragments F15 and F16 were either untreated or treated as follows: TILs from F16 were stimulated in vitro (IVS) with G13D 25-mer peptide pulsed DCs, or TILs from F15 and F16 were combined, activated (as described in Figures 1 and 2A-2B), and selected for CD4+ / 41BB+ / OX40+ expression before performing a rapid amplification protocol (REP). TILs from tumor fragments F21 and F22 were combined, selected for CD4+ / 41BB+ / OX40+ or ​​CD8+ / 41BB+ / OX40+ expression, and performed REP. REP was performed as follows. After sorting, cells were seeded in T25 flasks and rapidly amplified by adding 2e7 irradiated feeder cells to 20 mL of T cell medium supplemented with 3000 IU / mL of IL-2 and 30 ug / mL of anti-CD3 antibody (Ab) (OKT3). Cells were grown for 11–16 days. Treated TILs were co-cultured with target cells as described in Figures 1 and 2A–2B. Controls were also as described in Figures 1 and 2A–2B. Reactivity was tested by measuring the expression of one or both of 4-1BB and OX40 using flow cytometry assays. The results are shown in Figure 3. Reactive cells were sorted into single cells in 96-well plates by fluorescence-activated cell sorting (FACS) and sequenced to provide TCRα and TCRβ chains for 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-B1, and 4400 TCR-B2.

[0159] The binding activity of the concentrated population of TILs identified as reactive in Figure 3 was tested as follows: TILs were co-cultured with DCs pulsed with various concentrations of G13D 25-mer peptide or the corresponding WT 25-mer peptide. Reactivity was tested by IFNγ secretion using the ELISpot assay. The results are shown in Figures 4A-4B. Figure 4A shows the results obtained from TILs from tumor fragment F16 after G13D IVS (Figure 4A). Figure 4B shows the results obtained from TILs from tumor fragments F15 and F16 after activation, sorting for CD4+ / 41BB+ / OX40+, and REP (Figure 4B).

[0160] In short, without in vitro cell culture, four more TCRs (4400 TCR-E, 4400 TCR-J, 4400 TCR-N, and TCR-C) were identified by directly selecting and sequencing T cells from the tumor. The sequences of these TCRs were obtained by selecting T cells from a single-cell suspension of fresh tumor digestion and performing single-cell TCR sequencing along with RNA sequencing. Fourteen TCRs were selected because their transcriptional phenotypes were similar to those of neoantigen-responsive T cells observed in other patients. These 14 TCR plasmids were introduced into healthy donor PBLs and screened against the patient's potential neoantigens (peptides and tandem minigenes encoding tumor mutations). Four of these—4400 TCR-E, 4400 TCR-J, 4400 TCR-N, and 4400 TCR-C—were responsive to mutated KRAS.

[0161] By directly phenotypic-selecting and sequencing T cells from patient peripheral blood (PBL), a different TCR (TCR-20) was identified.

[0162] Five types of TCRs (TCR-A3, TCR-J2, TCR-N4, TCR-N12, and TCR-N13) were identified by in vitro stimulation (IVS) of T cells directly obtained from tumors (tumor-infiltrating T lymphocytes - TILs) or without in vitro cell culture.

[0163] The isolated TCRs are shown in Table 5.

[0164] [Table 5]

[0165] Table 6 shows the amino acid sequences of the variable regions of the alpha and beta chains. The CDR is underlined. The N-terminal signal peptide is in bold font.

[0166] [Table 6-1]

[0167] [Table 6-2]

[0168] [Table 6-3]

[0169] [Table 6-4]

[0170] [Table 6-5]

[0171] [Table 6-6]

[0172] Example 2 This example demonstrates the construction of retroviral vectors encoding each of the TCRs in Example 1.

[0173] The nucleotide sequences encoding the variable regions of the α and β chains of 4400 TCR-A1 (SEQ ID NO: 117), 4400 TCR-A2 (SEQ ID NO: 118), 4400 TCR-E (SEQ ID NO: 114), 4400 TCR-J (SEQ ID NO: 115), 4400 TCR-N (SEQ ID NO: 116), 4400 TCR-A3, 4400 TCR-J2, 4400 TCR-N4, 4400 TCR-N12, 4400 TCR-N13, 4400 TCR-C, or 4400 TCR-20 shown in Table 6 were obtained, and the codons were optimized. The VDJ region of TCRβ was fused to the mouse TCRβ constant chain. The VJ region of TCRα was fused to the mouse TCRα constant chain. Although not bound by any specific theory or mechanism, it is thought that replacing the constant regions of human TCRα and TCRβ chains with the corresponding mouse constant regions improves TCR expression and functionality (Cohen et al., Cancer Res., 66(17):8878-86(2006)).

[0174] Furthermore, the constant chains of mouse TCRα and TCRβ were modified with cysteine. Transmembrane hydrophobic mutations were introduced into the constant chain of mouse TCRα. Although not bound by any specific theory or mechanism, these modifications are thought to preferentially pair the introduced TCR chain, thereby enhancing TCR surface expression and functionality (Cohen et al., Cancer Res., 67(8):3898-903 (2007); Haga-Friedman et al., J.Immu., 188:5538-5546 (2012)). Table 7 shows the full-length α and β chains of each of the four TCRs, including these modifications to the constant region. In Table 7, CDRs are underlined, and modified amino acid residues in the constant region are underlined and shown in bold.

[0175] [Table 7-1]

[0176] [Table 7-2]

[0177] Table 7-3

[0178] Table 7-4

[0179] Table 7-5

[0180] Table 7-6

[0181] Table 7-7

[0182] Table 7-8

[0183] Table 7-9

[0184] Table 7-10

[0185] The nucleotide sequences encoding the variable regions of the α and β chains of 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-E, 4400 TCR-J, 4400 TCR-N, 4400 TCR-A3, 4400 TCR-J2, 4400 TCR-N4, 4400 TCR-N12, 4400 TCR-N13, 4400 TCR-C, or 4400 TCR-20 shown in Table 7 were independently cloned into an MSGV1-based retroviral vector having the following expression cassette configuration: 5'NcoI-VDJβ-mCβ-Fulin / SerGly / P2A-VJα-mCα-EcoRI3'. To facilitate the cloning of the TCR expression cassette to the 5'NcoI site of the MSGV1 vector, the second amino acid in the N-terminal signal peptide of the TCRVβ chain was changed to alanine (A).

[0186] The TCRβ and TCRα chains were separated by the furin Ser / Gly P2A linker peptide (SEQ ID NO: 105). Although not bound by any specific theory or mechanism, the linker peptide is thought to equalize the expression efficiency of the two chains (Szymczak et al., Nat. Biotechnol., 22(5):589-94 (2004)).

[0187] The retroviral vector's TCR expression cassette encoded the TCRβ and TCRα chains separated by the linker peptide from 5' to 3'. Table 8 shows the amino acid sequences encoded by the TCR expression cassette for each TCR. In Table 8, the CDR is underlined, the constant region is italicized, and the linker peptide is shown in bold.

[0188] [Table 8-1]

[0189] [Table 8-2]

[0190] [Table 8-3]

[0191] Example 3 This example demonstrates that Jurkat cells transfected with mRNA encoding 4400 TCR-A1 or 4400 TCR-A2 from Example 2 specifically recognize G13D.

[0192] The effector cells were Jurkat cell lines that stably expressed luciferase and CD4 coreceptor under transcriptional regulation by the NFAT promoter. These cells were transduced with a virus to mRNA encoding the alpha and beta strands of the TCR, which was prepared according to the sequencing described in Figure 3 (Example 1). The TCR was either 4400 TCR-A1 or 4400 TCR-A2 from Example 2, or 4400 TCR-B1 or 4400 TCR-B2 identified in Example 1.

[0193] Transcription under the control of the NFAT promoter is activated by TCR stimulation. TCR stimulation increases intracellular calcium concentration and activates calcium channels. Subsequently, the NFAT protein is dephosphorylated by calmumodin, translocates to the nucleus, where it binds to the NFAT promoter sequence and activates downstream gene expression. By placing luciferase under the transcriptional control of the NFAT promoter, it is predicted that luciferase will be expressed only when the TCR is stimulated by a target antigen.

[0194] The target cells were (i) transfected with full-length G13D KRAS mRNA (G13D FL) (variant B) or the corresponding full-length WT KRAS mRNA (WT FL) (variant B); and (ii) DCs pulsed with the G13D 25-mer peptide (G13D Mut LP) or the corresponding WT 25-mer peptide (G13 WT LP) from Example 1. Transfected cells co-cultured with DMSO-treated DCs and Jurkat cells not transfected with TCR were used as negative controls.

[0195] Effector cells were co-cultured with target cells. Luciferase expression was measured by measuring luminescence units (Figure 5). The results show that Jurkat cells transfected with 4400 TCR-A1 or 4400 TCR-A2 specifically recognize G13D.

[0196] Example 4 This example demonstrates that healthy donor PBLs transduced independently with retroviral vectors encoding 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-E, 4400 TCR-J, or 4400 TCR-N from Example 2 specifically recognize G13D.

[0197] The effector cells were healthy donor PBLs that had been independently transduced with retroviral vectors encoding 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-E, 4400 TCR-J, or 4400 TCR-N, or 4400 TCR-B1 or 4400 TCR-B2 from Example 2.

[0198] The target cells were DCs that were (i) transduced with full-length G13D KRAS mRNA (G13D FL) (variant B) or the corresponding full-length WT KRAS mRNA (WT FL) (variant B); (ii) pulsed with the G13D 25-mer peptide (G13D Mut LP) from Example 1 or the corresponding WT 25-mer peptide (G13 WT LP); or (iii) pulsed with the G12D 25-mer peptide (G12D Mut LP) or the G12V 25-mer peptide (G12V Mut LP).

[0199] Effector cells were co-cultured with target cells. Reactivity was tested by measuring IFNγ secretion using the ELISpot assay (Figure 6), and by measuring the expression of one or both of 4-1BB and OX40 using a gated flow cytometry assay of (i) CD3+ / mTCR+ / CD8+ cells (Figure 7A) or (ii) CD3+ / mTCR+ / CD4+ cells (Figure 7B).

[0200] Example 5 This example demonstrates that the TCR expressed by the retroviral vector of Example 2 recognizes the G13D RAS presented by the HLA-DQ heterodimer.

[0201] Exome and mRNA sequencing were used to determine the MHC class II molecules expressed in patient 4400. The expressed MHC class II molecules are shown in Figure 8.

[0202] HEK cells (target cells) were either untransfected (control) or independently transfected with the HLA heterodimers (alpha and beta) shown in Figure 8, followed by pulsed with the G13D 25-mer peptide from Example 1. Effector cells were healthy donor PBLs independently transfected with retroviral vectors encoding 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-E, 4400 TCR-J, or 4400 TCR-N from Example 2. Effector cells cultured in the presence of anti-CD3 / anti-CD28 Dynabeads were used as positive controls. Reactivity was tested by measuring IFNγ secretion using the ELISpot assay (Figure 8), and by measuring the expression of one or both 4-1BB and OX40 by a gated flow cytometry assay of CD3+ / mTCR+ / CD4+ cells (Figure 9).

[0203] As shown in Figures 8-9, the reactivity of target cells transduced with HLA-DQA1*05:01 / HLA-DQB1*03:01 heterodimers was observed when co-cultured with effector cells.

[0204] Example 6 This example demonstrates the binding activity of the TCR expressed by the retroviral vector of Example 2.

[0205] Healthy donor PBLs (effector cells) were transduced with the retroviral vectors of Example 2, each independently encoding 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-E, 4400 TCR-J, or 4400 TCR-N.

[0206] Self-DCs (target cells) were loaded with one of the various concentrations of the G13D 25-mer peptide of Example 1 or the corresponding WT 25-mer peptide shown in FIGS. 10A-10C, 11A-11C, 12A-12C, 13A-13C, and 14A-14C. The cells were washed twice and co-cultured overnight with transduced cells at a ratio of 6e4 DCs:5e4 T cells. Reactivity was tested by IFNγ-secretion (FIGS. 10A, 11A, 12A, 13A, and 14A) using an ELISpot assay, and also by measuring the expression of one or both of 4-BB and OX40 by flow cytometry assays gating on CD3+ / mTCR+ / CD4+ cells (FIGS. 10B, 11B, 12B, 13B, and 14B) or CD3+ / mTCR+ / CD8+ cells (FIGS. 10C, 11C, 12C, 13C, and 14C).

[0207] Example 7 This example shows that Jurkat cells transfected with 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-A3, 4400 TCR-E, 4400 TCR-J2, 4400 TCR-N4, 4400 TCR-N12, or 4400 TCR-N13 of Example 2 specifically recognize G13D.

[0208] The effector cells were Jurkat-NFAT-firefly luciferase CD4+ / CD8+ cell lines (described in Example 3) that were virally transduced with a retroviral vector independently encoding one of the following TCRs described in Example 2: 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-E, 4400 TCR-A3, 4400 TCR-J, 4400 TCR-J2, 4400 TCR-N, 4400 4400 TCR-N4, 4400 TCR-N12, or 4400 TCR-N13.

[0209] The target cells were those of patient 4400 that were (i) transfected overnight with full-length G13D KRAS mRNA (G13D FL) (variant B) or the corresponding full-length WT KRAS mRNA (WT FL) (variant B); or (ii) pulsed with the G13D 25-mer peptide (G13D Mut LP) or the corresponding WT 25-mer peptide (G13 WT LP) of Example 1. Pseudotransduction was used as a negative control.

[0210] After co-culturing effector cells with the target cells for 5 hours, the cells were lysed in the presence of luciferin reagent. Then, luminescence was measured as in Example 3. The results are shown in Figure 15. The results indicate that Jurkat-NFAT firefly luciferase cells transfected with 4400 TCR-A1, 4400 TCR-A2, 4400 TCR-E, TCR-J, 4400 TCR-A3, 4400 TCR-J2, 4400 TCR-N, 4400 4400 TCR-N4, 4400 TCR-N12, or 4400 TCR-N13 specifically recognize G13D.

[0211] Example 8 This example shows that the TCR expressed by the retroviral vector of Example 2 recognizes G13D RAS presented by HLA-DQ heterodimers.

[0212] Exosome and mRNA sequencing were used to determine the MHC class II molecules expressed by patient 4400. The expressed MHC class II molecules are shown in Figure 16.

[0213] COS7 cells (target cells) were independently transfected with either the HLA heterodimers (alpha and beta) shown in Figure 16 or HLA DRA1 alone, and then pulsed with the G13D 25-mer peptide from Example 1. The effector cells were the same as those described in Example 7. The effector cells were co-cultured with the target cells for 5 hours. Then, as described in Example 3, these cells were tested for luciferase activity. Untransduced Jurkat-NFAT firefly luciferase cells co-cultured with the same target cells were used as a negative control. The results are shown in Figure 16. As shown in Figure 16, the reactivity of effector cells co-cultured with target cells transduced with HLA-DQA1*05:01 / HLA-DQB1*03:01 heterodimers was observed.

[0214] Example 9 This example demonstrates the binding activity of the TCR expressed by the retroviral vector of Example 2.

[0215] The effector cells were the same as those described in Example 7. The target cells were autologous DCs of Patient 4000 loaded with either the G13D 25-mer peptide from Example 1 or the corresponding WT 25-mer peptide at various concentrations shown in Figures 17A-17K. These cells were washed twice and co-cultured with effector cells in a ratio of 6e4 target cells to 1.5e5 effector cells for 5 hours. These cells were then tested for luciferase activity as described in Example 3.

[0216] The results are shown in Figures 17A to 17J. Figure 17K shows the results obtained after the same experiments as those performed for Figures 17A to 17J, except that a control experiment was performed, i.e., the Jurkat-NFAT firefly luciferase cell line was transduced with a control plasmid (a backbone plasmid that does not contain the gene encoding the TCR) using a virus. The results showed that cells transduced with 4400 TCR-A1(17A), 4400 TCR-A2(17B), 4400 TCR-A3(17C), 4400 TCR-J(17D), 4400 TCR-J2(17E), 4400 TCR-E(17F), 4400 TCR-N(17G), 4400 TCR-N4(17H), 4400 TCR-N12(17I), or 4400 TCR-N13(17J) specifically and avidly recognized G13D.

[0217] Example 10 This example demonstrates that 4400 TCR-C and 4400 TCR-20 expressed by the retroviral vector of Example 2 recognize the G13D RAS presented by the HLA-DQ heterodimer.

[0218] COS7 cells (target cells) were transfected with HLA-DQA1*05:01 and HLA-DQB1*03:01 heterodimers, and then pulsed with the G13D 25-mer peptide from Example 1. Effector cells were independently Jurkat-NFAT-firefly luciferase CD4+ / CD8+ cell lines (described in Example 3) transfected with retroviral vectors encoding 4400 TCR-C or 4400 TCR-20 as described in Example 2. Effector cells were co-cultured with target cells for 5 hours. These cells were then tested for luciferase activity as described in Example 3. Effector cells were co-cultured with untransfected COS7 cells loaded with the G13D 25-mer peptide as a negative control. The results are shown in Figure 18. As shown in Figure 18, the reactivity of target cells transduced with HLA-DQA1*05:01 / HLA-DQB1*03:01 heterodimers was observed when co-cultured with effector cells.

[0219] Example 11 This example demonstrates that healthy donor PBLs transduced with retroviral vectors encoding 4400 TCR-C or 4400 TCR-20 from Example 2 specifically recognize G13D.

[0220] Effector cells were healthy donor PBLs independently transduced with retroviral vectors encoding 4400 TCR-C or 4400 TCR-20 from Example 2. Target cells were auto-DCs pre-loaded with one of the various concentrations of the G13D 25-mer peptide (G13D) from Example 1 or the corresponding WT 25-mer peptide, as shown in Figures 19A-19D. Target cells were washed twice and co-cultured overnight with effector cells in a ratio of 6e4 target cells to 1e5 effector cells.

[0221] Reactivity was tested by measuring the expression of one or both of 4-1BB and OX40 in (i) CD3+ / mTCR+ / CD8+ cells (Figures 19B and 19D) or (ii) CD3+ / mTCR+ / CD4+ cells (Figures 19A and 19C) using a gated flow cytometry assay.

[0222] The results showed that PBLs transfected with retroviral vectors encoding 4400 TCR-C (Figures 19A-19B) or 4400 TCR-20 (Figures 19D-19D) independently specifically recognized G13D.

[0223] All references cited herein, including publications, patent applications, and patents, are incorporated herein by reference to the same extent as they are incorporated herein by whole, with each reference being individually and specifically indicated as being incorporated herein by reference.

[0224] In connection with the description of the present invention (particularly in connection with the following claims), the terms “a,” “an,” “the,” and “at least one,” as well as similar references, should be interpreted as encompassing both singular and plural forms, unless otherwise specified herein or unless clearly contradicted by the context. The use of the term “at least one” after a list of one or more items (e.g., “at least one of A and B”) should be interpreted as meaning one item (A or B) selected from the enumerated items or any combination of two or more enumerated items (A and B), unless otherwise specified herein or unless clearly contradicted by the context. The terms “comprising,” “having,” “including,” and “containing” should be interpreted as open-ended terms (i.e., “including but not limited to these”), unless otherwise specified herein. The enumeration of value ranges in this specification is intended, unless otherwise specified herein, simply to function as an abbreviation for each distinct value within the range, and each distinct value is incorporated into the specification as if it were individually enumerated herein. All methods described herein may be performed in any preferred order unless otherwise specified herein or unless it is clearly inconsistent with the context. The use of any and all examples or exemplary expressions provided herein (e.g., "etc.") is intended, unless otherwise specifically asserted, merely to further elucidate the invention and not to propose any limitation of the scope of the invention. No expression in the specification should be construed as indicating that any unclaimed element is essential for the practice of the invention.

[0225] Preferred embodiments of the Invention, including the best mode known to the inventors for carrying out the Invention, are described herein. Variations of the preferred embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that those skilled in the art will use such variations as appropriate, and they intend that the Invention may be carried out in ways other than those specifically described herein. Accordingly, the Invention includes all variations and equivalents of the subject matter of the Invention enumerated in the claims appended herein, as permitted by applicable law. Furthermore, any combination of the above elements in all possible variations is encompassed by the Invention unless otherwise specified herein or is clearly inconsistent with the context.

Claims

1. An isolated or purified T cell receptor (TCR) having antigen specificity to a mutant human RAS amino acid sequence in which the glycine at position 13 is substituted with aspartic acid, presented by the human leukocyte antigen (HLA)-DQA1*05:01:HLA-DQB1*03:01 heterodimer, The aforementioned mutant human RAS amino acid sequence is the amino acid sequence of the mutant human Kirsten rat sarcoma virus oncogene homolog (KRAS), the mutant human Harvey rat sarcoma virus oncogene homolog (HRAS), or the mutant human neuroblastoma rat sarcoma virus oncogene homolog (NRAS). The 13th position is defined by referring to the proteins of wild-type human KRAS, wild-type human HRAS, or wild-type human NRAS, respectively. The aforementioned TCR, (a) Complementarity-determining region (CDR) 1 of the α chain containing the amino acid sequence of SEQ ID NO: 1, CDR 2 of the α chain containing the amino acid sequence of SEQ ID NO: 2, CDR 3 of the α chain containing the amino acid sequence of SEQ ID NO: 3, CDR 1 of the β chain containing the amino acid sequence of SEQ ID NO: 4, CDR 2 of the β chain containing the amino acid sequence of SEQ ID NO: 5, and CDR 3 of the β chain containing the amino acid sequence of SEQ ID NO: 6; (b) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 11, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 12, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 13, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 14, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 15, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 16; (c) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 21, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 22, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 23, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 24, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 25, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 26; (d) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 31, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 32, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 33, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 34, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 35, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 36; (e) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 41, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 42, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 43, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 44, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 45, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 46; (f) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 119, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 120, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 121, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 122, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 123, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 124; (g) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 129, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 130, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 131, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 132, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 133, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 134; (h) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 139, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 140, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 141, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 142, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 143, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 144; (i) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 149, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 150, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 151, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 152, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 153, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 154; (j) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 159, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 160, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 161, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 162, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 163, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 164; (k) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 169, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 170, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 171, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 172, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 173, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 174; or (l) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 179, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 180, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 181, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 182, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 183, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 184 TCR, including.

2. The TCR according to claim 1, wherein the mutant human RAS amino acid sequence is MTEYKLVVVGAGDVGKSALTIQLIQ (SEQ ID NO: 252).

3. The TCR according to claim 1 or 2, wherein it does not have antigen specificity to the wild-type human RAS amino acid sequence MTEYKLVVVGAGGVGKSALTIQLIQ (SEQ ID NO: 253).

4. (1) Sequence ID 7, (2) Sequence ID 8, (3) Sequence ID 9, (4) Sequence ID 10, (5) Sequence ID 17, (6) Sequence ID 18, (7) Sequence ID 19, (8) Sequence ID 20, (9) Sequence ID 27, (10) Sequence ID 28, (11) Sequence ID 29, (12) Sequence ID 30, (13) Sequence ID 37, (14) Sequence ID 38, (15) Sequence ID 39, (16) Sequence ID 40, (17) Sequence ID 47, (18) Sequence ID 48, (19) Sequence ID 49, (20) Sequence ID 50, (21) Sequence ID 125, (22) Sequence ID 126, (23) Sequence ID 127, (24) Sequence ID 128, (25) Sequence ID 135, (26) Sequence ID 136, (27) Sequence ID 137, (28) Sequence ID 138, (29) Sequence ID 145, (30) Sequence ID 146, (31) Sequence ID 147, (32) Sequence ID 148, (33) Sequence ID 155, (34) Sequence ID 156, (35) Sequence ID 157, (36) Sequence ID 158, (37) Sequence ID 165, (38) Sequence ID 166, (39) Sequence ID 167, (40) Sequence ID 168, (41) Sequence ID 175, (42) Sequence ID 176, (43) Sequence ID 177, (44) Sequence ID 178, (45) Sequence ID 185, (46) Sequence ID 186, (47) Sequence ID 187, (48) Sequence ID 188, (49) Both Sequence IDs 7 and 8, (50) Both Sequence IDs 9 and 10, (51) Both Sequence ID No. 17 and No. 18, (52) Both Sequence IDs 19 and 20, (53) Both Sequence IDs 27 and 28, (54) Both Sequence IDs 29 and 30, (55) Both Sequence IDs 37 and 38, (56) Both sequence numbers 39 and 40, (57) Both sequence numbers 47 and 48, (58) Both sequence numbers 49 and 50, (59) Both Sequence IDs 125 and 126, (60) Both sequence numbers 127 and 128, (61) Both sequence numbers 135 and 136, (62) Both sequence numbers 137 and 138, (63) Both sequence numbers 145 and 146, (64) Both sequence numbers 147 and 148, (65) Both Sequence IDs 155 and 156, (66) Both Sequence IDs 157 and 158, (67) Both Sequence IDs 165 and 166, (68) Both sequence numbers 167 and 168, (69) Both Sequence IDs 175 and 176, (70) Both Sequence IDs 177 and 178, (71) Both Sequence ID No. 185 and 186, or (72) Both Sequence IDs 187 and 188 A TCR according to any one of claims 1 to 3, comprising the amino acid sequence(s) of the following:

5. (a) The amino acid sequence of Sequence ID No. 59, (i) The X at position 48 of sequence number 59 is either Thr or Cys; (ii) The X at position 112 of sequence number 59 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 114 of sequence number 59 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 115 of sequence number 59 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (b) The amino acid sequence of Sequence ID No. 60 in which X at position 57 of Sequence ID No. 60 is Ser or Cys; or (c) Both (a) and (b) A TCR according to any one of claims 1 to 4, further comprising:

6. (a) The amino acid sequence of Sequence ID No. 65, (i) The X at position 180 of sequence number 65 is either Thr or Cys; (ii) The X at position 244 of sequence number 65 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of sequence number 65 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 247 of sequence number 65 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (b) The amino acid sequence of Sequence ID No. 66, wherein the X at position 188 of Sequence ID No. 66 is Ser or Cys; (c) Both (a) and (b); (d) The amino acid sequence of Sequence ID No. 67, (i) The X at position 158 of sequence number 67 is either Thr or Cys; (ii) The X at position 222 of sequence number 67 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 224 of sequence number 67 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 225 of sequence number 67 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (e) The amino acid sequence of Sequence ID No. 68, wherein the X at position 169 of Sequence ID No. 68 is Ser or Cys; (f) Both (d) and (e); (g) Amino acid sequence of SEQ ID NO: 69; (h) Amino acid sequence of Sequence ID No. 70; (i) Amino acid sequence of SEQ ID NO: 71; (j) Amino acid sequence of SEQ ID NO: 72; Both (k), (g), and (h); (l) (i) and (j); (m) The amino acid sequence of Sequence ID No. 73, (i) The X at position 180 of sequence number 73 is either Thr or Cys; (ii) The X at position 244 of sequence number 73 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of sequence number 73 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 247 of sequence number 73 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (n) The amino acid sequence of Sequence ID No. 74, wherein the X at position 188 of Sequence ID No. 74 is either Ser or Cys; Both (o), (m), and (n); (p) The amino acid sequence of Sequence ID No. 75, (i) The X at position 158 of sequence number 75 is either Thr or Cys; (ii) The X at position 222 of sequence number 75 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 224 of sequence number 75 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 225 of sequence number 75 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (q) The amino acid sequence of Sequence ID No. 76 in which X at position 169 is either Ser or Cys; Both (r), (p), and (q); (s) Amino acid sequence of SEQ ID NO: 77; (t) Amino acid sequence of Sequence ID No. 78; (u) Amino acid sequence of SEQ ID NO: 79; (v) Amino acid sequence of Sequence ID No. 80; Both (w), (s), and (t); Both (x), (u), and (v); (y) The amino acid sequence of sequence number 81, (i) The X at position 177 of sequence number 81 is either Thr or Cys; (ii) The X at position 241 of sequence number 81 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 243 of sequence number 81 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 244 of sequence number 81 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (z) The amino acid sequence of Sequence ID No. 82, where X at position 189 is Ser or Cys; Both (aa), (y), and (z); (bb) The amino acid sequence of Sequence ID No. 83, (i) The X at position 160 of sequence number 83 is either Thr or Cys; (ii) The X at position 224 of sequence number 83 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 226 of sequence number 83 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 227 of sequence number 83 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (cc) The amino acid sequence of Sequence ID No. 84, where X at position 170 is Ser or Cys; Both (dd), (bb), and (cc); (ee) Amino acid sequence of Sequence ID No. 85; (ff) Amino acid sequence of SEQ ID NO: 86; (gg) Amino acid sequence of SEQ ID NO: 87; (hh) Amino acid sequence of sequence number 88; (ii) (ee) and (ff) both; Both (jj), (gg), and (hh); (kk) The amino acid sequence of sequence number 89, (i) The X at position 183 of sequence number 89 is either Thr or Cys; (ii) The X at position 247 of sequence number 89 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 249 of sequence number 89 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 250 of sequence number 89 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (ll) The amino acid sequence of Sequence ID No. 90, where X at position 188 is Ser or Cys; Both (mm), (kk), and (ll); (nn) The amino acid sequence of sequence number 91, (i) The X at position 161 of sequence number 91 is either Thr or Cys; (ii) The X at position 225 of sequence number 91 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of sequence number 91 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 228 of sequence number 91 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (oo) The amino acid sequence of Sequence ID No. 92, where X at position 169 is either Ser or Cys; Both (pp)(nn) and (oo); (qq) Amino acid sequence of sequence number 93; (rr) Amino acid sequence of Sequence ID No. 94; (ss) Amino acid sequence of SEQ ID NO: 95; (tt) Amino acid sequence of Sequence ID No. 96; Both (uu), (qq), and (rr); Both (vv), (ss), and (tt); (ww) The amino acid sequence of sequence number 97, (i) The X at position 178 of sequence number 97 is either Thr or Cys; (ii) The X at position 242 of sequence number 97 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 244 of sequence number 97 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 245 of sequence number 97 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (xx) The amino acid sequence of sequence number 98, where X at position 188 is either Ser or Cys; Both (yy), (ww), and (xx); (zz) The amino acid sequence of sequence number 99, (i) The X at position 157 of sequence number 99 is either Thr or Cys; (ii) The X at position 221 of sequence number 99 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 223 of sequence number 99 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 224 of sequence number 99 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (aaa) The amino acid sequence of Sequence ID No. 100, where X at position 169 is Ser or Cys; Both (bbb), (zz), and (aaa); (ccc) Amino acid sequence of Sequence ID No. 101; (ddd) Amino acid sequence of SEQ ID NO: 102; (ee) Amino acid sequence of Sequence ID No. 103; (fff) Amino acid sequence of sequence number 104; Both (ggg), (ccc), and (ddd); Both (hhh), (eee), and (fff); (iii) The amino acid sequence of sequence number 189, (i) The X at position 176 of sequence number 189 is either Thr or Cys; (ii) The X at position 240 of sequence number 189 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 242 of sequence number 189 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 243 of sequence number 189 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (jjj) The amino acid sequence of Sequence ID No. 190, where X at position 188 is either Ser or Cys; Both (kkk), (iii), and (jjj); (lll) The amino acid sequence of sequence number 191, (i) The X at position 157 of sequence number 191 is either Thr or Cys; (ii) The X at position 221 of sequence number 191 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 223 of sequence number 191 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 224 of sequence number 191 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (mmm) The amino acid sequence of Sequence ID No. 192, where X at position 169 is Ser or Cys; Both (nnn), (lll), and (mmm); (ooo) Amino acid sequence of Sequence ID No. 193; (ppp) Amino acid sequence of Sequence ID No. 194; (qqq) Amino acid sequence of SEQ ID NO: 195; (rrr) Amino acid sequence of sequence number 196; Both (sss)(ooo) and (ppp); Both (ttt), (qqq), and (rrr); (uuu) The amino acid sequence of sequence number 197, (i) The X at position 181 of sequence number 197 is either Thr or Cys; (ii) The X at position 245 of sequence number 197 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 247 of sequence number 197 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 248 of sequence number 197 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (vvv) The amino acid sequence of sequence number 198, where X at position 188 is either Ser or Cys; Both (www), (uuu), and (vvv); (xxx) The amino acid sequence of sequence number 199, (i) The X at position 161 of sequence number 199 is either Thr or Cys; (ii) The X at position 225 of sequence number 199 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of sequence number 199 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 228 of sequence number 199 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (yyy) The amino acid sequence of Sequence ID No. 200, where X at position 169 is Ser or Cys; Both (zzz), (xxx), and (yyy); (aaaa) Amino acid sequence of Sequence ID No. 201; (bbbb) Amino acid sequence of Sequence ID No. 202; (cccc) Amino acid sequence of Sequence ID No. 203; (dddd) Amino acid sequence of SEQ ID NO: 204; Both (eeee), (aaaa), and (bbbb); Both (ffff), (cccc), and (dddd); (gggg) The amino acid sequence of sequence number 205, (i) The X at position 184 of sequence number 205 is either Thr or Cys; (ii) The X at position 248 of sequence number 205 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of sequence number 205 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 251 of sequence number 205 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (hhhh) The amino acid sequence of Sequence ID No. 206, where X at position 190 is Ser or Cys; Both (iiii), (gggg), and (hhhh); (jjjj) The amino acid sequence of sequence number 207, (i) The X at position 163 of sequence number 207 is either Thr or Cys; (ii) The X at position 227 of sequence number 207 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of sequence number 207 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 230 of sequence number 207 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (kkkk) The amino acid sequence of sequence number 208, where X at position 164 is either Ser or Cys; Both (llll) (jjjj) and (kkkk); (mmmm) Amino acid sequence of Sequence ID No. 209; (nnnn) Amino acid sequence of sequence number 210; (oooo) Amino acid sequence of sequence number 211; (pppp) Amino acid sequence of sequence number 212; Both (qqqq) (mmmm) and (nnnn); Both (rrrr)(oooo) and (pppp); (ssss) The amino acid sequence of sequence number 213, (i) The X at position 183 of sequence number 213 is either Thr or Cys; (ii) The X at position 247 of sequence number 213 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 249 of sequence number 213 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 250 of sequence number 213 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (tttt) The amino acid sequence of Sequence ID No. 214, where X at position 188 is either Ser or Cys; Both (uuuu), (ssss), and (tttt); (vvvv) The amino acid sequence of sequence number 215, (i) The X at position 161 of sequence number 215 is either Thr or Cys; (ii) The X at position 225 of sequence number 215 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 227 of sequence number 215 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 228 of sequence number 215 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (lol) The amino acid sequence of sequence number 216, where the X at position 169 is either Ser or Cys; Both (xxxx)(vvvv) and (wwww); (yyyy) Amino acid sequence of Sequence ID No. 217; (zzzz) Amino acid sequence of sequence number 218; (aaaaa) Amino acid sequence of SEQ ID NO: 219; (bbbbb) Amino acid sequence of Sequence ID No. 220; Both (cccccc), (yyyy), and (zzzz); Both (dddddd) (aaaaa) and (bbbbbb); (eeee) The amino acid sequence of sequence number 221, (i) The X at position 180 of sequence number 221 is either Thr or Cys; (ii) The X at position 244 of sequence number 221 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of sequence number 221 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 247 of sequence number 221 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (ffff) The amino acid sequence of sequence number 222, where X at position 188 is either Ser or Cys; Both (ggggg) (eeee) and (fffff); (hhhhh) The amino acid sequence of sequence number 223, (i) The X at position 158 of sequence number 223 is either Thr or Cys; (ii) The X at position 222 of sequence number 223 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 224 of sequence number 223 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 225 of sequence number 223 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iiiiii) The amino acid sequence of Sequence ID No. 224, in which position 169 of Sequence ID No. 224 is either Ser or Cys; Both (jjjjj) (hhhhh) and (iiiiii); (kkkkk) Amino acid sequence of sequence number 225; (llllll) Amino acid sequence of SEQ ID NO: 226; (mmmmm) Amino acid sequence of Sequence ID No. 227; (nnnnnn) Amino acid sequence of sequence number 228; Both (oooooo) (kkkkk) and (llllll); Both (ppppp), (mmmmm), and (nnnnnn); (qqqqq) The amino acid sequence of sequence number 229, (i) The X at position 184 of sequence number 229 is either Thr or Cys; (ii) The X at position 248 of sequence number 229 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of sequence number 229 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 251 of sequence number 229 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (rrrrr) The amino acid sequence of Sequence ID No. 230, where X at position 189 is Ser or Cys; Both (sssss) (qqqqq) and (rrrrr); (ttttt) The amino acid sequence of sequence number 231, (i) The X at position 163 of sequence number 231 is either Thr or Cys; (ii) The X at position 227 of sequence number 231 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of sequence number 231 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 230 of sequence number 231 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (uuuuu) The amino acid sequence of sequence number 232, where X at position 170 is either Ser or Cys; Both (vvvvv)(ttttt) and (uuuuu); (lol) Amino acid sequence of sequence number 233; (xxxxx) Amino acid sequence of sequence number 234; (yyyyy) Amino acid sequence of Sequence ID No. 235; (zzzzzz) Amino acid sequence of sequence number 236; Both (aaaaaa) (wwwww) and (xxxxx); Both (bbbbbb) (yyyyy) and (zzzzzz); (cccccc) The amino acid sequence of sequence number 237, (i) The X at position 184 of sequence number 237 is either Thr or Cys; (ii) The X at position 248 of sequence number 237 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of sequence number 237 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 251 of sequence number 237 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (dddddd) The amino acid sequence of SEQ ID NO: 238, where X at position 189 is Ser or Cys; Both (eeeeee), (ccccccc) and (dddddd); (ffffff) The amino acid sequence of sequence number 239, (i) The X at position 163 of sequence number 239 is either Thr or Cys; (ii) The X at position 227 of sequence number 239 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 229 of sequence number 239 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 230 of sequence number 239 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (gggggg) The amino acid sequence of Sequence ID No. 240, where X at position 170 is either Ser or Cys; Both (hhhhhh) (ffffff) and (ggggggg); (iiiiii) Amino acid sequence of SEQ ID NO: 241; (jjjjjj) Amino acid sequence of sequence number 242; (kkkkkk) Amino acid sequence of sequence number 243; (llllll) Amino acid sequence of sequence number 244; (mmmmmm)(iiiiiii) and (jjjjjj), or Both (nnnnnn) (kkkkkk) and (llllllll) The isolated or purified TCR according to any one of claims 1 to 5, comprising:

7. An isolated or purified polypeptide comprising a functional portion of the TCR according to any one of claims 1 to 6, The aforementioned functional portion has antigen specificity to a mutant human RAS amino acid sequence in which the glycine at position 13 is substituted with aspartic acid, which is presented by the human leukocyte antigen (HLA)-DQA1*05:01:HLA-DQB1*03:01 heterodimer. The aforementioned mutant human RAS amino acid sequence is the amino acid sequence of the mutant human Kirsten rat sarcoma virus oncogene homolog (KRAS), the mutant human Harvey rat sarcoma virus oncogene homolog (HRAS), or the mutant human neuroblastoma rat sarcoma virus oncogene homolog (NRAS). The 13th position is defined by referring to the proteins of wild-type human KRAS, wild-type human HRAS, or wild-type human NRAS, respectively. The aforementioned functional part, (a) Complementarity-determining region (CDR) 1 of the α chain containing the amino acid sequence of SEQ ID NO: 1, CDR 2 of the α chain containing the amino acid sequence of SEQ ID NO: 2, CDR 3 of the α chain containing the amino acid sequence of SEQ ID NO: 3, CDR 1 of the β chain containing the amino acid sequence of SEQ ID NO: 4, CDR 2 of the β chain containing the amino acid sequence of SEQ ID NO: 5, and CDR 3 of the β chain containing the amino acid sequence of SEQ ID NO: 6; (b) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 11, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 12, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 13, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 14, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 15, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 16; (c) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 21, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 22, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 23, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 24, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 25, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 26; (d) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 31, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 32, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 33, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 34, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 35, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 36; (e) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 41, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 42, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 43, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 44, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 45, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 46; (f) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 119, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 120, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 121, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 122, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 123, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 124; (g) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 129, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 130, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 131, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 132, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 133, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 134; (h) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 139, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 140, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 141, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 142, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 143, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 144; (i) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 149, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 150, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 151, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 152, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 153, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 154; (j) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 159, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 160, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 161, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 162, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 163, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 164; (k) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 169, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 170, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 171, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 172, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 173, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 174; or (l) CDR1 of the α chain containing the amino acid sequence of SEQ ID NO: 179, CDR2 of the α chain containing the amino acid sequence of SEQ ID NO: 180, CDR3 of the α chain containing the amino acid sequence of SEQ ID NO: 181, CDR1 of the β chain containing the amino acid sequence of SEQ ID NO: 182, CDR2 of the β chain containing the amino acid sequence of SEQ ID NO: 183, and CDR3 of the β chain containing the amino acid sequence of SEQ ID NO: 184 polypeptides, including

8. The aforementioned functional part, (1) Sequence ID 7, (2) Sequence ID 8, (3) Sequence ID 9, (4) Sequence ID 10, (5) Sequence ID 17, (6) Sequence ID 18, (7) Sequence ID 19, (8) Sequence ID 20, (9) Sequence ID 27, (10) Sequence ID 28, (11) Sequence ID 29, (12) Sequence ID 30, (13) Sequence ID 37, (14) Sequence ID 38, (15) Sequence ID 39, (16) Sequence ID 40, (17) Sequence ID 47, (18) Sequence ID 48, (19) Sequence ID 49, (20) Sequence ID 50, (21) Sequence ID 125, (22) Sequence ID 126, (23) Sequence ID 127, (24) Sequence ID 128, (25) Sequence ID 135, (26) Sequence ID 136, (27) Sequence ID 137, (28) Sequence ID 138, (29) Sequence ID 145, (30) Sequence ID 146, (31) Sequence ID 147, (32) Sequence ID 148, (33) Sequence ID 155, (34) Sequence ID 156, (35) Sequence ID 157, (36) Sequence ID 158, (37) Sequence ID 165, (38) Sequence ID 166, (39) Sequence ID 167, (40) Sequence ID 168, (41) Sequence ID 175, (42) Sequence ID 176, (43) Sequence ID 177, (44) Sequence ID 178, (45) Sequence ID 185, (46) Sequence ID 186, (47) Sequence ID 187, (48) Sequence ID 188, (49) Both Sequence IDs 7 and 8, (50) Both Sequence IDs 9 and 10, (51) Both Sequence ID No. 17 and No. 18, (52) Both Sequence IDs 19 and 20, (53) Both Sequence IDs 27 and 28, (54) Both Sequence IDs 29 and 30, (55) Both Sequence IDs 37 and 38, (56) Both sequence numbers 39 and 40, (57) Both sequence numbers 47 and 48, (58) Both sequence numbers 49 and 50, (59) Both Sequence IDs 125 and 126, (60) Both sequence numbers 127 and 128, (61) Both sequence numbers 135 and 136, (62) Both sequence numbers 137 and 138, (63) Both sequence numbers 145 and 146, (64) Both sequence numbers 147 and 148, (65) Both Sequence IDs 155 and 156, (66) Both Sequence IDs 157 and 158, (67) Both Sequence IDs 165 and 166, (68) Both sequence numbers 167 and 168, (69) Both Sequence IDs 175 and 176, (70) Both Sequence IDs 177 and 178, (71) Both Sequence ID No. 185 and 186, or (72) Both Sequence IDs 187 and 188 An isolated or purified polypeptide according to claim 7, comprising the amino acid sequence(s) of the following:

9. (a) The amino acid sequence of Sequence ID No. 59, (i) The X at position 48 of sequence number 59 is either Thr or Cys; (ii) The X at position 112 of sequence number 59 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 114 of sequence number 59 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 115 of sequence number 59 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (b) The amino acid sequence of Sequence ID No. 60 in which X at position 57 of Sequence ID No. 60 is Ser or Cys; or (c) Both (a) and (b) The isolated or purified polypeptide according to claim 7 or 8, further comprising:

10. (a) The amino acid sequence of Sequence ID No. 65, (i) The X at position 180 of sequence number 65 is either Thr or Cys; (ii) The X at position 244 of sequence number 65 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of sequence number 65 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 247 of sequence number 65 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (b) The amino acid sequence of Sequence ID No. 66, wherein the X at position 188 of Sequence ID No. 66 is Ser or Cys; (c) Both (a) and (b); (d) The amino acid sequence of Sequence ID No. 67, (i) The X at position 158 of sequence number 67 is either Thr or Cys; (ii) The X at position 222 of sequence number 67 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 224 of sequence number 67 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 225 of sequence number 67 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (e) The amino acid sequence of Sequence ID No. 68, wherein the X at position 169 of Sequence ID No. 68 is Ser or Cys; (f) Both (d) and (e); (g) Amino acid sequence of SEQ ID NO: 69; (h) Amino acid sequence of Sequence ID No. 70; (i) Amino acid sequence of SEQ ID NO: 71; (j) Amino acid sequence of SEQ ID NO: 72; Both (k), (g), and (h); (l) (i) and (j); (m) The amino acid sequence of Sequence ID No. 73, (i) The X at position 180 of sequence number 73 is either Thr or Cys; (ii) The X at position 244 of sequence number 73 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of sequence number 73 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 247 of sequence number 73 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (n) The amino acid sequence of Sequence ID No. 74, wherein the X at position 188 of Sequence ID No. 74 is either Ser or Cys; Both (o), (m), and (n); (p) The amino acid sequence of Sequence ID No. 75, (i) The X at position 158 of sequence number 75 is either Thr or Cys; (ii) The X at position 222 of sequence number 75 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 224 of sequence number 75 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 225 of sequence number 75 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (q) The amino acid sequence of Sequence ID No. 76 in which X at position 169 is either Ser or Cys; Both (r), (p), and (q); (s) Amino acid sequence of SEQ ID NO: 77; (t) Amino acid sequence of Sequence ID No. 78; (u) Amino acid sequence of SEQ ID NO: 79; (v) Amino acid sequence of Sequence ID No. 80; Both (w), (s), and (t); Both (x), (u), and (v); (y) The amino acid sequence of sequence number 81, (i) The X at position 177 of sequence number 81 is either Thr or Cys; (ii) The X at position 241 of sequence number 81 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 243 of sequence number 81 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 244 of sequence number 81 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (z) The amino acid sequence of Sequence ID No. 82, where X at position 189 is Ser or Cys; Both (aa), (y), and (z); (bb) The amino acid sequence of Sequence ID No. 83, (i) The X at position 160 of sequence number 83 is either Thr or Cys; (ii) The X at position 224 of sequence number 83 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 226 of sequence number 83 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 227 of sequence number 83 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (cc) The amino acid sequence of Sequence ID No. 84, where X at position 170 is Ser or Cys; Both (dd), (bb), and (cc); (ee) Amino acid sequence of Sequence ID No. 85; (ff) Amino acid sequence of SEQ ID NO: 86; (gg) Amino acid sequence of SEQ ID NO: 87; (hh) Amino acid sequence of sequence number 88; (ii) (ee) and (ff) both; Both (jj), (gg), and (hh); (kk) The amino acid sequence of sequence number 89, (i) The X at position 183 of sequence number 89 is either Thr or Cys; (ii) The X at position 247 of sequence number 89 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 249 of sequence number 89 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 250 of sequence number 89 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (ll) The amino acid sequence of Sequence ID No. 90, where X at position 188 is Ser or Cys; Both (mm), (kk), and (ll); (nn) The amino acid sequence of sequence number 91, (i) The X at position 161 of sequence number 91 is either Thr or Cys; (ii) The X at position 225 of sequence number 91 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of sequence number 91 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 228 of sequence number 91 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (oo) The amino acid sequence of Sequence ID No. 92, where X at position 169 is either Ser or Cys; Both (pp)(nn) and (oo); (qq) Amino acid sequence of sequence number 93; (rr) Amino acid sequence of Sequence ID No. 94; (ss) Amino acid sequence of SEQ ID NO: 95; (tt) Amino acid sequence of Sequence ID No. 96; Both (uu), (qq), and (rr); Both (vv), (ss), and (tt); (ww) The amino acid sequence of sequence number 97, (i) The X at position 178 of sequence number 97 is either Thr or Cys; (ii) The X at position 242 of sequence number 97 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 244 of sequence number 97 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 245 of sequence number 97 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (xx) The amino acid sequence of sequence number 98, where X at position 188 is either Ser or Cys; Both (yy), (ww), and (xx); (zz) The amino acid sequence of sequence number 99, (i) The X at position 157 of sequence number 99 is either Thr or Cys; (ii) The X at position 221 of sequence number 99 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 223 of sequence number 99 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 224 of sequence number 99 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (aaa) The amino acid sequence of Sequence ID No. 100, where X at position 169 is Ser or Cys; Both (bbb), (zz), and (aaa); (ccc) Amino acid sequence of Sequence ID No. 101; (ddd) Amino acid sequence of SEQ ID NO: 102; (ee) Amino acid sequence of Sequence ID No. 103; (fff) Amino acid sequence of sequence number 104; Both (ggg), (ccc), and (ddd); Both (hhh), (eee), and (fff); (iii) The amino acid sequence of sequence number 189, (i) The X at position 176 of sequence number 189 is either Thr or Cys; (ii) The X at position 240 of sequence number 189 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 242 of sequence number 189 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 243 of sequence number 189 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (jjj) The amino acid sequence of Sequence ID No. 190, where X at position 188 is either Ser or Cys; Both (kkk), (iii), and (jjj); (lll) The amino acid sequence of sequence number 191, (i) The X at position 157 of sequence number 191 is either Thr or Cys; (ii) The X at position 221 of sequence number 191 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 223 of sequence number 191 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 224 of sequence number 191 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (mmm) The amino acid sequence of Sequence ID No. 192, where X at position 169 is Ser or Cys; Both (nnn), (lll), and (mmm); (ooo) Amino acid sequence of Sequence ID No. 193; (ppp) Amino acid sequence of Sequence ID No. 194; (qqq) Amino acid sequence of SEQ ID NO: 195; (rrr) Amino acid sequence of sequence number 196; Both (sss)(ooo) and (ppp); Both (ttt), (qqq), and (rrr); (uuu) The amino acid sequence of sequence number 197, (i) The X at position 181 of sequence number 197 is either Thr or Cys; (ii) The X at position 245 of sequence number 197 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 247 of sequence number 197 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 248 of sequence number 197 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (vvv) The amino acid sequence of sequence number 198, where X at position 188 is either Ser or Cys; Both (www), (uuu), and (vvv); (xxx) The amino acid sequence of sequence number 199, (i) The X at position 161 of sequence number 199 is either Thr or Cys; (ii) The X at position 225 of sequence number 199 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of sequence number 199 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 228 of sequence number 199 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (yyy) The amino acid sequence of Sequence ID No. 200, where X at position 169 is Ser or Cys; Both (zzz), (xxx), and (yyy); (aaaa) Amino acid sequence of Sequence ID No. 201; (bbbb) Amino acid sequence of Sequence ID No. 202; (cccc) Amino acid sequence of Sequence ID No. 203; (dddd) Amino acid sequence of SEQ ID NO: 204; Both (eeee), (aaaa), and (bbbb); Both (ffff), (cccc), and (dddd); (gggg) The amino acid sequence of sequence number 205, (i) The X at position 184 of sequence number 205 is either Thr or Cys; (ii) The X at position 248 of sequence number 205 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of sequence number 205 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 251 of sequence number 205 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (hhhh) The amino acid sequence of Sequence ID No. 206, where X at position 190 is Ser or Cys; Both (iiii), (gggg), and (hhhh); (jjjj) The amino acid sequence of sequence number 207, (i) The X at position 163 of sequence number 207 is either Thr or Cys; (ii) The X at position 227 of sequence number 207 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of sequence number 207 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 230 of sequence number 207 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (kkkk) The amino acid sequence of sequence number 208, where X at position 164 is either Ser or Cys; Both (llll) (jjjj) and (kkkk); (mmmm) Amino acid sequence of Sequence ID No. 209; (nnnn) Amino acid sequence of sequence number 210; (oooo) Amino acid sequence of sequence number 211; (pppp) Amino acid sequence of sequence number 212; Both (qqqq) (mmmm) and (nnnn); Both (rrrr)(oooo) and (pppp); (ssss) The amino acid sequence of sequence number 213, (i) The X at position 183 of sequence number 213 is either Thr or Cys; (ii) The X at position 247 of sequence number 213 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 249 of sequence number 213 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 250 of sequence number 213 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (tttt) The amino acid sequence of Sequence ID No. 214, where X at position 188 is either Ser or Cys; Both (uuuu), (ssss), and (tttt); (vvvv) The amino acid sequence of sequence number 215, (i) The X at position 161 of sequence number 215 is either Thr or Cys; (ii) The X at position 225 of sequence number 215 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 227 of sequence number 215 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 228 of sequence number 215 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (lol) The amino acid sequence of sequence number 216, where the X at position 169 is either Ser or Cys; Both (xxxx)(vvvv) and (wwww); (yyyy) Amino acid sequence of Sequence ID No. 217; (zzzz) Amino acid sequence of sequence number 218; (aaaaa) Amino acid sequence of SEQ ID NO: 219; (bbbbb) Amino acid sequence of Sequence ID No. 220; Both (cccccc), (yyyy), and (zzzz); Both (dddddd) (aaaaa) and (bbbbbb); (eeee) The amino acid sequence of sequence number 221, (i) The X at position 180 of sequence number 221 is either Thr or Cys; (ii) The X at position 244 of sequence number 221 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of sequence number 221 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which X at position 247 of sequence number 221 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (ffff) The amino acid sequence of sequence number 222, where X at position 188 is either Ser or Cys; Both (ggggg) (eeee) and (fffff); (hhhhh) The amino acid sequence of sequence number 223, (i) The X at position 158 of sequence number 223 is either Thr or Cys; (ii) The X at position 222 of sequence number 223 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 224 of sequence number 223 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 225 of sequence number 223 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iiiiii) The amino acid sequence of Sequence ID No. 224, in which position 169 of Sequence ID No. 224 is either Ser or Cys; Both (jjjjj) (hhhhh) and (iiiiii); (kkkkk) Amino acid sequence of sequence number 225; (llllll) Amino acid sequence of SEQ ID NO: 226; (mmmmm) Amino acid sequence of Sequence ID No. 227; (nnnnnn) Amino acid sequence of sequence number 228; Both (oooooo) (kkkkk) and (llllll); Both (ppppp), (mmmmm), and (nnnnnn); (qqqqq) The amino acid sequence of sequence number 229, (i) The X at position 184 of sequence number 229 is either Thr or Cys; (ii) The X at position 248 of sequence number 229 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of sequence number 229 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 251 of sequence number 229 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (rrrrr) The amino acid sequence of Sequence ID No. 230, where X at position 189 is Ser or Cys; Both (sssss) (qqqqq) and (rrrrr); (ttttt) The amino acid sequence of sequence number 231, (i) The X at position 163 of sequence number 231 is either Thr or Cys; (ii) The X at position 227 of sequence number 231 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of sequence number 231 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 230 of sequence number 231 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (uuuuu) The amino acid sequence of sequence number 232, where X at position 170 is either Ser or Cys; Both (vvvvv)(ttttt) and (uuuuu); (lol) Amino acid sequence of sequence number 233; (xxxxx) Amino acid sequence of sequence number 234; (yyyyy) Amino acid sequence of Sequence ID No. 235; (zzzzzz) Amino acid sequence of sequence number 236; Both (aaaaaa) (wwwww) and (xxxxx); Both (bbbbbb) (yyyyy) and (zzzzzz); (cccccc) The amino acid sequence of sequence number 237, (i) The X at position 184 of sequence number 237 is either Thr or Cys; (ii) The X at position 248 of sequence number 237 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of sequence number 237 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 251 of sequence number 237 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (dddddd) The amino acid sequence of SEQ ID NO: 238, where X at position 189 is Ser or Cys; Both (eeeeee), (ccccccc) and (dddddd); (ffffff) The amino acid sequence of sequence number 239, (i) The X at position 163 of sequence number 239 is either Thr or Cys; (ii) The X at position 227 of sequence number 239 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 229 of sequence number 239 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) Amino acid sequences in which position 230 of sequence number 239 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (gggggg) The amino acid sequence of Sequence ID No. 240, where X at position 170 is either Ser or Cys; Both (hhhhhh) (ffffff) and (ggggggg); (iiiiii) Amino acid sequence of SEQ ID NO: 241; (jjjjjj) Amino acid sequence of sequence number 242; (kkkkkk) Amino acid sequence of sequence number 243; (llllll) Amino acid sequence of sequence number 244; (mmmmmm)(iiiiiii) and (jjjjjj), or both. Both (nnnnnn) (kkkkkk) and (llllllll) An isolated or purified polypeptide according to any one of claims 7 to 9, comprising:

11. An isolated or purified protein having antigen specificity to a mutant human RAS amino acid sequence in which the glycine at position 13 is substituted with aspartic acid, presented by the human leukocyte antigen (HLA)-DQA1*05:01:HLA-DQB1*03:01 heterodimer, The aforementioned mutant human RAS amino acid sequence is the amino acid sequence of the mutant human Kirsten rat sarcoma virus oncogene homolog (KRAS), the mutant human Harvey rat sarcoma virus oncogene homolog (HRAS), or the mutant human neuroblastoma rat sarcoma virus oncogene homolog (NRAS). The 13th position is defined by referring to the proteins of wild-type human KRAS, wild-type human HRAS, or wild-type human NRAS, respectively. The aforementioned protein, (a) A first polypeptide chain comprising an α-chain complementarity-determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 1, an α-chain CDR 2 containing the amino acid sequence of SEQ ID NO: 2, and an α-chain CDR 3 containing the amino acid sequence of SEQ ID NO: 3; and a second polypeptide chain comprising a β-chain CDR 1 containing the amino acid sequence of SEQ ID NO: 4, a β-chain CDR 2 containing the amino acid sequence of SEQ ID NO: 5, and a β-chain CDR 3 containing the amino acid sequence of SEQ ID NO: 6; (b) A first polypeptide chain comprising an α-chain CDR1 containing the amino acid sequence of SEQ ID NO: 11, an α-chain CDR2 containing the amino acid sequence of SEQ ID NO: 12, and an α-chain CDR3 containing the amino acid sequence of SEQ ID NO: 13; and a second polypeptide chain comprising a β-chain CDR1 containing the amino acid sequence of SEQ ID NO: 14, a β-chain CDR2 containing the amino acid sequence of SEQ ID NO: 15, and a β-chain CDR3 containing the amino acid sequence of SEQ ID NO: 16; (c) A first polypeptide chain comprising an α-chain CDR1 containing the amino acid sequence of SEQ ID NO: 21, an α-chain CDR2 containing the amino acid sequence of SEQ ID NO: 22, and an α-chain CDR3 containing the amino acid sequence of SEQ ID NO: 23; and a second polypeptide chain comprising a β-chain CDR1 containing the amino acid sequence of SEQ ID NO: 24, a β-chain CDR2 containing the amino acid sequence of SEQ ID NO: 25, and a β-chain CDR3 containing the amino acid sequence of SEQ ID NO: 26; (d) A first polypeptide chain comprising an α-chain CDR1 containing the amino acid sequence of SEQ ID NO: 31, an α-chain CDR2 containing the amino acid sequence of SEQ ID NO: 32, and an α-chain CDR3 containing the amino acid sequence of SEQ ID NO: 33; and a second polypeptide chain comprising a β-chain CDR1 containing the amino acid sequence of SEQ ID NO: 34, a β-chain CDR2 containing the amino acid sequence of SEQ ID NO: 35, and a β-chain CDR3 containing the amino acid sequence of SEQ ID NO: 36; (e) A first polypeptide chain comprising an α-chain CDR1 containing the amino acid sequence of SEQ ID NO: 41, an α-chain CDR2 containing the amino acid sequence of SEQ ID NO: 42, and an α-chain CDR3 containing the amino acid sequence of SEQ ID NO: 43; and a second polypeptide chain comprising a β-chain CDR1 containing the amino acid sequence of SEQ ID NO: 44, a β-chain CDR2 containing the amino acid sequence of SEQ ID NO: 45, and a β-chain CDR3 containing the amino acid sequence of SEQ ID NO: 46; (f) A first polypeptide chain comprising an α-chain CDR1 containing the amino acid sequence of SEQ ID NO: 119, an α-chain CDR2 containing the amino acid sequence of SEQ ID NO: 120, and an α-chain CDR3 containing the amino acid sequence of SEQ ID NO: 121; and a second polypeptide chain comprising a β-chain CDR1 containing the amino acid sequence of SEQ ID NO: 122, a β-chain CDR2 containing the amino acid sequence of SEQ ID NO: 123, and a β-chain CDR3 containing the amino acid sequence of SEQ ID NO: 124; (g) A first polypeptide chain comprising an α-chain CDR1 containing the amino acid sequence of SEQ ID NO: 129, an α-chain CDR2 containing the amino acid sequence of SEQ ID NO: 130, and an α-chain CDR3 containing the amino acid sequence of SEQ ID NO: 131; and a second polypeptide chain comprising a β-chain CDR1 containing the amino acid sequence of SEQ ID NO: 132, a β-chain CDR2 containing the amino acid sequence of SEQ ID NO: 133, and a β-chain CDR3 containing the amino acid sequence of SEQ ID NO: 134; (h) A first polypeptide chain comprising an α-chain CDR1 containing the amino acid sequence of SEQ ID NO: 139, an α-chain CDR2 containing the amino acid sequence of SEQ ID NO: 140, and an α-chain CDR3 containing the amino acid sequence of SEQ ID NO: 141; and a second polypeptide chain comprising a β-chain CDR1 containing the amino acid sequence of SEQ ID NO: 142, a β-chain CDR2 containing the amino acid sequence of SEQ ID NO: 143, and a β-chain CDR3 containing the amino acid sequence of SEQ ID NO: 144; (i) A first polypeptide chain comprising an α-chain CDR1 containing the amino acid sequence of SEQ ID NO: 149, an α-chain CDR2 containing the amino acid sequence of SEQ ID NO: 150, and an α-chain CDR3 containing the amino acid sequence of SEQ ID NO: 151; and a second polypeptide chain comprising a β-chain CDR1 containing the amino acid sequence of SEQ ID NO: 152, a β-chain CDR2 containing the amino acid sequence of SEQ ID NO: 153, and a β-chain CDR3 containing the amino acid sequence of SEQ ID NO: 154; (j) A first polypeptide chain comprising an α-chain CDR1 containing the amino acid sequence of SEQ ID NO: 159, an α-chain CDR2 containing the amino acid sequence of SEQ ID NO: 160, and an α-chain CDR3 containing the amino acid sequence of SEQ ID NO: 161; and a second polypeptide chain comprising a β-chain CDR1 containing the amino acid sequence of SEQ ID NO: 162, a β-chain CDR2 containing the amino acid sequence of SEQ ID NO: 163, and a β-chain CDR3 containing the amino acid sequence of SEQ ID NO: 164; (k) A first polypeptide chain comprising an α-chain CDR1 containing the amino acid sequence of SEQ ID NO: 169, an α-chain CDR2 containing the amino acid sequence of SEQ ID NO: 170, and an α-chain CDR3 containing the amino acid sequence of SEQ ID NO: 171, and a second polypeptide chain comprising a β-chain CDR1 containing the amino acid sequence of SEQ ID NO: 172, a β-chain CDR2 containing the amino acid sequence of SEQ ID NO: 173, and a β-chain CDR3 containing the amino acid sequence of SEQ ID NO: 174; or (l) A first polypeptide chain comprising CDR1 of an α chain containing the amino acid sequence of SEQ ID NO: 179, CDR2 of an α chain containing the amino acid sequence of SEQ ID NO: 180, and CDR3 of an α chain containing the amino acid sequence of SEQ ID NO: 181; and a second polypeptide chain comprising CDR1 of a β chain containing the amino acid sequence of SEQ ID NO: 182, CDR2 of a β chain containing the amino acid sequence of SEQ ID NO: 183, and CDR3 of a β chain containing the amino acid sequence of SEQ ID NO:

184. Isolated or purified proteins containing the above.

12. (i) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 7, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 8; (ii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 9, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 10; (iii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 17, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 18; (iv) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 19, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 20; (v) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 27, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 28; (vi) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 29, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 30; (vii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 37, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 38; (viiii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 39, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 40; (ix) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 47, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 48; (x) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 49, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 50; (xi) The first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 125, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 126; (xi) The first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 127, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 128; (xiii) The first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 135, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 136; (xiv) The first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138; (xv) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 145, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 146; (xvi) The first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148; (xvii) The first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156; (xviiii) The first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 157, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 158; (xix) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 165, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 166; (xx) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 167, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 168; (xxi) The first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 175, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 176; (xxii) The first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178; (xxiii) The first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185, and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186; or (xxiv) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 187, and the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 188; The isolated or purified protein according to claim 11.

13. (a) The first polypeptide chain, (i) The X at position 48 of sequence number 59 is either Thr or Cys; (ii) The X at position 112 of sequence number 59 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 114 of sequence number 59 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 59, further comprising the amino acid sequence of Sequence ID No. 59, wherein X at position 115 of Sequence ID No. 59 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (b) The second polypeptide chain further comprises the amino acid sequence of SEQ ID NO: 60, wherein the X at position 57 of SEQ ID NO: 60 is Ser or Cys; or (c) Both (a) and (b) The isolated or purified protein according to claim 11 or 12.

14. (a) The first polypeptide chain, (i) The X at position 180 of sequence number 65 is either Thr or Cys; (ii) The X at position 244 of sequence number 65 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of sequence number 65 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 65, wherein X at position 247 of Sequence ID No. 65 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (b) The second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 66, wherein the X at position 188 of SEQ ID NO: 66 is either Ser or Cys; (c) Both (a) and (b); (d) The first polypeptide chain (i) The X at position 158 of sequence number 67 is either Thr or Cys; (ii) The X at position 222 of sequence number 67 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 224 of sequence number 67 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 67, wherein X at position 225 of Sequence ID No. 67 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (e) The second polypeptide chain comprises the amino acid sequence of Sequence ID No. 68, wherein the X at position 169 of Sequence ID No. 68 is either Ser or Cys; (f)(d) and (e) are both; (g) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 69; (h) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 70; (i) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 71; (j) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 72; It is both (k), (g), and (h); (l)(i) and (j) are both; (m) The first polypeptide chain, (i) The X at position 180 of sequence number 73 is either Thr or Cys; (ii) The X at position 244 of sequence number 73 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of sequence number 73 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 73, wherein X at position 247 of Sequence ID No. 73 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (n) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 74, wherein the X at position 188 of SEQ ID NO: 74 is either Ser or Cys; It is both (o), (m), and (n); (p) The first polypeptide chain, (i) The X at position 158 of sequence number 75 is either Thr or Cys; (ii) The X at position 222 of sequence number 75 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 224 of sequence number 75 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 75, wherein X at position 225 of Sequence ID No. 75 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (q) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 76, wherein the X at position 169 of SEQ ID NO: 76 is either Ser or Cys; It is both (r), (p), and (q); (s) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 77; (t) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 78; (u) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 79; (v) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 80; It is both (w), (s), and (t); It is both (x), (u), and (v); (y) The first polypeptide chain, (i) The X at position 177 of sequence number 81 is either Thr or Cys; (ii) The X at position 241 of sequence number 81 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 243 of sequence number 81 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of SEQ ID NO: 81, wherein the X at position 244 of SEQ ID NO: 81 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (z) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 82, wherein the X at position 189 of SEQ ID NO: 82 is Ser or Cys; It is both (aa), (y), and (z); (bb) The first polypeptide chain, (i) The X at position 160 of sequence number 83 is either Thr or Cys; (ii) The X at position 224 of sequence number 83 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 226 of sequence number 83 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 83, wherein X at position 227 of Sequence ID No. 83 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (cc) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 84, wherein the X at position 170 of SEQ ID NO: 84 is either Ser or Cys; It is both (dd), (bb), and (cc); (ee) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 85; (ff) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 86; (gg) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 87; (hh) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 88; (ii) is both (ee) and (ff); It is both (jj), (gg), and (hh); (kk) The first polypeptide chain, (i) The X at position 183 of sequence number 89 is either Thr or Cys; (ii) The X at position 247 of sequence number 89 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 249 of sequence number 89 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 89, wherein the X at position 250 of Sequence ID No. 89 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (ll) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 90, wherein the X at position 188 of SEQ ID NO: 90 is either Ser or Cys; It is both (mm), (kk), and (ll); (nn) The first polypeptide chain, (i) The X at position 161 of sequence number 91 is either Thr or Cys; (ii) The X at position 225 of sequence number 91 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of sequence number 91 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 91, wherein X at position 228 of Sequence ID No. 91 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (oo) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 92, wherein the X at position 169 of SEQ ID NO: 92 is either Ser or Cys; It is both (pp)(nn) and (oo); (qq) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 93; (rr) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 94; (ss) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 95; (tt) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 96; It is both (uu)(qq) and (rr); It is both (vv), (ss), and (tt); (lol) The first polypeptide chain, (i) The X at position 178 of sequence number 97 is either Thr or Cys; (ii) The X at position 242 of sequence number 97 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 244 of sequence number 97 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 97, wherein X at position 245 of Sequence ID No. 97 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (xx) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 98, wherein the X at position 188 of SEQ ID NO: 98 is either Ser or Cys; It is both (yy), (ww), and (xx); (zz) The first polypeptide chain, (i) The X at position 157 of sequence number 99 is either Thr or Cys; (ii) The X at position 221 of sequence number 99 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 223 of sequence number 99 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 99, wherein X at position 224 of Sequence ID No. 99 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (aaa) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 100, wherein the X at position 169 of SEQ ID NO: 100 is either Ser or Cys; It is both (bbb)(zz) and (aaa); (ccc) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 101; (ddd) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 102; (ee) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 103; (fff) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 104; It is both (ggg), (ccc), and (ddd); It is both (hhh)(eee) and (fff); (iii) The first polypeptide chain, (i) The X at position 176 of sequence number 189 is either Thr or Cys; (ii) The X at position 240 of sequence number 189 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 242 of sequence number 189 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 189, wherein X at position 243 of Sequence ID No. 189 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (jjj) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 190, wherein the X at position 188 of SEQ ID NO: 190 is either Ser or Cys; It is both (kkk), (iii), and (jjj); (lll) The first polypeptide chain, (i) The X at position 157 of sequence number 191 is either Thr or Cys; (ii) The X at position 221 of sequence number 191 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 223 of sequence number 191 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 191, wherein X at position 224 of Sequence ID No. 191 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (mmm) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 192, wherein the X at position 169 of SEQ ID NO: 192 is either Ser or Cys; It is both (nnn)(lll) and (mmm); (ooo) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 193; (ppp) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 194; (qqq) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 195; (rrr) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 196; It is both (sss)(ooo) and (ppp); It is both (ttt), (qqq), and (rrr); (uuu) The first polypeptide chain, (i) The X at position 181 of sequence number 197 is either Thr or Cys; (ii) The X at position 245 of sequence number 197 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 247 of sequence number 197 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 197, wherein X at position 248 of Sequence ID No. 197 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (vvv) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 198, wherein the X at position 188 of SEQ ID NO: 198 is either Ser or Cys; It is both (www), (uuu), and (vvv); (xxx) The first polypeptide chain, (i) The X at position 161 of sequence number 199 is either Thr or Cys; (ii) The X at position 225 of sequence number 199 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 227 of sequence number 199 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 199, wherein X at position 228 of Sequence ID No. 199 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (yyy) The second polypeptide chain contains the amino acid sequence of Sequence ID No. 200, wherein the X at position 169 of Sequence ID No. 200 is either Ser or Cys; It is both (zzz)(xxx) and (yyy); (aaaa) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 201; (bbbb) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 202; (cccc) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 203; (dddd) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 204; It is both (eeee), (aaaa), and (bbbb); It is both (ffff), (cccc), and (dddd); (gggg) The first polypeptide chain, (i) The X at position 184 of sequence number 205 is either Thr or Cys; (ii) The X at position 248 of sequence number 205 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of sequence number 205 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 205, wherein X at position 251 of Sequence ID No. 205 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (hhhh) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 206, wherein the X at position 190 of SEQ ID NO: 206 is either Ser or Cys; It is both (iiii)(gggg) and (hhhh); (jjjj) The first polypeptide chain, (i) The X at position 163 of sequence number 207 is either Thr or Cys; (ii) The X at position 227 of sequence number 207 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of sequence number 207 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 207, wherein X at position 230 of Sequence ID No. 207 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (kkkk) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 208, wherein the X at position 164 of SEQ ID NO: 208 is either Ser or Cys; It is both (llll) (jjjj) and (kkkk); (mmmm) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 209; (nnnn) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 210; (oooo) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 211; (pppp) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 212; It is both (qqqq) (mmmm) and (nnnn); It is both (rrrr)(oooo) and (pppp); (ssss) The first polypeptide chain, (i) The X at position 183 of sequence number 213 is either Thr or Cys; (ii) The X at position 247 of sequence number 213 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 249 of sequence number 213 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of SEQ ID NO: 213, wherein the X at position 250 of SEQ ID NO: 213 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (tttt) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 214, wherein the X at position 188 of SEQ ID NO: 214 is either Ser or Cys; It is both (uuuu)(ssss) and (tttt); (vvvv) The first polypeptide chain, (i) The X at position 161 of sequence number 215 is either Thr or Cys; (ii) The X at position 225 of sequence number 215 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 227 of sequence number 215 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 215, wherein X at position 228 of Sequence ID No. 215 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (lol) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 216, wherein the X at position 169 of SEQ ID NO: 216 is either Ser or Cys; It is both (xxxx)(vvvv) and (wwww); (yyyy) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 217; (zzzz) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 218; (aaaaa) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 219; (bbbbb) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 220; It is both (cccccc), (yyyy), and (zzzz); It is both (dddddd)(aaaaa) and (bbbbbb); (eeee) The first polypeptide chain, (i) The X at position 180 of sequence number 221 is either Thr or Cys; (ii) The X at position 244 of sequence number 221 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 246 of sequence number 221 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of SEQ ID NO: 221, wherein X at position 247 of SEQ ID NO: 221 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (ffff) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 222, wherein the X at position 188 of SEQ ID NO: 222 is either Ser or Cys; It is both (ggggg) (eeee) and (fffff); (hhhhh) The first polypeptide chain, (i) The X at position 158 of sequence number 223 is either Thr or Cys; (ii) The X at position 222 of sequence number 223 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 224 of sequence number 223 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of SEQ ID NO: 223, wherein the X at position 225 of SEQ ID NO: 223 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iiiiii) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 224, wherein the X at position 169 of SEQ ID NO: 224 is either Ser or Cys; It is both (jjjjj) (hhhhh) and (iiiiii); (kkkkk) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 225; (llllll) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 226; (mmmmm) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 227; (nnnnnn) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 228; It is both (oooooo) (kkkkk) and (llllll); It is both (ppppp)(mmmmm) and (nnnnnn); (qqqqq) The first polypeptide chain, (i) The X at position 184 of sequence number 229 is either Thr or Cys; (ii) The X at position 248 of sequence number 229 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of sequence number 229 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 229, wherein X at position 251 of Sequence ID No. 229 is Gly, Al, Val, Leu, Ile, Pro, Phe, Met, or Trp; (rrrrr) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 230, wherein the X at position 189 of SEQ ID NO: 230 is either Ser or Cys; It is both (sssss) (qqqqq) and (rrrrr); (ttttt) The first polypeptide chain, (i) The X at position 163 of sequence number 231 is either Thr or Cys; (ii) The X at position 227 of sequence number 231 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 229 of sequence number 231 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of SEQ ID NO: 231, wherein the X at position 230 of SEQ ID NO: 231 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (uuuuu) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 232, wherein the X at position 170 of SEQ ID NO: 232 is either Ser or Cys; It is both (vvvvv)(ttttt) and (uuuuu); (lol) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 233; (xxxxx) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 234; (yyyyy) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 235; (zzzzzz) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 236; It is both (aaaaaa)(wwwww) and (xxxxx); It is both (bbbbbb)(yyyyy) and (zzzzzz); (cccccc) The first polypeptide chain, (i) The X at position 184 of sequence number 237 is either Thr or Cys; (ii) The X at position 248 of sequence number 237 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 250 of sequence number 237 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 237, wherein X at position 251 of Sequence ID No. 237 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (dddddd) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 238, wherein the X at position 189 of SEQ ID NO: 238 is either Ser or Cys; It is both (eeeeee) (ccccccc) and (ddddddd); (ffffff) The first polypeptide chain, (i) The X at position 163 of sequence number 239 is either Thr or Cys; (ii) The X at position 227 of sequence number 239 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) The X at position 229 of sequence number 239 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) The amino acid sequence of Sequence ID No. 239, wherein the X at position 230 of Sequence ID No. 239 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (gggggg) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 240, wherein the X at position 170 of SEQ ID NO: 240 is either Ser or Cys; It is both (hhhhhh) (ffffff) and (ggggggg); (iiiiiii) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 241; (jjjjjj) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 242; (kkkkkk) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 243; (llllll) The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 244; (mmmmmm)(iiiiiii) and (jjjjjj), or It is both (nnnnnn)(kkkkkk) and (llllllll). The isolated or purified protein according to any one of claims 11 to 13.

15. Isolated or purified nucleic acid comprising a nucleotide sequence encoding a TCR according to any one of claims 1 to 6, a polypeptide according to any one of claims 7 to 10, or a protein according to any one of claims 11 to 14.

16. Isolated or purified nucleic acid comprising a first nucleotide sequence and a second nucleotide sequence from 5' to 3', wherein the first and second nucleotide sequences are, respectively, sequence numbers 7 and 8; 8 and 7; 9 and 10; 10 and 9; 17 and 18; 18 and 17; 19 and 20; 20 and 19; 27 and 28; 28 and 27; 29 and 30; 30 and 29; 37 and 38; 38 and 37; 39 and 40; 40 and 39; 47 and 48; 48 and 47; 49 and 50; 50 and 49; 125 and 126; 126 and 125; 127 and 128; 128 and 127; 135 and 136; 136 and 135; 137 and 138; 138 and 137; 145 and 146; 146 and 145; 147 and 148; 148 and 147; 155 and 156; 156 and 155; 157 and 158; 158 and 157; 165 and 166; 166 and 165; 167 and 168; 168 and 167; 175 and 176; 176 and 175; 177 and 178; 178 and 177; 185 and 186; 186 and 185; 187 and 188; 188 and 187; 65 and 66; 66 and 65; 67 and 68; 68 and 67 ;69 and 70;70 and 69;71 and 72;72 and 71;73 and 74;74 and 73;75 and 76;76 and 75;77 and 78;78 and 77;79 and 80;80 and 79;81 and 82;82 and 81;83 and 84;84 and 83;85 and 86;86 and 85;87 and 88;88 and 87;89 and 90;90 and 89;91 and 92;92 and 91;93 and 94;94 and 93;95 and 96;96 and 95;97 and 98;98 and 97;99 and 100;100 and 99;101 and 102;102 and 101;103 and 104; 104 and 103; 189 and 190; 190 and 189; 191 and 192; 192 and 191; 193 and 194; 194 and 193; 195 and 196; 196 and 195; 197 and 198; 198 and 197; 199 and 200; 200 and 199; 201 and 202; 202 and 201; 203 and 204; 204 and 203; 205 and 206; 206 and 205; 207 and 208; 208 and 207; 209 and 210; 210 and 209; 211 and 212; 212 and 211; 213 and 214; 214 and 213;215 and 216; 216 and 215; 217 and 218; 218 and 217; 219 and 220; 220 and 219; 221 and 222; 222 and 221; 223 and 224; 224 and 223; 225 and 226; 226 and 225; 227 and 228; 228 and 227; 229 and 230; 230 and 229; 231 and 232; 232 and 231; 233 and 234; 234 and 233; 235 and 236; 236 and 235; 237 and 238; 238 and 237; 239 and 240; 240 and 239; 241 and 242; 242 and 241; 243 and 244; or 244 and 243; the nucleic acids encoding the amino sequences.

17. The isolated or purified nucleic acid according to claim 16, further comprising a third nucleotide sequence interposed between first and second nucleotide sequences, wherein the third nucleotide sequence encodes a cleavable linker peptide.

18. The isolated or purified nucleic acid according to claim 17, wherein the cleavable linker peptide comprises the amino acid sequence RAKRSGSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 105).

19. A recombinant expression vector comprising the nucleic acid described in any one of claims 15 to 18.

20. The recombinant expression vector according to claim 19, which is a transposon or a lentiviral vector.

21. Isolated or purified TCRs, polypeptides, or proteins encoded by the nucleic acid described in any one of claims 15 to 18 or the vector described in claim 19 or 20.

22. Isolated or purified TCRs, polypeptides, or proteins obtained as a result of intracellular expression of the nucleic acid described in any one of claims 15 to 18 or the vector described in claim 19 or 20.

23. An in vitro method for producing host cells expressing a TCR having antigen specificity to the peptide MTEYKLVVVGAGDVGKSALTIQLIQ (SEQ ID NO: 252), comprising contacting the cells with the vector under conditions that enable the introduction of the vector according to claim 19 or 20 into the cells.

24. Isolated or purified host cells comprising the nucleic acid according to any one of claims 15 to 18 or the recombinant expression vector according to claim 19 or 20.

25. The host cell according to claim 24, wherein the cell is a human lymphocyte.

26. A host cell according to claim 24 or 25, selected from the group consisting of T cells, natural killer T (NKT) cells, invariant natural killer T (iNKT) cells, and natural killer (NK) cells.

27. A population of isolated or purified cells comprising the host cells described in any one of claims 24 to 26.

28. A method for producing a TCR according to any one of claims 1 to 6, 21, or 22, a polypeptide according to any one of claims 7 to 10, 21, or 22, or a protein according to any one of claims 11 to 14, 21, or 22, comprising culturing a host cell according to any one of claims 24 to 26 or a population of host cells according to claim 27 so as to produce the TCR, polypeptide, or protein.

29. (a) a TCR according to any one of claims 1 to 6, 21, or 22; a polypeptide according to any one of claims 7 to 10, 21, or 22; a protein according to any one of claims 11 to 14, 21, or 22; a nucleic acid according to any one of claims 15 to 18; a recombinant expression vector according to claim 19 or 20; a host cell according to any one of claims 24 to 26; or a population of cells according to claim 27; and (b) a pharmaceutically acceptable carrier.

30. A pharmaceutical composition for inducing an immune response against cancer in mammals, comprising a TCR according to any one of claims 1 to 6, 21, or 22, a polypeptide according to any one of claims 7 to 10, 21, or 22, a protein according to any one of claims 11 to 14, 21, or 22, a nucleic acid according to any one of claims 15 to 18, a recombinant expression vector according to claim 19 or 20, a host cell according to any one of claims 24 to 26, or a population of cells according to claim 27, The aforementioned cancer expresses a mutant human RAS amino acid sequence in which glycine at position 13 is substituted with aspartic acid, presented by the human leukocyte antigen (HLA)-DQA1*05:01:HLA-DQB1*03:01 heterodimer. The aforementioned mutant human RAS amino acid sequence is the amino acid sequence of the mutant human Kirsten rat sarcoma virus oncogene homolog (KRAS), the mutant human Harvey rat sarcoma virus oncogene homolog (HRAS), or the mutant human neuroblastoma rat sarcoma virus oncogene homolog (NRAS). The 13th position is defined by referring to the proteins of wild-type human KRAS, wild-type human HRAS, or wild-type human NRAS, respectively. Pharmaceutical composition.

31. A pharmaceutical composition for treating or preventing cancer in mammals, comprising a TCR according to any one of claims 1 to 6, 21, or 22, a polypeptide according to any one of claims 7 to 10, 21, or 22, a protein according to any one of claims 11 to 14, 21, or 22, a nucleic acid according to any one of claims 15 to 18, a recombinant expression vector according to claim 19 or 20, a host cell according to any one of claims 24 to 26, or a population of cells according to claim 27, The aforementioned cancer expresses a mutant human RAS amino acid sequence in which glycine at position 13 is substituted with aspartic acid, presented by the human leukocyte antigen (HLA)-DQA1*05:01:HLA-DQB1*03:01 heterodimer. The aforementioned mutant human RAS amino acid sequence is the amino acid sequence of the mutant human Kirsten rat sarcoma virus oncogene homolog (KRAS), the mutant human Harvey rat sarcoma virus oncogene homolog (HRAS), or the mutant human neuroblastoma rat sarcoma virus oncogene homolog (NRAS). The 13th position is defined by referring to the proteins of wild-type human KRAS, wild-type human HRAS, or wild-type human NRAS, respectively. Pharmaceutical composition.

32. The pharmaceutical composition according to claim 30 or 31, wherein the mutant human RAS amino acid sequence is the amino acid sequence of a mutant human Kirsten rat sarcoma virus oncogene homolog (KRAS).

33. The pharmaceutical composition according to claim 30 or 31, wherein the mutant human RAS amino acid sequence is the amino acid sequence of a mutant human neuroblastoma rat sarcoma virus oncogene homolog (NRAS).

34. The pharmaceutical composition according to claim 30 or 31, wherein the mutant human RAS amino acid sequence is the amino acid sequence of a mutant human Harvey rat sarcoma virus oncogene homolog (HRAS).

35. The pharmaceutical composition according to any one of claims 30 to 34, wherein the cancer is cancer of the pancreas, colorectal, lung, endometrium, ovary, or prostate.

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