T cell receptors targeting g12v ras mutations and uses thereof

Abstract

The presently disclosed subject matter provides novel T cell receptors (TCRs) that target a mutated RAS protooncogene. The presently disclosed subject matter further provides cells comprising such TCRs, and methods of using such cells for treating cancers associated with RAS.

Description

[0001] 072734.1889

[0002] PATENT T CELL RECEPTORS TARGETING GUV RAS MUTATIONS AND USES THEREOF

[0003] CROSS-REFERENCES TO RELATED APPLICATIONS

[0004] This application claims the benefit of priority to U. S. Patent Provisional Application No. 63 / 735,054, filed December 17, 2024, the content of which is incorporated herein by reference in its entirety, and to which priority is claimed.

[0005] SEQUENCE LISTING

[0006] The present specification makes reference to a Sequence Listing (submitted as an.xml file named Sequence Listing_0727341889). The XML file was generated on December 15, 2025, and is 94,812 bytes in size. The entire contents of the Sequence Listing are hereby incorporated by reference.

[0007] INTRODUCTION

[0008] The presently disclosed subject matter provides novel T cell receptors (TCRs) that target mutated RAS proto-oncogenes. The presently disclosed subject matter further provides cells comprising such TCRs, and methods of using such cells for treating cancers associated with mutated RAS.

[0009] BACKGROUND OF THE INVENTION

[0010] Cell-based immunotherapy is a therapy with curative potential for treating cancers. Immunoresponsive cells (e.g., T cells) may be modified to target tumor antigens through the introduction of genetic material coding for TCRs specific to selected antigens. Targeted T cell therapy using specific TCRs has shown clinical success in treating diverse solid and hematologic malignancies.

[0011] Collectively, the RAS proteins are the most mutated family of oncoproteins in human cancer. Patients with oncogenic mutations encoding a RAS protein (e.g., KRAS, NRAS, and FIRAS) typically respond poorly to standard therapies. Activating oncogenic RAS mutations are frequently observed at residue positions 12, 13, and 61 in cancer patients. Among these, G12 is the most frequently mutated residue (89%) and it most often mutates to aspartate (G12D), valine (G12V), or cysteine (G12C). Accordingly, there are needs for novel therapeutic strategies to identify TCRs targeting epitopes derived from mutated RAS proteins. Further, there is unmet need for developing strategies capable of inducing potent cancer eradication with minimal toxicity and immunogenicity. 072734.1889

[0012] PATENT SUMMARY OF THE INVENTION

[0013] The presently disclosed subject matter relates to a T cell receptor (TCR) that binds to a RAS peptide.

[0014] In certain embodiments, the RAS peptide includes a G12 mutation. In certain embodiments, the RAS peptide includes a G12V mutation. In certain embodiments, the RAS peptide is 9-mer or 10-mer. In certain embodiments, the RAS peptide includes or consists of the amino acid sequence set forth in SEQ ID NO: 48 or SEQ ID NO: 49. In certain embodiments, the RAS peptide is associated with an HLA class I complex. In certain embodiments, the HLA class I complex is selected from an HLA-A, an HLA-B, and an HLA-C. In certain embodiments, the HLA class I complex is an HLA-A. In certain embodiments, the HLA-A is an HLA-A*03 superfamily member. In certain embodiments, the HLA-A*03 superfamily member is selected from the group consisting of HLA-A*03, HLA-A*11, HLA-A*31, HLA-A*33, HLA-A*66, HLA-A*68 and HLA-A*74. In certain embodiments, the HLA-A*03 superfamily member is HLA-A*03.

[0015] In certain embodiments, the TCR includes an extracellular domain that binds to the RAS peptide, wherein the extracellular domain includes an a chain and a P chain, wherein the a chain includes an a chain variable region and a chain constant region, and the P chain includes a P chain variable region and a P chain constant region.

[0016] In certain embodiments,

[0017] (a) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 7;

[0018] (b) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 15;

[0019] (c) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 23;

[0020] (d) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 28;

[0021] (e) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 32;

[0022] (f) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 38;

[0023] (g) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 42; 072734.1889

[0024] PATENT

[0025] (h) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 46;

[0026] (i) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 65;

[0027] (j) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 67;

[0028] (k) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 69;

[0029] (l) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 71;

[0030] (m) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 73; or

[0031] (n) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 75.

[0032] In certain embodiments,

[0033] (a) the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 8;

[0034] (b) the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 16;

[0035] (c) the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 24;

[0036] (d) the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 29;

[0037] (e) the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 33;

[0038] (f) the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 39;

[0039] (g) the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 43; or

[0040] (h) the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 47.

[0041] In certain embodiments,

[0042] (a) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 7, and the P chain variable region 072734.1889

[0043] PATENT

[0044] includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 8;

[0045] (b) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 15, and the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 16;

[0046] (c) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 23, the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 24;

[0047] (d) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 28, the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 29;

[0048] (e) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 32, the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 33;

[0049] (f) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 38, and the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 39;

[0050] (g) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 42, and the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 43;

[0051] (h) the a chain variable region includes a CDR1, a CDR2, and a CDR3 of the a chain including the amino acid sequence set forth in SEQ ID NO: 46, and the P chain variable region includes a CDR1, a CDR2, and a CDR3 of the P chain including the amino acid sequence set forth in SEQ ID NO: 47;

[0052] (i) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 65, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 8; 072734.1889

[0053] PATENT

[0054] (j) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 67, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16;

[0055] (k) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 69, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16;

[0056] (l) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 71, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16;

[0057] (m) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16;

[0058] (n) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 73, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16; or

[0059] (o) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 75, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0060] In certain embodiments,

[0061] (a) the a chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 3;

[0062] (b) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 11;

[0063] (c) the a chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 19; 072734.1889

[0064] PATENT

[0065] (d) the a chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 26;

[0066] (e) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 30;

[0067] (f) the a chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 36;

[0068] (g) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 40;

[0069] (h) the a chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 44;

[0070] (i) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64;

[0071] (j) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66;

[0072] (k) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68;

[0073] (l) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70;

[0074] (m) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; or (n) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74.

[0075] In certain embodiments, 072734.1889

[0076] PATENT

[0077] (a) the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 6;

[0078] (b) the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 14;

[0079] (c) the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 22;

[0080] (d) the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 27;

[0081] (e) the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 31;

[0082] (f) the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 37;

[0083] (g) the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 41; or

[0084] (h) the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 45.

[0085] In certain embodiments,

[0086] (a) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 3, the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 6;

[0087] (b) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 11, and the P chain 072734.1889

[0088] PATENT

[0089] variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 14;

[0090] (c) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 19, and the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 22;

[0091] (d) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 26, and the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 27;

[0092] (e) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 30, and the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 31;

[0093] (f) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 36, and the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 37;

[0094] (g) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 40, and the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 41; 072734.1889

[0095] PATENT

[0096] (h) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 44; and the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 45;

[0097] (i) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6;

[0098] (j) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;

[0099] (k) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;

[0100] (l) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;

[0101] (m) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in 072734.1889

[0102] PATENT SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;

[0103] (n) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; or

[0104] (o) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0105] In certain embodiments,

[0106] (a) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 7;

[0107] (b) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 15;

[0108] (c) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 23;

[0109] (d) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 28;

[0110] (e) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 32;

[0111] (f) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 38;

[0112] (g) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42;

[0113] (h) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 46;

[0114] (i) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 65; 072734.1889

[0115] PATENT

[0116] (j) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67;

[0117] (k) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 69;

[0118] (l) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 71;

[0119] (m) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 73; or (n) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 75.

[0120] In certain embodiments,

[0121] (a) the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8;

[0122] (b) the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; (c) the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 24;

[0123] (d) the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 29;

[0124] (e) the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 33;

[0125] (f) the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 39;

[0126] (g) the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43; or (h) the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 47.

[0127] In certain embodiments,

[0128] (a) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 7, and the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8;

[0129] (b) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 15, and the 072734.1889

[0130] PATENT

[0131] β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16;

[0132] (c) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 23, the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 24;

[0133] (d) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 28, the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 29;

[0134] (e) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 32, the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 33;

[0135] (f) the a chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 38, and the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 39;

[0136] (g) the α chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42, and the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43;

[0137] (h) the α chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 46, and the β chain variable region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 47;

[0138] (i) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 65, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8;

[0139] (j) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; 072734.1889

[0140] PATENT

[0141] (k) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 69, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16;

[0142] (l) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 71, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16;

[0143] (m) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16;

[0144] (n) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 73, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; or

[0145] (o) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 75, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16.

[0146] In certain embodiments,

[0147] (a) the α chain variable region includes the amino acid sequence set forth in SEQ ID NO: 7, and the β chain variable region includes the amino acid sequence set forth in SEQ ID NO: 8;

[0148] (b) the α chain variable region includes the amino acid sequence set forth in SEQ ID NO: 15, and the β chain variable region includes the amino acid sequence set forth in SEQ ID NO: 16;

[0149] (c) the α chain variable region includes the amino acid sequence set forth in SEQ ID NO: 23, the β chain variable region includes the amino acid sequence set forth in SEQ ID NO: 24;

[0150] (d) the α chain variable region includes the amino acid sequence set forth in SEQ ID NO: 28, the β chain variable region includes the amino acid sequence set forth in SEQ ID NO: 29; 072734.1889

[0151] PATENT

[0152] (e) the α chain variable region includes the amino acid sequence set forth in SEQ ID NO: 32, the β chain variable region includes the amino acid sequence set forth in SEQ ID NO: 33;

[0153] (f) the α chain variable region includes the amino acid sequence set forth in SEQ ID NO: 38, and the β chain variable region includes the amino acid sequence set forth in SEQ ID NO: 39;

[0154] (g) the α chain variable region includes the amino acid sequence set forth in SEQ ID NO: 42, and the β chain variable region includes the amino acid sequence set forth in SEQ ID NO: 43;

[0155] (h) the α chain variable region includes the amino acid sequence set forth in SEQ ID NO: 46, and the β chain variable region includes the amino acid sequence set forth in SEQ ID NO: 47;

[0156] (i) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 65, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8;

[0157] (j) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 67, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16;

[0158] (k) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 69, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16;

[0159] (l) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 71, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16;

[0160] (m) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16;

[0161] (n) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 73, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16; or

[0162] (o) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 75, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16. 072734.1889

[0163] PATENT

[0164] In certain embodiments, the α chain constant region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54. In certain embodiments, the α chain constant region includes the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54. In certain embodiments, the β chain constant region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57. In certain embodiments, the β chain constant region includes the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57. In certain embodiments,

[0165] (a) the α chain constant region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54; and

[0166] (b) the β chain constant region includes an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.

[0167] In certain embodiments,

[0168] (a) the α chain constant region includes the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54; and

[0169] (b) the β chain constant region includes the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.

[0170] In certain embodiments, the TCR is recombinant. In certain embodiments, the TCR is recombinantly expressed and / or expressed from a vector.

[0171] Further, the presently disclosed subject matter relates to a T cell receptor (TCR) including an extracellular domain that binds to the same TP53 peptide as a reference TCR or a functional fragment thereof, wherein the reference TCR or functional fragment thereof includes an a chain variable region and a P chain variable region, wherein:

[0172] (a) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 3, the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 6;

[0173] (b) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 072734.1889

[0174] PATENT

[0175] 10, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 11, and the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 14;

[0176] (c) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 19, and the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 22;

[0177] (d) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 26, and the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 27;

[0178] (e) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 30, and the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 31;

[0179] (f) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 36, and the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 37;

[0180] (g) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 40, and the P chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 41; 072734.1889

[0181] PATENT

[0182] (h) the α chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 44; and the β chain variable region includes a CDR1 including the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 including the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 including the amino acid sequence set forth in SEQ ID NO: 45;

[0183] (i) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6;

[0184] (j) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;

[0185] (k) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;

[0186] (l) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;

[0187] (m) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in 072734.1889

[0188] PATENT SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;

[0189] (n) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; or

[0190] (o) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0191] The presently disclosed subject matter also relates to a nucleic acid encoding the T cell receptor (TCR). In certain embodiments, the nucleic acid further includes a polynucleotide encoding a CD8 receptor or a CD4 receptor.

[0192] In addition, the presently disclosed subject matter relates to a vector including the nucleic acid disclosed herein. In certain embodiments, the vector is a γ-retroviral vector. In certain embodiments, the vector is a plasmid including a backbone including fewer than about 500 nucleotides.

[0193] The presently disclosed subject matter further relates to a lipid nanoparticle including the nucleic acid or the vector disclosed herein.

[0194] Moreover, the presently disclosed subject matter relates to a cell including the nucleic acid, the vector, or the lipid nanoparticle disclosed herein. Additionally, the presently disclosed subject matter relates to a cell including the TCRs disclosed herein.

[0195] In certain embodiments, the cell is transduced with the TCR. In certain embodiments, the TCR is constitutively expressed on the surface of the cell.

[0196] In certain embodiments, the cell is an immunoresponsive cell. In certain embodiments, the cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, and a pluripotent stem cell from which a lymphoid cell may be differentiated. In certain embodiments, the cell is a T cell. In certain embodiments, the T cell is selected from the group consisting of a cytotoxic T lymphocyte (CTL), a regulatory T cell, a γδ T cell, a Natural Killer- 072734.1889

[0197] PATENT

[0198] T cell (NK-T), a stem cell memory T cell, a central memory T cell, and an effector memory T cell.

[0199] In certain embodiments, the T cell is a y6 T cell. In certain embodiments, the T cell is a NK-T cell. In certain embodiments, the cell is an NK cell.

[0200] In certain embodiments, the TCR is integrated at a locus within the genome of the cell. In certain embodiments, the locus is selected from a TRAC locus, a TRBC locus, a TRDC locus, and a TRGC locus. In certain embodiments, the locus is a TRAC locus or a TRBC locus. In certain embodiments, the locus is selected from a PDCD1 locus, a CBLB locus, a CISH locus, and a RASA2 locus. In certain embodiments, the locus is a genomic safe harbor.

[0201] In certain embodiments, the cell further includes at least one recombinant or exogenous co-receptor. In certain embodiments, the co-receptor is a CD8 co-receptor. In certain embodiments, the co-receptor is a CD4 co-receptor.

[0202] The presently disclosed subject matter relates to a composition including the nucleic acid, the vector, the lipid nanoparticle, or the cell disclosed herein. In certain embodiments, the composition is a pharmaceutical composition further including a pharmaceutically acceptable carrier.

[0203] In certain non-limiting embodiments, the presently disclosed subject matter relates to a method for producing a cell that binds to a RAS peptide that includes a G12 mutation. In certain embodiments, the method includes introducing into the cell the nucleic acid, the vector, the lipid nanoparticle, or the composition thereof disclosed herein.

[0204] In certain embodiments, the presently disclosed subject matter relates to a method of treating and / or preventing a tumor associated with RAS in a subject. In certain embodiments, the method includes administering to the subject the cell or the composition disclosed herein. In certain embodiments, the tumor is associated with a RAS mutation. In certain embodiments, the RAS mutation is a G12V mutation.

[0205] In certain embodiments, the tumor is selected from the group consisting of pancreatic cancer, breast cancer, endometrial cancer, cervical cancer, anal cancer, bladder cancer, colorectal cancer, cholangiocarcinoma / bile duct cancer, lung cancer, ovarian cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, nonmelanoma skin cancer, salivary gland cancer, melanoma, appendiceal cancer, and multiple myeloma. In certain embodiments, the tumor is pancreatic cancer.

[0206] In certain embodiments, the subject is a human. In certain embodiments, the subject includes an HLA-A. In certain embodiments, the HLA-A is an HLA-A*03 superfamily member. In certain embodiments, the HLA-A*03 superfamily member is selected from the 072734.1889

[0207] PATENT

[0208] group consisting of HLA-A*03, HLA-A*11, HLA-A*31, HLA-A*33, HLA-A*66, HLA-A*68 and HLA-A*74. In certain embodiments, the HLA-A*03 superfamily member is HLA-A*03.

[0209] In certain embodiments, the presently disclosed subject matter relates to a cell or a composition disclosed herein for use in treating and / or preventing a tumor associated with RAS in a subject. In certain embodiments, the tumor is associated with a RAS mutation. In certain embodiments, the RAS mutation is a G12D mutation.

[0210] In certain embodiments, the tumor is selected from the group consisting of pancreatic cancer, breast cancer, endometrial cancer, cervical cancer, anal cancer, bladder cancer, colorectal cancer, cholangiocarcinoma / bile duct cancer, lung cancer, ovarian cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, nonmelanoma skin cancer, salivary gland cancer, melanoma, appendiceal cancer, and multiple myeloma. In certain embodiments, the tumor is pancreatic cancer.

[0211] In certain embodiments, the subject is a human. In certain embodiments, the subject includes an HLA-A. In certain embodiments, the HLA-A is an HLA-A*03 superfamily member. In certain embodiments, the HLA-A*03 superfamily member is selected from the group consisting of HLA-A*03, HLA-A*11, HLA-A*31, HLA-A*33, HLA-A*66, HLA-A*68 and HLA-A*74. In certain embodiments, the HLA-A*03 superfamily member is HLA-A*03.

[0212] In certain embodiments, the presently disclosed subject matter relates to a bispecific molecule comprising the T cell receptor (TCR) disclosed herein or a functional fragment thereof and a second binding specificity. In certain embodiments, the second binding specificity binds to a T cell. In certain embodiments, the second binding specificity binds to CD3, CD28, CD137, ICOS, CD4, CD8, or a combination thereof. In certain embodiments, the second binding specificity binds to an NK cell. In certain embodiments, the second binding specificity binds to CD16, CD335, NKp80, NKG2D, or a combination thereof.

[0213] In certain embodiments, the presently disclosed subject matter relates to a composition comprising the bispecific molecule disclosed herein. In certain embodiments, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0214] In certain embodiments, the presently disclosed subject matter relates to a nucleic acid encoding the bispecific molecule disclosed herein. Additionally or alternatively, the presently disclosed subject matter relates to a vector or a lipid nanoparticle comprising the nucleic acid encoding the bispecific molecule disclosed herein. 072734.1889

[0215] PATENT

[0216] In certain embodiments, the presently disclosed subject matter relates to a cell comprising the bispecific molecule disclosed herein or nucleic acids, vectors, or lipid nanoparticles encoding the same.

[0217] In certain embodiments, the presently disclosed subject matter relates to a method of treating and / or preventing a tumor associated with RAS in a subject, comprising administering to the bispecific molecule disclosed herein or the composition comprising thereof.

[0218] Finally, the presently disclosed subject matter relates to the bispecific molecule disclosed herein or the composition comprising thereof for use in treating and / or preventing a tumor associated with RAS in a subject.

[0219] BRIEF DESCRIPTION OF THE FIGURES

[0220] The following Detailed Description, given by way of example but not intended to limit the invention to specific embodiments described, may be understood in conjunction with the accompanying drawings.

[0221] Figure 1 depicts a graphical comparison of the amino acid sequence homology and location of hotspot mutations in the RAS family of oncoproteins. * = location of hotspot mutations; vertical bar = site of sequence variation between RAS family members. Zoom area shows the sequence of the hypervariable region of all four RAS proteins.

[0222] Figure 2 shows FACS analysis illustrating discovery of a panel of unique HLA-A*03-01-restricted RAS(G12V)-specific TCR gene sequences from cancer patients. PDAC= Pancreatic ductal adenocarcinoma, LUAD= Lung adenocarcinoma.

[0223] Figure 3 shows FACS analysis illustrating discovery of a panel of unique HLA-A*03:01-restricted RAS(G12V)-specific TCR gene sequences from healthy -donors.

[0224] Figure 4 shows multimer binding profile, recognition of endogenously processed / presented RAS(G12V) and minimal epitope of the full panel of reconstituted patient and healthy-donor derived TCR sequences.

[0225] Figure 5 shows functional recognition of endogenous and peptide pulsed targets by the panel of HLA-A*03:01 / RAS(G12V) TCR candidates.

[0226] Figure 6 shows FACS analysis demonstrating functional recognition of endogenous levels of RAS(G12V) mutant tumor lines by JM1822 TCR.

[0227] Figure 7 shows a schematic of the experimental methodology to identify additional TCRs. 072734.1889

[0228] PATENT

[0229] Figure 8 shows CDR3a sequences of retrieved alpha hemichains and functional avidities of reconstituted TCR-T cells including the DG7302beta. SEQ ID NO: 40, SEQ ID NO: 66, SEQ ID NO: 68; SEQ ID NO: 70; SEQ ID NO: 72; SEQ ID NO: 74, and SEQ ID NO: 83 are shown.

[0230] Figure 9 shows CDR3a sequences of retrieved alpha hemichains and functional avidities of reconstituted TCR-T cells including the CO83 lObeta. SEQ ID NO: 64 and SEQ ID NO: 84 are shown.

[0231] DETAILED DESCRIPTION OF THE INVENTION

[0232] The presently disclosed subject matter provides TCRs, targeting RAS comprising a mutation, e.g., a G12V mutation. Furthermore, the presently disclosed subject matter provides cells (e.g., T cells) comprising the RAS-targeted TCRs, and methods of using such cells for treating tumors associated with RAS mutation(s).

[0233] For purposes of clarity of disclosure and not by way of limitation, the detailed description is divided into the following subsections:

[0234] 1. Definitions;

[0235] 2. RAS,'

[0236] 3. TCRs;

[0237] 4. Cells

[0238] 5. Nucleic Acids and Genetic Modifications of Cell;

[0239] 6. Formulations and Administration;

[0240] 7. Methods of Treatments.

[0241] 1. Definitions

[0242] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which this invention belongs. The following references provide one of skill with a general definition of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991).

[0243] As used herein, the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, / .<., the limitations of the 072734.1889

[0244] PATENT

[0245] measurement system. For example, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.

[0246] As used herein, the term “cell population” refers to a group of at least two cells expressing similar or different phenotypes. In non-limiting examples, a cell population can include at least about 10, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000 cells expressing similar or different phenotypes.

[0247] As used herein, the term “vector” refers to any genetic element, such as a plasmid (e.g., a plasmid having a small backbone of less than about 500 base pairs, such as a Nanoplasmid™ vector system), phage, transposon, cosmid, chromosome, virus, virion, etc., which is capable of replication when associated with the proper control elements and which can transfer gene sequences into cells. Thus, the term includes cloning and expression vehicles, as well as viral vectors and plasmid vectors.

[0248] As used herein, the term “expression vector” refers to a recombinant nucleic acid sequence, e.g., a recombinant DNA molecule, containing a desired coding sequence and appropriate nucleic acid sequences necessary for the expression of the operably linked coding sequence in a particular host organism. Nucleic acid sequences necessary for expression in prokaryotes usually include a promoter, an operator (optional), and a ribosome binding site, often along with other sequences. Eukaryotic cells are known to utilize promoters, enhancers, and termination and polyadenylation signals.

[0249] As used herein, “CDRs” are defined as the complementarity determining region amino acid sequences of a TCR, which are the hypervariable regions of TCR a-chain and P-chain. Generally, a TCR comprises three CDRs in the a-chain variable region and three CDRs in the P-chain variable region. CDRs provide the majority of contact residues for the binding of the TCR to the antigen or epitope. CDRs regions can be delineated using the Kabat system (Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U. S. Department of Health and Human Services, NIH Publication No. 91-3242), the Chothia numbering system (Chothia et al., J Mol Biol. (1987) 196:901-17), the AbM numbering system (Abhinandan et al., Mol. Immunol. 2008, 45, 3832-3839), or the IMGT numbering system 072734.1889

[0250] PATENT

[0251] (Lefranc, Frontiers in immunology 5 (2014): 22). In certain embodiments, the CDRs regions are delineated using the IMGT numbering system.

[0252] The terms “substantially homologous” or “substantially identical” mean a polypeptide or nucleic acid molecule that exhibits at least 50% homology or identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein). For example, such a sequence is at least about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or even about 99% homologous or identical at the amino acid level or nucleic acid to the sequence used for comparison.

[0253] Sequence homology or sequence identity is typically measured using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis.

[0254] 53705, BLAST, BESTFIT, GAP, or PILEUP / PRETTYBOX programs). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or other modifications. In an exemplary approach to determining the degree of identity, a BLAST program may be used, with a probability score between e'3ande'100indicating a closely related sequence.

[0255] As used herein, the percent homology between two amino acid sequences is equivalent to the percent identity between the two sequences. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences ( / .<., % homology = # of identical positions / total # of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.

[0256] The percent homology between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17 (1988)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent homology between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol.

[0257] 48:444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

[0258] Additionally or alternatively, the amino acids sequences of the presently disclosed subject matter can further be used as a “query sequence” to perform a search against public 072734.1889

[0259] PATENT

[0260] databases to, for example, identify related sequences. Such searches can be performed using theXBLAST program (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to the specified sequences disclosed herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0261] As used herein, the term “a conservative sequence modification” refers to an amino acid modification that does not significantly affect or alter the binding characteristics of the presently disclosed TCR comprising the amino acid sequence. Conservative modifications can include amino acid substitutions, additions and deletions. Amino acids can be classified into groups according to their physicochemical properties such as charge and polarity. Conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid within the same group. For example, amino acids can be classified by charge: positively-charged amino acids include lysine, arginine, histidine, negatively-charged amino acids include aspartic acid, glutamic acid, neutral charge amino acids include alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In addition, amino acids can be classified by polarity: polar amino acids include arginine (basic polar), asparagine, aspartic acid (acidic polar), glutamic acid (acidic polar), glutamine, histidine (basic polar), lysine (basic polar), serine, threonine, and tyrosine; non-polar amino acids include alanine, cysteine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, and valine. Thus, one or more amino acid residues within a CDR region can be replaced with other amino acid residues from the same group and the altered TCR can be tested for retained function ( / .<., the functions set forth in (c) through (1) above) using the functional assays described herein. In certain embodiments, no more than one, no more than two, no more than three, no more than four, no more than five residues within a specified sequence or a CDR region are altered.

[0262] As used herein, the term “disease” refers to any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. Examples of diseases include neoplasm or pathogen infection of a cell.

[0263] An “effective amount” (or “therapeutically effective amount”) is an amount sufficient to affect a beneficial or desired clinical result upon treatment. An effective amount can be administered to a subject in one or more doses. In terms of treatment, an effective amount is 072734.1889

[0264] PATENT

[0265] an amount that is sufficient to palliate, ameliorate, stabilize, reverse or slow the progression of the disease (e.g., a tumor), prevent or delay the recurrence of a tumor, or otherwise reduce the pathological consequences of the disease (e.g., a tumor). The effective amount is generally determined by the physician on a case-by-case basis and is within the skill of one in the art. Several factors are typically taken into account when determining an appropriate dosage to achieve an effective amount. These factors include age, sex and weight of the subject, the condition being treated, the severity of the condition and the form and effective concentration of the immunoresponsive cells administered.

[0266] As used herein, the term “tumor” refers to an abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should. Tumors include benign tumors and malignant tumors (known as “cancers”). Benign tumors may grow large but do not spread into, or invade, nearby tissues or other parts of the body. Malignant tumors can spread into, or invade, nearby tissues. They can also spread to other parts of the body through the blood and lymph systems. Tumor is also called neoplasm. In certain embodiments, the tumor is cancer.

[0267] As used herein, the term “immunoresponsive cell” refers to a cell that functions in an immune response or a progenitor, or progeny thereof.

[0268] As used herein, the term “modulate” refers to positively or negatively alter. Exemplary modulations include an about 1%, about 2%, about 5%, about 10%, about 25%, about 50%, about 75%, or about 100% change.

[0269] As used herein, the term “increase” refers to alter positively by at least about 5%, including, but not limited to, alter positively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.

[0270] As used herein, the term “reduce” refers to alter negatively by at least about 5% including, but not limited to, alter negatively by about 5%, by about 10%, by about 25%, by about 30%, by about 50%, by about 75%, or by about 100%.

[0271] As used herein, the term “isolated,” “purified,” or “biologically pure” refers to material that is free to varying degrees from components which normally accompany it as found in its native state. “Isolate” denotes a degree of separation from original source or surroundings. “Purify” denotes a degree of separation that is higher than isolation. A “purified” or “biologically pure” protein is sufficiently free of other materials such that any impurities do not materially affect the biological properties of the protein or cause other adverse consequences. That is, a nucleic acid or polypeptide of the presently disclosed subject matter is purified if it is substantially free of cellular material, viral material, or culture medium when 072734.1889

[0272] PATENT

[0273] produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. Purity and homogeneity are typically determined using analytical chemistry techniques, for example, polyacrylamide gel electrophoresis or high performance liquid chromatography. The term “purified” can denote that a nucleic acid or protein gives rise to essentially one band in an electrophoretic gel. For a protein that can be subjected to modifications, for example, phosphorylation or glycosylation, different modifications may give rise to different isolated proteins, which can be separately purified.

[0274] As used herein, the term “isolated cell” refers to a cell that is separated from the molecular and / or cellular components that naturally accompany the cell.

[0275] As used herein, the term “treating” or “treatment” refers to clinical intervention in an attempt to alter the disease course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Therapeutic effects of treatment include, without limitation, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastases, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. By preventing progression of a disease or disorder, a treatment can prevent deterioration due to a disorder in an affected or diagnosed subject or a subject suspected of having the disorder, but also a treatment may prevent the onset of the disorder or a symptom of the disorder in a subj ect at risk for the disorder or suspected of having the disorder.

[0276] An “individual” or “subject” herein is a vertebrate, such as a human or non-human animal, for example, a mammal. Mammals include, but are not limited to, humans, primates, farm animals, sport animals, rodents and pets. Non-limiting examples of non-human animal subjects include rodents such as mice, rats, hamsters, guinea pigs, rabbits, dogs, cats, sheep, pigs, goats, cattle, horses; and non-human primates such as apes and monkeys.

[0277] As used herein, the terms “recombinant T cell receptor” or “recombinant TCR” refer to a T cell receptor that is produced by genetic engineering (i.e., recombinant DNA technology). In certain embodiments, the term “recombinant TCR” includes TCRs that are expressed in a prokaryotic or eukaryotic cell that contains a cloning vector or expression vector comprising a polynucleotide encoding the TCR. In certain embodiments, a recombinant T cell receptor refers to a T cell receptor that is prepared, expressed, generated, and / or isolated using recombinant technologies. Methods and procedures to prepare, express, generate, and / or isolate recombinant TCR are known in the art. 072734.1889

[0278] PATENT

[0279] As used herein, the term “neoantigens” or “NeoAgs” refers to peptides derived from the protein products of mutations found in a patient and presented by a patient’s complement of human leukocyte antigen (HLA) molecules. As used herein, the term “public neoantigen” refers to neoantigen derived from a common hotspot mutation seen in multiple patients as opposed to a “private neoantigen” which is exclusive to an individual patient.

[0280] 2. RAS

[0281] RAS is a family of oncoproteins encoding small GTPases involved in regulating cell growth, differentiation and survival of cells. In humans, the RAS family includes HRAS, NRAS, and KRAS. The KRAS gene has two splice variants, KRAS4A and KRAS4B. The expression of all isoforms is nearly ubiquitous, although they show quantitative and qualitative differences in expression depending on the tissue and / or developmental stage.

[0282] RAS proteins contain two domains: a G domain that binds guanosine nucleotides, and a C-terminal hypervariable region. The G domain is highly conserved between HRAS, NRAS, KRAS4A and KRAS4B and is responsible for binding and hydrolysis of guanine nucleotides. The hypervariable regions undergo differential post-translational modifications that in turn direct isoform-specific subcellular organization. RAS proteins act as binary molecular switches and cycle between an inactive GDP -bound and active GTP-bound state. Upon activation, RAS proteins recruit and activate proteins like c-Raf and PI3 -kinase that result in cell proliferation, migration and protection from apoptosis.

[0283] RAS mutations play a critical role in driving some of the most common and deadly carcinomas, including pancreatic, lung, and colorectal cancers, among numerous others. As illustrated in Figure 1, the conserved G domain includes several locations for hotspot mutations including G12, G13, and Q61. The most frequent mutations of RAS genes occur at codon 12 (i.e., G12A / C / D / F / L / R / S / V), which accounts for 98% of RAS mutations. Across cancers, one of the most common RAS mutations is G12V, which is a single point mutation with a glycine-to-valine substitution at codon 12.

[0284] 3. T-cell receptor (TCR)

[0285] A TCR is a disulfide-linked heterodimeric protein consisting of two variable chains expressed as part of a non-covalent complex with the invariant CD3 chain molecules (CD36, CD3s, CD3y, CD3Q. A TCR is found on the surface of T cells, and is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules. In certain embodiments, a TCR comprises an a chain and a P chain (encoded by TRA and TRB, 072734.1889

[0286] PATENT

[0287] respectively). In certain embodiments, a TCR comprises a y chain and a 6 chain (encoded by TRG and TRD, respectively).

[0288] Each chain of a TCR comprises two extracellular domains: a variable region and a constant region. The constant region is proximal to the cell membrane, followed by a transmembrane domain and a short cytoplasmic tail (i.e., an intracellular domain). The variable region binds to the peptide / MHC complex. The variable region of both chains each has three complementarity determining regions (CDRs).

[0289] In certain embodiments, a TCR can form a receptor complex with three dimeric signaling modules CD36 / s, CD3y / s and CD247

[0290]

[0291] or C / r|. When a TCR complex engages with its cognate peptide antigen / MHC (peptide / MHC), the T cell expressing the TCR complex is activated.

[0292] The presently disclosed subject matter provides recombinant TCRs. In certain embodiments, the recombinant TCR differs from any naturally occurring TCR by at least one amino acid residue. In certain embodiments, the recombinant TCR differs from any naturally occurring TCR by at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acid residues. In certain embodiments, the recombinant TCR is modified from a naturally occurring TCR by at least one amino acid residue. In certain embodiments, the recombinant TCR is modified from a naturally occurring TCR by at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100 or more amino acid residues.

[0293] In certain embodiments, the presently disclosed TCR targets or binds to a RAS peptide that comprises a mutation (“a mutant RAS peptide”). In certain embodiments, the mutation is a point mutation. In certain embodiments, the mutation is a G12 mutation. In certain embodiments, the RAS peptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 48. In certain embodiments, the RAS peptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 49. In certain embodiments, the presently disclosed TCR does not bind to a wildtype RAS. In certain embodiments, the presently disclosed TCR does not bind to a RAS peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 50. SEQ ID NOs: 48-50 are provided below.

[0294] WGAVGVGK [SEQ ID NO: 48 ]

[0295] VWGAVGVGK [SEQ ID NO: 49]

[0296] VWGAGGVGK [SEQ ID NO: 50]

[0297] In certain embodiments, the presently disclosed TCR targets or binds to KRAS comprising a RAS peptide comprising or consisting of the amino acid sequence set forth in 072734.1889

[0298] PATENT SEQ ID NO: 48. In certain embodiments, the presently disclosed TCR targets or binds to KRAS comprising a RAS peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 49.

[0299] In certain embodiments, the presently disclosed TCR targets or binds to NRAS comprising a RAS peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 48. In certain embodiments, the presently disclosed TCR targets or binds to NRAS comprising a RAS peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 49.

[0300] In certain embodiments, the presently disclosed TCR targets or binds to HRAS comprising a RAS peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 48. In certain embodiments, the presently disclosed TCR targets or binds to HRAS comprising a RAS peptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 49. In certain embodiments, the presently disclosed TCR targets or binds to a RAS peptide associated with an HLA class I complex, e.g., HLA-A, HLA-B and HLA-C.

[0301] In certain embodiments, the presently disclosed TCR targets or binds to a RAS peptide associated with an HLA-A*03 superfamily (e.g., in an HLA-A*03 superfamily dependent manner). In certain embodiments, the HLA*A03 superfamily members, include, but not limited to, alleles and sub-alleles in the HLA-A*03, HLA-A*11, HLA-A*31, HLA-A*33, HLA-A*66, HLA-A*68 and HLA-A*74. In certain embodiments, the presently disclosed TCR targets or binds to a RAS peptide associated with an HLA-A*03 molecule.

[0302] 3.1. TCRs

[0303] 3,1.1. Variable Regions

[0304] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 7. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0305] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 8. SEQ ID NO: 7 and SEQ ID NO: 8 are provided in Table 1.

[0306] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID 072734.1889

[0307] PATENT NO: 1 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3 or a conservative modification thereof. SEQ ID NOS: 1-3 are disclosed in Table 1. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6 or a conservative modification thereof. SEQ ID NOS: 4-6 are disclosed in Table 1.

[0308] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6.

[0309] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6 or a conservative modification thereof.

[0310] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6.

[0311] In certain embodiments, the CDRs sequences described above including Table 1 are delineated using the IMGT numbering system. 072734.1889

[0312] PATENT

[0313] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 7. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 7. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 7.

[0314] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8.

[0315] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 7; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 7; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8.

[0316] In certain embodiments, the TCR is designated as “CO8310”. In certain embodiments, the CO8310 binds to a RAS peptide comprising a G12V mutation.

[0317] Table 1. (CO8310)

[0318] CDRs 1 2 3

[0319] a-chain NSASDY [SEQ IRSNMDK [SEQ CAESRESYIPTF [SEQ ID ID NO: 1 ] ID NO: 2 ] NO: 3]

[0320]

[0321] 072734.1889

[0322] PATENT

[0323] P-chain SGHAT [SEQ ID FQNNGV [SEQ ID CASSQRGQGRRAKNIQYF NO: 4 ] NO: 5] [SEQ ID NO: 6]

[0324] a-chain MAGIRALFMYLWLQLDWVSRGESVGLHLPTLSVQEGDNS I INCAYSNSASDY variable FIWYKQESGKGPQFI IDIRSNMDKRQGQRVTVLLNKTVKHLSLQIAATQPGD SAVYFCAESRESYIPTFGRGTSLIVHP [SEQ ID NO: 7 ]

[0325] P-chain MGTRLLCWAALCLLGAELTEAGVAQSPRYKI IEKRQSVAFWCNPISGHATLY variable WYQQILGQGPKLLIQFQNNGWDDSQLPKDRFSAERLKGVDSTLKIQPAKLE DSAVYLCASSQRGQGRRAKNIQYFGAGTRLSVL [SEQ ID NO: 8 ]

[0326]

[0327] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 65. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 8.

[0328] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 65, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 8. SEQ ID NO: 65 and SEQ ID NO: 8 are provided in Table 2.

[0329] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64 or a conservative modification thereof. SEQ ID NOS: 62-64 are disclosed in Table 2. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6 or a conservative modification thereof. SEQ ID NOS: 4-6 are disclosed in Table 2.

[0330] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64. In certain embodiments, the P chain variable region comprises a CDR1 comprising 072734.1889

[0331] PATENT

[0332] the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6.

[0333] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6 or a conservative modification thereof.

[0334] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6.

[0335] In certain embodiments, the CDRs sequences described above including Table 2 are delineated using the IMGT numbering system.

[0336] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 65. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 65. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 65.

[0337] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 072734.1889

[0338] PATENT

[0339] about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8.

[0340] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 65; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 65; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8.

[0341] In certain embodiments, the TCR is designated as “CO8310_HDl_Al”. In certain embodiments, the CO8310 HD1 A1 binds to aRAS peptide comprising a G12V mutation.

[0342] Table 2. (CO8310 HD1 Al)

[0343] CDRs 1 2 3

[0344] a-chain TSGFNG [SEQ NVLDGL [SEQ ID CAPRKWGKLIF [SEQ ID ID NO: 62 ] NO: 63] NO: 64 ]

[0345] P-chain SGHAT [SEQ ID FQNNGV [SEQ ID CASSQRGQGRRAKNIQYF NO: 4 ] NO: 5] [SEQ ID NO: 6]

[0346] a-chain MWGVFLLYVSMKMGGTTGQNIDQPTEMTATEGAIVQINCTYQTSGFNGLFWY variable

[0347] QQHAGEAPTFLSYNVLDGLEEKGRFSSFLSRSKGYSYLLLKELQMKDSASYL CAPRKWGKLIFGQGTELSVKP [SEQ ID NO: 65]

[0348] P-chain MGTRLLCWAALCLLGAELTEAGVAQSPRYKI IEKRQSVAFWCNPISGHATLY variable WYQQILGQGPKLLIQFQNNGWDDSQLPKDRFSAERLKGVDSTLKIQPAKLE DSAVYLCASSQRGQGRRAKNIQYFGAGTRLSVL [SEQ ID NO: 8 ]

[0349]

[0350] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 15. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0351] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino 072734.1889

[0352] PATENT

[0353] acid sequence set forth in SEQ ID NO: 15, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16. SEQ ID NO: 15 and SEQ ID NO: 16 are provided in Table 3.

[0354] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof. SEQ ID NOS: 9-11 are disclosed in Table 3. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof. SEQ ID NOS: 12-14 are disclosed in Table 3.

[0355] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0356] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof.

[0357] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11; and the P chain variable region comprises a CDR1 comprising the amino acid 072734.1889

[0358] PATENT

[0359] sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0360] In certain embodiments, the CDRs sequences described above including Table 3 are delineated using the IMGT numbering system.

[0361] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 15. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 15. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 15.

[0362] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0363] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 15; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 15; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0364] In certain embodiments, the TCR is designated as “DG7302”. In certain embodiments, the DG7302 binds to a RAS peptide comprising a G12V mutation. 072734.1889

[0365] PATENT

[0366] Table3. (DG7302)

[0367] CDRs 1 2 3

[0368] a-chain TRDTTYY [SEQ RNSFDEQN [SEQ CALSEAGNYQLIW [SEQ ID ID NO: 9] ID NO: 10] NO: 11 ]

[0369] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSVDGAGQETQYF [SEQ NO: 12 ] NO: 13] ID NO: 14 ]

[0370] a-chain MLTASLLRAVIASICWSSMAQKVTQAQTEISWEKEDVTLDCVYETRDTTY variable YL FWYKQPPS GELVFL I RRNS FDEQNE I S GRYS WNFQKS T S S FNFT I TAS QV VDSAVYFCALSEAGNYQLIWGAGTKLI IKP [SEQ ID NO: 15] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSVDGAGQETQYFGPGTRLLVL [SEQ ID NO: 16]

[0371]

[0372] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 67. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0373] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 67, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16. SEQ ID NO: 67 and SEQ ID NO: 16 are provided in Table 4.

[0374] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66 or a conservative modification thereof. SEQ ID NOS: 9,10, and 66 are disclosed in Table 4. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof. SEQ ID NOS: 12-14 are disclosed in Table 4. 072734.1889

[0375] PATENT

[0376] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0377] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof.

[0378] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0379] In certain embodiments, the CDRs sequences described above including Table 4 are delineated using the IMGT numbering system.

[0380] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 67. 072734.1889

[0381] PATENT

[0382] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0383] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 67; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0384] In certain embodiments, the TCR is designated as “DG7302 HD1 A2”. In certain embodiments, the DG7302 HD1 A2 binds to a RAS peptide comprising a G12V mutation.

[0385] Table 4. (DG7302 HD1 A2)

[0386] CDRs 1 2 3

[0387] a-chain TRDTTYY [SEQ RNSFDEQN [SEQ CALSGAGSYQLTF [SEQ ID ID NO: 9] ID NO: 10] NO: 66]

[0388] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSVDGAGQETQYF [SEQ NO: 12 ] NO: 13] ID NO: 14 ]

[0389] a-chain MLTASLLRAVIASICWSSMAQKVTQAQTEISWEKEDVTLDCVYETRDTTY variable YL FWYKQPPS GELVFL I RRNS FDEQNE I S GRYS WNFQKS T S S FNFT I TAS QV VDSAVYFCALSGAGSYQLTFGKGTKLSVIP [SEQ ID NO: 67 ] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable

[0390] WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSVDGAGQETQYFGPGTRLLVL [SEQ ID NO: 16]

[0391]

[0392] 072734.1889

[0393] PATENT

[0394] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 69. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0395] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 69, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16. SEQ ID NO: 69 and SEQ ID NO: 16 are provided in Table 5.

[0396] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68 or a conservative modification thereof. SEQ ID NOS: 9, 10, and 68 are disclosed in Table 5. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof. SEQ ID NOS: 12-14 are disclosed in Table 5.

[0397] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0398] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification 072734.1889

[0399] PATENT

[0400] thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof.

[0401] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0402] In certain embodiments, the CDRs sequences described above including Table 5 are delineated using the IMGT numbering system.

[0403] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 69. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 69. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 69.

[0404] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0405] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 69; and the P chain variable region comprises an amino acid sequence that is at least about 80% e.g., at least 072734.1889

[0406] PATENT

[0407] about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 69; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0408] In certain embodiments, the TCR is designated as “DG7302 HD1 A3”. In certain embodiments, the DG7302 HD1 A3 binds to a RAS peptide comprising a G12V mutation.

[0409] Table 5. (DG7302 HD1 A3)

[0410] CDRs 1 2 3

[0411] a-chain TRDTTYY [SEQ RNSFDEQN [SEQ CALSEARDYKLSF [SEQ ID ID NO: 9] ID NO: 10] NO: 68 ]

[0412] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSVDGAGQETQYF [SEQ NO: 12 ] NO: 13] ID NO: 14 ]

[0413] a-chain MLTASLLRAVIASICWSSMAQKVTQAQTEISWEKEDVTLDCVYETRDTTY variable

[0414] YL FWYKQPPS GELVFL I RRNS FDEQNE I S GRYS WNFQKS T S S FNFT I TAS QV VDSAVYFCALSEARDYKLSFGAGTTVTVRA [SEQ ID NO: 69] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable

[0415] WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSVDGAGQETQYFGPGTRLLVL [SEQ ID NO: 16]

[0416]

[0417] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 71. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0418] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 71, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16. SEQ ID NO: 71 and SEQ ID NO: 16 are provided in Table 6.

[0419] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the 072734.1889

[0420] PATENT

[0421] amino acid sequence set forth in SEQ ID NO: 70 or a conservative modification thereof. SEQ ID NOS: 9, 10, and 70 are disclosed in Table 6. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof. SEQ ID NOS: 12-14 are disclosed in Table 6.

[0422] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0423] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof.

[0424] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0425] In certain embodiments, the CDRs sequences described above including Table 6 are delineated using the IMGT numbering system.

[0426] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) 072734.1889

[0427] PATENT

[0428] homologous or identical to the amino acid sequence set forth in SEQ ID NO: 71. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 71. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 71.

[0429] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0430] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 71; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 71; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0431] In certain embodiments, the TCR is designated as “DG7302 HD1 A4”. In certain embodiments, the DG7302 HD1 A4 binds to a RAS peptide comprising a G12V mutation.

[0432] Table 6. (DG7302 HD1 A4)

[0433] CDRs 1 2 3

[0434] a-chain TRDTTYY [SEQ RNSFDEQN [SEQ CALSEAGDYKLSF [SEQ ID ID NO: 9] ID NO: 10] NO: 70]

[0435] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSVDGAGQETQYF [SEQ NO: 12 ] NO: 13] ID NO: 14 ]

[0436]

[0437] 072734.1889

[0438] PATENT

[0439] a-chain MLTASLLRAVIASICWSSMAQKVTQAQTEISWEKEDVTLDCVYETRDTTY variable YL FWYKQPPS GELVFL I RRNS FDEQNE I S GRYS WNFQKS T S S FNFT I TAS QV VDSAVYFCALSEAGDYKLSFGAGTTVTVRA [SEQ ID NO: 71 ] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSVDGAGQETQYFGPGTRLLVL [SEQ ID NO: 16]

[0440]

[0441] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0442] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16. SEQ ID NO: 42 and SEQ ID NO: 16 are provided in Table 7.

[0443] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 or a conservative modification thereof. SEQ ID NOS: 9,10, and 40 are disclosed in Table 7. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof. SEQ ID NOS: 12-14 are disclosed in Table 7.

[0444] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid 072734.1889

[0445] PATENT

[0446] sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0447] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof.

[0448] In certain embodiments, the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0449] In certain embodiments, the CDRs sequences described above including Table 7 are delineated using the IMGT numbering system.

[0450] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42.

[0451] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 072734.1889

[0452] PATENT

[0453] about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0454] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0455] In certain embodiments, the TCR is designated as “DG7302 HD2 A2”. In certain embodiments, the DG7302 HD2 A2 binds to a RAS peptide comprising a G12V mutation.

[0456] Table 7. (DG7302 HD2 A2)

[0457] CDRs 1 2 3

[0458] a-chain TRDTTYY [SEQ RNSFDEQN [SEQ CALSEARTYKYI E [ SEQ ID NO:

[0459] ID NO: 9] ID NO: 10] 40]

[0460] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSVDGAGQETQYF [SEQ NO: 12 ] NO: 13] ID NO: 14 ]

[0461] a-chain MLTASLLRAVIASICWSSMAQKVTQAQTEISWEKEDVTLDCVYETRDTTY variable

[0462] YL FWYKQPPS GELVFL I RRNS FDEQNE I S GRYS WNFQKS T S S FNFT I TAS QV VDSAVYFCALSEARTYKYIFGTGTRLKVLA [SEQ ID NO: 42 ] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable

[0463] WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSVDGAGQETQYFGPGTRLLVL [SEQ ID NO: 16]

[0464]

[0465] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 73. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16. 072734.1889

[0466] PATENT

[0467] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 73, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16. SEQ ID NO: 73 and SEQ ID NO: 16 are provided in Table 8.

[0468] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 or a conservative modification thereof. SEQ ID NOS: 9, 10, and 72 are disclosed in Table 8. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof. SEQ ID NOS: 12-14 are disclosed in Table 8.

[0469] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0470] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof.

[0471] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence 072734.1889

[0472] PATENT

[0473] set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0474] In certain embodiments, the CDRs sequences described above including Table 8 are delineated using the IMGT numbering system.

[0475] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 73. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 73. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 73.

[0476] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0477] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 73; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 73; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16. 072734.1889

[0478] PATENT

[0479] In certain embodiments, the TCR is designated as “DG7302 HD2 A3”. In certain embodiments, the DG7302 HD2 A3 binds to a RAS peptide comprising a G12V mutation.

[0480] Table 8. (DG7302 HD2 A3)

[0481] CDRs 1 2 3

[0482] a- TRDTTYY [SEQ RNSFDEQN [SEQ CALSEAGTYKYIF [SEQ ID chain#3

[0483] ID NO: 9] ID NO: 10] NO: 72 ]

[0484] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSVDGAGQETQYF [SEQ NO: 12 ] NO: 13] ID NO: 14 ]

[0485] a-chain MLTASLLRAVIASICWSSMAQKVTQAQTEISWEKEDVTLDCVYETRDTTY variable

[0486] YL FWYKQPPS GELVFL I RRNS FDEQNE I S GRYS WNFQKS T S S FNFT I TAS QV

[0487] #3

[0488] VDSAVYFCALSEAGTYKYIFGTGTRLKVLA [SEQ ID NO: 73] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable

[0489] WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSVDGAGQETQYFGPGTRLLVL [SEQ ID NO: 16]

[0490]

[0491] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 75. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0492] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 75, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16. SEQ ID NO: 75 and SEQ ID NO: 16 are provided in Table 9.

[0493] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof. SEQ ID NOS: 9, 10, and 74 are disclosed in Table 9. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a 072734.1889

[0494] PATENT CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof. SEQ ID NOS: 12-14 are disclosed in Table 9.

[0495] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0496] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14 or a conservative modification thereof.

[0497] In certain embodiments, the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0498] In certain embodiments, the CDRs sequences described above including Table 9 are delineated using the IMGT numbering system.

[0499] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 75. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, 072734.1889

[0500] PATENT

[0501] about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 75. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 75.

[0502] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0503] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 75; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 75; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

[0504] In certain embodiments, the TCR is designated as “DG73O2_HD3_A1”. In certain embodiments, the DG7302 HD3 A1 binds to a RAS peptide comprising a G12V mutation.

[0505] Table 9. (DG7302 HD3 A1)

[0506] CDRs 1 2 3

[0507] a-chain TRDTTYY [SEQ RNSFDEQN [SEQ CALSPSSDYKLSF [SEQ ID ID NO: 9] ID NO: 10] NO: 74 ]

[0508] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSVDGAGQETQYF [SEQ NO: 12 ] NO: 13] ID NO: 14 ]

[0509] a-chain MLTASLLRAVIASICWSSMAQKVTQAQTEISWEKEDVTLDCVYETRDTTY variable

[0510] YL FWYKQPPS GELVFL I RRNS FDEQNE I S GRYS WNFQKS T S S FNFT I TAS QV VDSAVYFCALSPSSDYKLSFGAGTTVTVRA [SEQ ID NO: 75]

[0511]

[0512] 072734.1889

[0513] PATENT

[0514] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSVDGAGQETQYFGPGTRLLVL [SEQ ID NO: 16]

[0515]

[0516] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 23. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 24.

[0517] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 23, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 24. SEQ ID NO: 23 and SEQ ID NO: 24 are provided in Table 10.

[0518] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19 or a conservative modification thereof. SEQ ID NOS: 17-19 are disclosed in Table 10. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22 or a conservative modification thereof. SEQ ID NOS: 20-22 are disclosed in Table 10.

[0519] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22.

[0520] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17 or a conservative modification thereof, a 072734.1889

[0521] PATENT CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22 or a conservative modification thereof.

[0522] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22.

[0523] In certain embodiments, the CDRs sequences described above including Table 10 are delineated using the IMGT numbering system.

[0524] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 23. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 23. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 23.

[0525] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 24. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 24. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 24. 072734.1889

[0526] PATENT

[0527] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 23; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 24. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 23; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 24.

[0528] In certain embodiments, the TCR is designated as “JM1822”. In certain embodiments, the JM1822 binds to a RAS peptide comprising a G12V mutation.

[0529] Table 10. (JM1822)

[0530] CDRs 1 2 3

[0531] a-chain DRVSQS [SEQ ID IYSNGD [SEQ ID CAVNSGYSTLTF [SEQ ID NO: 17 ] NO: 18 ] NO: 19]

[0532] P-chain MNHNY [SEQ ID SVGAGI [SEQ ID CASRLRTGTMSTDTQYF [ SEQ NO: 20] NO: 21 ] ID NO: 22 ]

[0533] a-chain MKSLRVLLVILWLQLSWVWSQQKEVEQNSGPLSVPEGAIASLNCTYSDRVSQ variable

[0534] SFFWYRQYSGKSPELIMSIYSNGDKEDGRFTAQLNKASQYVSLLIRDSQPSD SATYLCAVNSGYSTLTFGKGTMLLVSP [SEQ ID NO: 23]

[0535] P-chain MSISLLCCAAFPLLWAGPVNAGVTQTPKFRILKIGQSMTLQCTQDMNHNYMY variable

[0536] WYRQDPGMGLKLIYYSVGAGITDKGEVPNGYNVSRSTTEDFPLRLELAAPSQ TSVYFCASRLRTGTMSTDTQYFGPGTRLTVL [SEQ ID NO: 24 ]

[0537]

[0538] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 28. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 29.

[0539] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 28, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 29. SEQ ID NO: 28 and SEQ ID NO: 29 are provided in Table 11. 072734.1889

[0540] PATENT

[0541] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof. SEQ ID NOS: 18, 25, and 26 are disclosed in Table 11. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof. SEQ ID NOS: 12, 13, and 27 are disclosed in Table 11.

[0542] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27.

[0543] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27 or a conservative modification thereof.

[0544] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth 072734.1889

[0545] PATENT

[0546] in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27.

[0547] In certain embodiments, the CDRs sequences described above including Table 11 are delineated using the IMGT numbering system.

[0548] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 28. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 28. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 28.

[0549] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 29. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 29. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 29.

[0550] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 27; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 28. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 27; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 28.

[0551] In certain embodiments, the TCR is designated as “HD0211”. In certain embodiments, the HD0211 binds to a RAS peptide comprising a G12V mutation.

[0552] Table 11. (HD0211) 072734.1889

[0553] PATENT CDRs 1 2 3

[0554] a-chain DRGSQS [SEQ IYSNGD [SEQ ID CAVKGGRGNSNYQLIW [SEQ ID NO: 25] NO: 18 ] ID NO: 26]

[0555] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASNTGTGGTEAFF [SEQ ID NO: 12 ] NO: 13] NO: 27 ]

[0556] a-chain MKSLRVLLVILWLQLSWVWSQQKEVEQNSGPLSVPEGAIASLNCTYSDRGSQ variable

[0557] SFFWYRQYSGKSPELIMSIYSNGDKEDGRFTAQLNKASQYVSLLIRDSQPSD SATYLCAVKGGRGNSNYQLIWGAGTKLI IKP [SEQ ID NO: 28 ] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable

[0558] WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASNTGTGGTEAFFGQGTRLTW [SEQ ID NO: 29]

[0559]

[0560] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 32. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 33.

[0561] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 32, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 33. SEQ ID NO: 32 and SEQ ID NO: 33 are provided in Table 12.

[0562] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 or a conservative modification thereof. SEQ ID NOS: 9, 10, and 30 are disclosed in Table 12. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31 or a conservative modification thereof. SEQ ID NOS: 12, 13, and 31 are disclosed in Table 12. 072734.1889

[0563] PATENT

[0564] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31.

[0565] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31 or a conservative modification thereof.

[0566] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31.

[0567] In certain embodiments, the CDRs sequences described above including Table 12 are delineated using the IMGT numbering system.

[0568] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 32. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 32. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 32. 072734.1889

[0569] PATENT

[0570] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 33. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 33. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 33.

[0571] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 32; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 33. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 32; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 33.

[0572] In certain embodiments, the TCR is designated as “HD0010 W6”. In certain embodiments, the HD0010 W6 binds to a RAS peptide comprising a G12V mutation.

[0573] Table 12. (HD0010 W6)

[0574] CDRs 1 2 3

[0575] a-chain TRDTTYY [SEQ RNSFDEQN [SEQ CALNGAGSYQLTF [SEQ ID ID NO: 9] ID NO: 10] NO: 30]

[0576] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSVDGGAQETQYF [SEQ NO: 12 ] NO: 13] ID NO: 31 ]

[0577] a-chain MLTASLLRAVIASICWSSMAQKVTQAQTEISWEKEDVTLDCVYETRDTTY variable

[0578] YL FWYKQPPS GELVFL I RRNS FDEQNE I S GRYS WNFQKS T S S FNFT I TAS QV VDSAVYFCALNGAGSYQLTFGKGTKLSVIP [SEQ ID NO: 32 ] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable

[0579] WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSVDGGAQETQYFGPGTRLLVL [SEQ ID NO: 33]

[0580]

[0581] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino 072734.1889

[0582] PATENT

[0583] acid sequence set forth in SEQ ID NO: 38. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 39.

[0584] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 38, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 39. SEQ ID NO: 38 and SEQ ID NO: 39 are provided in Table 13.

[0585] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36 or a conservative modification thereof. SEQ ID NOS: 34-36 are disclosed in Table 13. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37 or a conservative modification thereof. SEQ ID NOS: 12, 13, and 37 are disclosed in Table 13.

[0586] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37.

[0587] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 072734.1889

[0588] PATENT

[0589] or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37 or a conservative modification thereof.

[0590] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37.

[0591] In certain embodiments, the CDRs sequences described above including Table 13 are delineated using the IMGT numbering system.

[0592] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 38. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 38. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 38.

[0593] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 39. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 39. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 39.

[0594] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 38; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino 072734.1889

[0595] PATENT

[0596] acid sequence set forth in SEQ ID NO: 39. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 38; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 39.

[0597] In certain embodiments, the TCR is designated as “HDOOIO WH”. In certain embodiments, the HD0010 W11 binds to a RAS peptide comprising a G12V mutation.

[0598] Table 13. (HD0010 W11)

[0599] CDRs 1 2 3

[0600] a-chain TISGTDY [SEQ GLTSN [SEQ ID CILRDVQYGNKLVF [SEQ ID ID NO: 34 ] NO: 35] NO: 36]

[0601] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSVEGGGIEETQYF [SEQ NO: 12 ] NO: 13] ID NO: 37 ]

[0602] a-chain MKLVTSITVLLSLGIMGDAKTTQPNSMESNEEEPVHLPCNHSTISGTDYIHW variable YRQLPSQGPEYVIHGLTSNVNNRMASLAIAEDRKSSTLILHRATLRDAAVYY CILRDVQYGNKLVFGAGTILRVKS [SEQ ID NO: 38 ]

[0603] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSVEGGGIEETQYFGPGTRLLVL [SEQ ID NO: 39]

[0604]

[0605] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 43.

[0606] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 43. SEQ ID NO: 42 and SEQ ID NO: 43 are provided in Table 14.

[0607] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 or a conservative modification thereof. SEQ ID NOS: 9, 10, and 40 are disclosed in Table 14. In certain embodiments, the extracellular 072734.1889

[0608] PATENT

[0609] domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof. SEQ ID NOS: 12, 13, and 41 are disclosed in Table 14.

[0610] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41.

[0611] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41 or a conservative modification thereof.

[0612] In certain embodiments, the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41.

[0613] In certain embodiments, the CDRs sequences described above including Table 14 are delineated using the IMGT numbering system.

[0614] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42. For example, 072734.1889

[0615] PATENT

[0616] the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42.

[0617] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 43.

[0618] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 43.

[0619] In certain embodiments, the TCR is designated as “HD0010 W15”. In certain embodiments, the HD0010 W15 binds to a RAS peptide comprising a G12V mutation.

[0620] Table 14. (HD0010 _W15)

[0621] CDRs 1 2 3

[0622] a-chain TRDTTYY [SEQ RNSFDEQN [SEQ CALSEARTYKYIF [SEQ ID ID NO: 9] ID NO: 10] NO: 40]

[0623] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSVDGSAQETQYF [SEQ NO: 12 ] NO: 13] ID NO: 41 ]

[0624] a-chain MLTASLLRAVIASICWSSMAQKVTQAQTEISWEKEDVTLDCVYETRDTTY variable YL FWYKQPPS GELVFL I RRNS FDEQNE I S GRYS WNFQKS T S S FNFT I TAS QV VDSAVYFCALSEARTYKYIFGTGTRLKVLA [SEQ ID NO: 42 ]

[0625]

[0626] 072734.1889

[0627] PATENT

[0628] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSVDGSAQETQYFGPGTRLLVL [SEQ ID NO: 43]

[0629]

[0630] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 47.

[0631] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 46, and a P chain variable region comprising a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 47. SEQ ID NO: 46 and SEQ ID NO: 47 are provided in Table 15.

[0632] In certain embodiments, the extracellular domain of the TCR comprises an a chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof. SEQ ID NOS: 34-44 are disclosed in Table 15. In certain embodiments, the extracellular domain of the TCR comprises a P chain variable region comprising a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof. SEQ ID NOS: 12, 13, and 45 are disclosed in Table 15.

[0633] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44. In certain embodiments, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45. 072734.1889

[0634] PATENT

[0635] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44 or a conservative modification thereof; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12 or a conservative modification thereof, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13 or a conservative modification thereof, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45 or a conservative modification thereof.

[0636] In certain embodiments, the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45.

[0637] In certain embodiments, the CDRs sequences described above including Table 15 are delineated using the IMGT numbering system.

[0638] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 46. For example, the a chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 46. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 46.

[0639] In certain embodiments, the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 170%, or at least about 175%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 47. For example, the P chain variable region comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ 072734.1889

[0640] PATENT ID NO: 47. In certain embodiments, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 47.

[0641] In certain embodiments, the a chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 46; and the P chain variable region comprises an amino acid sequence that is at least about 80% (e.g., at least about 85%, at least about 90%, or at least about 95%) homologous or identical to the amino acid sequence set forth in SEQ ID NO: 47. In certain embodiments, the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 46; and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 47.

[0642] In certain embodiments, the TCR is designated as “HD0010_W21”. In certain embodiments, the HD0010 W21 binds to a RAS peptide comprising a G12V mutation.

[0643] Table 15. (HD0010 _W21)

[0644] CDRs 1 2 3

[0645] a-chain TISGTDY [SEQ GLTSN [SEQ ID CILSRKLTF [ SEQ ID NO:

[0646] ID NO: 34 ] NO: 35] 44 ]

[0647] P-chain SGDLS [SEQ ID YYNGEE [SEQ ID CASSLFAGTSGPTDTQYF NO: 12 ] NO: 13] [SEQ ID NO: 45] a-chain MKLVTSITVLLSLGIMGDAKTTQPNSMESNEEEPVHLPCNHSTISGTDYIHW variable YRQLPSQGPEYVIHGLTSNVNNRMASLAIAEDRKSSTLILHRATLRDAAVYY CILSRKLTFGTGTRLTI IP [SEQ ID NO: 46]

[0648] P-chain MGFRLLCCVAFCLLGAGPVDSGVTQTPKHLITATGQRVTLRCSPRSGDLSVY variable WYQQSLDQGLQFLIQYYNGEERAKGNILERFSAQQFPDLHSELNLSSLELGD SALYFCASSLFAGTSGPTDTQYFGPGTRLTVL [SEQ ID NO: 47 ]

[0649]

[0650] In certain embodiments, the a chain variable region and / or the P chain variable region amino acid sequences have at least about 80%, at least about 85%, at least about 90%, or at least about 95% (e.g., about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%) homology or identity to the specified sequences (e.g., SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID 072734.1889

[0651] PATENT NO: 73, and SEQ ID NO: 75) comprise modifications, including, but not limited to, substitutions (e.g., conservative substitutions), insertions, or deletions relative to the specified sequence(s), but retain the ability to bind to a mutant RAS peptide (e.g., a G12V mutant RAS peptide). In certain embodiments, such modifications are not within the CDR domains of the variable regions.

[0652] In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted and / or deleted in SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, or SEQ ID NO: 75. In certain embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs of the extracellular domain. In certain embodiments, the extracellular domain comprises an a chain variable region and / or a P chain variable region sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, or SEQ ID NO: 75 including post-translational modifications of that sequence (SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, or SEQ ID NO: 75).

[0653] 3,1.2. Constant Regions

[0654] In certain embodiments, the presently disclosed TCR comprises an a chain constant region that comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54. In certain embodiments, the a chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 51. In certain embodiments, the a chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 52. In certain embodiments, the a chain constant region comprises the amino acid 072734.1889

[0655] PATENT

[0656] sequence set forth in SEQ ID NO: 53. In certain embodiments, the a chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 54.

[0657] In certain embodiments, the presently disclosed TCR comprises a P chain constant region that comprises an amino acid sequence that is about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57. In certain embodiments, the P chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 55. In certain embodiments, the P chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 56. In certain embodiments, the P chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 57. SEQ ID NOs: 51-57 are provided below:

[0658] Human a chain constant region:

[0659] NIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVAWSNKSDFACAN AFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFNLLMTLRLWSS [ SEQ ID NO: 51]

[0660] Mouse a chain constant region (native):

[0661] DIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKTVLDMKAMDSKSNGAIAWSNQTSFTCQD IFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAGFNLLMTLRL [ SEQ ID NO: 52 ]

[0662] Mouse a chain constant region (cysteine-modification and LVL modification in transmembrane domain underlined):

[0663] NIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQD IFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS [ SEQ ID NO: 53]

[0664] Mouse a chain constant region (cysteine-modification and LVL modification in transmembrane domain underlined):

[0665] DIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKCVLDMKAMDSKSNGAIAWSNQTSFTCQD IFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLLVIVLRILLLKVAGFNLLMTLRLWSS [ SEQ ID NO: 54 ]

[0666] Human P chain constant region: 072734.1889

[0667] PATENT EDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYC LSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSVSYQQGVLSATILYE ILLGKATLYAVLVSALVLMAMVKRKDF [ SEQ ID NO: 55]

[0668] Human P chain constant region:

[0669] EDLKNVFPPEVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLKEQPALNDSRYC LSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGRADCGFTSESYQQGVLSATILYE ILLGKATLYAVLVSALVLMAMVKRKDSRG [ SEQ ID NO: 56]

[0670] Mouse β chain constant region (cysteine-modification underlined):

[0671] EDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVCTDPQA YKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGR ADCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLWMAMVKRKNS [SEQ ID NO: 57 ]

[0672] 3.2. TCRs that Bind to the Same RAS Peptide as TCR clonotypes

[0673] The presently disclosed subject matter further provides TCRs that bind to the same RAS peptide (e.g., a G12V mutant RAS peptide) as a TCR disclosed herein (e.g., a TCR disclosed in Section 3.1). In certain embodiments, the TCR binds to the same RAS peptide (e.g., a G12V mutant RAS peptide) as a reference TCR or a functional fragment thereof comprising the a chain variable region CDR1, CDR2, and CDR3 sequences and the P chain variable region CDR1, CDR2, and CDR3 sequences of, for example, any one of the TCRs disclosed herein (e.g., those disclosed in Section 3.1). In certain embodiments, the TCR binds to the same RAS peptide (e.g., a G12V mutant RAS peptide) as a reference TCR or a functional fragment thereof comprising the a chain variable region and the P chain variable region sequences of, for example, any one of the presently disclosed TCRs (e.g., those disclosed in Section 3.1).

[0674] 3.3. TCRs with Modifications within CDRs

[0675] In certain embodiments, a presently disclosed TCR (or a functional fragment thereof) comprises an a chain variable region comprising CDR1, CDR2, and CDR3 sequences and a P chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein one or more of these CDR sequences comprise specified amino acid sequences based on the TCR (or a functional fragments thereof) described herein, or modifications thereof, and wherein the TCR (or a functional fragments thereof) retains the desired functional properties of the mutant RAS 072734.1889

[0676] PATENT

[0677] peptide-specific TCR (or a functional fragments thereof) of the presently disclosed subject matter.

[0678] In certain embodiments, a presently disclosed TCR (or a functional fragment thereof) comprises an a chain constant region and a P chain constant region, wherein at least one of the constant regions comprises specified amino acid sequences based on the TCR (or a functional fragments thereof) described herein, or modifications thereof, and wherein the TCR (or a functional fragment thereof) retains the desired functional properties of the mutant RAS peptide-specific TCRs (or a functional fragments thereof) of the presently disclosed subject matter.

[0679] In certain embodiments, such modifications do not significantly affect or alter the binding characteristics of the TCR comprising the amino acid sequence. Non-limiting examples of such modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into the presently disclosed TCR or a functional fragment thereof by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.

[0680] The modifications can be conservative modifications, non-conservative modifications, or mixtures of conservative and non-conservative modifications. As discussed above, conservative amino acid substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. Exemplary conservative amino acid substitutions are shown in Table 16. In certain embodiments, amino acid substitutions may be introduced into a TCR of interest and the products screened for a desired activity, e.g., retained / improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

[0681] Table 16

[0682] Original Residue Exemplary conservative amino acid Substitutions

[0683] Ala (A) Vai; Leu; He

[0684] Arg (R) Lys; Gin; Asn

[0685] Asn (N) Gin; His; Asp, Lys; Arg

[0686] Asp (D) Glu; Asn

[0687] Cys (C) Ser; Ala

[0688] Gln (Q) Asn; Glu

[0689] Glu (E) Asp; Gin

[0690]

[0691] 072734.1889

[0692] PATENT

[0693] Original Residue Exemplary conservative amino acid Substitutions Gly (G) Ala

[0694] His (H) Asn; Gin; Lys; Arg

[0695] He (I) Leu; Vai; Met; Ala; Phe

[0696] Leu (L) He; Vai; Met; Ala; Phe

[0697] Lys (K) Arg; Gin; Asn

[0698] Met (M) Leu; Phe; He

[0699] Phe (F) Trp; Leu; Vai; lie; Ala; Tyr

[0700] Pro (P) Ala

[0701] Ser (S) Thr

[0702] Thr (T) Vai; Ser

[0703] Trp (W) Tyr; Phe

[0704] Tyr (Y) Trp; Phe; Thr; Ser

[0705] Vai (V) lie; Leu; Met; Phe; Ala

[0706]

[0707] Amino acids may be classified according to common side-chain properties:

[0708] • hydrophobic: Norleucine, Met, Ala, Vai, Leu, He;

[0709] • neutral hydrophilic: Cys, Ser, Thr, Asn, Gin;

[0710] • acidic: Asp, Glu;

[0711] • basic: His, Lys, Arg;

[0712] • residues that influence chain orientation: Gly, Pro;

[0713] • aromatic: Trp, Tyr, Phe.

[0714] In certain embodiments, one or more amino acid residues within a CDR region can be replaced with other amino acid residues from the same group and the altered TCR can be tested for retained function using the functional assays described herein.

[0715] Non-conservative substitutions entail exchanging a member of one of these classes for another class.

[0716] In certain embodiments, no more than one, no more than two, no more than three, no more than four, no more than five residues within a specified sequence or a CDR region are altered.

[0717] In certain embodiments, one or more amino acid residues within a constant region of a TCR can be modified to enhance stability and / or cell surface expression of the TCR. In certain 072734.1889

[0718] PATENT

[0719] embodiments, no more than one, no more than two, no more than three, no more than four, no more than five residues within a specified sequence or a constant region are altered. In certain embodiments, the modification includes but is not limited to, murinization, cysteine modification and transmembrane modification (see Cohen et al. Enhanced antitumor activity of murine-human hybrid T-cell receptor (TCR) in human lymphocytes is associated with improved pairing and TCR / CD3 stability, Cancer Res. 2006;66(17):8878-8886; Cohen et al. Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond, Cancer Res. 2007;67(8):3898-3903; Kuball et al. Facilitating matched pairing and expression of TCR chains introduced into human T cells, Blood 2007; 109(6):2331-2338; Haga-Friedman et al. Incorporation of transmembrane hydrophobic mutations in the TCR enhance its surface expression and T cell functional avidity, Journal of immunology 2012; 188(11):5538-5546, the contents of each of which are incorporated by reference in their entireties).

[0720] 3.4. Bispecific molecules

[0721] The presently disclosed subject matter provides bispecific molecules comprising a presently disclosed TCR (or a functional fragment thereof). A presently disclosed TCR or a functional fragment thereof can be derivatized or linked to another functional molecule, e.g, another peptide or protein (e.g, another antibody or ligand for a receptor) to generate a bispecific molecule that binds to at least two different binding sites or target molecules. The presently disclosed TCR or a functional fragment thereof can in fact be derivatized or linked to more than one other functional molecule to generate multi-specific molecules that bind to more than two different binding sites and / or target molecules; such multi-specific molecules are also intended to be encompassed by the term “bispecific molecule” as used herein. To create a bispecific molecule, a presently disclosed TCR or a functional fragment thereof can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other binding molecules, such as another antibody, antibody fragment, peptide or binding mimetic.

[0722] The presently disclosed subject matter provides bispecific molecules comprising at least a first binding specificity for a mutant RAS peptide and a second binding specificity for a second target peptide region. The second target epitope region can be a second RAS peptide, or a non-RAS peptide, e.g., a different antigen. In certain embodiments, the bispecific molecule is multi-specific, e.g., the molecule can further include a third binding specificity. Where a first portion of a bispecific molecule, e.g., antibody, binds to an antigen on a tumor cell, for example, and a second portion of a bispecific molecule recognizes an antigen on the surface of 072734.1889

[0723] PATENT

[0724] a human immune effector cell, the bispecific molecule is capable of recruiting the activity of that effector cell by specifically binding to the effector antigen on the human immune effector cell. In certain embodiments, bispecific molecules are able to form a link between effector cells, for example, T cells and tumor cells, thereby enhancing effector function. In certain embodiments, a presently disclosed bispecific molecule comprises at least a first binding to a mutant RAS peptide and at least a second binding to an immune cell or a molecule associated with an immune cell.

[0725] In certain embodiments, the presently disclosed bispecific molecules include a second specificity that binds to an immunoresponsive cell. In certain embodiments, the immune responsive cell is a T cell. In certain embodiments, the second specificity binds to a surface molecule of a T cell. In certain embodiments, the second specificity binds to CD3, CD28, CD137, ICOS, CD4, CD8, or a combination thereof. In certain embodiments, the immune responsive cell is an NK cell. In certain embodiments, the second specificity binds to a surface molecule of an NK cell. In certain embodiments, the second specificity binds to CD16, CD335, NKp80, NKG2D, or a combination thereof.

[0726] The bispecific molecules of the presently disclosed subject matter can be prepared by conjugating the constituent binding specificities using methods known in the art. For example, each binding specificity of the bispecific molecule can be generated separately and then conjugated to one another. When the binding specificities are proteins or peptides, a variety of coupling or cross-linking agents can be used for covalent conjugation. Non-limiting examples of cross-linking agents include protein A, carbodiimide, N-succinimidyl-S-acetyl-thioacetate (SATA), 5, 5'-dithiobis(2-nitrobenzoic acid) (DTNB), o-phenylenedimaleimide (oPDM), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), and sulfosuccinimidyl 4-(N-maleimidomethyl) cyclohaxane-1 -carboxylate (sulfo-SMCC) (see e.g., Karpovsky et al. (1984) J. Exp. Med. 160:1686; Liu, MA et al. (1985) Proc. Natl. Acad. Sci. USA 82:8648). Other methods include those described in Paulus (1985) Behring Ins. Mitt. No. 78, 118-132; Brennan et al. (1985) Science 229:81-83), and Glennie et al. (1987) J. Immunol. 139: 2367-2375). Conjugating agents can be SATA and sulfo-SMCC, both available from Pierce Chemical Co. (Rockford, IL).

[0727] When the binding specificities are antibodies, they can be conjugated via sulfhydryl bonding of the C-terminus hinge regions of the two heavy chains. In certain embodiments, the hinge region is modified to contain an odd number of sulfhydryl residues, preferably one, prior to conjugation. 072734.1889

[0728] PATENT

[0729] Alternatively, both binding specificities can be encoded in the same vector and expressed and assembled in the same host cell. This method is particularly useful where the bispecific molecule is a mAb and a mAb, a mAb and a Fab, a Fab and a F(ab’)2, or a ligand and a Fab fusion protein.

[0730] Binding of the bispecific molecules to their specific targets can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (e.g., growth inhibition), or Western Blot assay. Each of these assays generally detects the presence of protein-antibody complexes of particular interest by employing a labeled reagent (e.g., an antibody) specific for the complex of interest. Alternatively, the complexes can be detected using any of a variety of other immunoassays. For example, the antibody can be radioactively labeled and used in a radioimmunoassay (RIA) (see, for example, Weintraub, B., Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986, which is incorporated by reference herein). The radioactive isotope can be detected by such means as the use of a y counter or a scintillation counter or by autoradiography.

[0731] 4. Cells

[0732] The presently disclosed subject matter provides cells comprising a presently disclosed TCR (e.g., one disclosed in Section 3). In certain embodiments, the cell is selected from the group consisting of cells of lymphoid lineage, cells of myeloid lineage, stem cells from which cells of lymphoid lineage can be derived, and stem cells from which cells of myeloid lineage can be derived. In certain embodiments, the cell is an immunoresponsive cell. In certain embodiments, the immunoresponsive cell is a cell of lymphoid lineage.

[0733] In certain embodiments, the cell is a cell of the lymphoid lineage. Cells of the lymphoid lineage can provide production of antibodies, regulation of cellular immune system, detection of foreign agents in the blood, detection of cells foreign to the host, and the like. Non-limiting examples of cells of the lymphoid lineage include T cells and / or stem cells from which lymphoid cells may be differentiated. In certain embodiments, the stem cell is a pluripotent stem cell (e.g., embryonic stem cell).

[0734] In certain embodiments, the cell is a T cell. T cells can be lymphocytes that mature in the thymus and are chiefly responsible for cell-mediated immunity. T cells are involved in the adaptive immune system. The T cells of the presently disclosed subject matter can be any type of T cells, including, but not limited to, helper T cells, cytotoxic T cells, memory T cells (including central memory T cells, stem-cell-like memory T cells (or stem-like memory T cells), and two types of effector memory T cells: e.g., TEM cells and TEMRA cells, Regulatory 072734.1889

[0735] PATENT

[0736] T cells (also known as suppressor T cells), tumor-infiltrating lymphocyte (TIL), Natural killer T cells, Mucosal associated invariant T cells, and 76 T cells. Cytotoxic T cells (CTL or killer T cells) are a subset of T lymphocytes capable of inducing the death of infected somatic or tumor cells. A patient’s own T cells may be genetically modified to target specific antigens through the introduction of an antigen-recognizing receptor, e.g., a presently disclosed TCR. In certain embodiments, the immunoresponsive cell is a T cell. The T cell can be a CD4+T cell or a CD8+T cell. In certain embodiments, the T cell is a CD4+T cell. In certain embodiments, the T cell is a CD8+T cell. In certain embodiments, the TCR-expressing T cells express Foxp3 to achieve and maintain a T regulatory phenotype.

[0737] In certain embodiments, the T cell is a NK-T cell. Natural killer (NK) T cells can be lymphocytes that are part of cell-mediated immunity and act during the innate immune response. NK-T cells do not require prior activation in order to perform their cytotoxic effect on target cells.

[0738] In certain embodiments, the cell is a Natural Killer (NK) cell. NK cells constitute the predominant innate lymphocyte subset that physiologically mediates the anti-viral and antitumor immune responses. NK cells use an array of innate receptors to sense their environment and to respond to infections, cellular stress, and transformation. The resulting NK cell activation, including cytotoxicity and cytokine production, is a fundamental component of the early immune response. Types of human lymphocytes of the presently disclosed subject matter include, without limitation, peripheral donor lymphocytes, e.g., those disclosed in Sadelain et al., Nat Rev Cancer (2003); 3:35-45 (disclosing peripheral donor lymphocytes genetically modified to express CARs), in Morgan, R. A., et al. 2006 Science 314:126-129 (disclosing peripheral donor lymphocytes genetically modified to express a full-length tumor antigenrecognizing T cell receptor complex comprising the a and P heterodimer), in Panelli et al., J Immunol (2000); 164:495-504; Panelli et al., J Immunol (2000); 164:4382-4392 (disclosing lymphocyte cultures derived from tumor infiltrating lymphocytes (TILs) in tumor biopsies), and in Dupont et al., Cancer Res (2005);65:5417-5427; Papanicolaou et al., Blood (2003); 102:2498-2505 (disclosing selectively in vitro-expanded antigen-specific peripheral blood leukocytes employing artificial antigen-presenting cells (AAPCs) or pulsed dendritic cells).

[0739] The cells (e.g., T cells) can be autologous, non-autologous (e.g., allogeneic), or derived in vitro from engineered progenitor or stem cells. 072734.1889

[0740] PATENT

[0741] The cells of the presently disclosed subject matter can be cells of the myeloid lineage. Non-limiting examples of cells of the myeloid lineage include monocytes, macrophages, neutrophils, dendritic cells, basophils, neutrophils, eosinophils, megakaryocytes, mast cell, erythrocyte, thrombocytes, and stem cells from which myeloid cells may be differentiated. In certain embodiments, the stem cell is a pluripotent stem cell (e.g., an embryonic stem cell or an induced pluripotent stem cell).

[0742] In certain embodiments, the cell further comprises at least one recombinant or exogenous co-receptor. For example, a presently disclosed cell can be further transduced with at least one co-receptor, such that the cell co-expresses or is induced to co-express the presently disclosed TCR and the at least one co-receptor. The interaction between the presently disclosed TCR and at least one co-receptor with the MHC complex of the target cell (e.g., tumor cells expressing TP53) improves the antigen-specific signal required for full activation of an immunoresponsive cell (e.g., T cell).

[0743] In certain embodiments, the co-receptor is a CD8 co-receptor. In certain embodiments, the CD8 co-receptor comprises an a chain and a P chain. In certain embodiments, the a chain of the CD8 co-receptor comprises or consists of an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence having a UniProt Reference No: P01732, or fragments thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the a chain of the CD8 co-receptor comprises or consists of an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 58. In certain embodiments, the a chain of the CD8 co-receptor comprises or consists of the amino acid sequence set forth in SEQ ID NO: 58. In certain embodiments, the P chain of the CD8 co-receptor comprises or consists of an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence having a UniProt Reference No: P10966, or fragments thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the P chain of the 072734.1889

[0744] PATENT CD8 co-receptor comprises or consists of an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 59. In certain embodiments, the P chain of the CD8 co-receptor comprises or consists of the amino acid sequence set forth in SEQ ID NO: 59.

[0745] In certain embodiments, the CD8 co-receptor comprises an a chain comprising or consists of an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 58; and a P chain comprising or consists of an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 59. In certain embodiments, the CD8 co-receptor comprises an a chain comprising or consists of the amino acid sequence set forth in SEQ ID NO: 58; and a P chain comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 59. SEQ ID NO: 58 and SEQ ID NO: 59 are provided below.

[0746] MALPVTALLLPLALLLHAARPSQFRVSPLDRTWNLGETVELKCQVLLSNPTSGCSWLFQPRG AAASPTFLLYLSQNKPKAAEGLDTQRFSGKRLGDTFVLTLSDFRRENEGYYFCSALSNS IMY FSHFVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIW APLAGTCGVLLLSLVITLYCNHRNRRRVCKCPRPWKSGDKPSLSARYV [SEQ ID NO: 58 ]

[0747] MRPRLWLLLAAQLTVLHGNSVLQQTPAYIKVQTNKMVMLSCEAKISLSNMRIYWLRQRQAPS SDSHHEFLALWDSAKGTIHGEEVEQEKIAVFRDASRFILNLTSVKPEDSGIYFCMIVGSPEL TFGKGTQLSWDFLPTTAQPTKKSTLKKRVCRLPRPETQKGPLCSPITLGLLVAGVLVLLVS LGVAIHLCCRRRRARLRFMKQFYK [SEQ ID NO: 59]

[0748] In certain embodiments, the co-receptor is a CD4 co-receptor. In certain embodiments, the CD4 co-receptor comprises a polypeptide comprising or consisting of an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, 072734.1889

[0749] PATENT

[0750] about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence having a UniProt Reference No: P01730, or fragments thereof, and / or may optionally comprise up to one or up to two or up to three conservative amino acid substitutions. In certain embodiments, the CD4 co-receptor comprises a polypeptide comprising or consisting of an amino acid sequence that is at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 60. In certain embodiments, the CD4 co-receptor comprises a polypeptide comprising or consisting of the amino acid sequence set forth in SEQ ID NO: 60. SEQ ID NO: 60 is provided below:

[0751] MNRGVPFRHLLLVLQLALLPAATQGKKWLGKKGDTVELTCTASQKKS IQFHWKNSNQIKIL GNQGSFLTKGPSKLNDRADSRRSLWDQGNFPLI IKNLKIEDSDTYICEVEDQKEEVQLLVFG LTANSDTHLLQGQSLTLTLESPPGSSPSVQCRSPRGKNIQGGKTLSVSQLELQDSGTWTCTV LQNQKKVEFKIDIWLAFQKASSIVYKKEGEQVEFSFPLAFTVEKLTGSGELWWQAERASSS KSWITFDLKNKEVSVKRVTQDPKLQMGKKLPLHLTLPQALPQYAGSGNLTLALEAKTGKLHQ EVNLWMRATQLQKNLTCEVWGPTSPKLMLSLKLENKEAKVSKREKAVWVLNPEAGMWQCLL SDSGQVLLESNIKVLPTWSTPVQPMALIVLGGVAGLLLFIGLGI FFCVRCRHRRRQAERMSQ IKRLLSEKKTCQCPHRFQKTCSPI [SEQ ID NO: 60]

[0752] In certain embodiments, cell further comprises at least one recombinant or exogenous co-stimulatory ligand. For example, a presently disclosed cell can be further transduced with at least one co-stimulatory ligand, such that the cell co-expresses or is induced to co-express the presently disclosed TCR and the at least one co-stimulatory ligand. The interaction between the presently disclosed TCR and at least one co-stimulatory ligand provides a non-antigen-specific signal important for full activation of an immunoresponsive cell (e.g., T cell). Co-stimulatory ligands include, but are not limited to, members of the tumor necrosis factor (TNF) superfamily, and immunoglobulin (Ig) superfamily ligands. TNF is a cytokine involved in systemic inflammation and stimulates the acute phase reaction. Its primary role is in the regulation of immune cells. Members of TNF superfamily share a number of common features. The majority of TNF superfamily members are synthesized as type II transmembrane proteins (extracellular C-terminus) containing a short cytoplasmic segment and a relatively long 072734.1889

[0753] PATENT

[0754] extracellular region. TNF superfamily members include, without limitation, nerve growth factor (NGF), CD40L (CD40L) / CD154, CD137L / 4-1BBL, TNF-a, CD134L / OX40L / CD252, CD27L / CD70, Fas ligand (FasL), CD30L / CD153, tumor necrosis factor beta (TNF-P) / lymphotoxin-alpha (LTa), lymphotoxin-beta (LTP), CD257 / B cell-activating factor (BAFF) / Blys / THANK / Tall-1, glucocorticoid-induced TNF Receptor ligand (GITRL), and TNF-related apoptosis-inducing ligand (TRAIL), LIGHT (TNFSF14). The immunoglobulin (Ig) superfamily is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. These proteins share structural features with immunoglobulins - they possess an immunoglobulin domain (fold). Immunoglobulin superfamily ligands include, but are not limited to, CD80 and CD86, both ligands for CD28, PD-L1 / (B7-H1) that ligands for PD-1. In certain embodiments, the at least one co-stimulatory ligand is selected from the group consisting of 4-1BBL, CD80, CD86, CD70, OX40L, CD48, TNFRSF14, PD-L1, and combinations thereof. In certain embodiments, the cell comprises one recombinant co-stimulatory ligand that is 4-1BBL. In certain embodiments, the cell comprises two recombinant co-stimulatory ligands that are 4-1BBL and CD80.

[0755] In certain embodiments, a presently disclosed cell further comprises at least one exogenous cytokine. For example, a presently disclosed cell can be further transduced with at least one cytokine, such that the cell secretes the at least one cytokine as well as expresses the presently disclosed TCR. In certain embodiments, the at least one cytokine is selected from the group consisting of IL-2, IL-3, IL-6, IL-7, IL-11, IL-12, IL-15, IL-17, IL-18, and IL-21. In certain embodiments, the cytokine is IL-12.

[0756] 5. Nucleic Acids and Genetic Modifications of Cells

[0757] The present disclosed subject matter provides a nucleic acid encoding a presently disclosed TCR (e.g., one disclosed in Section 3). Further provided are cells comprising a vector comprising such nucleic acids. In certain embodiments, a promoter is operably linked to a polynucleotide encoding a presently disclosed TCR.

[0758] In certain embodiments, the promoter is endogenous or exogenous. In certain embodiments, the exogenous promoter is selected from the group consisting of a long terminal repeat (LTR) promoter, an elongation factor (EF)-l promoter, a cytomegalovirus immediate-early promoter (CMV) promoter, a simian virus 40 early promoter (SV40) promoter, a phosphoglycerate kinase (PGK) promoter, and a metallothionein promoter. In certain embodiment, the exogenous promoter is a LTR promoter. In certain embodiments, the promoter is an inducible promoter. In certain embodiment, the inducible promoter is selected 072734.1889

[0759] PATENT

[0760] from the group consisting of a NF AT transcriptional response element (TRE) promoter, a CD69 promoter, a CD25 promoter, and an IL-2 promoter.

[0761] In certain embodiments, the nucleic acid encodes both the a chain and the P chain of a presently disclosed TCR. In certain embodiments, the a chain and the P chain are separated by a self-cleavage peptide, e.g., a 2A-peptide. In certain embodiments, the a chain and the P chain are separated by a furin-2A-peptide. In certain embodiments, the peptide comprises the amino acid sequence set forth in SEQ ID NO: 61. SEQ ID NO: 61 is provided below:

[0762] RAKRSGSGATNFSLLKQAGDVEENPGP [SEQ ID NO: 61 ]

[0763] In certain embodiments, the nucleic acid encodes a polypeptide comprising an a chain and a P chain of one of the presently disclosed TCRs. In certain embodiments, the polypeptide further comprises a self-cleavable peptide (e.g., a self-cleavable peptide set forth in SEQ ID NO: 61).

[0764] In certain embodiments, the nucleic acid encodes a functional portion / fragment of a presently disclosed TCR. As used herein, the term “functional portion” or “functional fragment” refers to any portion, part or fragment of a presently disclosed TCR, which portion, part or fragment retains the biological activity of the TCR (the parent TCR). For example, functional portions encompass the portions, parts, or fragments of a presently disclosed TCR that retain the ability to recognize the RAS peptide (e.g., a RAS peptide comprising a G12V mutation) to a similar, same, or even a higher extent as the parent TCR. In certain embodiments, the nucleic acid encoding a functional portion of a presently disclosed TCR encodes a protein comprising, e.g., about 10%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95%, or more of the parent TCR.

[0765] Genetic modification of a cell (e.g., a T cell) can be accomplished by transducing a substantially homogeneous cell composition with a recombinant DNA or RNA construct. In certain embodiments, a retroviral vector (e.g., gamma-retroviral vector or lentiviral vector) is employed for the introduction of the DNA or RNA construct into the cell. For example, a polynucleotide encoding a presently disclosed TCR can be cloned into a retroviral vector and expression can be driven from its endogenous promoter, from the retroviral long terminal repeat, or from an alternative internal promoter, or from a promoter specific for a target cell type of interest. Non-viral vectors or RNA may be used as well. Random chromosomal integration, or targeted integration (e.g., using a nuclease, transcription activator-like effector nucleases (TALENs), Zinc-finger nucleases (ZFNs), and / or clustered regularly interspaced short palindromic repeats (CRISPRs), or transgene expression (e.g., using a natural or 072734.1889

[0766] PATENT

[0767] chemically modified RNA) can be used. For initial genetic modification of a cell to include a presently disclosed TCR, a retroviral vector can be employed for transduction, however any other suitable viral vector or non-viral delivery system can be used. The TCR can be constructed in a single, multicistronic expression cassette, in multiple expression cassettes of a single vector, or in multiple vectors. Examples of elements that create polycistronic expression cassette include, but is not limited to, various viral and non-viral Internal Ribosome Entry Sites (IRES, e.g., FGF-1 IRES, FGF-2 IRES, VEGF IRES, IGF-II IRES, NF-KB IRES, RUNX1 IRES, p53 IRES, hepatitis A IRES, hepatitis C IRES, pestivirus IRES, aphthovirus IRES, picornavirus IRES, poliovirus IRES and encephalomyocarditis virus IRES) and cleavable linkers (e.g., 2 A peptides, e.g., P2A, T2A, E2A and F2A peptides). Combinations of retroviral vector and an appropriate packaging line are also suitable, where the capsid proteins will be functional for infecting human cells. Various amphotropic virus-producing cell lines are known, including, but not limited to, PA12 (Miller et al., (1985) Mol Cell Biol (1985);5:431-437); PA317 (Miller., et al., Mol Cell Biol (1986); 6:2895-2902); and CRIP (Danos et al., Proc Natl Acad Sci USA (1988);85:6460-6464). Non-amphotropic particles are suitable too, e.g., particles pseudotyped with VSVG, RD114 or GALV envelope and any other known in the art.

[0768] Possible methods of transduction also include direct co-culture of the cells with producer cells (Bregni et al., Blood (1992);80: 1418-1422), or culturing with viral supernatant alone or concentrated vector stocks with or without appropriate growth factors and polycations (Xu etal., Exp Hemat (1994); 22:223-230; and Hughes et al. J Clin Invest (1992); 89:1817).

[0769] Other transducing viral vectors can be used to modify a cell. In certain embodiments, the chosen vector exhibits high efficiency of infection and stable integration and expression (see, e.g., Cayouette et al., Human Gene Therapy 8:423-430, 1997; Kido et al., Current Eye Research 15:833-844, 1996; Bloomer et al., Journal of Virology 71:6641-6649, 1997; Naldini et al., Science 272:263-267, 1996; and Miyoshi et al., Proc. Natl. Acad. Sci. U. S. A. 94:10319, 1997). Other viral vectors that can be used include, for example, adenoviral, lentiviral, and adeno-associated viral vectors, vaccinia virus, a bovine papilloma virus, or a herpes virus, such as Epstein-Barr Virus (also see, for example, the vectors of Miller, Human Gene Ther. (1990); 1:5-14; Friedman, Science 244:1275-1281, 1989; Eglitis et al., BioTechniques (1988);6:608-614; Tolstoshev et al., Cur Opin Biotechnol (1990); 1:55-61; Sharp, The Lancet (1991);337:1277-78; Cometta et al., Nucleic Acid Research and Molecular Biology 36:311-22, 1987; Anderson, Science (1984);226:401-409; Moen, Blood Cells 17:407-16, 1991; Miller et al., Biotechnol (1989);7:980-90; LeGal La Salle et al., Science (1993);259:988-90; and Johnson, Chest (1995)107:77S- 83S). Retroviral vectors are particularly well developed and 072734.1889

[0770] PATENT

[0771] have been used in clinical settings (Rosenberg et al., N Engl J Med (1990);323:370, 1990; Anderson et al., U. S. Patent. No. 5,399,346).

[0772] Non-viral approaches can also be employed for genetic modification of a cell. For example, a nucleic acid molecule can be introduced into a cell by administering the nucleic acid in the presence of lipofection (Feigner et al., Proc Natl Acad Sci U. S. A. (1987);84:7413; Ono et al., Neurosci Lett (1990); 17:259; Brigham et al., Am J Med Sci (1989);298:278; Staubinger et al., Methods in Enzymol (1983); 101:512, Wu et al., J Biol Chem (1988);263:14621; Wu et al., J Biol Chem (1989);264: 16985), or by micro-injection under surgical conditions (Wolff et al., Science (1990);247: 1465). Other non-viral means for gene transfer include transfection in vitro using calcium phosphate, DEAE dextran, electroporation, and protoplast fusion. Liposomes can also be potentially beneficial for delivery of DNA into a cell. Transplantation of normal genes into the affected tissues of a subject can also be accomplished by transferring a normal nucleic acid into a cultivatable cell type ex vivo (e.g., an autologous or heterologous primary cell or progeny thereof), after which the cell (or its descendants) are injected into a targeted tissue or are injected systemically. Recombinant receptors can also be derived or obtained using transposases or targeted nucleases (e.g. Zinc finger nucleases, meganucleases, or TALE nucleases, CRISPR). Transient expression may be obtained by RNA electroporation.

[0773] In certain embodiments, a presently disclosed TCR can be integrated into a selected locus of the genome of a cell. Any targeted genome editing methods can also be used to deliver a presently disclosed TCR to a cell or a subject. In certain embodiments, a CRISPR system is used to deliver a presently disclosed TCR. In certain embodiments, zinc-finger nucleases are used to deliver presently disclosed TCR. In certain embodiments, a TALEN system is used to deliver a presently disclosed TCR.

[0774] In certain embodiments, a presently disclosed TCR can be integrated at a locus encoding a T cell receptor. Non-limiting examples of the loci include a TRAC locus, a TRBC locus, a TRBC locus, and a TRGC locus. In certain embodiments, the locus is a TRAC locus or a TRBC locus. Methods of targeting a TCR to a site within the genome of T cell can be found in WO2017180989 and Eyquem et al., Nature. (2017 Mar 2); 543(7643): 113-117, both of which are incorporated by reference in their entireties.

[0775] In certain embodiments, a presently disclosed TCR can be integrated at a locus encoding an immune checkpoint. Non-limiting examples of the loci include a PDCD1 locus, a CBLB locus, a CISH locus, or a RASA2 locus. In certain embodiments, the locus is a PDCD1 locus. In certain embodiments, the locus is a CBLB locus. In certain embodiments, the locus 072734.1889

[0776] PATENT

[0777] is a CISH locus. In certain embodiments, the locus is a RASA2 locus. Non-limiting examples of methods of integrating a presently disclosed TCR to a locus encoding an immune checkpoint include CRISPR systems, zinc-finger nucleases, and TALEN systems.

[0778] In certain embodiments, a presently disclosed TCR can be integrated at a genomic safe harbor locus. As used herein, a “genomic safe harbor” or “GSH” refers to a chromosome location where an integrated transgene (e.g., encoding a presently disclosed TCR) can be predictably expressed without adversely affecting endogenous gene structure or expression. In certain embodiments, integrating a transgene at the GSH does not alter cell behavior and / or promote malignant transformation of the host cell or the organism. In certain embodiments, the GSH permits sufficient transgene expression to yield desirable levels of protein or noncoding RNA encoded by the transgene. Additional information on genomic safe harbor sites can be found in International Patent Publication No. WO 2021 / 055616, Sadelain et al., Nature Reviews Cancer 12.1 (2012): 51-58, and Aznauryan et al., Cell Reports Methods 2.1 (2022), the contents of each of which are incorporated by reference in their entirety.

[0779] In certain embodiments, the expression of the TCR is driven by an endogenous promoter / enhancer within or near the locus. In certain embodiments, the expression of the TCR is driven by an exogenous promoter integrated into the locus. The locus where the TCR is integrated is selected based on the expression level of the genes within the locus, and timing of the gene expression of the genes within the locus. The expression level and timing can vary under different stages of cell differentiation and mitogen / cytokine microenvironment, which are among the factors to be considered when making the selection.

[0780] In certain embodiments, the CRISPR system is used to integrate the TCR in selected loci of the genome of a cell. In certain embodiments, the CRISPR system uses a DNA donor template-guided homology directed repair at a defined genetic locus, e.g., a TRAC locus. Clustered regularly-interspaced short palindromic repeats (CRISPR) system is a genome editing tool discovered in prokaryotic cells. When utilized for genome editing, the system includes Cas9 (a protein able to modify DNA utilizing crRNA as its guide), CRISPR RNA (crRNA, contains the RNA used by Cas9 to guide it to the correct section of host DNA along with a region that binds to tracrRNA (generally in a hairpin loop form) forming an active complex with Cas9), trans-activating crRNA (tracrRNA, binds to crRNA and forms an active complex with Cas9), and an optional section of DNA repair template (DNA that guides the cellular repair process allowing insertion of a specific DNA sequence). CRISPR / Cas9 often employs a plasmid to transfect the target cells. In certain embodiments, CRISPR / Cas9 is a recombinant ribonucleoprotein complex that is transfected into target cells. The crRNA needs 072734.1889

[0781] PATENT

[0782] to be designed for each application as this is the sequence that Cas9 uses to identify and directly bind to the target DNA in a cell. The repair template carrying TCR expression cassette needs also be designed for each application, as it must overlap with the sequences on either side of the cut and code for the insertion sequence. Multiple crRNA's and the tracrRNA can be packaged together to form a single-guide RNA (sgRNA). This sgRNA can be joined together with the Cas9 gene and made into a plasmid in order to be transfected into cells. Methods of using the CRISPR system are described, for example, in WO 2014093661 A2, WO 2015123339 Al, and WO 2015089354 Al, which are incorporated by reference in their entireties.

[0783] In certain embodiments, zinc-finger nucleases are used to integrate the TCR in selected loci of the genome of a cell. A zinc-finger nuclease (ZFN) is an artificial restriction enzyme, which is generated by combining a zinc finger DNA-binding domain with a DNA-cleavage domain. A zinc finger domain can be engineered to target specific DNA sequences which allows a zinc-finger nuclease to target desired sequences within genomes. The DNA-binding domains of individual ZFNs typically contain a plurality of individual zinc finger repeats and can each recognize a plurality of base pairs. The most common method to generate new zinc-finger domain is to combine smaller zinc-finger "modules" of known specificity. The most common cleavage domain in ZFNs is the non-specific cleavage domain from the type Ils restriction endonuclease Fokl. Using the endogenous homologous recombination (HR) machinery and a homologous DNA template carrying TCR expression cassette, ZFNs can be used to insert the TCR expression cassette into genome. When the targeted sequence is cleaved by ZFNs, the HR machinery searches for homology between the damaged chromosome and the homologous DNA template, and then copies the sequence of the template between the two broken ends of the chromosome, whereby the homologous DNA template is integrated into the genome. Methods of using the ZFN system are described, for example, in WO 2009146179 Al, WO 2008060510 A2 and CN 102174576 A, which are incorporated by reference in their entireties.

[0784] In certain embodiments, the TALEN system is used to integrate the TCR in selected loci of the genome of an immunoresponsive cell. Transcription activator-like effector nucleases (TALEN) are restriction enzymes that can be engineered to cut specific sequences of DNA. TALEN system operates on almost the same principle as ZFNs. They are generated by combining a transcription activator-like effectors DNA-binding domain with a DNA cleavage domain. Transcription activator-like effectors (TALEs) are composed of 33-34 amino acid repeating motifs with two variable positions that have a strong recognition for specific 072734.1889

[0785] PATENT

[0786] nucleotides. By assembling arrays of these TALEs, the TALE DNA-binding domain can be engineered to bind desired DNA sequence, and thereby guide the nuclease to cut at specific locations in genome. Methods of using the TALEN system are described, for example, in WO 2014134412 Al, WO 2013163628 A2 and WO 2014040370 Al, which are incorporated by reference in their entireties.

[0787] cDNA expression for use in polynucleotide therapy methods can be directed from any suitable promoter (e.g., the human cytomegalovirus (CMV), simian virus 40 (SV40), or metallothionein promoters), and regulated by any appropriate mammalian regulatory element or intron (e.g. the elongation factor la enhancer / promoter / intron structure). For example, if desired, enhancers known to preferentially direct gene expression in specific cell types can be used to direct the expression of a nucleic acid. The enhancers used can include, without limitation, those that are characterized as tissue- or cell-specific enhancers. Alternatively, if a genomic clone is used as a therapeutic construct, regulation can be mediated by the cognate regulatory sequences or, if desired, by regulatory sequences derived from a heterologous source, including any of the promoters or regulatory elements described above.

[0788] Methods for delivering the genome editing agents / sy stems can vary depending on the need. In certain embodiments, the components of a selected genome editing method are delivered as DNA constructs in one or more plasmids. In certain embodiments, the components are delivered via viral vectors. Common delivery methods include but is not limited to, electroporation, microinjection, gene gun, impalefection, hydrostatic pressure, continuous infusion, sonication, magnetofection, adeno-associated viruses, envelope protein pseudotyping of viral vectors, replication-competent vectors cis and trans-acting elements, herpes simplex virus, and chemical vehicles (e.g., oligonucleotides, lipoplexes, polymersomes, polyplexes, dendrimers, inorganic Nanoparticles, and cell-penetrating peptides).

[0789] In certain embodiments, the delivery methods include the use of colloids. As used herein, the term “colloid” refers to systems in which there are two or more phases, with one phase (e.g., the dispersed phase) distributed in the other phase (e.g., the continuous phase). Moreover, at least one of the phases has small dimensions (in the range of about 10-9 to about 10-6 m). Non-limiting examples of colloids encompassed by the presently disclosed subject matter include macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems (e.g., micelles, liposomes, and lipid nanoparticles).

[0790] In certain embodiments, the delivery methods include the use of liposomes. The term “liposome,” as used herein, refers to single- or multi-layered spherical lipid bilayer structures produced from lipids dissolved in organic solvents and then dispersed in aqueous media. 072734.1889

[0791] PATENT

[0792] Experimentally and therapeutically used for delivering an active pharmaceutical ingredient (e.g., nucleic acid compositions disclosed herein) to cells, liposomes fuse with cell membranes so the contents are transferred into the cytoplasm.

[0793] In certain embodiments, the delivery methods include the use of lipid nanoparticles. As used herein, the term “lipid nanoparticle” refers to a particle having at least one dimension in the order of nanometers (e.g., from about 1 nm to about 1,000 nm) and including at least one lipid. In certain embodiments, the lipid nanoparticles can include an active pharmaceutical ingredient (e.g., nucleic acid compositions disclosed herein) for delivering to cells. The morphology of the lipid nanoparticles can be different from liposomes. While liposomes are characterized by a lipid bilayer surrounding a hydrophilic core, lipid nanoparticles have an electron-dense core where cationic lipids and / or ionizable lipids are organized into inverted micelles around an active pharmaceutical ingredient (e.g., nucleic acid compositions disclosed herein). Additional information on the morphology and properties of lipid nanoparticles and liposomes can be found in Wilczewska, et al., Pharmacological reports 64, no. 5 (2012): 1020-1037; Eygeris et al., Accounts of Chemical Research 55, no. 1 (2021): 2-12; Zhang et al., Chemical Reviews 121, no. 20 (2021): 12181-12277; and Fan et al., Journal of pharmaceutical and biomedical analysis 192 (2021): 113642.

[0794] In certain embodiments, the lipid nanoparticles have a mean diameter of from about 30 nm to about 150 nm, from about 40 nm to about 150 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, from about 70 nm to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, or 150 nm.

[0795] In certain embodiments, the lipid nanoparticles can include a cationic lipid or an ionizable lipid. The term “cationic lipid” refers to lipids including a head group with permanent positive charges. Non-limiting examples of cationic lipids encompassed by the presently disclosed subject matter include l,2-di-O-octadecenyl-3-trimethylammonium-propane (DOTMA), l,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 2,3-dioleyloxy-N-[2-(sperminecarboxamido)ethyl]-N, N-dimethyl-l-propanaminium trifluoroacetate (DOSPA), and ethylphosphatidylcholine (ePC).

[0796] As used herein, the term “ionizable lipid” refers to lipids that are protonated at low pH and are neutral at physiological pH. The pH-sensitivity of ionizable lipids is particularly 072734.1889

[0797] PATENT

[0798] beneficial for delivery in vivo (e.g., delivery of nucleic acid compositions disclosed herein), because neutral lipids have less interactions with the anionic membranes of blood cells and, thus, improve the biocompatibility of the lipid nanoparticles. Once trapped in endosomes, ionizable lipids are protonated and promote membrane destabilization to allow the endosomal escape of the nanoparticles. Non-limiting example of ionizable lipids encompassed by the presently disclosed subject matter include tetrakis(8-methylnonyl) 3,3 ',3 ",3"'-(((methylazanediyl) bis(propane-3,l diyl))bis (azanetriyl))tetrapropionate; decyl (2-(dioctylammonio)ethyl) phosphate; ((4-hydroxybutyl)azanediyl)bis(hexane-6,l-diyl)bis(2-hexyldecanoate); bis(2-(dodecyldisulfanyl)ethyl) 3,3 ' -((3-methyl-9-oxo-10-oxa-13,14-dithia-3,6-diazahexacosyl)azanediyl)dipropionate; 1,1 ' -((2-(4-(2-((2-(bis(2-hydroxydodecyl)amino)ethyl) (2-hydroxydodecyl)amino)ethyl) piperazin- 1 -yl)ethyl)azanediyl) bis(dodecan-2-ol); cKK-E12, 3,6-bis(4-(bis(2-hydroxydodecyl)amino)butyl)piperazine-2, 5-dione; (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen- 19-yl 4-(dimethylamino) butanoate; hexa(octan-3-yl) 9,9',9",9"', 9" ",9"' " - ((((benzene-l,3,5-tricarbonyl)yris(azanediyl)) tris (propane-3,1 -diyl)) tris(azanetriyl))hexanonanoate; heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino) octanoate; and (((3,6-dioxopiperazine-2,5-diyl)bis(butane-4, 1-diyl))bis(azanetriyl))tetrakis(ethane-2,l-diyl) (9Z,9 ' Z,9 " Z,9"'Z,12Z,12 ' Z,12" Z,12"'Z)-tetrakis (octadeca-9, 12-di enoate).

[0799] Additionally, in certain embodiments, the lipid nanoparticles can include other lipids. For example, but without any limitation, the lipid nanoparticles of the presently disclosed subject matter can include phospholipids, cholesterol, polyethylene glycol (PEG)-functionalized lipids (PEG-lipids). These lipids can improve certain properties of the lipid nanoparticles (e.g., stability, biodistribution, etc.). For example, cholesterol enhances the stability of the lipid nanoparticles by modulating their integrity and rigidity. Non-limiting examples of other lipids present in lipid nanoparticles include cholesterol, DC-cholesterol, P-sitosterol, BHEM-chole sterol, ALC-0159, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE) and dioleoyl-phosphatidylethanolamine 4-(N- maleimidom ethyl) -cyclohexane -1 -carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), 072734.1889

[0800] PATENT

[0801] distearoylphosphatidylethanolamine (DSPE), 16-0-monom ethyl PE, 16-O-dimethyl PE, 18-1 -trans PE, 1- stearioyl-2-oleoyl-phosphatidy ethanol amine (SOPE), and 1,2-dielaidoyl-sn-glycero-3- phophoethanolamine (transDOPE).

[0802] In certain embodiments, the lipid nanoparticles can include a targeting moiety that binds to a ligand. The use of the targeting moieties allows selective delivery of an active pharmaceutical ingredient (e.g., nucleic acid compositions disclosed herein) to target cells expressing the ligand (e.g., T cells). In certain embodiments, the targeting moiety can be an antibody or antigen-binding fragment thereof that binds to a cell surface receptor. For example, but without any limitation, the targeting domain is an antibody or antigen-binding fragment thereof that binds to a receptor expressed on the surface of a T cell (e.g., CD3, CD4, CD8, CD16, CD40L, CD95, FasL, CTLA-4, 0X40, GITR, LAG3, ICOS, and PD-1).

[0803] In certain embodiments, the delivery methods are in vivo delivery methods. In certain embodiments, the delivery methods are ex vivo delivery methods.

[0804] Modification can be made anywhere within the selected locus, or anywhere that can influence gene expression of the integrated TCR. In certain embodiments, the modification is introduced upstream of the transcriptional start site of the integrated TCR. In certain embodiments, the modification is introduced between the transcriptional start site and the protein coding region of the integrated TCR). In certain embodiments, the modification is introduced downstream of the protein coding region of the integrated TCR.

[0805] 6. Formulations and Administration

[0806] The presently disclosed subject matter also provides compositions comprising the presently disclosed cells (e.g., those disclosed in Section 4). Additionally or alternatively, the presently disclosed subject matter provides compositions comprising the presently nucleic acids, vectors, and / or lipid nanoparticles disclosed herein. In certain embodiments, the composition is a pharmaceutical composition that further comprises a pharmaceutically acceptable carrier.

[0807] Compositions comprising the presently disclosed cells can be conveniently provided as sterile liquid preparations, e.g., isotonic aqueous solutions, suspensions, emulsions, dispersions, or viscous compositions, which may be buffered to a selected pH. Liquid preparations are normally easier to prepare than gels, other viscous compositions, and solid compositions. Additionally, liquid compositions are somewhat more convenient to administer, especially by injection. Viscous compositions, on the other hand, can be formulated within the appropriate viscosity range to provide longer contact periods with specific tissues. Liquid or viscous compositions can comprise carriers, which can be a solvent or dispersing medium 072734.1889

[0808] PATENT

[0809] containing, for example, water, saline, phosphate buffered saline, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like) and suitable mixtures thereof.

[0810] Compositions comprising the presently disclosed cells can be provided systemically or directly to a subject for inducing and / or enhancing an immune response to an antigen and / or treating and / or preventing a tumor. In certain embodiments, the presently disclosed cells or compositions comprising thereof are directly injected into an organ of interest (e.g., an organ affected by a neoplasm). Alternatively, the presently disclosed cells or compositions comprising thereof are provided indirectly to the organ of interest, for example, by administration into the circulatory system e.g., the tumor vasculature). Expansion and differentiation agents can be provided prior to, during or after administration of the cells or compositions to increase production of cells in vitro or in vivo.

[0811] The quantity of cells to be administered can vary for the subject being treated. In certain embodiments, between about 104and about 1011, between about 104and about 107, between about 105and about 107, between about 105and about 109, or between about 106and about 108of the presently disclosed cells are administered to a subject. In certain embodiments, at least about 1 x 105cells can be administered, eventually reaching about 1 x 1010or more. In certain embodiments, at least about 1 x 106cells can be administered. In certain embodiments, from about 104to about 1011, from about 105to about 109, or from about 106to about 108the presently disclosed cells are administered to a subject. More effective cells may be administered in even smaller numbers. In certain embodiments, at least about 1 x 108, about 2 x 108, about 3 x 108, about 4 x 108, and about 5 x 108the presently disclosed cells are administered to a subject. The precise determination of what would be considered an effective dose can be based on factors individual to each subject, including their size, age, sex, weight, and condition of the particular subject. Dosages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art.

[0812] The presently disclosed cells and compositions can be administered by any method known in the art including, but not limited to, intravenous administration, subcutaneous administration, intranodal administration, intratumoral administration, intrathecal administration, intrapleural administration, intraosseous administration, intraperitoneal administration, pleural administration, and direct administration to the subject. The presently disclosed cells can be administered in any physiologically acceptable vehicle, normally intravascularly, although they may also be introduced into bone or other convenient site where the cells may find an appropriate site for regeneration and differentiation (e.g., thymus). 072734.1889

[0813] PATENT

[0814] 7. Methods of Treatment

[0815] The presently disclosed subject matter provides various methods of using the presently disclosed cells or compositions comprising thereof. The presently disclosed cells and compositions comprising thereof can be used in a therapy or medicament. For example, the presently disclosed subject matter provides methods for inducing and / or increasing an immune response in a subject in need thereof. The presently disclosed cells and compositions comprising thereof can be used for reducing tumor burden in a subject. The presently disclosed cells and compositions comprising thereof can reduce the number of tumor cells, reduce tumor size, and / or eradicate the tumor in the subject. The presently disclosed cells and compositions comprising thereof can be used for treating and / or preventing a tumor in a subject. The presently disclosed cells and compositions comprising thereof can be used for prolonging the survival of a subject suffering from a tumor.

[0816] In certain embodiments, each of the above-noted methods comprises administering the presently disclosed cells or a composition (e.g., a pharmaceutical composition) comprising thereof to achieve the desired effect, e.g., palliation of an existing condition or prevention of recurrence of tumor. For treatment, the amount administered is an amount effective in producing the desired effect. An effective amount can be provided in one or a series of administrations. An effective amount can be provided in a bolus or by continuous perfusion.

[0817] In certain embodiments, the tumor is associated with RAS. In certain embodiments, the tumor is associated with a RAS mutation or a RAS mutant. In certain embodiments, the RAS mutation is a G12 mutation. In certain embodiments, the RAS mutation is a G12V mutation.

[0818] In certain embodiments, the tumor is a cancer. In certain embodiments, the tumor is selected from the group consisting of pancreatic cancer, breast cancer, endometrial cancer, cervical cancer, anal cancer, bladder cancer, colorectal cancer, cholangiocarcinoma / bile duct cancer, lung cancer, ovarian cancer, esophageal cancer, gastric cancer (also known as “stomach cancer”), head and neck squamous cell carcinoma, nonmelanoma skin cancer, salivary gland cancer, melanoma, appendiceal cancer, and multiple myeloma. In certain embodiments, the cancer is pancreatic cancer.

[0819] In certain embodiments, the subject is a human subject. The subjects can have an advanced form of disease, in which case the treatment objective can include mitigation or reversal of disease progression, and / or amelioration of side effects. The subjects can have a history of the condition, for which they have already been treated, in which case the therapeutic objective will typically include a decrease or delay in the risk of recurrence. 072734.1889

[0820] PATENT

[0821] In certain embodiments, the subject comprises an HLA-A. In certain embodiments, the HLA-A is an HLA-A*03 superfamily member. In certain embodiments, the HLA-A*03 superfamily member is selected from the group consisting of HLA-A*03, HLA-A*11, HLA-A*31, HLA-A*33, HLA-A*66, HLA-A*68 and HLA-A*74. In certain embodiments, the HLA-A*03 superfamily member is HLA-A*03.

[0822] 8. Exemplary Embodiments

[0823] Embodiment 1. A T cell receptor (TCR) that binds to a RAS peptide, wherein the RAS peptide comprises a G12 mutation.

[0824] Embodiment 2. The TCR of embodiment 1, wherein the RAS peptide comprises a G12V mutation.

[0825] Embodiment 3. The TCR of embodiment 1 or 2, wherein the RAS peptide is 9-mer or 10-mer.

[0826] Embodiment 4. The TCR of any one of embodiments 1-3, wherein the RAS peptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 48 or SEQ ID NO: 49.

[0827] Embodiment 5. The TCR of any one of embodiments 1-4, wherein the RAS peptide is associated with an HLA class I complex.

[0828] Embodiment 6. The TCR of embodiment 5, wherein the HLA class I complex is selected from an HLA-A, an HLA-B, and an HLA-C.

[0829] Embodiment 7. The TCR of embodiment 5 or 6, wherein the HLA class I complex is an HLA-A.

[0830] Embodiment 8. The TCR of embodiment 6 or 7, wherein the HLA-A is an HLA-A*03 superfamily member.

[0831] Embodiment 9. The TCR of embodiment 8, wherein the HLA-A*03 superfamily member is selected from the group consisting of HLA-A*03, HLA-A*11, HLA-A*31, HLA-A*33, HLA-A*66, HLA-A*68 and HLA-A*74.

[0832] Embodiment 10. The TCR of embodiment 9, wherein the HLA-A*03 superfamily member is HLA-A*03.

[0833] Embodiment 11. The TCR of any one of embodiments 1-10, wherein the TCR comprises an extracellular domain that binds to the RAS peptide, wherein the extracellular domain comprises an a chain and a P chain, wherein the a chain comprises an a chain variable region and a chain constant region, and the P chain comprises a P chain variable region and a P chain constant region. 072734.1889

[0834] PATENT

[0835] Embodiment 12. The TCR of embodiment 11, wherein: (a) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 7; (b) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 15; (c) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 23; (d) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 28; (e) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 32; (f) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 38; (g) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42; (h) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 46; (i) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 65; (j) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 67; (k) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 69; (1) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 71; (m) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 73; or (n) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 75.

[0836] Embodiment 13. The TCR of embodiment 11 or 12, wherein: (a) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 8; (b) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16; (c) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 24; (d) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 29; (e) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 33; (f) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising 072734.1889

[0837] PATENT

[0838] the amino acid sequence set forth in SEQ ID NO: 39; (g) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 43; or (h) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 47.

[0839] Embodiment 14. The TCR of any of embodiments 11-13, wherein: (a) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 7, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 8; (b) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 15, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16; (c) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 23, the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 24; (d) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 28, the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 29; (e) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 32, the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 33; (f) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 38, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 39; (g) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 43; (h) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 46, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 47; (i) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 65, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid 072734.1889

[0840] PATENT

[0841] sequence set forth in SEQ ID NO: 8; (j) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 67, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16; (k) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 69, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16; (1) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 71, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16; (m) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16; (n) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 73, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16; or (o) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 75, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16.

[0842] Embodiment 15. The TCR of any one of embodiments 11-14, wherein: (a) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3; (b) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11; (c) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19; (d) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26; (e) the a chain variable region comprises a CDR1 comprising the 072734.1889

[0843] PATENT

[0844] amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30; (f) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36; (g) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40; (h) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44; (i) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64; (j) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66; (k) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; (1) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; (m) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; or (n) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74.

[0845] Embodiment 16. The TCR of any one of embodiments 11-15, wherein: (a) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (b) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 072734.1889

[0846] PATENT

[0847] comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (c) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22; (d) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27; (e) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31; (f) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37; (g) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41; or (h) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45.

[0848] Embodiment 17. The TCR of any one of embodiments 11-16, wherein: (a) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (b) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (c) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ 072734.1889

[0849] PATENT ID NO: 19, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22; (d) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27; (e) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31; (f) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37; (g) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41; (h) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; (i) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a 072734.1889

[0850] PATENT CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (j) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (k) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (1) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (m) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (n) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; or (o) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino 072734.1889

[0851] PATENT

[0852] acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0853] Embodiment 18. The TCR of any one of embodiments 1-17, wherein (a) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 7; (b) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 15; (c) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 23; (d) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 28; (e) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 32; (f) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 38; (g) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42; (h) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 46; (i) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 65; (j) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67; (k) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 69; (1) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 71; (m) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 73; or (n) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 75.

[0854] Embodiment 19. The TCR of any one of embodiments 1-18, wherein: (a) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or 072734.1889

[0855] PATENT

[0856] identical to the amino acid sequence set forth in SEQ ID NO: 8; (b) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; (c) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 24; (d) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 29; (e) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 33; (f) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 39; (g) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43; or (h) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 47.

[0857] Embodiment 20. The TCR of any of embodiments 11-19, wherein: (a) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 7, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8; (b) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 15, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; (c) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 23, the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 24; (d) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 28, the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 29; (e) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 32, the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 33; (f) the a chain variable region comprises an amino acid 072734.1889

[0858] PATENT

[0859] sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 38, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 39; (g) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43; (h) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 46, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 47; (i) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 65, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8; (j) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; (k) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 69, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; (1) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 71, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; (m) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; (n) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 73, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; or (o) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous 072734.1889

[0860] PATENT

[0861] or identical to the amino acid sequence set forth in SEQ ID NO: 75, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16.

[0862] Embodiment 21. The TCR of any of embodiments 11-20, wherein: (a) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 7, and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8; (b) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 15, and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16; (c) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 23, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 24; (d) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 28, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 29; (e) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 32, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 33; (f) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 38, and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 39; (g) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42, and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 43; (h) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 46, and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 47; (i) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 65, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8; (j) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 67, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16; (k) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 69, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16; (1) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 71, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16; (m) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16; (n) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 73, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16; or (o) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 75, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16. 072734.1889

[0863] PATENT

[0864] Embodiment 22. The TCR of any one of embodiments 11-21, wherein the a chain constant region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54.

[0865] Embodiment 23. The TCR of any one of embodiments 11-22, wherein the a chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54.

[0866] Embodiment 24. The TCR of any one of embodiments 11-23, wherein the P chain constant region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.

[0867] Embodiment 25. The TCR of any one of embodiments 11-24, wherein the P chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.

[0868] Embodiment 26. The TCR of any one of embodiments 11-25, wherein (a) the a chain constant region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54; and (b) the P chain constant region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.

[0869] Embodiment 27. The TCR of any one of embodiments 11-26, wherein (a) the a chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54; and (b) the P chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.

[0870] Embodiment 28. The TCR of any one of embodiments 1-27, wherein the TCR is recombinant.

[0871] Embodiment 29. The TCR of any one of embodiments 1-28, wherein the TCR is recombinantly expressed and / or expressed from a vector.

[0872] Embodiment 30. A T cell receptor (TCR) comprising an extracellular domain that binds to the same TP53 peptide as a reference TCR or a functional fragment thereof, wherein the reference TCR or functional fragment thereof comprises an a chain variable region and a P chain variable region, wherein: (a) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth 072734.1889

[0873] PATENT

[0874] in SEQ ID NO: 3, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (b) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (c) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22; (d) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27; (e) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31; (f) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37; (g) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the 072734.1889

[0875] PATENT

[0876] amino acid sequence set forth in SEQ ID NO: 40, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41; (h) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45; (i) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6; (j) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (k) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (1) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (m) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in 072734.1889

[0877] PATENT SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; (n) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; or (o) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

[0878] Embodiment 31. A nucleic acid encoding the T cell receptor (TCR) of any one of embodiments 1-30.

[0879] Embodiment 32. The nucleic acid of embodiment 31 further comprising a polynucleotide encoding a CD8 receptor or a CD4 receptor.

[0880] Embodiment 33. A vector comprising the nucleic acid of embodiment 31 or 32.

[0881] Embodiment 34. The vector of embodiment 33, wherein the vector is a γ-retroviral vector.

[0882] Embodiment 35. The vector of embodiment 33, wherein the vector is a plasmid comprising a backbone comprising fewer than about 500 nucleotides.

[0883] Embodiment 36. A lipid nanoparticle comprising the nucleic acid of embodiment 31 or 32.

[0884] Embodiment 37. A lipid nanoparticle comprising the vector of any one of embodiments 33-35.

[0885] Embodiment 38. A cell comprising the nucleic acid of embodiment 31 or 32, the vector of any one of claims 33-35, or the lipid nanoparticle of claim 36 or 37.

[0886] Embodiment 39. A cell comprising the TCR of any one of embodiments 1-30.

[0887] Embodiment 40. The cell of embodiment 38 or 39, wherein the cell is transduced with the TCR. 072734.1889

[0888] PATENT

[0889] Embodiment 41. The cell of any one of embodiments 38-40, wherein the TCR is constitutively expressed on the surface of the cell.

[0890] Embodiment 42. The cell of any one of embodiments 38-41, wherein the cell is an immunoresponsive cell.

[0891] Embodiment 43. The cell of any one of embodiments 38-42, wherein the cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, and a pluripotent stem cell from which a lymphoid cell may be differentiated.

[0892] Embodiment 44. The cell of embodiment 43, wherein the cell is a T cell.

[0893] Embodiment 45. The cell of embodiment 43 or 44, wherein the T cell is selected from the group consisting of a cytotoxic T lymphocyte (CTL), a regulatory T cell, a γδ T cell, a Natural Killer-T cell (NK-T), a stem cell memory T cell, a central memory T cell, and an effector memory T cell.

[0894] Embodiment 46. The cell of any one of embodiments 43-45, wherein the T cell is a yb T cell.

[0895] Embodiment 47. The cell of any one of embodiments 43-45, wherein the T cell is aNK-T cell.

[0896] Embodiment 48. The cell of embodiment 43, wherein the cell is an NK cell.

[0897] Embodiment 49. The cell of any one of embodiments 38-48, wherein the TCR is integrated at a locus within the genome of the cell.

[0898] Embodiment 50. The cell of embodiment 49, wherein the locus is selected from a TRAC locus, a TRBC locus, a TRDC locus, and a TRGC locus.

[0899] Embodiment 51. The cell of embodiment 49 or 50, wherein the locus is a TRAC locus or a TRBC locus.

[0900] Embodiment 52. The cell of embodiment 49, wherein the locus is selected from a PDCD1 locus, a CBLB locus, a CISH locus, and a RASA2 locus.

[0901] Embodiment 53. The cell of embodiments 49, wherein the locus is a genomic safe harbor.

[0902] Embodiment 54. The cell of any one of embodiments 38-53, wherein the cell further comprises at least one recombinant or exogenous co-receptor.

[0903] Embodiment 55. The cell of embodiment 54, wherein the co-receptor is a CD8 coreceptor.

[0904] Embodiment 56. The cell of embodiment 54, wherein the co-receptor is a CD4 co-receptor. 072734.1889

[0905] PATENT

[0906] Embodiment 57. A composition comprising the nucleic acid of embodiment 31 or 32, the vector of any one of embodiments 33-35, the lipid nanoparticle of embodiment 36 or 37, or the cell of any one of embodiments 38-56.

[0907] Embodiment 58. The composition of embodiment 57, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0908] Embodiment 59. A method for producing a cell that binds to a RAS peptide that comprises a G12 mutation, comprising introducing into the nucleic acid of embodiment 31 or 32, the vector of any one of embodiments 33-35, the lipid nanoparticle of embodiment 36 or 37, or the composition of embodiment 57 or 58.

[0909] Embodiment 60. A method of treating and / or preventing a tumor associated with RAS in a subject, comprising administering to the subject the cell of any one of embodiments 38-56 or the composition of embodiment 57 or 58.

[0910] Embodiment 61. The method of embodiment 60, wherein the tumor is associated with a RAS mutation.

[0911] Embodiment 62. The method of embodiment 61, wherein the RAS mutation is a G12V mutation.

[0912] Embodiment 63. The method of any one of embodiments 60-62, wherein the tumor is selected from the group consisting of pancreatic cancer, breast cancer, endometrial cancer, cervical cancer, anal cancer, bladder cancer, colorectal cancer, cholangiocarcinoma / bile duct cancer, lung cancer, ovarian cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, nonmelanoma skin cancer, salivary gland cancer, melanoma, and multiple myeloma.

[0913] Embodiment 64. The method of embodiment 63, wherein the tumor is pancreatic cancer.

[0914] Embodiment 65. The method of any one of embodiments 60-64, wherein the subject is a human.

[0915] Embodiment 66. The method of any one of embodiments 60-65, wherein the subject comprises an HLA-A.

[0916] Embodiment 67. The method of embodiment 66, wherein the HLA-A is an HLA-A*03 superfamily member.

[0917] Embodiment 68. The method of embodiment 67, wherein the HLA-A*03 superfamily member is selected from the group consisting of HLA-A*03, HLA-A*11, HLA-A*31, HLA-...

Claims

072734.1889PATENTWhat is claimed is:

1. A T cell receptor (TCR) that binds to a RAS peptide, wherein the RAS peptide comprises a G12 mutation.

2. The TCR of claim 1, wherein the RAS peptide comprises a G12V mutation.

3. The TCR of claim 2, wherein the RAS peptide is 9-mer or 10-mer.

4. The TCR of claim 1, wherein the RAS peptide comprises or consists of the amino acid sequence set forth in SEQ ID NO: 48 or SEQ ID NO: 49.

5. The TCR of claim 4, wherein the RAS peptide is associated with an HLA class I complex.

6. The TCR of claim 5, wherein the HLA class I complex is selected from an HLA-A, an HLA-B, and an HLA-C.

7. The TCR of claim 6, wherein the HLA class I complex is an HLA-A.

8. The TCR of claim 7, wherein the HLA-A is an HLA-A*03 superfamily member.

9. The TCR of claim 8, wherein the HLA-A*03 superfamily member is selected from the group consisting of HLA-A*03, HLA-A*11, HLA-A*31, HLA-A*33, HLA-A*66, HLA- A*68 and HLA-A*74.

10. The TCR of claim 9, wherein the HLA-A*03 superfamily member is HLA-A*03.

11. The TCR of claim 1, wherein the TCR comprises an extracellular domain that binds to the RAS peptide, wherein the extracellular domain comprises an a chain and a P chain, wherein the a chain comprises an a chain variable region and a chain constant region, and the P chain comprises a P chain variable region and a P chain constant region.

12. The TCR of claim 11, wherein:072734.1889PATENT(a) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 7;(b) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 15;(c) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 23;(d) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 28;(e) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 32;(f) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 38;(g) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42;(h) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 46;(i) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 65;(j) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 67;(k) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 69;(l) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 71;(m) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 73; or(n) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 75.

13. The TCR of claim 11, wherein:(a) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 8;(b) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16;072734.1889PATENT(c) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 24;(d) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 29;(e) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 33;(f) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 39;(g) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 43; or(h) the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 47.

14. The TCR of claim 11, wherein:(a) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 7, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 8;(b) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 15, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16;(c) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 23, the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 24;(d) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 28, the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 29;(e) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 32, the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 33;072734.1889PATENT(f) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 38, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 39;(g) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 43;(h) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 46, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 47;(i) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 65, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 8;(j) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 67, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16;(k) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 69, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16;(l) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 71, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16;(m) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 42, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16;(n) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 73, and the P chain variable072734.1889PATENTregion comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16; or(o) the a chain variable region comprises a CDR1, a CDR2, and a CDR3 of the a chain comprising the amino acid sequence set forth in SEQ ID NO: 75, and the P chain variable region comprises a CDR1, a CDR2, and a CDR3 of the P chain comprising the amino acid sequence set forth in SEQ ID NO: 16.

15. The TCR of claim 11, wherein:(a) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3;(b) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11;(c) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19;(d) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26;(e) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30;(f) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36;(g) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40;(h) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44;072734.1889PATENT(i) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64;(j) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66;(k) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68;(l) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70;(m) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; or (n) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74.

16. The TCR of claim 11, wherein:(a) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6;(b) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;(c) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22;(d) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27;072734.1889PATENT(e) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31;(f) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37;(g) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41; or (h) the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45.

17. The TCR of claim 11, wherein:(a) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6;(b) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;(c) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22;(d) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID072734.1889PATENT NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27;(e) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31;(f) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37;(g) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41;(h) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45;(i) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6;072734.1889PATENT(j) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;(k) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;(l) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;(m) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;(n) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; or(o) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in072734.1889PATENT SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

18. The TCR of claim 17, wherein(a) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 7;(b) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 15;(c) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 23;(d) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 28;(e) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 32;(f) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 38;(g) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42;(h) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 46;(i) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 65;(j) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67;(k) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 69;(l) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 71;(m) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 73; or (n) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 75.

19. The TCR of claim 17, wherein:072734.1889PATENT(a) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8;(b) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16;(c) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 24;(d) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 29;(e) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 33;(f) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 39;(g) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43; or (h) the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 47.

20. The TCR of claim 17, wherein:(a) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 7, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8;(b) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 15, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16;(c) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 23, the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 24;(d) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 28, the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 29;072734.1889PATENT(e) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 32, the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 33;(f) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 38, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 39;(g) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 43;(h) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 46, and the P chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 47;(i) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 65, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 8;(j) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 67, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16;(k) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 69, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16;(l) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 71, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16;(m) the a chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 42, and the072734.1889PATENTP chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16;(n) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 73, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16; or(o) the α chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 75, and the β chain variable region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 16.

21. The TCR of claim 17, wherein:(a) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 7, and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8;(b) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 15, and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16;(c) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 23, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 24;(d) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 28, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 29;(e) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 32, the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 33;(f) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 38, and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 39;(g) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42, and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 43;072734.1889PATENT(h) the a chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 46, and the P chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 47;(i) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 65, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 8;(j) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 67, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16;(k) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 69, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16;(l) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 71, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16;(m) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 42, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16;(n) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 73, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16; or(o) the α chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 75, and the β chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 16.

22. The TCR of claim 17, wherein the a chain constant region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54.

23. The TCR of claim 17, wherein the a chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54.072734.1889PATENT24. The TCR of claim 17, wherein the P chain constant region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.

25. The TCR of claim 17, wherein the P chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.

26. The TCR of claim 17, wherein(a) the a chain constant region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54; and(b) the P chain constant region comprises an amino acid sequence that is at least about 80% homologous or identical to the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.

27. The TCR of claim 17, wherein(a) the a chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54; and(b) the P chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 57.

28. The TCR of claim 17, wherein the TCR is recombinant.

29. The TCR of claim 17, wherein the TCR is recombinantly expressed and / or expressed from a vector.

30. A T cell receptor (TCR) comprising an extracellular domain that binds to the same TP53 peptide as a reference TCR or a functional fragment thereof, wherein the reference TCR or functional fragment thereof comprises an a chain variable region and a P chain variable region, wherein:(a) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 1, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 3, the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID072734.1889PATENT NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6;(b) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 11, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;(c) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 19, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 22;(d) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 27;(e) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 31;(f) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 36, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 37;(g) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID072734.1889PATENT NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40, and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 41;(h) the a chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 34, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 44; and the P chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 45;(i) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 62, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 63, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 64; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 4, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 6;(j) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 66; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;(k) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 68; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;(l) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 70; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;072734.1889PATENT(m) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 40; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14;(n) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 72; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14; or(o) the α chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 9, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 10, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 74; and the β chain variable region comprises a CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 12, a CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 13, and a CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 14.

31. A nucleic acid encoding the T cell receptor (TCR) of any one of claims 1-30.

32. The nucleic acid of claim 31 further comprising a polynucleotide encoding a CD8 receptor or a CD4 receptor.

33. A vector comprising the nucleic acid of claim 31 or 32.

34. The vector of claim 33, wherein the vector is a γ-retroviral vector.

35. The vector of claim 33, wherein the vector is a plasmid comprising a backbone comprising fewer than about 500 nucleotides.

36. A lipid nanoparticle comprising the nucleic acid of claim 31 or 32.

37. A lipid nanoparticle comprising the vector of any one of claims 33-35.072734.1889PATENT38. A cell comprising the nucleic acid of claim 31 or 32, the vector of any one of claims 33-35, or the lipid nanoparticle of claim 36 or 37.

39. A cell comprising the TCR of any one of claims 1-30.

40. The cell of claim 39, wherein the cell is transduced with the TCR.

41. The cell of any one of claims 38-40, wherein the TCR is constitutively expressed on the surface of the cell.

42. The cell of any one of claims 38-41, wherein the cell is an immunoresponsive cell.

43. The cell of any one of claims 38-42, wherein the cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, and a pluripotent stem cell from which a lymphoid cell may be differentiated.

44. The cell of claim 43, wherein the cell is a T cell.

45. The cell of claim 43 or 44, wherein the T cell is selected from the group consisting of a cytotoxic T lymphocyte (CTL), a regulatory T cell, a y6 T cell, a Natural Killer-T cell (NK-T), a stem cell memory T cell, a central memory T cell, and an effector memory T cell.

46. The cell of any one of claims 43-45, wherein the T cell is a y6 T cell.

47. The cell of any one of claims 43-45, wherein the T cell is a NK-T cell.

48. The cell of claim 43, wherein the cell is an NK cell.

49. The cell of any one of claims 38-48, wherein the TCR is integrated at a locus within the genome of the cell.

50. The cell of claim 49, wherein the locus is selected from a TRAC locus, a TRBC locus, a TRDC locus, and a TRGC locus.072734.1889PATENT51. The cell of claim 49 or 50, wherein the locus is a TRAC locus or a TRBC locus.

52. The cell of claim 49, wherein the locus is selected from a PDCD1 locus, a CBLB locus, a CISH locus, and a RASA2 locus.

53. The cell of claims 49, wherein the locus is a genomic safe harbor.

54. The cell of any one of claims 38-53, wherein the cell further comprises at least one recombinant or exogenous co-receptor.

55. The cell of claim 54, wherein the co-receptor is a CD8 co-receptor.

56. The cell of claim 54, wherein the co-receptor is a CD4 co-receptor.

57. A composition comprising the nucleic acid of claim 31 or 32, the vector of any one of claims 33-35, the lipid nanoparticle of claim 36 or 37, or the cell of any one of claims 38-56.

58. The composition of claim 57, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

59. A method for producing a cell that binds to a RAS peptide that comprises a G12 mutation, comprising introducing into the nucleic acid of claim 31 or 32, the vector of any one of claims 33-35, the lipid nanoparticle of claim 36 or 37, or the composition of claim 57 or 58.

60. A method of treating and / or preventing a tumor associated with RAS in a subject, comprising administering to the subject the cell of any one of claims 38-56 or the composition of claim 57 or 58.

61. The method of claim 60, wherein the tumor is associated with a RAS mutation.

62. The method of claim 61, wherein the RAS mutation is a G12V mutation.

63. The method of any one of claims 60-62, wherein the tumor is selected from the group consisting of pancreatic cancer, breast cancer, endometrial cancer, cervical cancer, anal cancer,072734.1889PATENTbladder cancer, colorectal cancer, cholangiocarcinoma / bile duct cancer, lung cancer, ovarian cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, nonmelanoma skin cancer, salivary gland cancer, melanoma, and multiple myeloma.

64. The method of claim 63, wherein the tumor is pancreatic cancer.

65. The method of any one of claims 60-64, wherein the subject is a human.

66. The method of any one of claims 60-65, wherein the subject comprises an HLA-A.

67. The method of claim 66, wherein the HLA-A is an HLA-A*03 superfamily member.

68. The method of claim 67, wherein the HLA-A*03 superfamily member is selected from the group consisting of HLA-A*03, HLA-A*11, HLA-A*31, HLA-A*33, HLA-A*66, HLA-A*68 and HLA-A*74.

69. The method of claim 68, wherein the HLA-A*03 superfamily member is HLA-A*03.

70. The cell of any one of claims 38-56 or the composition of claim 57 or 58 for use in treating and / or preventing a tumor associated with RAS in a subject.

71. The cell or the composition for use of claim 70, wherein the tumor is associated with a RAS mutation.

72. The cell or the composition for use of claim 71, wherein the RAS mutation is a G12D mutation.

73. The cell or the composition for use of any one of claims 70-72, wherein the tumor is selected from the group consisting of pancreatic cancer, breast cancer, endometrial cancer, cervical cancer, anal cancer, bladder cancer, colorectal cancer, cholangiocarcinoma / bile duct cancer, lung cancer, ovarian cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, nonmelanoma skin cancer, salivary gland cancer, melanoma, and multiple myeloma.

74. The cell or the composition for use of claim 73, wherein the tumor is pancreatic cancer.072734.1889PATENT75. The cell or the composition for use of any one of claims 70-74, wherein the subject is a human.

76. The cell or the composition for use of any one of claims 70-75, wherein the subject comprises an HLA-A.

77. The cell or the composition for use of claim 76, wherein the HLA-A is an HLA-A*03 superfamily member.

78. The cell or the composition for use of claim 77, wherein the HLA-A*03 superfamily member is selected from the group consisting of HLA-A*03, HLA-A*11, HLA-A*31, HLA-A*33, HLA-A*66, HLA-A*68 and HLA-A*74.

79. The cell or the composition for use of claim 77 or 78, wherein the HLA-A*03 superfamily member is HLA-A*03.

80. A bispecific molecule comprising the T cell receptor (TCR) of any one of claims 1-30 or a functional fragment thereof and a second binding specificity.

81. The bispecific molecule of claim 80, wherein the second binding specificity binds to a T cell.

82. The bispecific molecule of claim 80 or 81, wherein the second binding specificity binds to CD3, CD28, CD137, ICOS, CD4, CD8, or a combination thereof.

83. The bispecific molecule of claim 80, wherein the second binding specificity binds to an NK cell.

84. The bispecific molecule of claim 80 or 83, wherein the second binding specificity binds to CD16, CD335, NKp80, NKG2D, or a combination thereof.

85. A composition comprising the bispecific molecule of any one of claims 80-84.

86. The composition of claim 85, which is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.072734.1889PATENT87. A nucleic acid encoding the bispecific molecule of any one of claims 80-84.

88. A vector comprising the nucleic acid of claim 87.

89. The vector of claim 88, wherein the vector is a γ-retroviral vector.

90. A lipid nanoparticle comprising the nucleic acid of claim 87.

91. A cell comprising the bispecific molecule of any one of claims 80-84, the nucleic acid of claim 87, the vector of claim 88 or 89, or the lipid nanoparticle of claim 90.

92. A method of treating and / or preventing a tumor associated with RAS in a subject, comprising administering to the bispecific molecule of any one of claims 80-84 or the composition of claim 85 or 86.

93. The bispecific molecule of any one of claims 80-84 or the composition of claim 85 or 86 for use in treating and / or preventing a tumor associated with RAS in a subject.

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