T cell receptor constructs and uses thereof

Abstract

The present disclosure provides T cell receptors (TCRs) against peptide-MHC complexes, isolated nucleic acid molecules encoding TCRs against peptide-MHC complexes, T cells expressing TCRs against peptide-MHC complexes, and pharmaceutical compositions for use in the treatment of diseases.

Description

WSGR Docket No. 50401-811.601T CELL RECEPTOR CONSTRUCTS AND USES THEREOF CROSS REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 750,637, filed on January 28, 2025, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] T cell receptors (TCRs) are members of the immunoglobulin superfamily and usually consist of two subunits, namely the a- and [3-subunits. These possess one N-terminal immunoglobulin (Ig)-variable (V) domain, one Ig-constant (C) domain, a transmembrane / cell membrane -spanning region, and a short cytoplasmic tail at the C-terminal end. The variable domains of both the TCR a-chain and [3-chain have three hypervariable or complementarity determining regions (CDRs), whereas the variable region of the [3-chain has an additional area of hypervariability (HV4) that does not normally contact antigen and therefore is not considered a CDR.

[0003] CDR3 is the principal CDR responsible for recognizing processed antigen, although CDR1 of the alpha chain has also been shown to interact with the N-terminal part of the antigenic peptide, whereas CDR1 of the [3-chain interacts with the C-terminal part of the peptide. CDR2 is thought to recognize the MHC. The constant domain of the TCR domain consists of short connecting sequences in which a cysteine residue forms disulfide bonds, which forms a link between the two chains. The affinity of TCR’s for a specific antigen makes them valuable for several therapeutic approaches. For example, cancer patients, such as melanoma patients, can be effectively treated by using adoptive immunotherapy as TCRs are exquisitely sensitive for their antigen and can direct immune responses at tumor cells expressing their cognate antigen. Accordingly, there is a need for TCRs against peptide-MHC complexes for development of new and effective therapeutics.SUMMARY

[0004] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NO: 8 or 39. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 8 or 39. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 8 or 39. In some embodiments, the TCR beta chain construct comprises a variable region havingWSGR Docket No. 50401-811.601an amino acid sequence set forth in SEQ ID NOs: 8 or 39. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 1; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 2; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 4 or 38. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 4 or 38. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 4 or 38. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 4 or 38. In some embodiments, the TCR binds to an epitope from human RAS comprising a mutation G12D. In some embodiments, the epitope from human RAS comprising the mutation G12D is SEQ ID NOs: 9 or 10. In some embodiments, the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12D and (ii) an MHC protein encoded by an HLA-C08:02 allele.

[0005] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 18 or 41. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 18 or 41. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 18 or 41. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 18 or 41. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 11; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 12; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 14 or 40. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 14 or 40. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 14 or 40. In some embodiments, the TCR alpha chain construct comprises a variableWSGR Docket No. 50401-811.601region having an amino acid sequence set forth in SEQ ID NOs: 14 or 40. In some embodiments, the TCR binds to an epitope from human RAS comprising a mutation G12D. In some embodiments, the epitope from human RAS comprising the mutation G12D is SEQ ID NO: 19. In some embodiments, the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12D and (ii) an MHC protein encoded by an HLA-A11:01 allele.

[0006] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 26. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 24. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 27 or 43. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 27 or 43. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 27 or 43. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 27 or 43. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 20; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 21; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 23 or 42. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 23 or 42. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 23 or 42. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 23 or 42. In some embodiments, the TCR binds to an epitope from human RAS comprising a mutation G12D. In some embodiments, the epitope from human RAS comprising the mutation G12D is SEQ ID NO: 19. In some embodiments, the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12D and (ii) an MHC protein encoded by an HLA-A11:01 allele.

[0007] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 34. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2WSGR Docket No. 50401-811.601(CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 33. In some embodiments, the TCRbeta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 35 or 45. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 35 or 45. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 35 or 45. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 35 or 45. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 28; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 29; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 31 or 44. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 31 or 44. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 31 or 44. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 31 or 44. In some embodiments, the TCR binds to an epitope from human RAS comprising a mutation G12V. In some embodiments, the epitope from human RAS comprising the mutation G12V is SEQ ID NOs: 36 or 37. In some embodiments, the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12V and (ii) an MHC protein encoded by an HLA-A03:01 allele.

[0008] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 59. In some embodiments, the TCRbeta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCRbeta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 60 or 61. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 60 or 61. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 60 or 61. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 60 or 61. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 52; the CDR2 has an amino acid sequence set forth in SEQWSGR Docket No. 50401-811.601ID NO: 53; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 54. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 55 or 56. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 55 or 56. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 55 or 56. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 55 or 56.1n some embodiments, the TCR binds to an epitope from human RAS comprising a mutation G12D. In some embodiments, the epitope from human RAS comprising the mutation G12D is SEQ ID NO: 10 In some embodiments, the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12D and (ii) an MHC protein encoded by an HLA-C08:02 allele.

[0009] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 69. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 70 or 71. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 70 or 71. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 70 or 71. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 70 or 71. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 62; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 63; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 64. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 65 or 66. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 65 or 66. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 65 or 66. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 65 or 66.

[0010] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:WSGR Docket No. 50401-811.60177. In some embodiments, the TCRbeta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCRbeta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 78 or 79. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 78 or 79. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 78 or 79. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 78 or 79. In some embodiments, TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 73; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 29; and the CDR3 has an amino acid sequence set forth in SEQ ID NO: 74. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 75 or 76. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 75 or 76. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 75 or 76. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 75 or 76.

[0011] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 87. In some embodiments, the TCRbeta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 85. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 86. In some embodiments, the TCRbeta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 88 or 89. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 88 or 89. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 88 or 89. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 88 or 89. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 80; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 81 ; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 82. In some embodiments,WSGR Docket No. 50401-811.601the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 83 or 84. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 83 or 84. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 83 or 84. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 83 or 84.

[0012] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 97. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 95. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 96. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 98 or 99. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 98 or 99. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 98 or 99. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 98 or 99. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 90; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 91; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 93 or 94.

[0013] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 105. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 103. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 104. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequenceWSGR Docket No. 50401-811.601identity to an amino acid sequence set forth in SEQ ID NOs: 106 or 107. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 106 or 107. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 106 or 107. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 106 or 107. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 52; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 53; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 100. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 101 or 102. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 101 or 102. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 101 or 102. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 101 or 102.

[0014] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 109. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 108. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 110 or 111. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 110 or 111. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 110 or 111. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 110 or 111. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 90; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 91; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94. In some embodiments, the TCRWSGR Docket No. 50401-811.601alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 93 or 94.

[0015] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 117. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 118 or 119. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 118 or 119. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 118 or 119. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 118 or 119. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 112; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 113; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 114. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 115 or 116. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 115 or 116. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 115 or 116. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 115 or 116.

[0016] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 127. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 125. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 126. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 128 or 129. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 128 or 129. In some embodiments, the TCR beta chain constructWSGR Docket No. 50401-811.601comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 128 or 129. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 128 or 129. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 120; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 121; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 122. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 123 or 124. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 123 or 124. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 123 or 124. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 123 or 124.

[0017] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 135. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 133. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 134. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 136 or 137. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 136 or 137. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 136 or 137. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 136 or 137. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 20; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 21; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 130. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 131 or 132. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 131 or 132. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 131 or 132. In some embodiments, the TCRWSGR Docket No. 50401-811.601alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 131 or 132.

[0018] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 143. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 125. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 126. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 144 or 145. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 144 or 145. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 144 or 145. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 144 or 145. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 138; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 139; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 140. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 141 or 142. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 141 or 142. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 141 or 142. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 141 or 142.

[0019] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 151. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 152 or 153. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 152 or 153. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQWSGR Docket No. 50401-811.601ID NOs: 152 or 153. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 152 or 153. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 146; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 147; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 148. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 149 or 150. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 149 or 150. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 149 or 150. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 149 or 150.

[0020] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 159. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 157. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 158. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 160 or 161. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 160 or 161. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 160 or 161. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 160 or 161. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 138; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 139; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 154. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 155 or 156. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 155 or 156. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 155 or 156. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 155 or 156.WSGR Docket No. 50401-811.601

[0021] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 168. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 168. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 169 or 170. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 169 or 170. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 169 or 170. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 169 or 170. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 162; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 163; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 164. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 165 or 166. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 165 or 166. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 165 or 166. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 165 or 166.

[0022] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 176. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 177 or 178. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 177 or 178. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 177 or 178. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 177 or 178. In some embodiments, the TCRWSGR Docket No. 50401-811.601further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 171; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 172; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 173. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 174 or 175. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 174 or 175. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 174 or 175. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 174 or 175.

[0023] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 184. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 185 or 186. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 185 or 186. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 185 or 186. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 185 or 186. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 179; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 180; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 181. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 182 or 183. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 182 or 183. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 182 or 183. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 182 or 183.

[0024] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 190. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57. In someWSGR Docket No. 50401-811.601embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 191 or 192. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 191 or 192. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 191 or 192. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 191 or 192. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 20; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 21; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 187. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 188 or 189. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 188 or 189. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 188 or 189. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 188 or 189.

[0025] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 198. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 196. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 197. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 199 or 200. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 199 or 200. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 199 or 200. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 199 or 200. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 90; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 91; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 193. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 194 or 195. In someWSGR Docket No. 50401-811.601embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 194 or 195. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 194 or 195. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 194 or 195.

[0026] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 204. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 205 or 206. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 205 or 206. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 205 or 206. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 205 or 206. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 138; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 139; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 201. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 202 or 203. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 202 or 203. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 202 or 203. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 202 or 203.

[0027] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 210. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 211 or 212. In some embodiments, the TCR beta chain constructWSGR Docket No. 50401-811.601comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 211 or 212. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 211 or 212. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 211 or 212. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 112; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 113; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 207. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 208 or 209. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 208 or 209. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 208 or 209. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 208 or 209.

[0028] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 216. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 133. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 134. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 217 or 218. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 217 or 218. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 217 or 218. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 217 or 218. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 62; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 63; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 213. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 214 or 215. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 214 or 215. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 214 or 215. In some embodiments, the TCRWSGR Docket No. 50401-811.601alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 214 or 215.

[0029] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 222. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 133. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 134. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 223 or 224. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 223 or 224. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 223 or 224. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 223 or 224. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 62; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 63; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 219. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 220 or 221. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 220 or 221. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 220 or 221. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 220 or 221.

[0030] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 228. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 229 or 230. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 229 or 230. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQWSGR Docket No. 50401-811.601ID NOs: 229 or 230. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 229 or 230. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 179; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 180; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 225. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 226 or 227. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 226 or 227. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 226 or 227. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 226 or 227.

[0031] Provided herein is a T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 234. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 235 or 236. In some embodiments, the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 235 or 236. In some embodiments, the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 235 or 236. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 235 or 236. In some embodiments, the TCR further comprises a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3, wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 179; the CDR2 has an amino acid sequence set forth in SEQ ID NO: 180; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 231. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 232 or 233. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 232 or 233. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 232 or 233. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 232 or 233.

[0032] In some embodiments, the TCR binds to an epitope from human RAS comprising a mutation G12V. In some embodiments, the epitope from human RAS comprising the mutation G12V is SEQ IDWSGR Docket No. 50401-811.601NO: 72. In some embodiments, the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12V and (ii) an MHC protein encoded by an HLA-C01:02 allele.

[0033] In some embodiments, the TCR is a soluble TCR. In some embodiments, the TCR is a transmembrane protein.

[0034] Provided herein is a recombinant nucleic acid encoding for the TCR of any one of the embodiments disclosed herein.

[0035] Provided herein is a vector comprising the recombinant nucleic acid of any one of the embodiments disclosed herein. In some embodiments, the vector is a viral vector. In some embodiments, the vector is a lentiviral vector. In some embodiments, the vector is a retroviral vector.

[0036] Provided herein is a lipid nanoparticle comprising the recombinant nucleic acid of any one of the embodiments disclosed herein, the vector of any one of the embodiments disclosed herein, or the TCR of any one of the embodiments disclosed herein.

[0037] Provided herein is a cell comprising the recombinant nucleic acid of any one of the embodiments disclosed herein. In some embodiments, the cell is a CD4+ T cell. In some embodiments, the cell is a CD8+ T cell. In some embodiments, the cell is isolated from a subject having a RAS mutation.

[0038] Provided herein is a cell comprising a TCR encoded by the recombinant nucleic acid of any one of the embodiments disclosed herein. In some embodiments, the cell is a CD4+ T cell. In some embodiments, the cell is a CD8+ T cell. In some embodiments, the cell is isolated from a subject having a RAS mutation.

[0039] A pharmaceutical composition comprising: (i) the recombinant nucleic acid of any one of the embodiments disclosed herein or (ii) the TCR of any one of the embodiments disclosed herein; and (b) a pharmaceutically acceptable excipient or diluent. In some embodiments, the pharmaceutical composition is for use in treating an immune disease or cancer.

[0040] Provided herein is a use of the pharmaceutical composition disclosed herein for treating an immune disease or cancer.

[0041] Provided herein is a method of treating a subject having a disease or condition, comprising administering to the subject the pharmaceutical composition disclosed herein.

[0042] Provided herein is a method of treating a subject with cancer comprising administering to the subject the pharmaceutical composition disclosed herein.

[0043] Provided herein is a method of identifying a subject with cancer as a candidate for a therapeutic, wherein the method comprising determining the subject as a subject that expresses a protein encoded by an HLA-C08:02 allele, HLA-All:01 allele, HLA-C01:02 allele, or HLA-A03:01 allele, wherein the therapeutic is the pharmaceutical composition of any one of the embodiments disclosed herein.WSGR Docket No. 50401-811.601INCORPORATION BY REFERENCE

[0044] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0046] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0047] FIG. 1A shows CD69 activation after co-culturing Jurkat cells transduced with RAS TCR Clone92 with target cells expressing HLA-C08:02 loaded with RAS G12D peptide (9-mer) or KRAS wildtype peptide.

[0048] FIG. IB shows CD69 activation after co-culturing Jurkat cells transduced with RAS TCR GB TCR7 with target cells expressing HLA-C08:02 loaded with RAS G12D peptide (10-mer) or KRAS wildtype peptide.

[0049] FIG. 2A shows percent lysis of HLA-C08:02 expressing AGS upon co-culturing with human T cells transduced with TCRs of interest (Clone92, Ros 9b) or irrelevant TCR (Irrv TCR). Cln 92 refers to Clone 92.

[0050] FIG. 2B shows percent lysis of HLA-C08:02 expressing HPAC upon co-culturing with human T cells transduced with TCR of interest (Clone92) or irrelevant TCR (Irrv TCR). GB 92 refers to Clone92.

[0051] FIG. 3 shows percent lysis of HLA-C08:02 expressing AGS upon co-culturing with human T cells transduced with TCRs of interest (Ros 10, GB TCR7) or irrelevant TCR (Irrv TCR).

[0052] FIG. 4A shows CD69 activation after co-culturing Jurkat cells transduced with RAS TCR 24-077 with target cells expressing HLA-A11:01 loaded with RAS G12D peptide or KRAS wildtype peptide.

[0053] FIG.4B shows CD69 activation after co-culturing Jurkat cells transduced with RAS TCR 24-093 with target cells expressing HLA-A11:01 loaded with RAS G12D peptide or KRAS wildtype peptide.

[0054] FIG. 5A shows percent lysis of HLA-A 11:01 expressing AGS upon co-culturing with human T cells transduced with TCR of interest (24-077) or irrelevant TCR (Irrv TCR).

[0055] FIG. 5B shows percent lysis of HLA-A11:01 expressing PANC-1 upon co-culturing with human T cells transduced with TCR of interest (24-077) or irrelevant TCR (Irrv TCR).

[0056] FIG. 5C shows percent lysis of HLA-A 11:01 expressing AGS upon co-culturing with human T cells transduced with TCR of interest (24-093) or irrelevant TCR (Irrv TCR).WSGR Docket No. 50401-811.601

[0057] FIG.6 shows CD69 activation after co-culturing Jurkat cells transduced with RAS TCR 24-094.2 with target cells expressing HLA-A03:01 loaded with RAS G12V peptide or KRAS wildtype peptide.

[0058] FIG.7 shows ECso measured after co-culturing Jurkat cells transduced with RAS TCRs of interest (24-196.2, 24-197, 24-198, 24-199, 24-200, 24-201, 24-202, 24-203, 24-204, 24-205, 24-206, 24-207, 24-208, 24-209, 24-210.1, 24-211, 24-212, 24-213, 24-246, 24-247, 24-248, 24-249.1, 24-250) with target cells expressing HLA-C01:02 loaded with RAS G12V peptide.

[0059] FIG. 8 shows percent lysis of SW620 (left) and Panc03.27 (middle) upon co-culturing with G12V / C*01:02 specific TCR T-cells expressing benchmark TCR (NCI-4385), TCR (24-246), or irrelevant TCR. FIG. 8 also shows IFNy measurement (right) of supernatant collected from Panc03.27 co-cultured with G12V / C*01:02 specific TCR T-cells expressing benchmark TCR, TCR (24-246), or irrelevant TCR.DETAILED DESCRIPTION

[0060] 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, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 20%, up to 10%, up to 5%, or 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. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0061] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. The details of one or more particular embodiments are set forth in the description below.I. Definitions

[0062] Unless otherwise stated, the term “TCR” should be understood to encompass full TCRs as well as antigen-binding portions or antigen-binding fragments (also called MHC -peptide binding fragments) thereof. In some embodiments, the TCR is an intact or full-length TCR. In some embodiments, the TCR is an antigen-binding portion that is less than a full-length TCR but that binds to a specific antigenic peptide bound to (e.g., in the context of) an MHC molecule, e.g., an MHC-peptide complex. In some cases, an antigen-binding portion or fragment of a TCR can contain only a portion of the structural domains of a full-length or intact TCR, but yet is able to bind the epitope (e.g., MHC-peptide complex) to which the full TCR binds. In some cases, an antigen-binding portion or fragment of a TCR contains the variable domains of a TCR, such as variable a chain and variable [3 chain of a TCR, sufficient to form a binding site for binding to a specific MHC-peptide complex, such as generally where each chain contains threeWSGR Docket No. 50401-811.601complementarity determining regions. Polypeptides or proteins having a binding domain which is an antigen-binding domain or is homologous to an antigen-binding domain are included. Complementarity determining region (CDR) grafted TCRs and other humanized TCRs (including CDR modifications and framework region modifications) are also contemplated by these terms. It should be noted that while reference may be made only to immunoglobulin chains (e.g. , heavy chains and lights chains), the disclosed invention can be applied to multiple other different types of paired sequences, e.g., T cell receptor chain pairs (TCRa and TCRP chains and TCRy and TCRS chains), and is not limited to immunoglobulins.

[0063] The terms “complementarity determining region,” and “CDR,” synonymous with “hypervariable region” or “HVR,” are known in the art to refer to non-contiguous sequences of amino acids within TCR variable regions, which confer specificity and / or binding affinity to an MHC-peptide complex. In general, there are three CDRs in each alpha chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each beta chain variable region (CDR-L1, CDR-L2, CDR-L3). “Framework regions” and “FR” are known in the art to refer to the non-CDR portions of the variable regions of the alpha and beta chains. In general, there are four FRs in each full-length alpha chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length beta chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4).

[0064] The term “variable region” or “variable domain” refers to the domain of a TCR alpha, beta, gamma, or delta chain, that is involved in binding the TCR to antigen-MHC complexes. The variable domains of the alpha chain and beta chain (Va and Vp, respectively), and the gamma chain and delta chain (Vy and VS, respectively) of a native TCR generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three CDRs. A single Va or VP domain, or Vy or VS domain, may be sufficient to confer binding specificity to a peptide-MHC complex.

[0065] Also provided herein are TCR fragments, including antigen-binding fragments. In some embodiments, the TCR is an antigen-binding portion thereof, such as a variant of a full-length TCR not containing the transmembrane and / or cytoplasmic region(s) thereof, which may be referred to as a full soluble TCR. In some embodiments, the TCR is a dimeric TCR (dTCR). In some embodiments, the TCR is a single-chain TCR (scTCR), such as a scTCR having a structure as described in PCT patent publication numbers W02003 / 020763, W02004 / 033685, or WO2011 / 044186. In certain embodiments, the TCR is a single-chain TCR fragment comprising an alpha chain variable region linked to a beta chain variable region, such as a scTv. In some embodiments, a scTv is also referred to as a scFv. A single-chain Tv or scTv refers in some aspects TCR fragments that comprise the variable alpha or gamma chain (Va or Vy) and variable beta or delta chain (VP or V5) domains of a TCR, wherein these domains are present in a single polypeptide chain. Generally, the Tv polypeptide further comprises a polypeptide linker between the Va and VP domains or Vy and V5 domains which enables the scTv to form the desired structure for antigen binding. A diabody refers in some aspects to TCR fragments with two antigen-binding sites, which fragments comprise a Va connected to a VP in the same polypeptide chain (Va-VP) or a Vy connected to a V5 in the same polypeptide chain (Vy-V5). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains ofWSGR Docket No. 50401-811.601another chain and create two antigen-binding sites. Exemplary diabodies are described more fully in, for example, EP404097 and WO93111161. Fv refers in some aspects to a TCR fragment which contains a complete peptide-MHC complex recognition and peptide-MHC complex binding site. This region consists of a dimer of one TCRa chain and one TCRP chain or one TCRy chain and one TCR5 chain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define a peptide-MHC complex binding site on the surface of the Va-Vp dimer or Vy-V5 dimer. Collectively, a combination of one or more of the CDRs from each of the Va-Vp chains or Vy-V5 chains confers peptide-MHC complex binding specificity to the TCR. For example, it would be understood that, for example, the CDRa3 and CDRP3 or CDRy3 and CDR53 could be sufficient to confer antigen-binding specificity to a TCR when transferred to Va and VP chains or Vy-V5 chains of a recipient selected TCR or antigen-binding fragment thereof and this combination of CDRs can be tested for binding, affinity, etc. Furthermore, although the two domains of a Tv fragment (Va and VP or Vy and V5 ), are coded for by separate genes, they can be joined using recombinant methods by a synthetic linker that enables them to be made as a single protein chain in which the Va and VP or Vy and V5 chain regions pair to form monovalent molecules (known as single chain Tv (scTv). Such scTvs are also intended to be encompassed within the peptide-MHC complex binding portion of a TCR.

[0066] A “bispecific TCR” refers in some aspects to a TCR that shows specificities to two different peptide-MHC complexes or two different types of peptide-MHC complexes. The terms as used herein specifically include, without limitation, TCRs which show binding specificity for a target peptide-MHC complex and to another peptide-MHC complex that facilitates delivery to a particular tissue. Similarly, multi-specific TCRs have two or more binding specificities. A linear TCR refers in some aspects to a pair of tandem Fd segments (e.g. , V a-Cai-V a-Cai) which form a pair of antigen binding regions. Linear TCRs can be bispecific or monospecific.

[0067] An “antigen-binding domain” refers in some aspects to one or more fragments of a TCR that retain the ability to specifically bind to a peptide-MHC complex. Non-limiting examples of TCR fragments included within such terms include, but are not limited to, (i) a Tab fragment, a monovalent fragment consisting of the Vp, Va, Cp and Ca domains; (ii) a T(ab’)2 fragment, a bivalent fragment containing two Tab fragments linked by a disulfide bridge at the hinge region; (iii) a Td fragment consisting of the Va and Cai domains; (iv) a Tv fragment containing the V and Va domains of a single arm of a TCR, including scTvs, (v) a dAb fragment (Ward et al., (1989) Nature 341:544546), which contains a Va domain; and (vi) an isolated CDR. Included in this definition are TCRs with a single alpha chain or a single beta chain.

[0068] Among the provided TCRs are humanized and human TCRs. A “humanized” TCR is a TCR in which all or substantially all CDR amino acid residues are derived from non-human CDRs and all or substantially all FR amino acid residues are derived from human FRs. A humanized TCR optionally may include at least a portion of a TCR constant region derived from a human TCR. A “humanized form” of a non-human TCR, refers to a variant of the non-human TCR that has undergone humanization, typically to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-humanWSGR Docket No. 50401-811.601TCR. In some embodiments, some FR residues in a humanized TCR are substituted with corresponding residues from a non-human TCR (e.g., the TCR from which the CDR residues are derived), e.g., to restore or improve TCR specificity or affinity. A “human TCR” is a TCR with an amino acid sequence corresponding to that of a TCR produced by a human or a human cell, or non-human source that utilizes human TCR repertoires or other human TCR-encoding sequences, including human TCR libraries. The term excludes humanized forms of non-human TCRs comprising non-human peptide-MHC complex binding regions, such as those in which all or substantially all CDRs are non-human. Human TCRs may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human TCRs or intact TCRs with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human TCR loci, which replace the endogenous TCR loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic animals, the endogenous TCR loci have generally been inactivated. Human TCRs also may be derived from human TCR libraries, including phage display and cell-free libraries, containing TCR-encoding sequences derived from a human repertoire.

[0069] The term “cancer neoantigen” or “neoantigen” or “neoepitope” can refer to antigens that are not encoded in a normal, non-mutated host genome. A neoantigen can relate to an antigen including one or more amino acid modifications compared to the parental antigen. For example, a neoantigen may be a tumor-associated neoantigen, wherein the term “tumor-associated neoantigen” can include a peptide or protein including amino acid modifications due to tumor-specific mutations. In some instances, a neoantigen represents either oncogenic viral proteins or abnormal proteins that arise as a consequence of somatic mutations. For example, a neoantigen can arise by the disruption of cellular mechanisms through the activity of viral proteins. Another example can be an exposure of a carcinogenic compound, which in some cases can lead to a somatic mutation. This somatic mutation can ultimately lead to the formation of a tumor / cancer. A neoantigen can be a class of tumor antigens which arise from tumor-specific changes in proteins. Neoantigens encompass, but are not limited to, tumor antigens which arise from, for example, a substitution in a protein sequence, a frame shift mutation, a fusion polypeptide, an in-frame deletion, an insertion, and expression of an endogenous retroviral polypeptide. A neoepitope can be an epitope that is not present in a reference, such as a non-diseased cell, e.g., a non-cancerous cell or a germline cell, but is found in a diseased cell, e.g., a cancer cell. This includes situations where a corresponding epitope is found in a normal non-diseased cell or a germline cell but, due to one or more mutations in a diseased cell, e.g., a cancer cell, the sequence of the epitope is changed so as to result in the neoepitope.

[0070] An “epitope” refers in some aspects to a portion of an antigen or other macromolecule capable of forming a binding interaction with the variable region binding pocket of a TCR. In some aspects, an epitope refers to a portion of a peptide-MHC complex capable of forming a binding interaction with the variable region binding pocket of a TCR. Such binding interactions can be manifested as an intermolecular contact with one or more amino acid residues of one or more CDRs. Peptide-MHC complex binding can involve, for example, a CDR3, a CDR3 pair, or in some instances, interactions of up to all six CDRs of the Va andWSGR Docket No. 50401-811.601VP chains or Vy or V5 chains. An epitope can be a linear peptide sequence (e.g., “continuous”) or can be composed of noncontiguous amino acid sequences (e.g., “conformational” or “discontinuous”). A TCR can recognize one or more amino acid sequences. Therefore, an epitope can define more than one distinct amino acid sequence. In some aspects, a TCR can recognize one or more amino acid sequences or epitopes in the context of an MHC. Epitopes recognized by TCRs can be determined by peptide mapping and sequence analysis techniques well known to one of skill in the art. Binding interactions are manifested as intermolecular contacts with one or more amino acid residues of a CDR. An epitope can refer to an antigenic determinant in a molecule such as an antigen, e.g., to a part in or fragment of the molecule that is recognized by the immune system, for example, that is recognized by a T cell, in particular when presented in the context of MHC molecules. An epitope of a protein such as a tumor antigen can comprise a continuous or discontinuous portion of the protein and can be between 5 and 100, 5 and 50, 8 and 30, or 10 and 25 amino acids in length, for example, the epitope may be 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 2021, 22, 23, 24 or 25 amino acids in length.

[0071] The term “binding” refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic and / or hydrogen-bond interactions under physiological conditions, and includes interactions such as salt bridges and water bridges, as well as any other conventional means of binding.

[0072] In some embodiments, reference to a TCR with “specific binding” refers to a situation in which a TCR will not show any significant binding to molecules other than the peptide-MHC complex containing the epitope recognized by the TCR. The term is also applicable where for example, an antigen binding domain is specific for a particular epitope which is carried by a number of peptide-MHC complexes, in which case the selected TCR or peptide-MHC complex binding fragment thereof carrying the peptide-MHC complex binding domain will be able to bind to the various peptide-MHC complexes carrying the epitope. The terms “preferentially binds” or “specifically binds” mean that the TCRs or fragments thereof bind to an epitope with greater affinity than it binds unrelated amino acid sequences, and, if cross-reactive to other polypeptides containing the epitope, are not toxic at the levels at which they are formulated for administration to human use. In one aspect, such affinity is at least 1-fold greater, at least 2-fold greater, at least 3 -fold greater, at least 4-fold greater, at least 5 -fold greater, at least 6-fold greater, at least 7-fold greater, at least 8-fold greater, at least 9-fold greater, 10-fold greater, at least 20-fold greater, at least 30-fold greater, at least 40-fold greater, at least 50-fold greater, at least 60-fold greater, at least 70-fold greater, at least 80-fold greater, at least 90-fold greater, at least 100-fold greater, or at least 1000-fold greater than the affinity of the TCR or fragment thereof for unrelated amino acid sequences.

[0073] The term “affinity” refers to a measure of the strength of binding between two members of a binding pair (e.g., a human leukocyte antigen (HLA)-binding peptide and a class I or II HLA, or a peptide-HLA complex and a T cell receptor (TCR)). Affinity can be expressed as an equilibrium constant of the reversible binding of two agents and can be expressed as KD,KA, Koff 0v Kon. Kn refers to the dissociation constant between two members of a binding pair and has units of molarity. K refers to the affinity constantWSGR Docket No. 50401-811.601between two members of a binding pair is the inverse of the dissociation constant. Affinity may be determined experimentally, for example by surface plasmon resonance (SPR) using commercially available Biacore SPR units. Kott refers to the off-rate constant of two members of a binding pair, (e.g., the off-rate constant of an HLA-binding peptide and a class I or II HLA, or a peptide-HLA complex and a TCR). Konrefers to the on-rate constant of two members of a binding pair, (e.g. , the on-rate constant of an HLA-binding peptide and a class I or II HLA, or a peptide-HLA complex and a TCR). Affinity of a binding protein to a ligand such as affinity of a TCR for an epitope can be, for example, from about 100 nanomolar (nM) to about 0.1 nM, from about 100 nM to about 1 picomolar (pM), or from about 100 nM to about 1 femtomolar (fM). The term “avidity” refers to the resistance of a complex of two or more agents to dissociation after dilution.

[0074] Throughout this disclosure, “binding data” results may be expressed in terms of an “IC50 ” Affinity may also be expressed as the inhibitory concentration 50 (IC50), or the concentration at which 50% of a first member of a binding pair (e.g., a peptide) is displaced. Likewise, In(ICso) refers to the natural log of the IC50. For example, an IC50 may be the concentration of a tested peptide in a binding assay at which 50% inhibition of binding of a labeled reference peptide is observed. Given the conditions in which the assays are run (e.g., limiting HLA protein concentrations and / or labeled reference peptide concentrations), these values can approximate Ab values. Assays for determining binding are well known in the art and are described in detail, for example, in PCT publications WO 94 / 20127 and WO 94 / 03205, and other publications such as Sidney et al., Current Protocols in Immunology 18.3.1 (1998); Sidney, et al., J. Immunol. 154:247 (1995); and Sette, et al., Mol. Immunol. 31:813 (1994). Alternatively, binding can be expressed relative to binding by a reference standard peptide. Binding can also be determined using other assay systems including those using: live cells (e.g., Ceppellini et al., Nature 339:392 (1989); Christnick et al., Nature 352:67 (1991); Busch et al., Int. Immunol. 2:443 (1990); Hill et al., J. Immunol. 147:189 (1991); del Guercio et al., J. Immunol. 154:685 (1995)), cell free systems using detergent lysates (e.g., Cerundolo et al., J. Immunol. 21:2069 (1991)), immobilized purified MHC (e.g., Hill et al., J. Immunol.152, 2890 (1994); Marshall et al., J. Immunol. 152:4946 (1994)), ELISA systems (e.g., Reay et al., EMBO J. 11:2829 (1992)), surface plasmon resonance (e.g., Khilko et al., J. Biol. Chem. 268: 15425 (1993)); high flux soluble phase assays (Hammer et al., J. Exp. Med. 180:2353 (1994)), and measurement of class I MHC stabilization or assembly (e.g., Ljunggren et al., Nature 346:476 (1990); Schumacher et al., Cell 62:563 (1990); Townsend et al., Cell 62:285 (1990); Parker et al., J. Immunol. 149:1896 (1992)).

[0075] The terms “major histocompatibility complex” and the abbreviation “MHC” can include MHC class I and MHC class II molecules and relate to a complex of genes which occurs in all vertebrates. MHC proteins or molecules can be important for signaling between lymphocytes and antigen presenting cells or diseased cells in immune reactions, wherein the MHC proteins or molecules bind peptides and present them for recognition by T cell receptors. The proteins encoded by the MHC can be expressed on the surface of cells, and display both self-antigens (peptide fragments from the cell itself) and non-self-antigens (e.g., fragments of invading microorganisms) to a T cell. The MHC region can be divided into three subgroups,WSGR Docket No. 50401-811.601class I, class II, and class III. MHC class I proteins can contain an a-chain and [32-microglobulin (not part of the MHC encoded by chromosome 15). They can present antigen fragments to cytotoxic T cells. MHC class II proteins can contain a- and [3-chains and they can present antigen fragments to T-helper cells. MHC class III region can encode for other immune components, such as complement components and cytokines. The MHC can be both polygenic (there are several MHC class I and MHC class II genes) and polymorphic (there are multiple alleles of each gene).

[0076] The term “haplotype” can refer to the human leukocyte antigen (HLA) alleles found on one chromosome and the proteins encoded thereby. Haplotype may also refer to the allele present at any one locus within the MHC. Each class of MHC is represented by several loci: e.g., HLA-A (Human Leukocyte Antigen-A). HLA-B, HLA-C, HLA-E, HLA-F, HLA-G, HLA-H, HLA-J, HLA-K, HLA-L, HLA-P and HLA-V for class I and HLA-DRA, HLA-DRB1-9, HLA-DQA1, HLA-DQB1, HLA-DPA1, HLA-DPB1, HLA-DPB2, HLA-DMA, HLA-DMB, HLA-DOA, and HLA-DOB for class II. The terms “HLA allele” and “MHC allele” are used interchangeably herein.

[0077] The terms “polynucleotide,” “nucleotide,” “nucleotide sequence,” “nucleic acid” and “oligonucleotide” are used interchangeably. They can refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three dimensional structure, and may perform any function, known or unknown. The following are nonlimiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. Polynucleotides can include nonstandard nucleotides, such as nucleotide analogs or modified nucleotides. In some embodiments, nonstandard nucleotides can stabilize hybrid formation. In some embodiments, nonstandard nucleotides can destabilize hybrid formation. In some embodiments, nonstandard nucleotides can enhance hybridization specificity. In some embodiments, nonstandard nucleotides can reduce hybridization specificity. Examples of nonstandard nucleotide modifications include 2’ O-Me, 2’ O-allyl, 2’ O-propargyl, 2’ O-alkyl, 2’ fluoro, 2’ arabino, 2’ xylo, 2’ fluoro arabino, phosphorothioate, phosphorodithioate, phosphoroamidates, 2’ Amino, 5-alkyl-substituted pyrimidine, 3’ deoxyguanosine, 5 -halo-substituted pyrimidine, alkyl-substituted purine, halo-substituted purine, bicyclic nucleotides, 2’MOE, PNA molecules, LNA-molecules, LNA-like molecules, diaminopurine, S2T, 5-fluorouracil, 5 -bromouracil, 5 -chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl)uracil, 5 -carboxymethylaminomethyl -2 -thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1 -methylinosine, 2,2-dimethylguanine, 2-m ethyladenine, 2-WSGR Docket No. 50401-811.601methylguanine, 3 -methylcytosine, 5-methylcytosine, N6-adenine, 7-methyl guanine, 5-methylaminomethyluracil, 5 -methoxyaminomethyl -2 -thiouracil, beta-D-mannosylqueosine, 5’-methoxy carboxymethyluracil, 5 -methoxyuracil, 2-methylthio-D46-isopentenyladenine, uracil-5 -oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5- methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5 -methyluracil, uracil-5 -oxyacetic acid methylester, uracil-5 -oxy acetic acid (v), 5 -methyl -2-thiouracil, 3-(3-amino-3-N-2- carboxypropyl) uracil, (acp3)w, 2,6-diaminopurine, and derivatives thereof. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component.

[0078] “Complementarity” can refer to the ability of a nucleic acid to form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types. A percent complementarity can indicate the percentage of residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary, respectively). “Perfectly complementary” can mean that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. “Substantially complementary” refers to a degree of complementarity that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% over a region of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, or more nucleotides, or can refer to two nucleic acids that hybridize under stringent conditions. Sequence identity, such as for the purpose of assessing percent complementarity, may be measured by any suitable alignment algorithm, including but not limited to the Needleman-Wunsch algorithm (e.g., the EMBOSS Needle aligner available at www.ebi.ac.uk / Tools / psa / emboss_needle / nucleotide.html, optionally with default settings), the BLAST algorithm (see e.g., the BLAST alignment tool available at blast.ncbi.nlm.nih.gov / Blast.cgi, optionally with default settings), or the Smith-Waterman algorithm. Optimal alignment may be assessed using any suitable parameters of a chosen algorithm, including default parameters.

[0079] The terms “polypeptide” and “protein” are used interchangeably to refer to a polymer of amino acid residues, and are not limited to a minimum length. Lor example, a polypeptide can comprise at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 peptides or amino acids. Examples of polypeptides include, but are not limited to, amino acid chains, proteins, peptides, hormones, polypeptide saccharides, lipids, glycolipids, phospholipids, antibodies, enzymes, kinases, receptors, transcription factors, and ligands. Polypeptides, including the provided TCRs and TCR chains and other peptides, e.g., linkers and binding peptides, may include amino acid residues including natural and / or non-natural amino acid residues. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. In some aspects, the polypeptides may contain modifications with respect to a native or natural sequence, as long as the protein maintains the desiredWSGR Docket No. 50401-811.601activity. These modifications may be deliberate, as through site-directed mutagenesis, or may be accidental, such as through mutations of hosts which produce the proteins or errors due to PCR amplification.

[0080] As used herein, the twenty conventional amino acids and their abbreviations known to one skilled in the art follow conventional usage. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as a-, a-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for polypeptides of the present invention. Examples of unconventional amino acids include: 4-hydroxyproline, y-carboxyglutamate, 8-N,N,N-trimethyllysine, e-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5 -hydroxylysine, o-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left hand direction is the amino terminal direction and the right hand direction is the carboxy-terminal direction, in accordance with standard usage and convention. Percent (%) sequence identity with respect to a reference polypeptide sequence (or nucleic acid sequence) is the percentage of amino acid residues (or nucleotides in case of nucleic acid sequence) in a candidate sequence that are identical with the amino acid residues (or nucleotides) in the reference polypeptide sequence (or nucleic acid sequence), after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Lor purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Lrancisco, Calif., or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary. In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y, where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specificallyWSGR Docket No. 50401-811.601stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0081] A “germline sequence” refers to a genetic sequence from the haploid gametes and those diploid cells from which they are formed. Germline DNA contains multiple gene segments that encode a single TCRa or TCR[3 chain, or a single TCRy or TCR5 chain. These gene segments are carried in the germ cells but cannot be transcribed and translated until they are arranged into functional genes. During T cell differentiation in the bone marrow, these gene segments are randomly shuffled by a dynamic genetic system capable of generating more than 108specificities.

[0082] Inhibition, “treatment” and “treating” are used interchangeably and refer to, for example, stasis of symptoms, prolongation of survival, partial or full amelioration of symptoms, and partial or full eradication of a condition, disease or disorder associated with excess levels of protein or correlated with protein activity. For example, treatment of cancer includes, but is not limited to, stasis, partial or total elimination of a cancerous growth or tumor. Treatment or partial elimination includes, for example, a fold reduction in growth or tumor size and / or volume such as about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 10-fold, about 20-fold, about 50-fold, or any fold reduction in between. Similarly, treatment or partial elimination can include a percent reduction in growth or tumor size and / or volume of about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or any percentage reduction in between. Prevention refers to prophylaxis, prevention of onset of symptoms, prevention of progression of a disease or disorder associated with excess levels of protein or correlated with protein activity.

[0083] A “subject,” “individual,” “host” or “patient” refers to living organisms such as mammals. Examples of subjects and hosts include, but are not limited to, horses, cows, camels, sheep, pigs, goats, dogs, cats, rabbits, guinea pigs, rats, mice (e.g., humanized mice), gerbils, non-human primates (e.g., macaques), humans and the like, non-mammals, including, e.g., non-mammalian vertebrates, such as birds (e.g., chickens or ducks) fish (e.g., sharks) or frogs (e.g, Xenopus), and non-mammalian invertebrates, as well as transgenic species thereof. In certain aspects, a subject refers to a single organism (e.g., human). In certain aspects, or a group of individuals composing a small cohort having either a common immune factor to study and / or disease, and / or a cohort of individuals without the disease (e.g., negative / normal control) are provided. A subject from whom samples are obtained can either be inflicted with a disease and / or disorder (e.g., one or more allergies, infections, cancers or autoimmune disorders or the like) and can be compared against a negative control subject which is not affected by the disease.

[0084] A “kit” refers to a delivery system for delivering materials or reagents for carrying out a method disclosed herein. In some embodiments, kits include systems that allow for the storage, transport, or delivery of reaction reagents (e.g., probes, enzymes, etc. in the appropriate containers) and / or supporting materials (e.g. , buffers, written instructions for performing the assay etc.) from one location to another. For example, kits include one or more enclosures (e.g., boxes) containing the relevant reaction reagents and / or supporting materials. Such contents may be delivered to the intended recipient together or separately. For example, a first container may contain an enzyme for use in an assay, while a second container contains aWSGR Docket No. 50401-811.601plurality of primers. A packaging material refers to a physical structure housing the components of the kit. The packaging material can maintain the components sterilely and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampules, etc.). The label or packaging insert can include appropriate written instructions. Kits, therefore, can additionally include labels or instructions for using the kit components in any method of the invention. A kit can include a compound in a pack, or dispenser together with instructions for administering the compound in a method described herein.

[0085] The term “resistance mutation” refers to a mutation in a gene that allows the gene or the host cell containing the gene to become resistant to treatment with a drug. For example, BTK C481S mutation is a resistance mutation which can confer ibrutinib resistance.II. Overview

[0086] The present disclosure provides T cell receptors (TCRs) against neoantigens, isolated nucleic acid molecules encoding TCRs against neoantigens, T cells expressing said TCRs, and pharmaceutical compositions for use in the treatment of diseases involving malignant cells expressing said neoantigens.

[0087] In yet another aspect, the present disclosure provides a host cell comprising the nucleic acid encoding a TCR against a neoantigen provided herein, a vector containing the nucleic acid sequence, or a protein encoded by the nucleic acid provided herein. In some embodiments, the host cell is a CD4+T cell. In some embodiments, the host cell is a CD8+T cell. The host cell may be a natural killer (NK) cell or a B cell. The host cell may be an immortalized cell line.

[0088] In yet another aspect, the present disclosure provides pharmaceutical compositions comprising the nucleic acid encoding a TCR against a neoantigen provided herein, a host cell comprising the nucleic acid encoding a TCR against a neoantigen provided herein, a vector containing the nucleic acid sequence, or a protein encoded by the nucleic acid provided herein. In some embodiments, provided herein also comprises a method of using the pharmaceutical compositions disclosed herein.

[0089] Also provided herein in an additional aspect is a method of treating a subject with a disease or condition, comprising administering to the subject a pharmaceutical composition disclosed herein. In some embodiments, the subject has cancer.III. T Cell Receptors (TCRs)

[0090] The ability of T cells to recognize antigens associated with various cancers or infectious organisms is conferred by its TCR, which is made up of both an alpha (a) chain and a beta ( ) chain or a gamma (y) and a delta (5) chain. The proteins which make up these chains are encoded by DNA, which employs a unique mechanism for generating the tremendous diversity of the TCR. This multi-subunit immune recognition receptor associates with the CD3 complex and binds peptides presented by the MHC class I and II proteins on the surface of antigen-presenting cells (APCs). Binding of a TCR to the antigenic peptide on the APC is a central event in T cell activation, which occurs at an immunological synapse at the point of contact between the T cell and the APC.WSGR Docket No. 50401-811.601

[0091] Each TCR contains variable complementarity determining regions (CDRs), as well as framework regions (FRs) and a constant region. The constant region can comprise an a chain constant and a [3 chain constant. The a chain constant and the [3 chain constant can be derived from mouse. For example, mouse TCR a chain constant can be Uniprot accession P01849, and mouse [3 chain constant can be Uniprot accession P01852 or P01851. In some cases, the a chain constant and the [3 chain constant can be derived from human. For example, human TCR a chain constant can be Uniprot accession P01848, and human [3 chain constant can be Uniprot accession P01850 or A0A5B9. The amino acid sequence of the third complementarity-determining region (CDR3) loops of the a and [3 chain variable domains largely determines the sequence diversity of a[3 T cells arising from recombination between variable (V[3), diversity (D[3), and joining (J[3) gene segments in the [3 chain locus, and between analogous Va and Ja gene segments in the a chain locus, respectively. The existence of multiple such gene segments in the TCR a and [3 chain loci allows for a large number of distinct CDR3 sequences to be encoded. Independent addition and deletion of nucleotides at the V[3-D[3, D[3-J[3, and Va-Ja junctions during the process of TCR gene rearrangement further increases CDR3 sequence diversity. In this respect, immunocompetence is reflected in the diversity of TCRs. The y5 TCR is distinctive from the a[3 TCR in that it encodes a receptor that interacts closely with the innate immune system. TCRyS, is expressed early in development, has specialized anatomical distribution, has unique pathogen and small-molecule specificities, and has a broad spectrum of innate and adaptive cellular interactions. Early in ontogeny, as the restricted subsets of TCRyS cells populate various tissues prenatally, a biased pattern of TCRy V and J segment expression is established.

[0092] In some embodiments, the TCR disclosed herein is a soluble TCR. The TCR may not comprise a constant domain. The TCR may be a single chain soluble TCR. The single chain soluble TCR can comprise the TCR alpha variable domain linked to the TCR beta variable domain via a linker. The TCR may be a full-length TCR. The TCR may be the antigen-binding fragment of a full-length TCR. In some embodiments, the TCR disclosed herein is a transmembrane protein.

[0093] The TCRs provided herein target may be engineered TCRs, for example, chimeric antigen receptors (CARs). CARs can be composed of three regions: an ectodomain, a transmembrane domain and an endodomain.

[0094] An ectodomain can be the region of the receptor that is exposed to the extracellular fluid and can consist of an antigen recognition region. In some embodiments, an ectodomain further comprises and a spacer. In some embodiments, an ectodomain further comprises and a signal peptide. A signal peptide can direct the nascent protein into the endoplasmic reticulum. A signal protein in a CAR may be a single -chain variable fragment (scFv). A fusion protein may be a protein that is formed by merging two or more genes that code originally for different proteins but when they are translated in the cell, the translation produces one or more polypeptides with functional properties derived for each of the original genes. A scFv is a chimeric protein made up of a light chain domain and heavy chain variable domain connected with a short linker peptide. The linker may comprise hydrophilic residues with stretches of glycine and / or serine residues. The linker may comprise stretches of glutamate and lysine residues, which can improve solubility.WSGR Docket No. 50401-811.601

[0095] A transmembrane domain can be a hydrophobic domain that spans the membrane. In some embodiments, a transmembrane domain comprises an alpha-helical domain. A transmembrane domain may be functional for the stability of the receptor as a whole. In some embodiments, a transmembrane domain comprises a transmembrane domain from the most membrane proximal component of an endodomain. In some embodiments, a transmembrane domain comprises a CD3-zeta transmembrane domain. In some embodiments, a transmembrane domain allows for incorporation of an artificial TCR into a native TCR complex. In some embodiments, a transmembrane domain comprises a CD28 transmembrane domain.

[0096] An endodomain can be a functional intracellular portion of a receptor, such as a TCR or CAR. After antigen recognition, receptors cluster and a signal may be transmitted to the cell. In some embodiments, an endodomain comprises aCD3-zeta intracellular domain. In some embodiments, an endodomain comprises at least one ITAM. In some embodiments, an endodomain comprises at least 3 or at least 3 ITAMs. In some embodiments, an endodomain comprises a CD28 intracellular domain. In some embodiments, an endodomain comprises an 0X40 intracellular domain. In some embodiments, an endodomain comprises a chimeric intracellular domain. For example, an endodomain can comprises aCD28 intracellular domain, an 0X40 intracellular domain and a CD3-zeta intracellular domain.

[0097] Provided herein is a T cell receptor (TCR) or a recombinant nucleic acid encoding the TCR disclosed herein. In some embodiments, the TCR comprises a TCR beta chain construct comprising a complementarity determining region 3 (CDR3), a complementarity determining region 2 (CDR2), or a complementarity determining region 1 (CDR1). In some embodiments, the TCR comprises a TCR alpha chain construct comprising a complementarity determining region 3 (CDR3), a complementarity determining region 2 (CDR2), or a complementarity determining region 1 (CDR1). Table 1 provides example RAS TCR sequences.

[0098] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 7. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 7. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 6. In someWSGR Docket No. 50401-811.601embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 8 or 39. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 8 or 39. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 3. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 4 or 38. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 4 or 38. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12D mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C08:02 allele.

[0099] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 17. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 17. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 15. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 15. In some embodiments,WSGR Docket No. 50401-811.601the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 18 or 41. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 18 or 41. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 13. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 13. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 14 or 40. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 14 or 40. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12D mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-A11:01 allele.

[0100] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 26. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 26. In some embodiments, the TCRWSGR Docket No. 50401-811.601beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 24. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 24. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 27 or 43. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 27 or 43. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 22. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 22. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 23 or 42. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 23 or 42. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12D mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-A11:01 allele.WSGR Docket No. 50401-811.601

[0101] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 34. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 34. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 33. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 33. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 35 or 45. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 35 or 45. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 30. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 31 or 44. In someWSGR Docket No. 50401-811.601embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 31 or 44. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-A03:01 allele.

[0102] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 59. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 59. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 60 or 61. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 60 or 61. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 54. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 54. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 52. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 52. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 53. In someWSGR Docket No. 50401-811.601embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 53. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 55 or 56. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 55 or 56. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12D mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C08:02 allele.

[0103] The EC50 or avidity of a RAS TCR described herein can be at most 400 nM, at most 300 nM, at most 200 nM, at most 100 nM, at most 50 nM, at most 25 nM, at most 15 nM, at most 10 nM, at most 5 nM, or less. In some cases, the EC50 can be at least .5 nM, at least 1 nM, at least 5 nM, at least 10 nM, at least 15 nM, at least 20 nM, at least 25 nM, at least 50 nM, or at least 100 nM. The ECso or avidity can be measured by T cell activation of the T cells transduced with the RAS TCR described herein incubated with the target cells expressing an HLA loaded with a RAS peptide at various peptide concentrations.

[0104] The percentage of cell lysis induced by a RAS TCR described herein can be at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In some cases, the percentage of cell lysis induced by a RAS TCR described herein can be 100%. Cell lysis can be measured by the percentage of target cells lysed upon incubation with T cells transduced with the RAS TCR described herein. Target cell lysis can be measured to assess cytotoxicity effect of a RAS TCR described herein.

[0105] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 69. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 69. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, the TCR beta chain construct further comprises a complementarity determiningWSGR Docket No. 50401-811.601region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 70 or 71. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 70 or 71. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 64. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 64. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 62. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 62. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 63. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 63. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 65 or 66. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 65 or 66. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0106] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 77. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 77. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1WSGR Docket No. 50401-811.601(CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 78 or 79. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 78 or 79. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 74. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 74. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 73. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 73. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 29. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 75 or 76. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 75 or 76. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0107] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 87. In someWSGR Docket No. 50401-811.601embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 87. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 85. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 85. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 86. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 86. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 88 or 89. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 88 or 89. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 82. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 82. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 80. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 80. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 81. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 81. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 83 or 84. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 83 or 84. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation.WSGR Docket No. 50401-811.601In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C01:02 allele.

[0108] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 97. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 97. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 95. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 95. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 96. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 96. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 98 or 99. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 98 or 99. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 92. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%,WSGR Docket No. 50401-811.601at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 93 or 94. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0109] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 105. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 105. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 103. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 103. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 104. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 104. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 106 or 107. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 106 or 107. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 100. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 100. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 52. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 52. In some embodiments, the TCR alpha chain construct further comprises aWSGR Docket No. 50401-811.601complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 53. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 53. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 101 or 102. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 101 or 102. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0110] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 109. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 109. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 108. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 108. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 110 or 111. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 100 or 111. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 92. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the TCR alpha chain constructWSGR Docket No. 50401-811.601further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 93 or 94. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0111] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 117. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 117. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 118 or 119. In some embodiments, the TCR beta chain construct comprises a variable region having an aminoWSGR Docket No. 50401-811.601acid sequence set forth in SEQ ID NOs: 118 or 119. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 114. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 114. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 114. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 114. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 115 or 116. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 115 or 116. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0112] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 127. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 127. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 125. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 125. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 126. In some embodiments, the TCR beta chain construct further comprises aWSGR Docket No. 50401-811.601complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 126. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 128 or 129. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 128 or 129. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 122. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 122. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 120. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 120. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 121. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 121. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 123 or 124. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 123 or 124. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0113] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 135. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 135. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 133. In someWSGR Docket No. 50401-811.601embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 133. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 134. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 134. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 136 or 137. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 136 or 137. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 130. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 130. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 131 or 132. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 131 or 132. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0114] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein theWSGR Docket No. 50401-811.601CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 143. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 143. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 125. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 125. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 126. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 126. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 144 or 145. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 144 or 145. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 140. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 140. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 138. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 138. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 139. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 139. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 141 or 142. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs:WSGR Docket No. 50401-811.601141 or 142. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C01:02 allele.

[0115] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 151. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 151. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 68. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 152 or 153. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 152 or 153. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 148. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 148. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 146. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 146. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 147. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2WSGR Docket No. 50401-811.601(CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 147. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 149 or 150. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 149 or 150. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0116] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 159. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 159. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 157. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 157. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 158. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 158. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 160 or 161. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 160 or 161. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 154. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 154. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 138. In some embodiments, the TCR alpha chain construct further comprises aWSGR Docket No. 50401-811.601complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 138. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 139. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 139. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 155 or 156. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 155 or 156. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0117] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 168. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 168. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 168. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 168. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 169 or 170. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 169 or 170. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identityWSGR Docket No. 50401-811.601to an amino acid sequence forth in SEQ ID NO: 164. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 164. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 162. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 162. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 163. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 163. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 165 or 166. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 165 or 166. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0118] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 176. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 176. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, atWSGR Docket No. 50401-811.601least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 177 or 178. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 177 or 178. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 173. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 173. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 171. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 171. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 172. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 172. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 174 or 175. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 174 or 175. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C01 : 02 allele.

[0119] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 184. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 184. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments,WSGR Docket No. 50401-811.601the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 185 or 186. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 185 or 186. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 181. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 181. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 179. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 179. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 180. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 180. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 182 or 183. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 182 or 183. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0120] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 190. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 190. In some embodiments, the TCRWSGR Docket No. 50401-811.601beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 191 or 192. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 91 or 192. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 187. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 187. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 21. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 188 or 189. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 188 or 189. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.WSGR Docket No. 50401-811.601

[0121] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 198. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 198. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 196. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 196. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 197. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 197. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 199 or 200. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 199 or 200. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 193. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 193. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequenceWSGR Docket No. 50401-811.601identity to an amino acid sequence set forth in SEQ ID NOs: 194 or 195. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 194 or 195. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0122] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 204. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 204. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 205 or 206. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 205 or 206. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 201. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 201. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 138. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 138. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%,WSGR Docket No. 50401-811.601at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 139. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 139. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 202 or 203. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 202 or 203. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C01 : 02 allele.

[0123] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 210. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 210. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 211 or 212. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 211 or 212. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 207. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 207. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), whereinWSGR Docket No. 50401-811.601the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 113. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 113. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 208 or 209. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 208 or 209. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C01 : 02 allele.

[0124] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 216. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 216. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 133. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 133. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 134. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 134. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 217 or 218. In some embodiments, the TCR beta chain constructWSGR Docket No. 50401-811.601comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 217 or 218. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 213. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 213. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 62. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 62. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 63. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 63. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 214 or 215. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 214 or 215. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0125] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 222. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 222. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 133. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 133. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth inWSGR Docket No. 50401-811.601SEQ ID NO: 134. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 134. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 223 or 224. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 223 or 224. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 219. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 219. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 62. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 62. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 63. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 63. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 220 or 221. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 220 or 221. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C0E02 allele.

[0126] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 228. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 228. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at leastWSGR Docket No. 50401-811.60195% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 229 or 230. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 229 or 230. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 225. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 225. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 179. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 179. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 180. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 180. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 226 or 227. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 226 or 227. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-C01 : 02 allele.WSGR Docket No. 50401-811.601

[0127] In some embodiments, a TCR beta chain construct comprises a complementarity determining region 3 (CDR3). In some embodiments, the TCR beta chain construct comprises a CDR3, wherein the CDR3 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence of SEQ ID NO: 234. In some embodiments, the CDR3 has an amino acid sequence of SEQ ID NO: 234. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the TCR beta chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 235 or 236. In some embodiments, the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 235 or 236. In some embodiments, a TCR alpha chain construct comprises a CDR3 having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence forth in SEQ ID NO: 231. In some embodiments, the TCR alpha chain construct comprises a CDR3, wherein the CDR3 has an amino acid sequence set forth in SEQ ID NO: 231. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 179. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 179. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 180. In some embodiments, the TCR alpha chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 180. In some embodiments, the TCR alpha chain construct comprises a variable region having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to anWSGR Docket No. 50401-811.601amino acid sequence set forth in SEQ ID NOs: 232 or 233. In some embodiments, the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 232 or 233. In some embodiments, the TCR binds to a mutated epitope from human RAS. In some embodiments, the mutated epitope from human RAS is characterized by a G12V mutation. In some embodiments, the TCR binds to a mutated epitope from human RAS in complex with a human MHC encoded by an HLA-CO 1 : 02 allele.

[0128] The TCRs identified using the methods described herein can be recombinantly generated or expressed as soluble TCRs or membrane-bound TCRs expressed on cell surface. In some cases, the TCRs described herein can be soluble TCRs. In some cases, the TCRs described herein may not comprise a constant domain. In some cases, the TCRs described herein can be expressed on cell surface. The TCRs described herein can comprise human constant domains or murine constant domains. Table 2 provides sequences of constant domains.

[0129] In some embodiments, the TCRs are generated using a mouse T cell receptor alpha constant region (TRAC), having the following sequence for the mouse TRAC region: XIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKTVLDMKAMDSKSNGAIA WSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAGFNLL MTLRLWSS; (SEQ ID NO: 47); wherein, X is D, N, or absent.

[0130] In some embodiments, a TCR thus generated comprises a sequence that has a mouse TCR alpha constant chain having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the mouse TRAC sequence: XIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKTVLDMKAMDSKSNGAIA WSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAGFNLL MTLRLWSS; (SEQ ID NO: 47); wherein, X is D, N, or absent.

[0131] In one embodiment, a TCR thus generated comprises a sequence that has a mouse TCR alpha constant chain having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to the mouse TRAC sequence: XIQNPEPAVYQLKDPRSQDSTLCLFTDFDSQINVPKTMESGTFITDKTVLDMKAMDSKSNGAIA WSNQTSFTCQDIFKETNATYPSSDVPCDATLTEKSFETDMNLNFQNLSVMGLRILLLKVAGFNLL MTLRLWSS; (SEQ ID NO: 47); wherein, X is D, N, or absent.

[0132] In some embodiments, the TCRs are generated using a mouse T cell receptor beta constant region (TRBC1), having the following sequence for the mouse TRBC1 region:X1DLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVX2TDPQA YKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRA DCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS; (SEQ ID NO: 50); wherein, XI is K, E, or absent; X2 is S or C.WSGR Docket No. 50401-811.601

[0133] In some embodiments, a TCR thus generated comprises a sequence of a mouse T cell receptor beta constant region (TRBC1), having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the mouse TRBC1 sequence:X1DLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVX2TDPQA YKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRA DCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS; (SEQ ID NO: 50); wherein, XI is K, E, or absent; X2 is S or C.

[0134] In some embodiments, a TCR thus generated comprises a sequence of a mouse T cell receptor beta constant region (TRBC1), having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to the mouse TRBC1 sequence:X1DLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVX2TDPQA YKESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRA DCGITSASYQQGVLSATILYEILLGKATLYAVLVSTLVVMAMVKRKNS; (SEQ ID NO: 50); wherein, XI is K, E, or absent; X2 is S or C.

[0135] In some embodiments, the TCRs are generated using a mouse T cell receptor beta constant region (TRBC2), having the following sequence for the mouse TRBC2 region:XDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVSTDPQAY KESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRAD CGITSASYHQGVLSATILYEILLGKATLYAVLVSGLVLMAMVKKKNS; (SEQ ID NO: 51); wherein, X is K, E, or absent.

[0136] In some embodiments, a TCR thus generated comprises a sequence of a mouse T cell receptor beta constant region (TRBC2), having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the mouse TRBC2 sequence:XDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVSTDPQAY KESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRAD CGITSASYHQGVLSATILYEILLGKATLYAVLVSGLVLMAMVKKKNS; (SEQ ID NO: 51); wherein, X is K, E, or absent.

[0137] In some embodiments, a TCR thus generated comprises a sequence of a mouse T cell receptor beta constant region (TRBC2), having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to the mouse TRBC2 sequence:XDLRNVTPPKVSLFEPSKAEIANKQKATLVCLARGFFPDHVELSWWVNGKEVHSGVSTDPQAY KESNYSYCLSSRLRVSATFWHNPRNHFRCQVQFHGLSEEDKWPEGSPKPVTQNISAEAWGRAD CGITSASYHQGVLSATILYEILLGKATLYAVLVSGLVLMAMVKKKNS; (SEQ ID NO: 51); wherein, X is K, E, or absent.WSGR Docket No. 50401-811.601

[0138] In some embodiments, the TCRs are generated using a human TCR alpha chain constant region (TRAC), having the following sequence for the human TRAC sequence:XIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVA WSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFN LLMTLRLWSS; (SEQ ID NO: 46); wherein, X is D, N, or absent.

[0139] In some embodiments, a TCR thus generated comprises a sequence of a human TCR alpha chain constant region (TRAC), having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the human TRAC sequence:XIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVA WSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFN LLMTLRLWSS; (SEQ ID NO: 46); wherein, X is D, N, or absent.

[0140] In some embodiments, a TCR thus generated comprises a sequence of a human TCR alpha chain constant region (TRAC), having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to the human TRAC sequence:XIQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNSAVA WSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFRILLLKVAGFN LLMTLRLWSS; (SEQ ID NO: 46); wherein, X is D, N, or absent.

[0141] In some embodiments, the TCRs are generated using a human TCR beta chain constant region (TRBC1), having the following sequence for the human TRBC1 sequence:XDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLK EQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWG RADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF; (SEQ ID NO: 48); wherein, X is K, E, or absent.

[0142] In some embodiments, a TCR thus generated comprises a sequence of a human TCR beta chain constant region (TRBC1), having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the human TRBC1 sequence:XDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLK EQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWG RADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF; (SEQ ID NO: 48); wherein, X is K, E, or absent.

[0143] In some embodiments, a TCR thus generated comprises a sequence of a human TCR beta chain constant region (TRBC1), having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to the human TRBC1 sequence:XDLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQPLK EQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWGWSGR Docket No. 50401-811.601 RADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF; (SEQ ID NO: 48); wherein, X is K, E, or absent.

[0144] In some embodiments, the TCRs are generated using a human TCR beta chain constant region (TRBC2), having the following sequence for the human TRBC2 sequence:XDLKNVFPPKVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLK EQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWG RADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG; (SEQ ID NO: 49); wherein, X is K, E, or absent.

[0145] In some embodiments, a TCR thus generated comprises a sequence of a human TCR beta chain constant region (TRBC2), having at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the human TRBC2 sequence:XDLKNVFPPKVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLK EQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWG RADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG; (SEQ ID NO: 49); wherein, X is K, E, or absent.

[0146] In some embodiments, the TCRs are generated using a human TCR beta chain constant region (TRBC2), having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity the human TRBC2 sequence:XDLKNVFPPKVAVFEPSEAEISHTQKATLVCLATGFYPDHVELSWWVNGKEVHSGVSTDPQPLK EQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIVSAEAWG RADCGFTSESYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDSRG; (SEQ ID NO: 49); wherein, X is K, E, or absent.

[0147] The recombinant nucleic acid sequences encoding any TCRs described herein may encode any suitable signal peptides.

[0148] In some embodiments, the TCR specifically binds to the mutated epitope with a ECso of at most 1000 nM.

[0149] In various embodiments, the nucleic acid sequence encoding a TCR is codon optimized.

[0150] In various embodiments, the TCR binds to an MHCRAS peptide complex. Mutations in any one of the three ras genes, H-ras. K-ras and -ras are one of the most common events in human tumorigenesis. About 30% of all human tumors are found to carry at least one mutation in any of the canonical ras genes. Ras mutations are evident in, for example, adenocarcinoma of the biliary tract, transitional cell carcinoma of the bladder, breast carcinoma, cervical adenocarcinoma, colon adenocarcinoma, colon adenoma, neuroblastoma (autonomic ganglia), acute myeloid leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, acute lymphoblastic leukemia, Burkitt’s lymphoma, Hodgkin’s lymphoma, plasma cell myeloma, hepatocellular carcinoma, large cell carcinoma, non-small cell carcinoma, ductal carcinoma, endocrine tumor, prostrate adenocarcinoma, basal cellWSGR Docket No. 50401-811.601carcinoma, squamous cell carcinoma, malignant melanoma, angiosarcoma, leiomyosarcoma, liposarcoma, rhabdomyosarcoma, myxoma, malignant fibrous histiocytoma, pleomorphic sarcoma, germinoma, seminoma, anaplastic carcinoma, follicular carcinoma, papillary carcinoma and Hurthle cell carcinoma. Ras mutations are found in cancers affecting many tissues and organs of the body, for example, lung, liver, breast, bladder, colon, cervix, pancreas, prostate gland, stomach, thyroid, testis, soft tissue, skin, and blood.

[0151] In various embodiments, the TCR binds to an MHC:RAS peptide complex, wherein the RAS peptide comprises a G12D mutation. In various embodiments, the TCR binds to an MHC:RAS peptide complex, wherein the RAS peptide comprises a G12V mutation. In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the RAS peptide comprises a sequence of gaDgvgksa (SEQ ID NO: 9), orgaDgvgksal (SEQ ID NO: 10). In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the RAS peptide comprises a sequence of vvvgaDgvgk (SEQ ID NO: 19). In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the RAS peptide comprises a sequence of vvgaVgvgk (SEQ ID NO: 36), or wvgaVgvgk (SEQ ID NO: 37). In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the RAS peptide comprises a sequence of aVgvgksal (SEQ ID NO: 72).

[0152] In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the human MHC is encoded by an HLA-C08:02 allele. In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the human MHC is encoded by an HLA-A11 :01 allele. In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the human MHC is encoded by an HLA-A03:01 allele . In various embodiments, the TCR binds to an MHC : RAS peptide complex, wherein the human MHC is encoded by an HLA-C0E02 allele.

[0153] In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the human MHC is encoded by an HLA-C08:02 allele and wherein the RAS peptide comprises a sequence of gaDgvgksa (SEQ ID NO: 9) or gaDgvgksal (SEQ ID NO: 10). In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the human MHC is encoded by an HLA-All:01 allele and wherein the RAS peptide comprises a sequence of vvvgaDgvgk (SEQ ID NO: 19). In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the human MHC is encoded by an HLA-A03:01 allele and wherein the RAS peptide comprises a sequence of vvgaVgvgk (SEQ ID NO: 36) or wvgaVgvgk (SEQ ID NO: 37). In various embodiments, the TCR binds to an MHCRAS peptide complex, wherein the human MHC is encoded by an HLA- CO 1:02 allele and wherein the RAS peptide comprises a sequence of aVgvgksal (SEQ ID NO: 72).

[0154] In some embodiments, one TCR as disclosed herein, exhibits a specific binding affinity to an epitope peptide containing a point mutation found in cancer when the epitope peptide is in complex with an MHC encoded by the specific allele; and additionally the TCR may exhibit a different binding affinity to another epitope peptide containing a different point mutation of the same cancer protein, when the epitope peptide is in complex with an MHC encoded by the specific allele, but do not exhibit binding affinity to the WT peptide which does not contain any mutation.WSGR Docket No. 50401-811.601IV. T cells

[0155] Provided herein is a cell comprising a recombinant nucleic acid encoding a TCR disclosed herein. Also provided herein is a cell comprising a TCR encoded by a recombinant nucleic acid disclosed herein. In some embodiments, the cell is isolated from a subject having a RAS mutation. In some embodiments, the cell is a T cell. In some embodiments, the cell is a CD4+ T cell. In some embodiments, the cell is a CD8+ T cell.

[0156] T cells belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. T cells include CD4+T cells (helper T cells) and CD8+T cells (cytotoxic T cells). CD4+T cells can assist other white blood cells in immunologic processes, including maturation of B-cells and activation of cytotoxic T cells and macrophages. CD4+T cells are activated when presented with peptide antigens by MHC class II molecules expressed on the surface of antigen presenting cells (APCs). Once activated, the T cells can divide rapidly and secrete cytokines that regulate the active immune response. CD8+T cells can destroy virally infected cells and tumor cells, and can also be implicated in transplant rejection. CD8+T cells can recognize their targets by binding to antigen associated with MHC class I, which is present on the surface of nearly every cell of the body. Most T cells have a T cell receptor (TCR). The ability of T cells to recognize antigens associated with various cancers or infectious organisms is conferred by its TCR, which is made up of both an alpha (a) chain and a beta (P) chain or a gamma (y) and a delta (5) chain. The proteins which make up these chains are encoded by DNA, which employs a unique mechanism for generating the diversity of the TCR. This multi-subunit immune recognition receptor can associate with the CD3 complex and bind peptides presented by the MHC class I and II proteins on the surface of antigen-presenting cells (APCs). The first signal in activation of T cells can be provided by binding of the T cell receptor to a short peptide presented by the MHC on another cell. This ensures that only a T cell with a TCR specific to that peptide is activated. The partner cell is usually an antigen presenting cell such as a professional antigen presenting cell, usually a dendritic cell in the case of naive responses, although B-cells and macrophages can be important APCs. Binding of a TCR to the antigenic peptide on the APC can be a central event in T cell activation, which occurs at an immunological synapse at the point of contact between the T cell and the APC.

[0157] T cells can be prepared according to methods known in the art. T cells can be an enriched T cell preparation, an APC-depleted cell preparation, or a substantially purified T cell preparation. T cells can be a mixed T cell population or a purified T cell subset. T cells can be an enriched T cell preparation containing a number or percentage of T cells that is increased with respect to an isolated population of T cells.

[0158] T cells, or a subset of T cells, can be obtained from various lymphoid tissues. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells (PBMCs), bone marrow, thymus, tissue biopsy, tumor, lymph node tissue, gut associated lymphoid tissue, mucosa associated lymphoid tissue, spleen tissue, lymphoid tissue, and tumors. The term “peripheral blood lymphocytes” (PBL) and its grammatical equivalents as used herein can refer to lymphocytes that circulate in the bloodWSGR Docket No. 50401-811.601(e.g., peripheral blood). Peripheral blood lymphocytes can refer to lymphocytes that are not localized to organs. Peripheral blood lymphocytes can comprise T cells, NK cells, B cell, or any combinations thereof.

[0159] The method can comprise isolating T cells from a subject. The method can comprise obtaining T cells isolated from a subject. T cells can be obtained from T cell lines. T cells can be obtained from autologous sources. T cells can be obtained from allogeneic sources. T cells may also be obtained from a xenogeneic source, for example, from mouse, rat, non-human primate, and pig.

[0160] T cells can be an APC-depleted cell preparation. T cells can be substantially free of APCs. For example, T cells can comprise T cells separated from over 75% of APCs. In an exemplary embodiment, peripheral blood mononuclear cells (PBMCs) can be obtained from blood, e.g., in heparinized vials. PBMCs can be separated from red blood cells by centrifugation and PBMCs recovered from the interface. The recovered PBMCs optionally can be washed (e.g., with PBS).

[0161] T cell purification can be achieved, for example, by positive or negative selection including, but not limited to, the use of antibodies directed to CD2, CD3, CD4, CD5, CD8, CD14, CD19, and / or MHC class II molecules. A specific T cell subset, such as CD28+, CD4+, CD8+, CD45RA+, and / or CD45RO+T cells, can be isolated by positive or negative selection techniques. For example, CD3+, CD28+T cells can be positively selected using CD3 / CD28 conjugated magnetic beads. In one aspect of the present invention, enrichment of a T cell population by negative selection can be accomplished with a combination of antibodies directed to surface markers unique to the negatively selected cells.

[0162] For example, a T cell sample can comprise cells from a subject’s circulating blood and can be obtained by apheresis or leukapheresis. A T cell sample may contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and / or platelets. Undesirable components of the T cell sample can be removed and the remaining T cells can be suspended in culture media. For example, cells can be washed to remove the plasma fraction. For example, T cells can be isolated from peripheral blood lymphocytes by lysing the red blood cells and by centrifugation through a PERCOLL™ gradient.

[0163] In some embodiments, a T cell comprises at least one T cell receptor (TCR) comprising a TCR alpha chain construct and / or TCR beta chain construct capable of specifically binding to an epitope from RAS in complex with a human MHC. In some embodiments, a host cell comprises at least one TCR disclosed herein, wherein the host cell is a CD4+ T cell. In some embodiments, the host cell is a CD8+ T cell. In some embodiments, the host cell is an autologous cell. In some embodiments, the host cell is an allogeneic cell. In some embodiments, the host cell is a human cell. In some other cases, a host cell may be natural killer (NK) cell, a B cell, or an immortalized cell line.

[0164] In some embodiments, T cells can be obtained by positive selection and / or negative selection. In positive selection, an affinity agent (such as an antibody, an antibody fragment, and aptamer) can be used to bind a cell surface marker expressed on the population of cells, for example, CD3 for T cells. Using the affinity agent, the T cells can be labeled. The labeled T cells can then be enriched using various methods that are well-known in the art. Non-limiting examples of those methods include fluorescent-activated cellWSGR Docket No. 50401-811.601sorting (FACS) and (para)magnetic particle -based cell separation (e.g., MACS cell separation kits from Miltenyi Biotec).

[0165] In negative selection, affinity agents can be used to bind cell surface markers expressed on blood cells other than the desired population. For example, when attempting to isolate T cells, a cocktail of affinity agents can be used to label B cells, NK cells, monocytes, platelets, dendritic cells, granulocytes, and erythrocytes. The labeled cells can then be depleted, leaving the T cells enriched. The exemplary methods to deplete labeled cells include FACS and (para)magnetic particle-based cell separation.

[0166] In addition to labeling-based isolation, special growth condition may be used to promote the growth of one particular cell population. For example, the special growth condition can be obtained using special cytokines or growth factors. For another example, in culture media containing phytohemagglutinin (PHA), IL-2, and / or IL- 15, T cells may preferentially proliferate.

[0167] In some situations, non-fimctional markers may be used to isolate T cells since binding of functional markers such as binding of CD3 by anti-CD3 antibody (alone or conjugated to magnetic particles) may trigger unwanted signaling events on T cells. Therefore, a cocktail of antibodies against CD14, CD15, CD16, CD19, CD34, CD36, CD56, CD123, and CD235a (glycophorin A) can be used to isolate T cells.

[0168] Detailed protocol can be found in published literatures (e.g., see Lefort et al., J Vis Exp. 2010; (40): 2017) which are incorporated by reference herein. T cell isolation kits can be obtained from, for example, STEMCELL Technologies, Thermofisher, and Miltenyi Biotec.

[0169] The T cell described herein may be an allogeneic T cell.

[0170] In some embodiments, the T cell may be a genetically-modified cell comprising in its genome a modified human T cell receptor (TCR) alpha chain gene and / or a modified human TCR beta chain gene, wherein the cell has reduced cell-surface expression of the endogenous TCR.

[0171] Gene-editing nucleases may be employed in order to disrupt components of the TCR. The TCR alpha chain (TCRa) is encoded by a single TRAC gene and pairs with the TCR beta chain (TCR ) encoded by two TCRB genes. Since the TCR a / p dimer can produce a fully functioning TCR complex, disrupting TCRa and / or TCR function may reduce (even eliminate) endogenous TCR expression.

[0172] Various methods may be used to disrupt endogenous TCRa or TCR genes. For example, four classes of gene editing proteins exist that share a common mode of action in binding a user defined sequence of DNA and mediating a double stranded DNA break (DSB). Zinc finger nucleases (ZFN) are heterodimeric arrays that co-localize at a target DNA site. ZFNs include individual finger subunits that bind DNA and are tethered to the Fokl nuclease domain that cleaves DNA. Transcription activator-like effector nucleases (TALEN) include repeating units that bind DNA by virtue of a hypervariable two amino acid sequence (repeat variable diresidue; RVD) that governs DNA base recognition. Similar to ZFNS, TALENs function as dimeric proteins that are fused to the Fokl endonuclease domain for DSB generation. Meganucleases (MN) are monomeric proteins with innate nuclease activity that are derived from bacterial homing endonucleases and engineered for a unique target site. The clustered regularly interspaced shortWSGR Docket No. 50401-811.601palindromic repeats (CRISPR) and associated Cas9 nuclease platform involves a small guide RNA (gRNA) transcript that contacts a target DNA sequence via Watson-Crick base pairing and the Cas9 nuclease that cleaves the DNA.

[0173] In some embodiments, introducing the genome -editing nuclease into the T cell includes introducing into the T cell a polynucleotide that encodes the genome-editing nuclease.

[0174] In some embodiments, introducing the genome -editing nuclease into the T cell includes introducing into the T cell a Cas9 polypeptide. In some embodiments, the genome-editing nuclease includes a TALEN nuclease, a CRISPR / Cas9 nuclease, or a megaTAL nuclease.

[0175] In some embodiments, the CRISPR / Cas9 nuclease is derived from either Streptococcus pyogenes or Staphylococcus aureus. In some of these embodiments, the CRISPR / Cas9 nuclease includes a nuclease-resistant gRNA such as, for example, at least one 2'-OMe-phosphorothioate modified base, at least one 2'-O-methyl modified base, or at least one 2'-O-methyl 3' thioPACE modified base.

[0176] In some embodiments, the TALEN nuclease or the megaTAL nuclease is encoded by an RNA that has an exogenous polyadenylation signal.

[0177] In some embodiments, the method described herein may further include culturing the T cell under conditions effective for expanding the population of genome-modified T cells.

[0178] In some embodiments, disrupting expression of TCRa and / or TCR[3 further disrupts assembly of TCRa and TCR[3. In some embodiments, disrupting expression of TCRa further disrupts formation of a complex between TCR and CD3. In some embodiments, disrupting expression of TCRa involves further disrupting assembly of TCRa and TCR[3.

[0179] In some embodiments, a genetically-modified T cell comprises a disrupted TCR alpha chain and / or beta chain and an inactivated gene encoding immune checkpoint protein such as PD1 and CTLA-4. This may be made possible by gene inactivation using specific TALE-nucleases directed against TCRalpha or TCRbeta coupled with inactivation of genes encoding immune checkpoint protein such as PD1 and CTLA-4.

[0180] In some embodiments, the genetic modification relies on the inactivation of one gene, or two genes selected from the group consisting of PD1, CTLA-4, LAG3, Tim3, BTLA, BY55, TIGIT, B7H5, LAIR1 , SIGLEC 10, 2B4, TCR alpha and TCR beta. In some embodiments, the genetic modification relies on the inactivation of two genes selected from the group consisting of PD 1 and TCR alpha, PD 1 and TCR beta, CTLA-4 and TCR alpha, CTLA-4 and TCR beta, LAG 3 and TCR alpha, LAG 3 and TCR beta, Tim3 and TCR alpha, Tim3 and TCR beta, BTLA and TCR alpha, BTLA and TCR beta, BY55 and TCR alpha, BY55 and TCR beta, TIGIT and TCR alpha, TIGIT and TCR beta, B7H5 and TCR alpha, B7H5 and TCR beta, LAIR1 and TCRalpha, LAIR1 and TCRbeta, SIGLEC 10 and TCRalpha, SIGLEC 10 and TCRbeta, 2B4 and TCR alpha, 2B4 and TCR beta. In some embodiments, the genetic modification relies on the inactivation of more than two genes. The genetic modification may be operated ex-vivo.V. Delivery of Nucleic Acid or VectorWSGR Docket No. 50401-811.601

[0181] Nucleic acids encoding TCRs or vectors containing such nucleic acids can be delivered to host cells for expression and processing.

[0182] Terms such as “transferring,” “introducing” or “transfecting” are used interchangeably herein and relate to the introduction of nucleic acids, in particular exogenous or heterologous nucleic acids, into a cell.

[0183] Cells can be transfected with any carriers with which nucleic acid can be associated, e.g., by forming complexes with the nucleic acid or forming vesicles in which the nucleic acid is enclosed or encapsulated, resulting in increased stability of the nucleic acid compared to naked nucleic acid. Carriers useful according to the present disclosure include, for example, lipid-containing carriers such as cationic lipids, liposomes, in particular cationic liposomes, and micelles, and nanoparticles. Cationic lipids may form complexes with negatively charged nucleic acids. Any cationic lipid may be used according to the present disclosure.

[0184] In various embodiments, a nucleic acid encoding a TCR disclosed herein is operably linked to a promoter. Furthermore, the present disclosure provides a vector, e.g., a plasmid, shuttle vector, phagemide, cosmid, expression vector, retroviral vector, adenoviral vector, or particle and / or vector to be used in gene therapy, which comprises one or more of the nucleic acids as disclosed above. A “vector” is a nucleic acid molecule that is capable of transporting another nucleic acid. The vector comprises the nucleic acid insert, which encodes the polypeptide or protein desired for expression in a cell, such as a host cell. For the purposes of the disclosure, an insert may be a nucleic acid encoding a TCR; an alpha chain or a beta chain or both of a TCR. The term “incorporating” a nucleic acid sequence in a vector may mean preparing a suitable expression vector with an insert comprising said nucleic acid sequence. An “expression vector” is a vector that can direct the expression of a protein encoded by one or more genes carried by the vector when it is present in the appropriate environment. “Retroviruses” are viruses having an RNA genome. “Gammaretrovirus” refers to a genus of the retroviridae family. Exemplary gammaretroviruses include, but are not limited to, mouse stem cell virus, murine leukemia virus, feline leukemia virus, feline sarcoma virus, and avian reticuloendotheliosis viruses. “Lentivirus” refers to a genus of retroviruses that are capable of infecting dividing and non-dividing cells. Several examples of lentiviruses include HIV (human immunodeficiency virus: including HIV type 1, and HIV type 2); equine infectious anemia virus; feline immunodeficiency virus (FIV); bovine immune deficiency virus (BIV); and simian immunodeficiency virus (SIV). A vector that encodes a core virus is also known as a “viral vector.” There are a large number of available viral vectors that are suitable for use with the invention, including those identified for human gene therapy applications, such as those described by Pfeifer and Verma (Pfeifer, A. and I. M. Verma.2001. Ann. Rev. Genomics Hum. Genet. 2: 177-211). Suitable viral vectors include vectors based on RNA viruses, such as retrovirus-derived vectors, e.g., Moloney murine leukemia virus (MLV)-derived vectors, and include more complex retrovirus-derived vectors, e.g., lentivirus-derived vectors. HIV-l-derived vectors belong to this category. Other examples include lentivirus vectors derived from HIV-2, FIV, equine infectious anemia virus, SIV, and maedi / visna virus. Methods of using retroviral and lentiviral viral vectors and packaging cells for transducing mammalian target cells with viral particles containing TCRs transgenesWSGR Docket No. 50401-811.601are well known in the art and have been previous described, for example, in U.S. Pat. No. 8,119,772; Walchli et al., 2011, PLoS One 6:327930; Zhao et al., J. Immunol., 2005, 174:4415-4423; Engels et al., 2003, Hum. Gene Ther. 14:1155-68; Frecha et al., 2010, Mol. Ther. 18:1748-57; Verhoeyen et al., 2009, Methods Mol. Biol. 506:97-114. Retroviral and lentiviral vector constructs and expression systems are also commercially available. In some embodiments, a viral vector is used to introduce the non-endogenous nucleic acid sequence encoding TCRa chain specific for the peptide antigen into the hematopoietic progenitor cells. The viral vector may be a retroviral vector or a lentiviral vector. The viral vector may also include a nucleic acid sequence encoding a marker for transduction. Transduction markers for viral vectors are known in the art and include selection markers, which may confer drug resistance, or detectable markers, such as fluorescent markers or cell surface proteins that can be detected by methods such as flow cytometry. Where the viral vector genome comprises more than one nucleic acid sequence to be expressed in the host cell as separate transcripts, the viral vector may also comprise additional sequence between the two (or more) transcripts allowing bicistronic or multicistronic expression. Examples of such sequences used in viral vectors include internal ribosome entry sites (IRES), furin cleavage sites, viral 2A peptide. Other vectors also can be used for polynucleotide delivery including DNA viral vectors, including, for example adenovirus-based vectors and adeno-associated virus (AAV)-based vectors; vectors derived from herpes simplex viruses (HSVs), including amplicon vectors, replication-defective HSV and attenuated HSV (Krisky et al., 1998, Gene Ther. 5: 1517-30). Other vectors include those derived from baculoviruses and alpha-viruses. (Jolly D J. 1999. Emerging viral vectors, pp 209-40 in Friedmann T. ed. 1999. The development of human gene therapy. New York: Cold Spring Harbor Lab).

[0185] A vector may include nucleic acid sequences that permit the nucleic acid to replicate in a host cell, such as an origin of replication. A vector may also include one or more selectable marker genes and other genetic elements known to those of ordinary skill in the art. A vector preferably is an expression vector that includes a nucleic acid according to the present invention operably linked to sequences allowing for the expression of said nucleic acid.

[0186] In some embodiments, provided herein is a vector comprising a nucleic acid encoding a TCR disclosed herein. In some embodiments, the vector is a self-amplifying RNA replicon, plasmid, phage, transposon, cosmid, virus, or virion. In some embodiments, the vector is a viral vector. In some embodiments, the vector is derived from a retrovirus, lentivirus, adenovirus, adeno-associated virus, herpes virus, pox virus, alpha virus, vaccina virus, hepatitis B virus, human papillomavirus or a pseudotype thereof. In some embodiments, the vector is a non-viral vector. In some embodiments, the non-viral vector is a nanoparticle, a cationic lipid, a cationic polymer, a metallic nanopolymer, a nanorod, a liposome, a micelle, a microbubble, a cell-penetrating peptide, or a liposphere.

[0187] Presented herein are constructs, for example, nucleic acid constructs that encode an alpha chain and a beta chain of a TCR for expression in a cell. In some embodiments, the constructs comprise one or more polynucleotides encoding a TCR alpha chain and a TCR beta chain. In some embodiments, the polynucleotides are incorporated in a suitable vector. In some embodiments, the polynucleotides encodingWSGR Docket No. 50401-811.601the alpha chain and the beta chain are incorporated in the same vector. In some embodiments, the polynucleotides encoding the alpha chain and the beta chain are incorporated in different vectors, and both vectors are delivered for expression in the single cell.

[0188] In some embodiments, a cell may be transduced or transfected with a nucleic acid encoding a TCR, wherein the cell is capable of expressing the TCR and the cell is used as a therapeutic. In some embodiments the cell is derived from a subject or a host, wherein the subject or the host is a human. In some embodiments, the subject or the host comprises a cell having a mutation in an epitope, and the TCR expressed in the cell is capable of binding specifically to the epitope having the mutation. In some embodiments, the cell is a lymphocyte cell. In some embodiments, the T-lymphocyte. In some embodiments, the cell is a lymphocytic precursor cell. In some embodiments, the cell is a T lymphocyte precursor cell. In some embodiments, the cell is a T lymphocyte progenitor cell. In some embodiments the cell is a thymocyte.

[0189] In some embodiments, the T cells are immature T cells. In some embodiments, the T cells are antigen naive T cells. The host cell may be cultured ex vivo for 1, 2, 3, 4, 5 or more days for monitoring and recover after transfection or transduction with the polynucleotide(s) encoding the TCR.

[0190] In some embodiments, the recombinant nucleic acid disclosed herein, the vector disclosed herein or the TCR disclosed herein is present in the form of lipid nanoparticles (LNPs). LNPs typically comprise four components: cationically ionizable lipid, neutral lipids such as phospholipids, a steroid such as cholesterol, and a polymer-conjugated lipid such as PEG-lipid. LNPs may be prepared by mixing lipids dissolved in ethanol with the recombinant nucleic acid disclosed herein, the vector disclosed herein or the TCR disclosed herein in an aqueous buffer.

[0191] In some embodiments, the recombinant nucleic acid disclosed herein, the vector disclosed herein or the TCR disclosed herein is present in the LNP described herein is bound by cationically ionizable lipid that occupies the central core of the LNP. Polymer-conjugated lipid forms the surface of the LNP, along with phospholipids. In some embodiments, cholesterol and cationically ionizable lipid can be distributed throughout the LNP.

[0192] In some embodiments, the LNP comprises one or more cationically ionizable lipids, and one or more stabilizing lipids. Stabilizing lipids include neutral lipids and polymer-conjugated lipids.

[0193] In some embodiments, the LNP comprises a cationically ionizable lipid, a neutral lipid, a steroid, a polymer-conjugated lipid; and the DNA and / or RNA, encapsulated within or associated with the lipid nanoparticle.

[0194] In some embodiments, the LNP comprises from 35 to 65 mol percent, 40 to 60 mol percent, 40 to 55 mol percent, from 45 to 55 mol percent, or from 45 to 50 mol percent of the cationically ionizable lipid.

[0195] In some embodiments, the neutral lipid is present in a concentration ranging from 5 to 15 mol percent, from 7 to 13 mol percent, or from 9 to 11 mol percent.WSGR Docket No. 50401-811.601

[0196] In some embodiments, the steroid is present in a concentration ranging from 30 to 50 mol percent, from 30 to 45 mol percent, from 35 to 45 mol percent or from 35 to 43 mol percent.

[0197] In some embodiments, the LNP comprises from 1 to 10 mol percent, from 1 to 5 mol percent, or from 1 to 2.5 mol percent of the polymer-conjugated lipid.

[0198] In some embodiments, the LNP comprises from 45 to 55 mol percent of a cationically ionizable lipid; from 5 to 15 mol percent of a neutral lipid; from 30 to 45 mol percent of a steroid; from 1 to 5 mol percent of a polymer-conjugated lipid; and the DNA and / or RNA, encapsulated within or associated with the lipid nanoparticle.

[0199] In some embodiments, the mol percent is determined based on total mol of lipid present in the lipid nanoparticle. In some embodiments, the mol percent is determined based on total mol of cationically ionizable lipid, neutral lipid, steroid and polymer-conjugated lipid present in the lipid nanoparticle.

[0200] In some embodiments, the neutral lipid is selected from the group consisting of DSPC, DPPC, DMPC, DOPC, POPC, DOPE, DOPG, DPPG, POPE, DPPE, DMPE, DSPE, and SM. In some embodiments, the neutral lipid is selected from the group consisting of DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM. In some embodiments, the neutral lipid is DSPC.

[0201] In some embodiments, the steroid is cholesterol.

[0202] In some embodiments, the polymer conjugated lipid is a pegylated lipid, e.g., a pegylated lipid as described above.VI. Neoantigens

[0203] The TCRs disclosed herein are specific to immunogenic neoantigens. In some embodiments, the neoantigen peptide is from RAS. In some embodiments, one or more neoantigen peptides are loaded on to APCs, wherein the peptide loaded APCs are then used to stimulate T cells to produce antigen specific T cells. In some embodiments, the APCs used for peptide loading are dendritic cells. Immunogenic neoantigen sequences can be identified by any suitable method known in the art.

[0204] In various embodiments, the neoantigen comprises an epitope. In both animals and humans, mutated epitopes can be potentially effective in inducing an immune response or activating T cells. In some embodiments, the epitope comprises a mutation. In some embodiments, the mutation is selected from the group consisting of a point mutation, a splice-site mutation, a frame shift mutation, a read-through mutation, a gene fusion mutation, and any combination thereof.

[0205] In some embodiments, the epitope has a length of at least 8 amino acids. In some embodiments, the epitope has a length of at least 16 amino acids. In some embodiments, the epitope has a length of from 8-25 amino acids. In some embodiments, the epitope has a length of from 8-12 amino acids. In some embodiments, the epitope has a length of from 16-25 amino acids. In some embodiments, the epitope has a length of 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acids.

[0206] In certain embodiments, a neoantigen or epitope thereof can comprise, but is not limited to, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, aboutWSGR Docket No. 50401-811.60127, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120 or greater amino acid residues, and any range derivable therein. In specific embodiments, a neoantigen or epitope thereof is equal to or less than 100 amino acids.

[0207] In some embodiments, a neoantigen or epitope thereof for MHC Class I is 13 residues or less in length and usually consists of between about 8 and about 11 residues, particularly 9 or 10 residues. In some embodiments, a neoantigen or epitope thereof for MHC Class II is 9-24 residues in length.

[0208] In some embodiments, neoantigens bind an HLA protein (e.g., HLA class I or HLA class II). In specific embodiments neoantigens bind an HLA protein with greater affinity than a corresponding wildtype peptide. In specific embodiments, the neoantigenic peptide or polypeptide has an IC50 of at least less than 5000 nM, at least less than 500 nM, at least less than 100 nM, at least less than 50 nM or less.

[0209] In some embodiments, the epitope binds to the human MHC with a greater affinity than a corresponding wild-type epitope. In some embodiments, the epitope binds to the human MHC with a Ab or an IC50 less than 500 nM, 250 nM, 150 nM, 100 nM, 50 nM, 25 nM, 10 nM, or 5 nM. In some embodiments, the epitope binds to the human MHC with a Ab or an IC50 of at most 500 nM, 250 nM, 150 nM, 100 nM, 50 nM, 25 nM, 10 nM, or 5 nM. In some embodiments, the epitope binds to the human MHC with a ECsoor avidity less than 100000 nM, 10000 nM, 1000 nM, 500 nM, 250 nM, 150 nM, 100 nM, 50 nM, 25 nM, 10 nM, or 5 nM. In some embodiments, the epitope binds to the human MHC with a ECsoor avidity of least about 100000 nM, 10000 nM, 1000 nM, 500 nM, 250 nM, 150 nM, 100 nM, 50 nM, 25 nM, 10 nM, or 5 nM. In some embodiments, the epitope comprises a mutation, wherein the mutation is not present in non-cancer cells of a subject. In some embodiments, the epitope is encoded by a gene or an expressed gene of a subject’s cancer cells. In some embodiments, the TCR binds to an HLA-peptide complex with a Ab or an IC50 of less than 500 nM, 250 nM, 150 nM, 100 nM, 50 nM, 25 nM,10 nM, or 5 nM. In some embodiments, the TCR binds to an HLA-peptide complex with a Ab or an IC50 of at most 500 nM, 250 nM, 150 nM, 100 nM, 50 nM, 25 nM,10 nM, or 5 nM. In some embodiments, the TCR binds to an HLA-peptide complex with a EC50 or avidity less than 100000 nM, 10000 nM, 1000 nM, 500 nM, 250 nM, 150 nM, 100 nM, 50 nM, 25 nM, 10 nM, or 5 nM. In some embodiments, the TCR binds to an HLA-peptide complex with a EC50 or avidity of least about 100000 nM, 10000 nM, 1000 nM, 500 nM, 250 nM, 150 nM, 100 nM, 50 nM, 25 nM, 10 nM, or 5 nM.

[0210] In some embodiments, the neoantigenic peptide can be from about 8 and about 50 amino acid residues in length, or from about 8 and about 30, from about 8 and about 20, from about 8 and about 18, from about 8 and about 15, or from about 8 and about 12 amino acid residues in length. In some embodiments, the neoantigenic peptide can be from about 8 and about 500 amino acid residues in length, or from about 8 and about 450, from about 8 and about 400, from about 8 and about 350, from about 8 and about 300, from about 8 and about 250, from about 8 and about 200, from about 8 and about 150, fromWSGR Docket No. 50401-811.601about 8 and about 100, from about 8 and about 50, or from about 8 and about 30 amino acid residues in length.

[0211] In some embodiments, the neoantigenic peptide can be at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or more amino acid residues in length. In some embodiments, the neoantigenic peptide can be at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500 or more amino acid residues in length. In some embodiments, the neoantigenic peptide can be at most 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or less amino acid residues in length. In some embodiments, the neoantigenic peptide can be at most 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, or less amino acid residues in length.

[0212] In some embodiments, the neoantigenic peptide has a total length of at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, or at least 500 amino acids.

[0213] In some embodiments, the neoantigenic peptide has a total length of at most 8, at most 9, at most 10, at most 11, at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 21, at most 22, at most 23, at most 24, at most 25, at most 26, at most 27, at most 28, at most 29, at most 30, at most 40, at most 50, at most 60, at most 70, at most 80, at most 90, at most 100, at most 150, at most 200, at most 250, at most 300, at most 350, at most 400, at most 450, or at most 500 amino acids.

[0214] In some embodiments, the neoantigenic peptide can have a pl value of about 0.5 and about 12, about 2 and about 10, or about 4 and about 8. In some embodiments, the neoantigenic peptide can have a pl value of at least 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or more. In some embodiments, the neoantigenic peptide can have a pl value ofat most 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or less.

[0215] In some embodiments, the neoantigenic peptide can have an HLA binding affinity of between about IpM and about ImM, about lOOpM and about 500pM, about 500pM and about lOpM, about InM and about IpM, or about lOnM and about IpM. In some embodiments, the neoantigenic peptide can have an HLA binding affinity ofat least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 700, 800, 900 pM, or more. In some embodiments, the neoantigenic peptide can have an HLA binding affinity of at most 2, 3, 4, 5, 6, 7,WSGR Docket No. 50401-811.6018, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 700, 800, 900 pM.

[0216] In some embodiments, a neoantigenic peptide described herein can comprise carriers such as those well known in the art, e.g., thyroglobulin, albumins such as human serum albumin, tetanus toxoid, polyamino acid residues such as poly L-lysine, poly L-glutamic acid, influenza virus proteins, hepatitis B virus core protein, and the like.

[0217] In some embodiments, a neoantigenic peptide described herein can be modified by terminal-NH2 acylation, e.g., by alkanoyl (C1-C20) or thioglycolyl acetylation, terminal-carboxyl amidation, e.g., ammonia, methylamine, etc. In some embodiments, these modifications can provide sites for linking to a support or other molecule.

[0218] In some embodiments, a neoantigenic peptide described herein can contain modifications such as but not limited to glycosylation, side chain oxidation, biotinylation, phosphorylation, addition of a surface active material, e.g., a lipid, or can be chemically modified, e.g., acetylation, etc. Moreover, bonds in the peptide can be other than peptide bonds, e.g., covalent bonds, ester or ether bonds, disulfide bonds, hydrogen bonds, ionic bonds, etc.

[0219] In some embodiments, a neoantigenic peptide described herein can contain substitutions to modify a physical property (e.g., stability or solubility) of the resulting peptide. For example, neoantigenic peptides can be modified by the substitution of a cysteine (C) with a-amino butyric acid (“B”). Due to its chemical nature, cysteine has the propensity to form disulfide bridges and sufficiently alter the peptide structurally so as to reduce binding capacity. Substituting a-amino butyric acid for C not only alleviates this problem, but actually improves binding and cross-binding capability in certain instances. Substitution of cysteine with a-amino butyric acid can occur at any residue of a neoantigenic peptide, e.g., at either anchor or non-anchor positions of an epitope or analog within a peptide, or at other positions of a peptide.

[0220] In some embodiments, a neoantigenic peptide described herein can comprise amino acid mimetics or unnatural amino acid residues, e.g. D- or L-naphylalanine; D- or L-phenylglycine; D- or L-2-thieneylalanine; D- or L-l, -2, 3-, or 4-pyreneylalanine; D- or L-3 thieneylalanine; D- or L-(2-pyridinyl)-alanine; D- or L-(3-pyridinyl)-alanine; D- or L-(2-pyrazinyl)-alanine; D- or L-(4-isopropyl)-phenylglycine; D-(trifluoromethyl)-phenylglycine; D-(trifluoro-methyl)-phenylalanine; D-.rho. -fluorophenylalanine; D-or L-.rho.-biphenyl-phenylalanine; D- or L-.rho. -methoxybiphenylphenylalanine; D- or L-2-indole(allyl)alanines; and, D- or L-alkylalanines, where the alkyl group can be a substituted or unsubstituted methyl, ethyl, propyl, hexyl, butyl, pentyl, isopropyl, iso-butyl, sec-isotyl, iso-pentyl, or a non-acidic amino acid residues. Aromatic rings of a non-natural amino acid include, e.g., thiazolyl, thiophenyl, pyrazolyl, benzimidazolyl, naphthyl, furanyl, pyrrolyl, and pyridyl aromatic rings. Modified peptides that have various amino acid mimetics or unnatural amino acid residues are particularly useful, as they tend to manifest increased stability in vivo. Such peptides can also possess improved shelf-life or manufacturing properties.WSGR Docket No. 50401-811.601

[0221] Peptide stability can be assayed in a number of ways. For instance, peptidases and various biological media, such as human plasma and serum, have been used to test stability. See, e.g., Verhoef, et al., Eur. J. Drug Metab. Pharmacokinetics 11:291 (1986). Half-life of the peptides described herein is conveniently determined using a 25% human serum (v / v) assay. The protocol is as follows: pooled human serum (Type AB, non-heat inactivated) is dilapidated by centrifugation before use. The serum is then diluted to 25 % with RPMI- 1640 or another suitable tissue culture medium . At predetermined time intervals, a small amount of reaction solution is removed and added to either 6% aqueous trichloroacetic acid (TCA) or ethanol. The cloudy reaction sample is cooled (4oC) for 15 minutes and then spun to pellet the precipitated serum proteins. The presence of the peptides is then determined by reversed-phase HPLC using stability-specific chromatography conditions.

[0222] In some embodiments, a neoantigenic peptide described herein can be prepared synthetically, by recombinant DNA technology or chemical synthesis, or can be isolated from natural sources such as native tumors or pathogenic organisms. Epitopes can be synthesized individually or joined directly or indirectly in a peptide. Although a neoantigenic peptide described herein will be substantially free of other naturally occurring host cell proteins and fragments thereof, in some embodiments, the peptide can be synthetically conjugated to be joined to native fragments or particles.

[0223] In some embodiments, a neoantigenic peptide described herein can be prepared in a wide variety of ways. In some embodiments, the peptides can be synthesized in solution or on a solid support according to conventional techniques. Various automatic synthesizers are commercially available and can be used according to known protocols. (See, for example, Stewart & Young, SOLID PHASE PEPTIDE SYNTHESIS, 2D. ED., Pierce Chemical Co., 1984). Further, individual peptides can be joined using chemical ligation to produce larger peptides that are still within the bounds of the invention.

[0224] Alternatively, recombinant DNA technology can be employed wherein a nucleotide sequence which encodes a peptide inserted into an expression vector, transformed, or transfected into an appropriate host cell and cultivated under conditions suitable for expression. These procedures are generally known in the art, as described generally in Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (1989). Thus, recombinant peptides, which comprise or consist of one or more epitopes described herein, can be used to present the appropriate T cell epitope.VII. Pharmaceutical Compositions

[0225] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active agents into preparations which can be used pharmaceutically. Proper formulation can be dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients can be used as suitable and as understood in the art.

[0226] In some cases, a pharmaceutical composition is formulated as cell based therapeutic, e.g., a T cell therapeutics. In some embodiments, a pharmaceutical composition comprises a peptide-based therapy, aWSGR Docket No. 50401-811.601nucleic acid-based therapy, an antibody-based therapy, and / or a cell-based therapy. In some embodiments, a pharmaceutical composition comprises a peptide-based therapeutic, or nucleic acid based therapeutic in which the nucleic acid encodes the polypeptides. A composition can comprise T cells specific for two or more immunogenic antigen or neoantigen peptides. In some embodiments, the T cell specific therapeutic may be supplemented by one or more additional therapies.

[0227] In some embodiments, a pharmaceutical composition comprising: a nucleic acid encoding a TCR targeting a neoantigen disclosed herein, a vector containing the nucleic acid, the protein encoded by the nucleic acid, or a host cell comprising the nucleic acid, the protein, or the vector; and a pharmaceutically acceptable excipient or diluent. In some embodiments, the pharmaceutical composition further comprises an immunomodulatory agent or an adjuvant. In some embodiments, the immunomodulatory agent is a cytokine. In some embodiments, the adjuvant is poly I:C.

[0228] Also provided herein is the use of the pharmaceutical compositions in treating an immune disease or cancer.

[0229] Pharmaceutical compositions can include, in addition to active ingredient, a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration. Acceptable carriers, excipients, or stabilizers are those that are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN®, PLURONICS® or polyethylene glycol (PEG).

[0230] Acceptable carriers are physiologically acceptable to the administered patient and retain the therapeutic properties of the compounds with / in which it is administered. Acceptable carriers and their formulations are generally described in, for example, Remington’s Pharmaceutical Sciences (18th ed. A. Gennaro, Mack Publishing Co., Easton, PA 1990). One example of carrier is physiological saline. A pharmaceutically acceptable carrier is a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting the subject compounds from the administration site of one organ, or portion of the body, to another organ, or portion of the body, or in an in vitro assay s...

Claims

WSGR Docket No. 50401-811.601CLAIMSWhat is claimed is:

1. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

210.

2. The TCR of claim 1, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167.

3. The TCR of claim 1 or 2, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25.

4. The TCR of any one of claims 1-3, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 211 or 212.

5. The TCR of any one of claims 1-4, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 211 or 212.

6. The TCR of any one of claims 1-5, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 211 or 212.

7. The TCR of any one of claims 1-6, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 211 or 212.

8. The TCR of any one of claims 1-7, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 112;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 113; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 207.

9. The TCR of claim 8, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 208 or 209.

10. The TCR of claim 8 or 9, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 208 or 209.

11. The TCR of any one of claims 8-10, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 208 or 209.

12. The TCR of any one of claims 8-11, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 208 or 209.WSGR Docket No. 50401-811.60113. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 7.

14. The TCR of claim 13, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 5.

15. The TCR of claim 13 or 14, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 6.

16. The TCR of any one of claims 13-15, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NO: 8 or 39.

17. The TCR of any one of claims 13-16, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 8 or 39.

18. The TCR of any one of claims 13-17, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NO: 8 or 39.

19. The TCR of any one of claims 13-18, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 8 or 39.

20. The TCR of any one of claims 13-19, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 1;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 2; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 3.

21. The TCR of claim 20, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 4 or 38.

22. The TCR of claim 20 or 21, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 4 or 38.

23. The TCR of any one of claims 20-22, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 4 or 38.

24. The TCR of any one of claims 20-23, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 4 or 38.

25. The TCR of any one of claims 13-24, wherein the TCR binds to an epitope from human RAS comprising a mutation G12D.WSGR Docket No. 50401-811.60126. The TCR of claim 25, wherein the epitope from human RAS comprising the mutation G12D is SEQ ID NOs: 9 or 10.

27. The TCR of claim 25 or 26, wherein the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12D and (ii) an MHC protein encoded by an HLA- C08:02 allele.

28. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

17.

29. The TCR of claim 28, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 15.

30. The TCR of claim 28 or 29, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 16.

31. The TCR of any one of claims 28-30, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 18 or 41.

32. The TCR of any one of claims 28-31, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 18 or 41.

33. The TCR of any one of claims 28-32, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 18 or 41.

34. The TCR of any one of claims 28-33, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 18 or 41.

35. The TCR of any one of claims 28-34, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 11;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 12; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 13.

36. The TCR of claim 35, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 14 or 40.

37. The TCR of claim 35 or 36, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 14 or 40.

38. The TCR of any one of claims 35-37, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 14 or 40.WSGR Docket No. 50401-811.60139. The TCR of any one of claims 35-38, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 14 or 40.

40. The TCR of any one of claims 28-39, wherein the TCR binds to an epitope from human RAS comprising a mutation G12D.

41. The TCR of claim 40, wherein the epitope from human RAS comprising the mutation G12D is SEQ ID NO: 19.

42. The TCR of claim 40 or 41, wherein the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12D and (ii) an MHC protein encoded by an HLA- A1E01 allele.

43. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

26.

44. The TCR of claim 43, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 24.

45. The TCR of claim 43 or 44, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25.

46. The TCR of any one of claims 43-45, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 27 or 43.

47. The TCR of any one of claims 43-46, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 27 or 43.

48. The TCR of any one of claims 43-47, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 27 or 43.

49. The TCR of any one of claims 43-48, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 27 or 43.

50. The TCR of any one of claims 43-49, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 20;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 21; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 22.

51. The TCR of claim 50, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 23 or 42.WSGR Docket No. 50401-811.60152. The TCR of claim 50 or 51, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 23 or 42.

53. The TCR of any one of claims 50-52, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 23 or 42.

54. The TCR of any one of claims 50-53, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 23 or 42.

55. The TCR of any one of claims 43-54, wherein the TCR binds to an epitope from human RAS comprising a mutation G12D.

56. The TCR of claim 55, wherein the epitope from human RAS comprising the mutation G12D is SEQ ID NO: 19.

57. The TCR of claim 55 or 56, wherein the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12D and (ii) an MHC protein encoded by an HLA- A1E01 allele.

58. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

34.

59. The TCR of claim 58, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 32.

60. The TCR of claim 58 or 59, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 33.

61. The TCR of any one of claims 58-60, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 35 or 45.

62. The TCR of any one of claims 58-61, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 35 or 45.

63. The TCR of any one of claims 58-62, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 35 or 45.

64. The TCR of any one of claims 58-63, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 35 or 45.

65. The TCR of any one of claims 58-64, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 28;WSGR Docket No. 50401-811.601the CDR2 has an amino acid sequence set forth in SEQ ID NO: 29; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 30.

66. The TCR of claim 65, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 31 or 44.

67. The TCR of claim 65 or 66, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 31 or 44.

68. The TCR of any one of claims 65-67, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 31 or 44.

69. The TCR of any one of claims 65-68, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 31 or 44.

70. The TCR of any one of claims 58-69, wherein the TCR binds to an epitope from human RAS comprising a mutation G12V.

71. The TCR of claim 70, wherein the epitope from human RAS comprising the mutation G12V is SEQ ID NOs: 36 or 37.

72. The TCR of claim 70 or 71, wherein the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12V and (ii) an MHC protein encoded by an HLA- A03:01 allele.

73. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

59.

74. The TCR of claim 73, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57.

75. The TCR of claim 73 or 74, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58.

76. The TCR of any one of claims 73-75, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 60 or 61.

77. The TCR of any one of claims 73-76, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 60 or 61.

78. The TCR of any one of claims 73-77, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 60 or 61.WSGR Docket No. 50401-811.60179. The TCR of any one of claims 73-78, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 60 or 61.

80. The TCR of any one of claims 73-79, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 52;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 53; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 54.

81. The TCR of claim 80, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 55 or 56.

82. The TCR of claim 80 or 81, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 55 or 56.

83. The TCR of any one of claims 80-82, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 55 or 56.

84. The TCR of any one of claims 80-83, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 55 or 56.

85. The TCR of any one of claims 73-84, wherein the TCR binds to an epitope from human RAS comprising a mutation G12D.

86. The TCR of claim 85, wherein the epitope from human RAS comprising the mutation G12D is SEQ ID NO: 10.

87. The TCR of claim 85 or 86, wherein the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12D and (ii) an MHC protein encoded by an HLA- C08:02 allele.

88. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

69.

89. The TCR of claim 88, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67.

90. The TCR of claim 88 or 89, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 68.

91. The TCR of any one of claims 88-90, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 70 or 71.WSGR Docket No. 50401-811.60192. The TCR of any one of claims 88-91, wherein the TCRbeta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 70 or 71.

93. The TCR of any one of claims 88-92, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 70 or 71.

94. The TCR of any one of claims 88-93, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 70 or 71.

95. The TCR of any one of claims 88-94, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 62;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 63; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 64.

96. The TCR of claim 95, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 65 or 66.

97. The TCR of claim 95 or 96, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 65 or 66.

98. The TCR of any one of claims 95-97, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 65 or 66.

99. The TCR of any one of claims 95-98, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 65 or 66.

100. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

77.

101. The TCR of claim 100, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57.

102. The TCR of claim 100 or 101, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58.

103. The TCR of any one of claims 100-102, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 78 or 79.

104. The TCR of any one of claims 100-103, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 78 or 79.WSGR Docket No. 50401-811.601105. The TCR of any one of claims 100-104, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 78 or 79.

106. The TCR of any one of claims 100-105, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 78 or 79.

107. The TCR of any one of claims 100-106, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 73;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 29; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 74.

108. The TCR of claim 107, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 75 or 76.

109. The TCR of claim 107 or 108, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 75 or 76.

110. The TCR of any one of claims 107-109, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 75 or 76.

111. The TCR of any one of claims 107-110, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 75 or 76.

112. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 87.

113. The TCR of claim 112, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 85.

114. The TCR of claim 112 or 113, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 86.

115. The TCR of any one of claims 112-114, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 88 or 89.

116. The TCR of any one of claims 112-115, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 88 or 89.WSGR Docket No. 50401-811.601117. The TCR of any one of claims 112-116, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 88 or 89.

118. The TCR of any one of claims 112-117, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 88 or 89.

119. The TCR of any one of claims 112-118, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 80;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 81; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 82.

120. The TCR of claim 119, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 83 or 84.

121. The TCR of claim 119 or 120, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 83 or 84.

122. The TCR of any one of claims 119-121, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 83 or 84.

123. The TCR of any one of claims 119-122, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 83 or 84.

124. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO: 97.

125. The TCR of claim 124, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 95.

126. The TCR of claim 124 or 125, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 96.

127. The TCR of any one of claims 124-126, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 98 or 99.

128. The TCR of any one of claims 124-127, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 98 or 99.WSGR Docket No. 50401-811.601129. The TCR of any one of claims 124-128, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 98 or 99.

130. The TCR of any one of claims 124-129, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 98 or 99.

131. The TCR of any one of claims 124-130, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 90;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 91; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 92.

132. The TCR of claim 131, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94.

133. The TCR of claim 131 or 132, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94.

134. The TCR of any one of claims 131-133, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94.

135. The TCR of any one of claims 131-134, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 93 or 94.

136. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

105.

137. The TCR of claim 136, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 103.

138. The TCR of claim 136 or 137, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 104.

139. The TCR of any one of claims 136-138, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 106 or 107.

140. The TCR of any one of claims 136-139, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 106 or 107.WSGR Docket No. 50401-811.601141. The TCR of any one of claims 136-140, wherein the TCRbeta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 106 or 107.

142. The TCR of any one of claims 136-141, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 106 or 107.

143. The TCR of any one of claims 136-142, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 52;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 53; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 100.

144. The TCR of claim 143, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 101 or 102.

145. The TCR of claim 143 or 144, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 101 or 102.

146. The TCR of any one of claims 143-145, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 101 or 102.

147. The TCR of any one of claims 143-146, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 101 or 102.

148. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

109.

149. The TCR of claim 148, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67.

150. The TCR of claim 148 or 149, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 108.

151. The TCR of any one of claims 148-150, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 110 or 111.

152. The TCR of any one of claims 148-151, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 110 or 111.WSGR Docket No. 50401-811.601153. The TCR of any one of claims 148-152, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 110 or 111.

154. The TCR of any one of claims 148-153, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 110 or 111.

155. The TCR of any one of claims 148-154, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 90;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 91; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 92.

156. The TCR of claim 155, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94.

157. The TCR of claim 155 or 156, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94.

158. The TCR of any one of claims 155-157, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 93 or 94.

159. The TCR of any one of claims 155-158, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 93 or 94.

160. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

117.

161. The TCR of claim 160, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67.

162. The TCR of claim 160 or 161, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 68.

163. The TCR of any one of claims 160-162, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 118 or 119.

164. The TCR of any one of claims 160-163, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 118 or 119.WSGR Docket No. 50401-811.601165. The TCR of any one of claims 160-164, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 118 or 119.

166. The TCR of any one of claims 160-165, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 118 or 119.

167. The TCR of any one of claims 160-166, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 112;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 113; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 114.

168. The TCR of claim 167, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 115 or 116.

169. The TCR of claim 167 or 168, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 115 or 116.

170. The TCR of any one of claims 167-169, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 115 or 116.

171. The TCR of any one of claims 167-170, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 115 or 116.

172. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

127.

173. The TCR of claim 172, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 125.

174. The TCR of claim 172 or 173, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 126.

175. The TCR of any one of claims 172-174, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 128 or 129.

176. The TCR of any one of claims 172-175, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 128 or 129.WSGR Docket No. 50401-811.601177. The TCR of any one of claims 172-176, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 128 or 129.

178. The TCR of any one of claims 172-177, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 128 or 129.

179. The TCR of any one of claims 172-178, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 120;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 121; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 122.

180. The TCR of claim 179, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 123 or 124.

181. The TCR of claim 179 or 180, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 123 or 124.

182. The TCR of any one of claims 179-181, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 123 or 124.

183. The TCR of any one of claims 179-182, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 123 or 124.

184. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

135.

185. The TCR of claim 184, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 133.

186. The TCR of claim 184 or 185, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 134.

187. The TCR of any one of claims 184-186, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 136 or 137.

188. The TCR of any one of claims 184-187, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 136 or 137.WSGR Docket No. 50401-811.601189. The TCR of any one of claims 184-188, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 136 or 137.

190. The TCR of any one of claims 184-189, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 136 or 137.

191. The TCR of any one of claims 184-190 further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 20;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 21; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 130.

192. The TCR of claim 191, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 131 or 132.

193. The TCR of claim 191 or 192, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 131 or 132.

194. The TCR of any one of claims 191-193, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 131 or 132.

195. The TCR of any one of claims 191-194, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 131 or 132.

196. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

143.

197. The TCR of claim 196, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 125.

198. The TCR of claim 196 or 197, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 126.

199. The TCR of any one of claims 196-198, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 144 or 145.

200. The TCR of any one of claims 196-199, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 144 or 145.WSGR Docket No. 50401-811.601201. The TCR of any one of claims 196-200, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 144 or 145.

202. The TCR of any one of claims 196-201, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 144 or 145.

203. The TCR of any one of claims 196-202, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 138;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 139; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 140.

204. The TCR of claim 203, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 141 or 142.

205. The TCR of claim 203 or 204, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 141 or 142.

206. The TCR of any one of claims 203-205, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 141 or 142.

207. The TCR of any one of claims 203-206, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 141 or 142.

208. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

151.

209. The TCR of claim 208, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 67.

210. The TCR of claim 208 or 209, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 68.

211. The TCR of any one of claims 208-210, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 152 or 153.

212. The TCR of any one of claims 208-211, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 152 or 153.WSGR Docket No. 50401-811.601213. The TCR of any one of claims 208-212, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 152 or 153.

214. The TCR of any one of claims 208-213, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 152 or 153.

215. The TCR of any one of claims 208-214, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 146;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 147; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 148.

216. The TCR of claim 215, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 149 or 150.

217. The TCR of claim 215 or 216, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 149 or 150.

218. The TCR of any one of claims 215-217, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 149 or 150.

219. The TCR of any one of claims 215-218, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 149 or 150.

220. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

159.

221. The TCR of claim 220, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 157.

222. The TCR of claim 220 or 221, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 158.

223. The TCR of any one of claims 220-222, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 160 or 161.

224. The TCR of any one of claims 220-223, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 160 or 161.WSGR Docket No. 50401-811.601225. The TCR of any one of claims 220-224, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 160 or 161.

226. The TCR of any one of claims 220-225, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 160 or 161.

227. The TCR of any one of claims 220-226, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 138;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 139; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 154.

228. The TCR of claim 227, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 155 or 156.

229. The TCR of claim 227 or 228, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 155 or 156.

230. The TCR of any one of claims 227-229, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 155 or 156.

231. The TCR of any one of claims 227-230, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 155 or 156.

232. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

168.

233. The TCR of claim 232, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167.

234. The TCR of claim 232 or 233, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 168.

235. The TCR of any one of claims 232-234, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 169 or 170.

236. The TCR of any one of claims 232-235, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 169 or 170.WSGR Docket No. 50401-811.601237. The TCR of any one of claims 232-236, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 169 or 170.

238. The TCR of any one of claims 232-237, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 169 or 170.

239. The TCR of any one of claims 232-238, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 162;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 163; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 164.

240. The TCR of claim 239, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 165 or 166.

241. The TCR of claim 239 or 240, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 165 or 166.

242. The TCR of any one of claims 239-241, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 165 or 166.

243. The TCR of any one of claims 239-242, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 165 or 166.

244. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

176.

245. The TCR of claim 244, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167.

246. The TCR of claim 244 or 245, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25.

247. The TCR of any one of claims 244-246, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 177 or 178.

248. The TCR of any one of claims 244-247, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 177 or 178.WSGR Docket No. 50401-811.601249. The TCR of any one of claims 244-248, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 177 or 178.

250. The TCR of any one of claims 244-249, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 177 or 178.

251. The TCR of any one of claims 244-250, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 171;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 172; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 173.

252. The TCR of claim 251, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 174 or 175.

253. The TCR of claim 251 or 252, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 174 or 175.

254. The TCR of any one of claims 251-253, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 174 or 175.

255. The TCR of any one of claims 251-254, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 174 or 175.

256. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

184.

257. The TCR of claim 256, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57.

258. The TCR of claim 256 or 257, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58.

259. The TCR of any one of claims 256-258, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 185 or 186.

260. The TCR of any one of claims 256-259, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 185 or 186.WSGR Docket No. 50401-811.601261. The TCR of any one of claims 256-260, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 185 or 186.

262. The TCR of any one of claims 256-261, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 185 or 186.

263. The TCR of any one of claims 256-262, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 179;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 180; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 181.

264. The TCR of claim 263, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 182 or 183.

265. The TCR of claim 263 or 264, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 182 or 183.

266. The TCR of any one of claims 263-265, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 182 or 183.

267. The TCR of any one of claims 263-266, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 182 or 183.

268. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

190.

269. The TCR of claim 268, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 57.

270. The TCR of claim 268 or 269, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 58.

271. The TCR of any one of claims 268-270, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 191 or 192.

272. The TCR of any one of claims 268-271, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 191 or 192.WSGR Docket No. 50401-811.601273. The TCR of any one of claims 268-272, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 191 or 192.

274. The TCR of any one of claims 268-273, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 191 or 192.

275. The TCR of any one of claims 268-274, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 20;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 21; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 187.

276. The TCR of claim 275, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 188 or 189.

277. The TCR of claim 275 or 276, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 188 or 189.

278. The TCR of any one of claims 275-277, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 188 or 189.

279. The TCR of any one of claims 275-278, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 188 or 189.

280. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

198.

281. The TCR of claim 280, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 196.

282. The TCR of claim 280 or 281, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 197.

283. The TCR of any one of claims 280-282, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 199 or 200.

284. The TCR of any one of claims 280-283, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 199 or 200.WSGR Docket No. 50401-811.601285. The TCR of any one of claims 280-284, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 199 or 200.

286. The TCR of any one of claims 280-285, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 199 or 200.

287. The TCR of any one of claims 280-286, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 90;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 91; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 193.

288. The TCR of claim 287, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 194 or 195.

289. The TCR of claim 287 or 288, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 194 or 195.

290. The TCR of any one of claims 287-289, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 194 or 195.

291. The TCR of any one of claims 287-290, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 194 or 195.

292. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

204.

293. The TCR of claim 292, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167.

294. The TCR of claim 292 or 293, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25.

295. The TCR of any one of claims 292-294, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 205 or 206.

296. The TCR of any one of claims 292-295, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 205 or 206.WSGR Docket No. 50401-811.601297. The TCR of any one of claims 292-296, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 205 or 206.

298. The TCR of any one of claims 292-297, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 205 or 206.

299. The TCR of any one of claims 292-298, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 138;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 139; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 201.

300. The TCR of claim 299, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 202 or 203.

301. The TCR of claim 299 or 300, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 202 or 203.

302. The TCR of any one of claims 299-301, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 202 or 203.

303. The TCR of any one of claims 299-302, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 202 or 203.

304. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

216.

305. The TCR of claim 304, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 133.

306. The TCR of claim 304 or 305, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 134.

307. The TCR of any one of claims 304-306, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 217 or 218.

308. The TCR of any one of claims 304-307, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 217 or 218.WSGR Docket No. 50401-811.601309. The TCR of any one of claims 304-308, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 217 or 218.

310. The TCR of any one of claims 304-309, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 217 or 218.

311. The TCR of any one of claims 304-310, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 62;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 63; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 213.

312. The TCR of claim 311, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 214 or 215.

313. The TCR of claim 311 or 312, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 214 or 215.

314. The TCR of any one of claims 311-313, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 214 or 215.

315. The TCR of any one of claims 311-314, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 214 or 215.

316. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

222.

317. The TCR of claim 316, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 133.

318. The TCR of claim 316 or 317, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 134.

319. The TCR of any one of claims 316-318, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 223 or 224.

320. The TCR of any one of claims 316-319, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 223 or 224.WSGR Docket No. 50401-811.601321. The TCR of any one of claims 316-320, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 223 or 224.

322. The TCR of any one of claims 316-321, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 223 or 224.

323. The TCR of any one of claims 316-322, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 62;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 63; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 219.

324. The TCR of claim 323, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 220 or 221.

325. The TCR of claim 323 or 324, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 220 or 221.

326. The TCR of any one of claims 323-325, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 220 or 221.

327. The TCR of any one of claims 323-326, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 220 or 221.

328. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

228.

329. The TCR of claim 328, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167.

330. The TCR of claim 328 or 329, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25.

331. The TCR of any one of claims 328-330, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 229 or 230.

332. The TCR of any one of claims 328-331, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 229 or 230.WSGR Docket No. 50401-811.601333. The TCR of any one of claims 328-332, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 229 or 230.

334. The TCR of any one of claims 328-333, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 229 or 230.

335. The TCR of any one of claims 328-334, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 179;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 180; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 225.

336. The TCR of claim 335, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 226 or 227.

337. The TCR of claim 335 or 336, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 226 or 227.

338. The TCR of any one of claims 335-337, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 226 or 227.

339. The TCR of any one of claims 335-338, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 226 or 227.

340. A T cell receptor (TCR) comprising a TCR beta chain construct comprising a complementarity determining region 3 (CDR3) having an amino acid sequence set forth in SEQ ID NO:

234.

341. The TCR of claim 340, wherein the TCR beta chain construct further comprises a complementarity determining region 1 (CDR1), wherein the CDR1 has an amino acid sequence set forth in SEQ ID NO: 167.

342. The TCR of claim 340 or 341, wherein the TCR beta chain construct further comprises a complementarity determining region 2 (CDR2), wherein the CDR2 has an amino acid sequence set forth in SEQ ID NO: 25.

343. The TCR of any one of claims 340-342, wherein the TCR beta chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 235 or 236.

344. The TCR of any one of claims 340-343, wherein the TCR beta chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 235 or 236.WSGR Docket No. 50401-811.601345. The TCR of any one of claims 340-344, wherein the TCR beta chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 235 or 236.

346. The TCR of any one of claims 340-345, wherein the TCR beta chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 235 or 236.

347. The TCR of any one of claims 340-346, further comprising a TCR alpha chain construct having a CDR1, a CDR2, and a CDR3,wherein, the CDR1 has an amino acid sequence set forth in SEQ ID NO: 179;the CDR2 has an amino acid sequence set forth in SEQ ID NO: 180; and, the CDR3 has an amino acid sequence set forth in SEQ ID NO: 231.

348. The TCR of claim 347, wherein the TCR alpha chain construct comprises a variable region having at least 80% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 232 or 233.

349. The TCR of claim 347 or 348, wherein the TCR alpha chain construct comprises a variable region having at least 90% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 232 or 233.

350. The TCR of any one of claims 347-349, wherein the TCR alpha chain construct comprises a variable region having at least 95%, 96%, 97%, 98% or 99% sequence identity to an amino acid sequence set forth in SEQ ID NOs: 232 or 233.

351. The TCR of any one of claims 347-350, wherein the TCR alpha chain construct comprises a variable region having an amino acid sequence set forth in SEQ ID NOs: 232 or 233.

352. The TCR of any one of claims 1-12, 88-351, wherein the TCR binds to an epitope from human RAS comprising a mutation G12V.

353. The TCR of claim 352, wherein the epitope from human RAS comprising the mutation G12V is SEQ ID NO: 72.

354. The TCR of claim 351 or 352, wherein the TCR binds to a complex comprising (i) the epitope from human RAS comprising the mutation G12V and (ii) an MHC protein encoded by an HLA- C01:02 allele.

355. The TCR of any one of claims 1-354, wherein the TCR is a soluble TCR.

356. The TCR of any one of claims 1-354, wherein the TCR is a transmembrane protein.

357. A recombinant nucleic acid encoding the TCR of any one of claims 1-356.

358. A vector comprising the recombinant nucleic acid of claim 357.

359. The vector of claim 358, wherein the vector is a viral vector.

360. The vector of claim 358, wherein the viral vector is a lentiviral vector.

361. The vector of claim 358, wherein the viral vector is a retroviral vector.

362. A lipid nanoparticle comprising the recombinant nucleic acid of claim 357, the vector of any one of claims 358-361, or the TCR of any one of claims 1-356.WSGR Docket No. 50401-811.601363. A cell comprising the recombinant nucleic acid of claim 357.

364. A cell comprising the TCR of any one of claims 1-356 or a TCR encoded by the recombinant nucleic acid of claim 357.

365. The cell of claim 363 or 364, wherein the cell is a CD4+ T cell.

366. The cell of claim 363 or 364, wherein the cell is a CD8+ T cell.

367. The cell of any one of claims 363-366, wherein the cell is isolated from a subject having a RAS mutation.

368. A pharmaceutical composition comprising: (i) the recombinant nucleic acid of claim 357 or (ii) the TCR of any one of claims 1-356; and (b) a pharmaceutically acceptable excipient or diluent.

369. The pharmaceutical composition of claim 368, for use in treating an immune disease or cancer.

370. Use of the pharmaceutical composition of claim 368, for treating an immune disease or cancer.

371. A method of treating a subject having a disease or condition, comprising administering to the subject the pharmaceutical composition of claim 368.

372. A method of treating a subject with cancer comprising administering to the subject the pharmaceutical composition of claim 368.

373. A method of identifying a subject with cancer as a candidate for a therapeutic, wherein the method comprises determining the subject as a subject that expresses a protein encoded by an HLA-C08:02 allele, HLA-All:01 allele, HLA-C01:02 allele, or HLA-A03:01 allele, wherein the therapeutic is the pharmaceutical composition of claim 368 or 369.

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