EP-4735474-A1 - T CELL RECEPTORS TARGETING RAS WITH G12D, G12R, OR G12V MUTATION

Abstract

Disclosed are isolated or purified T cell receptors (TCRs), wherein the TCR has antigenic specificity for a mutated human RAS amino acid sequence with a substitution of glycine at position 12 with aspartic acid, valine, or arginine. Related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions are also provided. Also disclosed are methods of detecting the presence of cancer in a mammal and methods of treating or preventing cancer in a mammal.

Inventors

• LEVIN, Noam
• ROSENBERG, STEVEN A.
• KIM, SANGHYUN
• LOWERY, III, Frank J.
• PARKHURST, MARIA R.
• BERA, Alakesh

Assignees

• The United States of America, as represented by the Secretary, Department of Health and Human Services

Dates

Publication Date

20260506

Application Date

20240613

Claims (1)

1. Leydig 771261 HHS E-132-2023-0-PC-01 72 CLAIM(S): 1. An isolated or purified T-cell receptor (TCR) having antigenic specificity for a mutated human RAS amino acid sequence with a substitution of glycine at position 12 with aspartic acid, valine, or arginine, wherein the mutated human RAS amino acid sequence is a mutated human Kirsten rat sarcoma viral oncogene homolog (KRAS), a mutated human Harvey rat sarcoma viral oncogene homolog (HRAS), or a mutated human Neuroblastoma rat sarcoma viral oncogene homolog (NRAS) amino acid sequence, wherein position 12 is defined by reference to the wild-type human KRAS, wild-type human HRAS, or wild-type human NRAS protein, respectively, and wherein the TCR comprises the amino acid sequences of: (1) all of SEQ ID NOs: 1-6; (2) all of SEQ ID NOs: 11-16; (3) all of SEQ ID NOs: 21-26; (4) all of SEQ ID NOs: 31-36; (5) all of SEQ ID NOs: 41-46; (6) all of SEQ ID NOs: 51-56; (7) all of SEQ ID NOs: 61-66; (8) all of SEQ ID NOs: 71-76; (9) all of SEQ ID NOs: 81-86; (10) all of SEQ ID NOs: 91-96; (11) all of SEQ ID NOs: 101-106; (12) all of SEQ ID NOs: 111-116; (13) all of SEQ ID NOs: 121-126; (14) all of SEQ ID NOs: 131-136; or (15) all of SEQ ID NOs: 141-146. 2. The TCR of claim 1, wherein the TCR comprises the amino acid sequence(s) of: (1) SEQ ID NO: 7, (2) SEQ ID NO: 8, (3) SEQ ID NO: 9, (4) SEQ ID NO: 10, Leydig 771261 HHS E-132-2023-0-PC-01 73 (5) SEQ ID NO: 17, (6) SEQ ID NO: 18, (7) SEQ ID NO: 19, (8) SEQ ID NO: 20, (9) SEQ ID NO: 27, (10) SEQ ID NO: 28, (11) SEQ ID NO: 29, (12) SEQ ID NO: 30, (13) SEQ ID NO: 37, (14) SEQ ID NO: 38, (15) SEQ ID NO: 39, (16) SEQ ID NO: 40, (17) SEQ ID NO: 47, (18) SEQ ID NO: 48, (19) SEQ ID NO: 49, (20) SEQ ID NO: 50, (21) SEQ ID NO: 57, (22) SEQ ID NO: 58, (23) SEQ ID NO: 59, (24) SEQ ID NO: 60, (25) SEQ ID NO: 67, (26) SEQ ID NO: 68, (27) SEQ ID NO: 69, (28) SEQ ID NO: 70, (29) SEQ ID NO: 77, (30) SEQ ID NO: 78, (31) SEQ ID NO: 79, (32) SEQ ID NO: 80, (33) SEQ ID NO: 87, (34) SEQ ID NO: 88, (35) SEQ ID NO: 89, (36) SEQ ID NO: 90, (37) SEQ ID NO: 97, Leydig 771261 HHS E-132-2023-0-PC-01 74 (38) SEQ ID NO: 98, (39) SEQ ID NO: 99, (40) SEQ ID NO: 100, (41) SEQ ID NO: 107, (42) SEQ ID NO: 108, (43) SEQ ID NO: 109, (44) SEQ ID NO: 110, (45) SEQ ID NO: 117, (46) SEQ ID NO: 118, (47) SEQ ID NO: 119, (48) SEQ ID NO: 120, (49) SEQ ID NO: 127, (50) SEQ ID NO: 128, (51) SEQ ID NO: 129, (52) SEQ ID NO: 130, (53) SEQ ID NO: 137, (54) SEQ ID NO: 138, (55) SEQ ID NO: 139, (56) SEQ ID NO: 140, (57) SEQ ID NO: 147, (58) SEQ ID NO: 148, (59) SEQ ID NO: 149, (60) SEQ ID NO: 150, (61) both of SEQ ID NOs: 7 and 8, (62) both of SEQ ID NOs: 9 and 10, (63) both of SEQ ID NOs: 17 and 18, (64) both of SEQ ID NOs: 19 and 20, (65) both of SEQ ID NOs: 27 and 28, (66) both of SEQ ID NOs: 29 and 30, (67) both of SEQ ID NOs: 37 and 38, (68) both of SEQ ID NOs: 39 and 40, (69) both of SEQ ID NOs: 47 and 48, (70) both of SEQ ID NOs: 49 and 50, Leydig 771261 HHS E-132-2023-0-PC-01 75 (71) both of SEQ ID NOs: 57 and (72) both of SEQ ID NOs: 59 and 60, (73) both of SEQ ID NOs: 67 and 68, (74) both of SEQ ID NOs: 69 and 70, (75) both of SEQ ID NOs: 77 and 78, (76) both of SEQ ID NOs: 79 and 80, (77) both of SEQ ID NOs: 87 and 88, (78) both of SEQ ID NOs: 89 and 90, (79) both of SEQ ID NOs: 97 and 98, (80) both of SEQ ID NOs: 99 and 100, (81) both of SEQ ID NOs: 107 and 108, (82) both of SEQ ID NOs: 109 and 110, (83) both of SEQ ID NOs: 117 and 118, (84) both of SEQ ID NOs: 119 and 120, (85) both of SEQ ID NOs: 127 and 128, (86) both of SEQ ID NOs: 129 and 130, (87) both of SEQ ID NOs: 137 and 138, (88) both of SEQ ID NOs: 139 and 140, (89) both of SEQ ID NOs: 147 and 148, or (90) both of SEQ ID NOs: 149 and 150. 3. The TCR of claim 1 or 2, wherein the TCR further comprises: (a) the amino acid sequence of SEQ ID NO: 153, wherein: (i) X at position 48 of SEQ ID NO: 153 is Thr or Cys; (ii) X at position 112 of SEQ ID NO: 153 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 114 of SEQ ID NO: 153 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 115 of SEQ ID NO: 153 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (b) the amino acid sequence of SEQ ID NO: 154, wherein X at position 57 of SEQ ID NO: 154 is Ser or Cys; or (c) both (a) and (b). Leydig 771261 HHS E-132-2023-0-PC-01 76 4. The TCR of claim 1, wherein the TCR comprises the amino acid sequences of: (1) SEQ ID NO: 155; (2) SEQ ID NO: 156; (3) both of SEQ ID NOs: 155 and 156; (4) SEQ ID NO: 157; (5) SEQ ID NO: 158; (6) both of SEQ ID NOs: 157 and 158; (7) SEQ ID NO: 159; (8) SEQ ID NO: 160; (9) both of SEQ ID NOs: 159 and 160; (10) SEQ ID NO: 161; (11) SEQ ID NO: 162; (12) both of SEQ ID NOs: 161 and 162; (13) SEQ ID NO: 163; (14) SEQ ID NO: 164; (15) both of SEQ ID NOs: 163 and 164; (16) SEQ ID NO: 165; (17) SEQ ID NO: 166; (18) both of SEQ ID NOs: 165 and 166; (19) SEQ ID NO: 167; (20) SEQ ID NO: 168; (21) both of SEQ ID NOs: 167 and 168; (22) SEQ ID NO: 169; (23) SEQ ID NO: 170; (24) both of SEQ ID NOs: 169 and 170; (25) SEQ ID NO: 171; (26) SEQ ID NO: 172; (27) both of SEQ ID NOs: 171 and 172; (28) SEQ ID NO: 173; (29) SEQ ID NO: 174; (30) both of SEQ ID NOs: 173 and 174; (31) SEQ ID NO: 175; Leydig 771261 HHS E-132-2023-0-PC-01 77 (32) SEQ ID NO: 176; (33) both of SEQ ID NO: 175 and 176; (34) SEQ ID NO: 177; (35) SEQ ID NO: 178; (36) both of SEQ ID NO: 177 and 178; (37) SEQ ID NO: 179; (38) SEQ ID NO: 180; (39) both of SEQ ID NO: 179 and 180; (40) SEQ ID NO: 181; (41) SEQ ID NO: 182; (42) both of SEQ ID NO: 181 and 182; (43) SEQ ID NO: 183; (44) SEQ ID NO: 184; (45) both of SEQ ID NO: 183 and 184; (46) SEQ ID NO: 185; (47) SEQ ID NO: 186; (48) both of SEQ ID NO: 185 and 186; (49) SEQ ID NO: 187; (50) SEQ ID NO: 188; (51) both of SEQ ID NO: 187 and 188; (52) SEQ ID NO: 189; (53) SEQ ID NO: 190; (54) both of SEQ ID NO: 189 and 190; (55) SEQ ID NO: 191; (56) SEQ ID NO: 192; (57) both of SEQ ID NO: 191 and 192; (58) SEQ ID NO: 193; (59) SEQ ID NO: 194; (60) both of SEQ ID NO: 193 and 194; (61) SEQ ID NO: 195; (62) SEQ ID NO: 196; (63) both of SEQ ID NO: 195 and 196; (64) SEQ ID NO: 197; Leydig 771261 HHS E-132-2023-0-PC-01 78 (65) SEQ ID NO: 198; (66) both of SEQ ID NO: 197 and 198; (67) SEQ ID NO: 199; (68) SEQ ID NO: 200; (69) both of SEQ ID NO: 199 and 200; (70) SEQ ID NO: 201; (71) SEQ ID NO: 202; (72) both of SEQ ID NO: 201 and 202; (73) SEQ ID NO: 203; (74) SEQ ID NO: 204; (75) both of SEQ ID NO: 203 and 204; (76) SEQ ID NO: 205; (77) SEQ ID NO: 206; (78) both of SEQ ID NO: 205 and 206; (79) SEQ ID NO: 207; (80) SEQ ID NO: 208; (81) both of SEQ ID NO: 207 and 208; (82) SEQ ID NO: 209; (83) SEQ ID NO: 210; (84) both of SEQ ID NO: 209 and 210; (85) SEQ ID NO: 211; (86) SEQ ID NO: 212; (87) both of SEQ ID NO: 211 and 212; (88) SEQ ID NO: 213; (89) SEQ ID NO: 214; or (90) both of SEQ ID NO: 213 and 214. 5. The TCR of any one of claims 1-4, wherein the mutated human RAS amino acid sequence is: (a) AVGVGKSAL (SEQ ID NO: 232); (b) VVVGADGVGK (SEQ ID NO: 238); (c) MTEYKLVVVGARGVGKSALTIQLI (SEQ ID NO: 241); (d) MTEYKLVVVGAVGVGKSALTIQLI (SEQ ID NO: 242); Leydig 771261 HHS E-132-2023-0-PC-01 79 (e) GADGVGKSA (SEQ ID NO: ; or (f) GADGVGKSAL (SEQ ID NO: 247). 6. The TCR of any one of claims 1-5, wherein the TCR does not have antigenic specificity for the wild-type human RAS amino acid sequence of: (a) AGGVGKSAL (SEQ ID NO: 233); (b) VVVGAGGVGK (SEQ ID NO: 239); (c) MTEYKLVVVGAGGVGKSALTIQLI (SEQ ID NO: 240); (d) GAGGVGKSA (SEQ ID NO: 246); or (e) GAGGVGKSAL (SEQ ID NO: 248). 7. An isolated or purified polypeptide comprising a functional portion of the TCR of any one of claims 1-6, wherein the polypeptide comprises the amino acid sequences of: (1) all of SEQ ID NOs: 1-6; (2) all of SEQ ID NOs: 11-16; (3) all of SEQ ID NOs: 21-26; (4) all of SEQ ID NOs: 31-36 (5) all of SEQ ID NOs: 41-46; (6) all of SEQ ID NOs: 51-56; (7) all of SEQ ID NOs: 61-66; (8) all of SEQ ID NOs: 71-76 (9) all of SEQ ID NOs: 81-86; (10) all of SEQ ID NOs: 91-96; (11) all of SEQ ID NOs: 101-106; (12) all of SEQ ID NOs: 111-116; (13) all of SEQ ID NOs: 121-126; (14) all of SEQ ID NOs: 131-136; or (15) all of SEQ ID NOs: 141-146. 8. The polypeptide of claim 7, wherein the polypeptide comprises the amino acid sequences of: (1) SEQ ID NO: 7, (2) SEQ ID NO: 8, Leydig 771261 HHS E-132-2023-0-PC-01 80 (3) SEQ ID NO: 9, (4) SEQ ID NO: 10, (5) SEQ ID NO: 17, (6) SEQ ID NO: 18, (7) SEQ ID NO: 19, (8) SEQ ID NO: 20, (9) SEQ ID NO: 27, (10) SEQ ID NO: 28, (11) SEQ ID NO: 29, (12) SEQ ID NO: 30, (13) SEQ ID NO: 37, (14) SEQ ID NO: 38, (15) SEQ ID NO: 39, (16) SEQ ID NO: 40, (17) SEQ ID NO: 47, (18) SEQ ID NO: 48, (19) SEQ ID NO: 49, (20) SEQ ID NO: 50, (21) SEQ ID NO: 57, (22) SEQ ID NO: 58, (23) SEQ ID NO: 59, (24) SEQ ID NO: 60, (25) SEQ ID NO: 67, (26) SEQ ID NO: 68, (27) SEQ ID NO: 69, (28) SEQ ID NO: 70, (29) SEQ ID NO: 77, (30) SEQ ID NO: 78, (31) SEQ ID NO: 79, (32) SEQ ID NO: 80, (33) SEQ ID NO: 87, (34) SEQ ID NO: 88, (35) SEQ ID NO: 89, Leydig 771261 HHS E-132-2023-0-PC-01 81 (36) SEQ ID NO: 90, (37) SEQ ID NO: 97, (38) SEQ ID NO: 98, (39) SEQ ID NO: 99, (40) SEQ ID NO: 100, (41) SEQ ID NO: 107, (42) SEQ ID NO: 108, (43) SEQ ID NO: 109, (44) SEQ ID NO: 110, (45) SEQ ID NO: 117, (46) SEQ ID NO: 118, (47) SEQ ID NO: 119, (48) SEQ ID NO: 120, (49) SEQ ID NO: 127, (50) SEQ ID NO: 128, (51) SEQ ID NO: 129, (52) SEQ ID NO: 130, (53) SEQ ID NO: 137, (54) SEQ ID NO: 138, (55) SEQ ID NO: 139, (56) SEQ ID NO: 140, (57) SEQ ID NO: 147, (58) SEQ ID NO: 148, (59) SEQ ID NO: 149, (60) SEQ ID NO: 150, (61) both of SEQ ID NOs: 7 and 8, (62) both of SEQ ID NOs: 9 and 10, (63) both of SEQ ID NOs: 17 and 18, (64) both of SEQ ID NOs: 19 and 20, (65) both of SEQ ID NOs: 27 and 28, (66) both of SEQ ID NOs: 29 and 30, (67) both of SEQ ID NOs: 37 and 38, (68) both of SEQ ID NOs: 39 and 40, Leydig 771261 HHS E-132-2023-0-PC-01 82 (69) both of SEQ ID NOs: 47 and (70) both of SEQ ID NOs: 49 and 50, (71) both of SEQ ID NOs: 57 and 58, (72) both of SEQ ID NOs: 59 and 60, (73) both of SEQ ID NOs: 67 and 68, (74) both of SEQ ID NOs: 69 and 70, (75) both of SEQ ID NOs: 77 and 78, (76) both of SEQ ID NOs: 79 and 80, (77) both of SEQ ID NOs: 87 and 88, (78) both of SEQ ID NOs: 89 and 90, (79) both of SEQ ID NOs: 97 and 98, (80) both of SEQ ID NOs: 99 and 100, (81) both of SEQ ID NOs: 107 and 108, (82) both of SEQ ID NOs: 109 and 110, (83) both of SEQ ID NOs: 117 and 118, (84) both of SEQ ID NOs: 119 and 120, (85) both of SEQ ID NOs: 127 and 128, (86) both of SEQ ID NOs: 129 and 130, (87) both of SEQ ID NOs: 137 and 138, (88) both of SEQ ID NOs: 139 and 140, (89) both of SEQ ID NOs: 147 and 148, or (90) both of SEQ ID NOs: 149 and 150. 9. The polypeptide of claim 7 or 8, wherein the polypeptide further comprises: (a) the amino acid sequence of SEQ ID NO: 153, wherein: (i) X at position 48 of SEQ ID NO: 153 is Thr or Cys; (ii) X at position 112 of SEQ ID NO: 153 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 114 of SEQ ID NO: 153 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 115 of SEQ ID NO: 153 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; Leydig 771261 HHS E-132-2023-0-PC-01 83 (b) the amino acid sequence of SEQ NO: 154, wherein X at position 57 of SEQ ID NO: 154 is Ser or Cys; or (c) both (a) and (b). 10. The polypeptide of any one of claims 7-9, wherein the polypeptide comprises the amino acid sequences of: (1) SEQ ID NO: 155; (2) SEQ ID NO: 156; (3) both of SEQ ID NOs: 155 and 156; (4) SEQ ID NO: 157; (5) SEQ ID NO: 158; (6) both of SEQ ID NOs: 157 and 158; (7) SEQ ID NO: 159; (8) SEQ ID NO: 160; (9) both of SEQ ID NOs: 159 and 160; (10) SEQ ID NO: 161; (11) SEQ ID NO: 162; (12) both of SEQ ID NOs: 161 and 162; (13) SEQ ID NO: 163; (14) SEQ ID NO: 164; (15) both of SEQ ID NOs: 163 and 164; (16) SEQ ID NO: 165; (17) SEQ ID NO: 166; (18) both of SEQ ID NOs: 165 and 166; (19) SEQ ID NO: 167; (20) SEQ ID NO: 168; (21) both of SEQ ID NOs: 167 and 168; (22) SEQ ID NO: 169; (23) SEQ ID NO: 170; (24) both of SEQ ID NOs: 169 and 170; (25) SEQ ID NO: 171; (26) SEQ ID NO: 172; (27) both of SEQ ID NOs: 171 and 172; Leydig 771261 HHS E-132-2023-0-PC-01 84 (28) SEQ ID NO: 173; (29) SEQ ID NO: 174; (30) both of SEQ ID NOs: 173 and 174; (31) SEQ ID NO: 175; (32) SEQ ID NO: 176; (33) both of SEQ ID NO: 175 and 176; (34) SEQ ID NO: 177; (35) SEQ ID NO: 178; (36) both of SEQ ID NO: 177 and 178; (37) SEQ ID NO: 179; (38) SEQ ID NO: 180; (39) both of SEQ ID NO: 179 and 180; (40) SEQ ID NO: 181; (41) SEQ ID NO: 182; (42) both of SEQ ID NO: 181 and 182; (43) SEQ ID NO: 183; (44) SEQ ID NO: 184; (45) both of SEQ ID NO: 183 and 184; (46) SEQ ID NO: 185; (47) SEQ ID NO: 186; (48) both of SEQ ID NO: 185 and 186; (49) SEQ ID NO: 187; (50) SEQ ID NO: 188; (51) both of SEQ ID NO: 187 and 188; (52) SEQ ID NO: 189; (53) SEQ ID NO: 190; (54) both of SEQ ID NO: 189 and 190; (55) SEQ ID NO: 191; (56) SEQ ID NO: 192; (57) both of SEQ ID NO: 191 and 192; (58) SEQ ID NO: 193; (59) SEQ ID NO: 194; (60) both of SEQ ID NO: 193 and 194; Leydig 771261 HHS E-132-2023-0-PC-01 85 (61) SEQ ID NO: 195; (62) SEQ ID NO: 196; (63) both of SEQ ID NO: 195 and 196; (64) SEQ ID NO: 197; (65) SEQ ID NO: 198; (66) both of SEQ ID NO: 197 and 198; (67) SEQ ID NO: 199; (68) SEQ ID NO: 200; (69) both of SEQ ID NO: 199 and 200; (70) SEQ ID NO: 201; (71) SEQ ID NO: 202; (72) both of SEQ ID NO: 201 and 202; (73) SEQ ID NO: 203; (74) SEQ ID NO: 204; (75) both of SEQ ID NO: 203 and 204; (76) SEQ ID NO: 205; (77) SEQ ID NO: 206; (78) both of SEQ ID NO: 205 and 206; (79) SEQ ID NO: 207; (80) SEQ ID NO: 208; (81) both of SEQ ID NO: 207 and 208; (82) SEQ ID NO: 209; (83) SEQ ID NO: 210; (84) both of SEQ ID NO: 209 and 210; (85) SEQ ID NO: 211; (86) SEQ ID NO: 212; (87) both of SEQ ID NO: 211 and 212; (88) SEQ ID NO: 213; (89) SEQ ID NO: 214; or (90) both of SEQ ID NO: 213 and 214. 11. An isolated or purified protein comprising first and second polypeptide chains, wherein: Leydig 771261 HHS E-132-2023-0-PC-01 86 (1) the first polypeptide chain the amino acid sequences of all of SEQ ID NOs: 1-3 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 4-6; (2) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 11-13 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 14-16; (3) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 21-23 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 24-26; (4) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 31-33 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 34-36; (5) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 41-43 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 44-46; (6) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 51-53 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 54-56; (7) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 61-63 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 64-66; (8) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 71-73 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 74-76; (9) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 81-83 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 84-86; (10) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 91-93 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 94-96; (11) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 101-103 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 104-106; Leydig 771261 HHS E-132-2023-0-PC-01 87 (12) the first polypeptide chain the amino acid sequences of all of SEQ ID NOs: 111-113 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 114-116; (13) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 121-123 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 124-126; (14) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 131-133 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 134-136; or (15) the first polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 141-143 and the second polypeptide chain comprises the amino acid sequences of all of SEQ ID NOs: 144-146. 12. The protein of claim 11, wherein: (1) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 7; (2) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 8; (3) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 7 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 8; (4) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9; (5) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10; (6) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10; (7) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17; (8) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18; (9) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18; (10) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 19; (11) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 20; Leydig 771261 HHS E-132-2023-0-PC-01 88 (12) the first polypeptide chain the amino acid sequence of SEQ ID NO: 19 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 20; (13) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 27; (14) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 28; (15) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 27 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 28; (16) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 29; (17) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 30; (18) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 29 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 30; (19) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 37; (20) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 38; (21) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 37 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 38; (22) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 39; (23) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 40; (24) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 39 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 40; (25) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 47; (26) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 48; (27) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 47 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 48; Leydig 771261 HHS E-132-2023-0-PC-01 89 (28) the first polypeptide chain the amino acid sequence of SEQ ID NO: 49; (29) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 50; (30) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 49 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 50; (31) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 57; (32) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 58; (33) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 57 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 58; (34) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 59; (35) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 60; (36) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 59 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 60; (37) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 67; (38) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 68; (39) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 67 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 68; (40) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 69; (41) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 70; (42) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 69 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 70; (43) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 77; Leydig 771261 HHS E-132-2023-0-PC-01 90 (44) the second polypeptide chain the amino acid sequence of SEQ ID NO: 78; (45) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 77 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 78; (46) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 79; (47) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 80; (48) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 79 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 80; (49) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 87; (50) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 88; (51) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 87 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 88; (52) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 89; (53) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 90; (54) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 89 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 90; (55) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 97; (56) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 98; (57) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 97 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 98; (58) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 99; (59) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100; Leydig 771261 HHS E-132-2023-0-PC-01 91 (60) the first polypeptide chain the amino acid sequence of SEQ ID NO: 99 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100; (61) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107; (62) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 108; (63) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 108; (64) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 109; (65) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 110; (66) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 109 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 110; (67) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 117; (68) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 118; (69) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 117 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 118; (70) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 119; (71) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 120; (72) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 119 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 120; (73) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 127; Leydig 771261 HHS E-132-2023-0-PC-01 92 (74) the second polypeptide chain the amino acid sequence of SEQ ID NO: 128; (75) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 127 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 128; (76) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129; (77) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130; (78) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130; (79) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137; (80) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138; (81) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138; (82) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139; (83) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140; (84) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140; (85) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147; (86) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148; (87) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148; Leydig 771261 HHS E-132-2023-0-PC-01 93 (88) the first polypeptide chain the amino acid sequence of SEQ ID NO: 149; (89) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 150; or (90) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 149 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 150. 13. The isolated or purified protein of claim 11 or 12, wherein: (a) the first polypeptide chain further comprises the amino acid sequence of SEQ ID NO: 153, wherein: (i) X at position 48 of SEQ ID NO: 153 is Thr or Cys; (ii) X at position 112 of SEQ ID NO: 153 is Ser, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (iii) X at position 114 of SEQ ID NO: 153 is Met, Ala, Val, Leu, Ile, Pro, Phe, or Trp; and (iv) X at position 115 of SEQ ID NO: 153 is Gly, Ala, Val, Leu, Ile, Pro, Phe, Met, or Trp; (b) the second polypeptide chain further comprises the amino acid sequence of SEQ ID NO: 154, wherein X at position 57 of SEQ ID NO: 154 is Ser or Cys; or (c) both (a) and (b). 14. The protein of any one of claims 11-13, wherein: (1) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155; (2) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156; (3) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156; (4) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 157; (5) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 158; Leydig 771261 HHS E-132-2023-0-PC-01 94 (6) the first polypeptide chain the amino acid sequence of SEQ ID NO: 157 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 158; (7) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 159; (8) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 160; (9) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 159 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 160; (10) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161; (11) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162; (12) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162; (13) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163; (14) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164; (15) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164; (16) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 165; (17) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 166; (18) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 165 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 166; (19) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 167; (20) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 168; Leydig 771261 HHS E-132-2023-0-PC-01 95 (21) the first polypeptide chain the amino acid sequence of SEQ ID NO: 167 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 168; (22) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169; (23) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170; (24) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170; (25) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171; (26) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172; (27) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172; (28) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 173; (29) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 174; (30) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 173 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 174; (31) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 175; (32) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 176; (33) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 175 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 176; (34) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177; Leydig 771261 HHS E-132-2023-0-PC-01 96 (35) the second polypeptide chain the amino acid sequence of SEQ ID NO: 178; (36) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178; (37) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179; (38) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 180; (39) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 180; (40) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 181; (41) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 182; (42) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 181 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 182; (43) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 183; (44) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 184; (45) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 183 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 184; (46) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185; (47) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186; (48) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186; Leydig 771261 HHS E-132-2023-0-PC-01 97 (49) the first polypeptide chain the amino acid sequence of SEQ ID NO: 187; (50) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188; (51) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 187 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188; (52) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 189; (53) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 190; (54) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 189 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 190; (55) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 191; (56) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 192; (57) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 191 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 192; (58) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 193; (59) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 194; (60) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 193 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 194; (61) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 195; (62) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: Leydig 771261 HHS E-132-2023-0-PC-01 98 (63) the first polypeptide chain the amino acid sequence of SEQ ID NO: 195 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 196; (64) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 197; (65) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 198; (66) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 197 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 198; (67) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 199; (68) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 200; (69) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 199 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 200; (70) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 201; (71) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 202; (72) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 201 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 202; (73) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 203; (74) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 204; (75) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 203 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 204; (76) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 205; Leydig 771261 HHS E-132-2023-0-PC-01 99 (77) the second polypeptide chain the amino acid sequence of SEQ ID NO: 206; (78) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 205 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 206; (79) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 207; (80) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 208; (81) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 207 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 208; (82) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 209; (83) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 210; (84) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 209 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 210; (85) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 211; (86) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 212; (87) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 211 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 212; (88) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 213; (89) the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 214; or (90) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 213 and the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 214. Leydig 771261 HHS E-132-2023-0-PC-01 100 15. A bispecific engager TCR fusion protein comprising (i) the TCR according to any one of claims 1-6, the polypeptide according to any one of claims 7-10, or the protein according to any one of claims 11-15 and (ii) an anti-CD3 effector. 16. An isolated or purified nucleic acid comprising a nucleotide sequence encoding the TCR of any one of claims 1-6, the polypeptide of any one of claims 7-10, the protein of any one of claims 11-15. 17. An isolated or purified nucleic acid comprising, from 5’ to 3’, a first nucleic acid sequence and a second nucleotide sequence, wherein the first and second nucleotide sequence, respectively, encode the amino sequences of SEQ ID NOs: 7 and 8; 8 and 7; 9 and 10; 10 and 9; 17 and 18; 18 and 17; 19 and 20; 20 and 19; 27 and 28; 28 and 27; 29 and 30; 30 and 29; 37 and 38; 38 and 37; 39 and 40; 40 and 39; 47 and 48; 48 and 47; 49 and 50; 50 and 49; 57 and 58; 58 and 57; 59 and 60; 60 and 59; 67 and 68; 68 and 67; 69 and 70; 70 and 69; 77 and 78; 78 and 77; 79 and 80; 80 and 79; 87 and 88; 88 and 87; 89 and 90; 90 and 89; 97 and 98; 98 and 97; 99 and 100; 100 and 99; 107 and 108; 108 and 107; 109 and 110; 110 and 109; 117 and 118; 118 and 117; 119 and 120; 120 and 119; 127 and 128; 128 and 127; 129 and 130; 130 and 129; 137 and 138; 139 and 137; 139 and 140; 140 and 139; 147 and 148; 148 and 147; 149 and 150; or 150 and 149. 18. The isolated or purified nucleic acid of claim 17, further comprising a third nucleotide acid sequence interposed between the first and second nucleotide sequence, wherein the third nucleotide sequence encodes a cleavable linker peptide. 19. The isolated or purified nucleic acid of claim 18, wherein the cleavable linker peptide comprises the amino acid sequence of RAKRSGSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 231). 20. A recombinant expression vector comprising the nucleic acid of any one of claims 16-19. Leydig 771261 HHS E-132-2023-0-PC-01 101 21. The recombinant expression of claim 20, which is a transposon or a lentiviral vector. 22. An isolated or purified TCR, polypeptide, or protein encoded by the nucleic acid of any one of claims 16-19 or the vector of claim 20 or 21. 23. An isolated or purified TCR, polypeptide, or protein that results from expression of the nucleic acid of any one of claims 16-19 or the vector of claim 20 or 21 in a cell. 24. A method of producing a host cell expressing a TCR that has antigenic specificity for a human RAS G12V , human RAS G12D , or human RAS G12R amino acid sequence, the method comprising contacting a cell in vitro with the vector of claim 20 or 21 under conditions that allow introduction of the vector into the cell. 25. An isolated or purified host cell comprising the nucleic acid of any one of claims 16-19 or the recombinant expression vector of claim 20 or 21. 26. The host cell of claim 25, wherein the cell is a human lymphocyte. 27. The host cell of claim 25, wherein the cell is selected from the group consisting of a T cell, a natural killer T (NKT) cell, an invariant natural killer T (iNKT) cell, a natural killer (NK) cell, a macrophage, a pluripotent cell, and a multipotent cell. 28. An isolated or purified population of cells comprising the host cell of any one of claims 25-27. 29. A method of producing the TCR of any one of claims 1-6, 22, or 23, the polypeptide of any one of claims 7-10, 22, or 23, or the protein of any one of claims 11-15, 22, or 23, the method comprising culturing the host cell of any one of claims 25-27, or the population of host cells of claim 28, so that the TCR, polypeptide, or protein is produced. 30. A pharmaceutical composition comprising (a) the TCR of any one of claims 1-6, 22, or 23, the polypeptide of any one of claims 7-10, 22, or 23, or the protein of any one of Leydig 771261 HHS E-132-2023-0-PC-01 102 claims 11-15, 22, or 23, the nucleic acid of any one of claims 16-19, the recombinant expression vector of claim 20 or 21, the host cell of any one of claims 25-27, or the population of host cells of claim 28 and (b) a pharmaceutically acceptable carrier. 31. A method of detecting the presence of cancer in mammal, the method comprising: (a) contacting a sample comprising cells of the cancer with the TCR of any one of claims 1-6, 22, or 23, the polypeptide of any one of claims 7-10, 22, or 23, or the protein of any one of claims 11-15, 22, or 23, the nucleic acid of any one of claims 16-19, the recombinant expression vector of claim 20 or 21, the host cell of any one of claims 25-27, the population of host cells of claim 28, or the pharmaceutical composition of claim 30, thereby forming a complex; and (b) detecting the complex, wherein detection of the complex is indicative of the presence of cancer in the mammal. 32. The TCR of any one of claims 1-6, 22, or 23, the polypeptide of any one of claims 7-10, 22, or 23, or the protein of any one of claims 11-15, 22, or 23, the nucleic acid of any one of claims 16-19, the recombinant expression vector of claim 20 or 21, the host cell of any one of claims 25-27, the population of host cells of claim 28, or the pharmaceutical composition of claim 30, for use in the inducement of an immune response against cancer in a mammal. 33. The TCR of any one of claims 1-6, 22, or 23, the polypeptide of any one of claims 7-10, 22, or 23, or the protein of any one of claims 11-15, 22, or 23, the nucleic acid of any one of claims 16-19, the recombinant expression vector of claim 20 or 21, the host cell of any one of claims 25-27, the population of host cells of claim 28, or the pharmaceutical composition of claim 30, for use in the treatment or prevention of cancer in a mammal. 34. The population of cells for the use of claim 32 or 33, wherein the population of cells is autologous to the mammal. Leydig 771261 HHS E-132-2023-0-PC-01 103 35. The population of cells for the use of claim 32 or 33, wherein the population of cells is allogeneic to the mammal. 36. The method of claim 31, or the TCR, polypeptide, protein, nucleic acid, recombinant expression vector, host cell, population of cells, or pharmaceutical composition for the use of any one of claims 32-35, wherein the cancer expresses a mutated human RAS amino acid sequence with a substitution of glycine at position 12 with aspartic acid, valine, or arginine, wherein the mutated human RAS amino acid sequence is a mutated human Kirsten rat sarcoma viral oncogene homolog (KRAS), a mutated human Harvey rat sarcoma viral oncogene homolog (HRAS), or a mutated human Neuroblastoma rat sarcoma viral oncogene homolog (NRAS) amino acid sequence, and wherein position 12 is defined by reference to the wild-type human KRAS, wild-type human HRAS, or wild-type human NRAS protein, respectively. 37. The method according to claim 31, or the TCR, polypeptide, protein, nucleic acid, recombinant expression vector, host cell, population of cells, or pharmaceutical composition for the use of any one of claims 32-36, wherein the cancer is pancreatic, colorectal, lung, endometrial, ovarian, or prostate cancer.

Description

Leydig 771261 HHS E-132-2023-0-PC-01 1 T CELL RECEPTORS TARGETING RAS WITH G12D, G12R, OR G12V MUTATION CROSS-REFERENCE TO RELATED APPLICATION This patent application claims the benefit of U.S. Provisional Patent Application No.63/510,817, filed June 28, 2023, which is incorporated by reference in its entirety herein. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under project number ZIA- BC-010984 by the National Institutes of Health, National Cancer Institute. The Government has certain rights in the invention. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY Incorporated by reference in its entirety herein is a computer-readable nucleotide/amino acid sequence listing submitted concurrently herewith and identified as follows: One 283,472 Byte XML file named “771261.XML,” dated June 5, 2024. BACKGROUND OF THE INVENTION Some cancers may have very limited treatment options, particularly when the cancer becomes metastatic and unresectable. Despite advances in treatments such as, for example, surgery, chemotherapy, and radiation therapy, the prognosis for many cancers, such as, for example, pancreatic, colorectal, lung, endometrial, ovarian, and prostate cancers, may be poor. Accordingly, there exists an unmet need for additional treatments for cancer. BRIEF SUMMARY OF THE INVENTION An aspect of the invention provides an isolated or purified T-cell receptor (TCR) having antigenic specificity for a mutated human RAS amino acid sequence with a substitution of glycine at position 12 with aspartic acid, valine, or arginine, wherein the mutated human RAS amino acid sequence is a mutated human Kirsten rat sarcoma viral oncogene homolog (KRAS), a mutated human Harvey rat sarcoma viral oncogene homolog (HRAS), or a mutated human Neuroblastoma rat sarcoma viral oncogene homolog (NRAS) amino acid sequence, wherein position 12 is defined by reference to the wild-type human Leydig 771261 HHS E-132-2023-0-PC-01 2 KRAS, wild-type human HRAS, or wild- human NRAS protein, respectively, and wherein the TCR comprises the amino acid sequences of: (1) all of SEQ ID NOs: 1-6; (2) all of SEQ ID NOs: 11-16; (3) all of SEQ ID NOs: 21-26; (4) all of SEQ ID NOs: 31-36; (5) all of SEQ ID NOs: 41-46; (6) all of SEQ ID NOs: 51-56; (7) all of SEQ ID NOs: 61-66; (8) all of SEQ ID NOs: 71-76; (9) all of SEQ ID NOs: 81-86; (10) all of SEQ ID NOs: 91-96; (11) all of SEQ ID NOs: 101-106; (12) all of SEQ ID NOs: 111-116; (13) all of SEQ ID NOs: 121-126; (14) all of SEQ ID NOs: 131-136; or (15) all of SEQ ID NOs: 141-146. Further aspects of the invention provide polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions relating to the TCRs of the invention. Another aspect of the invention provides an isolated or purified nucleic acid comprising, from 5’ to 3’, a first nucleic acid sequence and a second nucleotide sequence, wherein the first and second nucleotide sequence, respectively, encode the amino sequences of SEQ ID NOs: 7 and 8; 8 and 7; 9 and 10; 10 and 9; 17 and 18; 18 and 17; 19 and 20; 20 and 19; 27 and 28; 28 and 27; 29 and 30; 30 and 29; 37 and 38; 38 and 37; 39 and 40; 40 and 39; 47 and 48; 48 and 47; 49 and 50; 50 and 49; 57 and 58; 58 and 57; 59 and 60; 60 and 59; 67 and 68; 68 and 67; 69 and 70; 70 and 69; 77 and 78; 78 and 77; 79 and 80; 80 and 79; 87 and 88; 88 and 87; 89 and 90; 90 and 89; 97 and 98; 98 and 97; 99 and 100; 100 and 99; 107 and 108; 108 and 107; 109 and 110; 110 and 109; 117 and 118; 118 and 117; 119 and 120; 120 and 119; 127 and 128; 128 and 127; 129 and 130; 130 and 129; 137 and 138; 139 and 137; 139 and 140; 140 and 139; 147 and 148; 148 and 147; 149 and 150; or 150 and 149. Still further aspects of the invention provide methods of detecting the presence of cancer in a mammal, methods of inducing an immune response against a cancer in a mammal, and methods of treating or preventing cancer in a mammal. Additional aspects of the invention provide methods of producing a host cell expressing the TCR and methods of producing the TCR, polypeptide, or protein. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS Figures 1A-1C are graphs showing the percentage of effector cells expressing 4- 1BB and/or OX40 following co-culture of effector cells with target cells. Effector cells were healthy donor PBL independently transduced with a retroviral expression vector encoding the 4385 TCR-Z (A), 4394 TCR-10 (B), or 4394 TCR-A (C). The target cells were HLA- C*01:02 positive COS-C*01:02 cells which had been incubated with the mutant RASG12V 9- Leydig 771261 HHS E-132-2023-0-PC-01 3 mer peptide (unshaded circles) or the WT peptide (shaded circles) at the indicated concentration of peptides. Figures 1D-1E are graphs showing IFN-gamma secretion measured following co- culture of effector cells with 4391 PDX cells, which are relevant target cells expressing RASG12V