HLA class II-restricted DRB T cell receptors against RAS with G12D mutation
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsNoam Levin, Rami Yoseph, Gal Cafri, Steven A. Rosenberg
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Abstract
Disclosed is an isolated or purified T cell receptor (TCR), 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. The TCRs may recognize G12D RAS presented by an HLA-DR heterodimer. 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.
Claims38
An isolated or purified nucleic acid comprising a nucleotide sequence encoding a T-cell receptor (TCR) comprising:
- (a) the alpha chain complementarity determining region (CDR)1 amino acid sequence of SEQ ID NO:
- 1, the alpha chain CDR2 amino acid sequence of SEQ ID NO:
- 2, the alpha chain CDR3 amino acid sequence of SEQ ID NO:
- 3, the beta chain CDR1 amino acid sequence of SEQ ID NO:
- 4, the beta chain CDR2 amino acid sequence of SEQ ID NO:
- 5, and the beta chain CDR3 amino acid sequence of SEQ ID NO:
- 6;
- (b) the alpha chain CDR1 amino acid sequence of SEQ ID NO:
- 11, the alpha chain CDR2 amino acid sequence of SEQ ID NO:
- 12, the alpha chain CDR3 amino acid sequence of SEQ ID NO:
- 13, the beta chain CDR1 amino acid sequence of SEQ ID NO:
- 14, the beta chain CDR2 amino acid sequence of SEQ ID NO:
- 15, and the beta chain CDR3 amino acid sequence of SEQ ID NO:
- 16;
- (c) the alpha chain CDR1 amino acid sequence of SEQ ID NO:
- 21, the alpha chain CDR2 amino acid sequence of SEQ ID NO:
- 22, the alpha chain CDR3 amino acid sequence of SEQ ID NO:
- 23, the beta chain CDR1 amino acid sequence of SEQ ID NO:
- 24, the beta chain CDR2 amino acid sequence of SEQ ID NO:
- 25, and the beta chain CDR3 amino acid sequence of SEQ ID NO:
- 26;
- or
- (d) the alpha chain CDR1 amino acid sequence of SEQ ID NO:
- 31, the alpha chain CDR2 amino acid sequence of SEQ ID NO:
- 32, the alpha chain CDR3 amino acid sequence of SEQ ID NO:
- 33, the beta chain CDR1 amino acid sequence of SEQ ID NO:
- 34, the beta chain CDR2 amino acid sequence of SEQ ID NO:
- 35, and the beta chain CDR3 amino acid sequence of SEQ ID NO:
- 36,
- 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,
- 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.
An isolated or purified nucleic acid comprising a nucleotide sequence encoding a protein, wherein the protein comprises:
- (a) a first polypeptide chain comprising the amino acid sequences of SEQ ID NOs:
- 1-3 and a second polypeptide chain comprising the amino acid sequences of SEQ ID NOs:
- 4-6;
- (b) a first polypeptide chain comprising the amino acid sequences of SEQ ID NOs:
- 11-13 and a second polypeptide chain comprising the amino acid sequences of SEQ ID NOs:
- 14-16;
- (c) a first polypeptide chain comprising the amino acid sequences of SEQ ID NOs:
- 21-23 and a second polypeptide chain comprising the amino acid sequences of SEQ ID NOs:
- 24-26;
- or
- (d) a first polypeptide chain comprising the amino acid sequences of SEQ ID NOs:
- 31-33 and a second polypeptide chain comprising the amino acid sequences of SEQ ID NOs:
- 34-36.
An isolated or purified nucleic acid comprising, from 5′ to 3′, a first nucleotide 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;
- 55 and 56;
- 56 and 55;
- 57 and 58;
- 58 and 57;
- 59 and 60;
- 60 and 59;
- 61 and 62;
- 62 and 61;
- 63 and 64;
- 64 and 63;
- 65 and 66;
- 66 and 65;
- 67 and 68;
- 68 and 67;
- 69 and 70;
- 70 and 69;
- 71 and 72;
- 72 and 71;
- 73 and 74;
- 74 and 73;
- 75 and 76;
- 76 and 75;
- 77 and 78;
- 78 and 77;
- 79 and 80;
- 80 and 79;
- 81 and 82;
- 82 and 81;
- 83 and 84;
- 84 and 83;
- 85 and 86;
- or 86 and 85.
Dependencies are inferred from the claim text.