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US 2026/0265338 A1Published application
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 Servic
InventorsNoam Levin, Rami Yoseph, Gal Cafri, Steven A. Rosenberg
Life of this patent
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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.
Claims20
An isolated or purified 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.
29 more elements
A polypeptide 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.
26 more elements
An isolated or purified protein, comprising:
- (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.
10 more elements
Dependencies are inferred from the claim text.