US 2019/0336529 A1 · T-CELL RECEPTORS WHICH RECOGNISE FRAMESHIFT MUTANTS OF TGFBRII

Abstract

The present invention relates to TCR molecules which recognise neopeptides produced as a result of the cancer-associated “−1A” frameshift mutation in human TGFβRII. The TCR molecules are capable of binding a peptide of SEQ ID NO: 1 when said peptide is presented by a Class I MHC, and comprise an α-chain domain and a β-chain domain, each chain domain comprising three CDR sequences, wherein a) CDRs 1, 2 and 3 of the α-chain domain have the sequences of SEQ ID NOs: 2, 3 and 4 respectively; and b) CDRs 1, 2 and 3 of the β-chain domain have the sequences of SEQ ID NOs: 5, 6 and 7 respectively, and wherein one or more of said CDR sequences may optionally be modified by substitution, addition or deletion of 1 or 2 amino acids. Nucleic acid molecules encoding such TCRs are provided, as are soluble TCR molecules with these CDR sequences. The nucleic acid molecules of the invention can be used to modify immune effector cells to express a TCR as defined herein, and such modified immune effector cells are useful in therapy for cancer, as are soluble TCRs as defined above.

Claims43

Dependent claims

A nucleic acid molecule encoding a T-cell receptor (TCR) molecule directed against a mutated TGFβRII protein which comprises the sequence of SEQ ID NO:

1, wherein said TCR molecule is capable of binding a peptide of SEQ ID NO:
1 when said peptide is presented by a Class I Major Histocompatibility Complex (MHC) comprising HLA-A2, and wherein said TCR molecule comprises an α-chain domain and a β-chain domain, each chain domain comprising three CDR sequences, wherein
a) CDRs 1, 2 and 3 of the α-chain domain have the sequences of SEQ ID NOs:
2, 3 and 4 respectively;
and
b) CDRs 1, 2 and 3 of the β-chain domain have the sequences of SEQ ID NOs:
5, 6 and 7 respectively;
and
wherein said α-chain domain comprises:
i) a variable region comprising the amino acid sequence set forth in SEQ ID NO:
72;
or an amino acid sequence with at least 95% sequence identity thereto;
and
ii) a constant region comprising the amino acid sequence set forth in SEQ ID NO:
9, or a modified version thereof comprising one or more amino acid substitutions or insertions relative to SEQ ID NO:
9 and having at least 95% sequence identity to SEQ ID NO:
9, or a murinised version of SEQ ID NO:
9;
and
said β-chain domain comprises:
i) a variable region comprising the amino acid sequence set forth in SEQ ID NO:
75;
or an amino acid sequence with at least 95% sequence identity thereto;
and
ii) a constant region comprising the amino acid sequence set forth in SEQ ID NO:
14, or an amino acid sequence with at least 95% sequence identity to SEQ ID NO:
14, or a murinised version of SEQ ID NO:
14.

25 more elements

A nucleic acid molecule encoding a soluble T-cell receptor (TCR) molecule directed against a mutated TGFβRII protein which comprises the sequence of SEQ ID NO:

1, wherein said TCR molecule is capable of binding a peptide of SEQ ID NO:
1 when said peptide is presented by a Class I Major Histocompatibility Complex (MHC) comprising HLA-A2, and wherein said soluble TCR molecule comprises an α-chain domain and a β-chain domain, each chain domain comprising three CDR sequences, wherein
a) CDRs 1, 2 and 3 of the α-chain domain have the sequences of SEQ ID NOs:
2, 3 and 4 respectively;
and
b) CDRs 1, 2 and 3 of the β-chain domain have the sequences of SEQ ID NOs:
5, 6 and 7 respectively;
and
wherein said α-chain domain comprises:
i) a variable region comprising the amino acid sequence set forth in SEQ ID NO:
72, or an amino acid sequence with at least 95% sequence identity thereto;
and
ii) a constant region comprising the amino acid sequence set forth in SEQ ID NO:
60, or an amino acid sequence with at least 95% sequence identity thereto;
and
said β-chain domain comprises:
i) a variable region comprising the amino acid sequence set forth in SEQ ID NO:
75, or an amino acid sequence with at least 95% sequence identity thereto;
and
ii) a constant region comprising the amino acid sequence set forth in SEQ ID NO:
62, or an amino acid sequence with at least 95% sequence identity thereto, wherein said TCR is soluble.

18 more elements

Dependencies are inferred from the claim text.

T-cell receptors which recognise frameshift mutants of tgfbrii

Life of this patent

T-cell receptors which recognise frameshift mutants of tgfbrii

Life of this patent

Abstract

Claims43