Nucleic acid molecules encoding non-naturally occurring T cell receptors and cells thereof
AssigneeImmunocore Limited
InventorsBent Karsten Jakobsen, Naomi Harwood, Nathaniel Ross Liddy
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Abstract
A T cell receptor (TCR) having the property of binding to the gp100 YLEPGPVTA peptide-HLA-A2 complex and comprising a TCR alpha variable domain and/or a TCR beta variable domain, characterized in that the domains are mutated relative to a TCR having the extracellular alpha and beta chain sequences SEQ ID NOs: 2 and that the TCR has a binding affinity for, and/or a binding half-life for, the YLEPGPVTA-HLA-A2 complex at least double that of a reference TCR. Embodiments of the invention such as the use of such TCRs in adoptive therapy, and fusions of such TCRs with therapeutic agents are also described.
Claims66
A DNA or RNA molecule encoding a T cell receptor (TCR) that binds to a YLEPGPVTA (SEQ ID NO:
- 1)-HLA-A2 complex comprising a TCR alpha chain variable domain and a TCR beta chain variable domain, wherein:
- (a) the alpha chain variable domain has
- (i) at least 90% sequence identity to the amino acid sequence comprising amino acids 1 to 109 of SEQ ID NO:
- 2, or
- (ii) at least 90% sequence identity to the amino acids 1 to 109 of SEQ ID NO:
- 2 and has a mutation at one or more positions selected from the group consisting of:
- 94D, 97L, 98V and 102G;
- (b) the beta chain variable domain has
- (i) amino acids 1 to 112 of SEQ ID NO:
- 3, and a mutation at one or more positions selected from the group consisting of:
- 27L, 28N, 29H, 30D, 31A, 50Q, 51I, 52V, 53N, 54D, 61A, 94S, 95I, 96G, 97G, 98P and 100E, or
- (ii) at least 90% sequence identity to the amino acid sequence comprising amino acids 1 to 112 of SEQ ID NO:
- 3;
- (c) the TCR has a binding affinity for, and/or a binding half-life for, the YLEPGPVTA-(SEQ ID NO:
- 1) HLA-A2 complex which is at least double that of a reference TCR, the reference TCR having an extracellular alpha chain sequence of SEQ ID NO:
- 45 and an extracellular beta chain sequence of SEQ ID NO:
- 46;
- and
- (d) at least one of the alpha and beta chain variable domains has at least one mutation.
The DNA or RNA molecule according to 11, wherein alpha chain amino acid sequence is (i) and the beta chain-anti-CD3 amino acid sequence is (vii).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (i) and the beta chain-anti-CD3 amino acid sequence is (x).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (ix).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (v) and the beta chain-anti-CD3 amino acid sequence is (viii).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (vii).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (i) and the beta chain-anti-CD3 amino acid sequence is (xi).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (i) and the beta chain-anti-CD3 amino acid sequence is (xii).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (i) and the beta chain-anti-CD3 amino acid sequence is (xiii).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xiv).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xv).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xvi).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (v) and the beta chain-anti-CD3 amino acid sequence is (xvii).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (v) and the beta chain-anti-CD3 amino acid sequence is (xviii).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (v) and the beta chain-anti-CD3 amino acid sequence is (xix).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xi).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xii).
The DNA or RNA molecule according to 11, wherein the alpha chain amino acid sequence is (vi) and the beta chain-anti-CD3 amino acid sequence is (xiii).
An isolated cell presenting a TCR that binds to a YLEPGPVTA (SEQ ID NO:
- 1)-HLA-A2 complex comprising a TCR alpha chain variable domain and a TCR beta chain variable domain, wherein:
- (a) the alpha chain variable domain has
- (i) at least 90% sequence identity to the amino acid sequence comprising amino acids 1 to 109 of SEQ ID NO:
- 2, or
- (ii) at least 90% sequence identity to the amino acids 1 to 109 of SEQ ID NO:
- 2 and has a mutation at one or more positions selected from the group consisting of:
- 94D, 97L, 98V and 102G;
- (b) the beta chain variable domain has
- (i) amino acids 1 to 112 of SEQ ID NO:
- 3, and a mutation at one or more positions selected from the group consisting of:
- 27L, 28N, 29H, 30D, 31A, 50Q, 51I, 52V, 53N, 54D, 61A, 94S, 95I, 96G, 97G, 98P and 100E, or
- (ii) at least 90% sequence identity to the amino acid sequence comprising amino acids 1 to 112 of SEQ ID NO:
- 3;
- (c) the TCR has a binding affinity for, and/or a binding half-life for, the YLEPGPVTA-(SEQ ID NO:
- 1) HLA-A2 complex which is at least double that of a reference TCR, the reference TCR having an extracellular alpha chain sequence of SEQ ID NO:
- 45 and an extracellular beta chain sequence of SEQ ID NO:
- 46;
- and
- (d) at least one of the alpha and beta chain variable domains has at least one mutation.
Dependencies are inferred from the claim text.