T cell receptor mutants
A T cell receptor (TCR) having the property of binding to EVDPIGHLY HLA-A1 complex and comprising a specified wild type TCR which has specific mutations in the TCR alpha variable domain and/or the TCR beta variable domain to increase affinity. Such TCRs are useful for adoptive therapy.
1. A T cell receptor (TCR) having the property of binding to SEQ ID NO: 1-Human Leukocyte Antigen (HLA)-A1 complex and comprising a TCR α variable domain and a TCR β variable domain, wherein:
the TCR α variable domain has the amino acid sequence from K1 to P114 of SEQ ID NO: 2 and the TCR β variable domain has the amino acid sequence from K1 to T112 of SEQ ID NO: 3
except that, in the TCR a variable domain, at least one of the following mutations is present:
50I is mutated to 50V;
51Q is mutated to 51R;
52S is mutated to 52P;
53S is mutated to 53Y; and/or
in the TCR beta variable domain, at least one of the following mutations is present:
50F is mutated to 50T;
51S is mutated to 51D;
52E is mutated to 52M;
53T is mutated to 53L;
54Q is mutated to 54L.
2. A TCR as claimed in claim 1 comprising one of the α chain variable domain amino acid sequences SEQ ID NOs: 8 and 9.
3. A TCR as claimed in claim 1 comprising one of the β chain variable domain amino acid sequences SEQ ID NOs: 10 and 11.
4. A TCR as claimed in claim 1 , also having α chain TCR alpha constant(TRAC) constant domain and a β chain TCR beta constant(TRBC)1 or TRBC2 constant domain, or having an α chain TRAC and β chain TRBC1 or TRBC2 constant domains modified by truncation or substitution to delete the native disulfide bond between Cys4 of exon 2 of TRAC and Cys2 of exon 2 of TRBC1.
5. A TCR as claimed in claim 1 which is an αβ heterodimeric TCR, and which has α and β chain constant domain sequences in which cysteine residues are substituted for Thr 48 of T-cell receptor alpha constant (TRAC) and Ser 57 of TRBC1 or TRBC2, the said cysteines forming a disulfide bond between the α and β constant domains of the TCR.