High affinity HIV T cell receptors
View Patent ↗The present invention provides TCRs having high affinity. The TCR binds to SLYNTVATL (SEQ ID NO:16)-HLA-A*0201 with a K D of less than or equal to 1 μM and/or an off-rate (k off ) of 1×10 −3 S −1 or slower using Surface Plasmon Resonance. The TCRs are non-native, isolated or recombinant. The TCRs are useful, either alone, or with a therapeutic agent, for targeting HIV infected cells that present the SLYNTVATL (SEQ ID NO:16)-HLA-A*0201 complex.
1. A cell transduced with an expression vector comprising nucleic acid encoding a T-cell receptor (TCR) comprising an α chain variable domain and a β chain variable domain wherein: the TCR binds to SLYNTVATL (SEQ ID NO: 16)-HLA-A*0201 with a K D of less than or equal to 1 μM, and the α chain variable domain comprises SEQ ID NO: 1, and the β chain variable domain comprises SEQ ID NO: 2.
2. A pharmaceutical composition comprising a plurality of cells as claimed in claim 1 , together with a pharmaceutically acceptable carrier.
3. A cell transduced with an expression vector comprising nucleic acid encoding a TCR comprising an α chain variable domain and a β chain variable domain wherein: the TCR binds to SLYNTVATL (SEQ ID NO: 16)-HLA-A*0201 with a K D of less than or equal to 1 μM and/or an off-rate (k off ) of 1×10 −3 S −1 or slower using Surface Plasmon Resonance, and the α chain variable domain comprises SEQ ID NO: 1 with at least one mutation in at least one complementarity determining region selected from the group consisting of at least one of 95T, 96N, 97S, 98G and 100A, or the β chain variable domain comprises SEQ ID NO: 2 with at least one mutation in at least one complementarity determining region selected from the group consisting of at least one of 51Y, 52E, 53E and 54E wherein: if the α chain variable domain is mutated, the β chain variable domain comprises SEQ ID NO: 2, and if the β chain variable domain is mutated, the α chain variable domain comprises SEQ ID NO: 1.
4. A cell transduced with an expression vector comprising nucleic acid encoding a TCR comprises an α chain variable domain and a β chain variable domain wherein: the TCR binds to SLYNTVATL (SEQ ID NO: 16)-HLA-A*0201 with a K D of less than or equal to 1 μM and/or an off-rate (k off ) of 1×10 −3 S −1 or slower using Surface Plasmon Resonance, and the α chain variable domain comprises SEQ ID NO: 1 with at least one mutation in at least one complementarity determining region selected from the group consisting of, 95T, 96N, 97S, 98G and 100A, and the β chain variable domain comprises SEQ ID NO:2 with at least one mutation in at least one complementarity determining region selected from the group consisting of, 51 Y, 52E, 53E and 54E.
5. The cell of claim 4 wherein the TCR comprises the α chain variable domain wherein all of 95T, 96N, 97S, 98G and 100A are mutated, and the β chain variable domain wherein all of 51Y, 52E, 53E or 54E are mutated.
6. A cell transduced with an expression vector comprising nucleic acid encoding a TCR comprising an α chain variable domain and a β chain variable domain wherein: the TCR binds to SLYNTVATL (SEQ ID NO: 16)-HLA-A*0201 with a K D of less than or equal to 1 μM and/or an off-rate (k off ) of 1×10 −3 S −1 or slower using Surface Plasmon Resonance, and the α chain variable domain comprises SEQ ID NO: 1 with one or more of amino acids 95S, 95G, 96A, 97H, 98D or 100S, and is hence mutated relative to SEQ ID NO:1, and the β chain variable domain comprises SEQ ID NO:2 with one or more of amino acids 51V, 51A, 52R, 52L, 53G or 54V, and is hence mutated relative to SEQ ID NO:2.
7. The cell of claim 6 wherein α chain variable domain comprises amino acids 95S, 95G, 96A, 97H, 98D and 100S, mutated relative to SEQ ID NO: 1; and the β chain variable domain comprises amino acids 51V, 51A, 52R, 52L, 53G and 54V, mutated relative to SEQ ID NO: 2.
8. A cell transduced with an expression vector comprising nucleic acid encoding a TCR comprising an α chain variable domain and a β chain variable domain wherein: the TCR binds to SLYNTVATL (SEQ ID NO: 16)-HLA-A*0201 with a K D of less than or equal to 1 μM and/or an off-rate (k off ) of 1×10 −3 S −1 or slower using Surface Plasmon Resonance, and the α chain variable domain comprises the amino acid sequence shown in any one of SEQ ID NOS: 11-13, and the β chain variable domain comprises the amino acid sequence shown in any one of SEQ ID NOS: 14-15.
9. A cell transduced with an expression vector comprising nucleic acid encoding a TCR comprising an α chain variable domain and a β chain variable domain wherein: the TCR binds to SLYNTVATL (SEQ ID NO: 16)-HLA-A*0201 with a K D of less than or equal to 1 μM and/or an off-rate (k off ) of 1×10″ 3 S −1 or slower using Surface Plasmon Resonance, and the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 1 and the βchain variable domain comprises the amino acid sequence shown in SEQ ID NO: 14; or the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 1 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 15; or the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 11 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 2; or the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 12 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 2; or the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 13 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 2; or the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 12 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 15; or the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 13 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 15; or the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 12 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 14; or the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 13 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 14.
10. The cell of claim 9 wherein the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 1 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 14.
11. The cell of claim 9 wherein the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 1 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 15.
12. The cell of claim 9 wherein the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 11 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 2.
13. The cell of claim 9 wherein the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 12 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 2.
14. The cell of claim 9 wherein the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 13 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 2.
15. The cell of claim 9 wherein the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 12 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 15.
16. The cell of claim 9 wherein the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 13 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 15.
17. The cell of claim 9 wherein the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 12 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 14.
18. The cell of claim 9 wherein the α chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 13 and the β chain variable domain comprises the amino acid sequence shown in SEQ ID NO: 14.
19. A pharmaceutical composition comprising a plurality of cells as claimed in any of claims 3 to 18 , together with a pharmaceutically acceptable carrier.