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. An isolated or recombinant 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. An isolated or recombinant 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/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.
3. An isolated or recombinant 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/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, 51Y, 52E, 53E and 54E.
4. The TCR of claim 3 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.
5. An isolated or recombinant 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/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.
6. The TCR of claim 5 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.
7. An isolated or recombinant 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/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.
8. An isolated or recombinant 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/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 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: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.
9. The TCR of claim 8 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.
10. The TCR of claim 8 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.
11. The TCR of claim 8 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.
12. The TCR of claim 8 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.
13. The TCR of claim 8 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.
14. The TCR of claim 8 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.
15. The TCR of claim 8 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.
16. The TCR of claim 8 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.
17. The TCR of claim 8 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.
18. The TCR of any one of claims 1 , 2 , 3 - 7 , 8 - 17 associated with a therapeutic agent or detectable moiety.
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and the TCR of any one of claims 1 , 2 , 3 - 7 , 8 - 17 .
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a plurality of cells having the TCR of any one of claims 1 , 2 , 3 - 7 , 8 - 17 .
21. The pharmaceutical composition of claim 20 wherein the cells are T cells.
22. The pharmaceutical composition of claim 21 wherein the T cells are CD8 + T cells.
23. The TCR of any one of claims 1 , 2 , 3 - 7 , 8 - 17 which is a recombinant TCR.
24. The TCR of any one of claims 1 , 2 , 3 - 7 , 8 - 17 which is an isolated TCR.