PD-1 antibodies
A humanised agonistic antibody which binds human PD-1 comprising a heavy chain and a light chain wherein the variable domain of the heavy chain comprises the sequence given in SEQ ID NO:1 for CDR-H1, the sequence given in SEQ ID NO:2 for CDR-H2 and the sequence given in SEQ ID NO:3 for CDR-H3 and the variable domain of the light chain comprises the sequence given in SEQ ID NO:4 for CDR-L1, the sequence given in SEQ ID NO:5 for CDR-L2 and the sequence given in SEQ ID NO:7 for CDR-L3. The invention also extends to therapeutic uses of the antibody molecules, compositions and methods for producing said antibody molecules.
1. A humanised agonistic antibody which binds human PD-1 comprising a heavy chain and a light chain wherein the variable domain of the heavy chain comprises the sequence given in SEQ ID NO:1 for CDR-H1, the sequence given in SEQ ID NO:2 for CDR-H2 and the sequence given in SEQ ID NO:3 for CDR-H3 and the variable domain of the light chain comprises the sequence given in SEQ ID NO:4 for CDR-L1, the sequence given in SEQ ID NO:5 for CDR-L2 and the sequence given in SEQ ID NO:7 for CDR-L3.
2. A humanised agonistic antibody according to claim 1 , which binds human PD-1 comprising a heavy chain wherein the variable domain of the heavy chain comprises the sequence given in SEQ ID NO:1 for CDR-H1, the sequence given in SEQ ID NO:2 for CDR-H2 and the sequence given in SEQ ID NO:3 for CDR-H3 and the heavy chain framework region is derived from human sub-group sequence VH 1-3 1-46+JH4 (SEQ ID NO: 52).
3. A humanised antibody according to claim 2 wherein the residue at at least one of positions 25, 37, 41, 48, 71, 73 and 76 of the variable domain of the heavy chain is a donor residue.
4. A humanised antibody according to claim 3 having the heavy chain variable domain sequence given in SEQ ID NO:30, SEQ ID NO:38 or SEQ ID NO:40.
5. A humanised agonistic antibody according to claim 1 , which binds human PD-1 comprising a heavy chain wherein the variable domain of the heavy chain comprises the sequence given in SEQ ID NO:1 for CDR-H1, the sequence given in SEQ ID NO:2 for CDR-H2 and the sequence given in SEQ ID NO:3 for CDR-H3 and the heavy chain framework region is derived from human sub-group sequence VH 1-2 1-e+JH4 (SEQ ID NO: 54).
6. A humanised antibody according to claim 5 having the heavy chain variable domain sequence given in SEQ ID NO:46.
7. A humanised antibody according to claim 5 wherein the residue at, at least one of, positions 25, 37, 41, 48, 71, 76 and 78 of the variable domain of the heavy chain is a donor residue.
8. A humanised antibody according to claim 7 having the heavy chain variable domain sequence given in SEQ ID NO:42 or SEQ ID NO:44.
9. A humanised agonistic antibody according to claim 1 , which binds human PD-1 comprising a light chain wherein the variable domain of the light chain comprises the sequence given in SEQ ID NO:4 for CDR-L1, the sequence given in SEQ ID NO:5 for CDR-L2 and the sequence given in SEQ ID NO:7 for CDR-L3 and the light chain framework region is derived from human sub-group sequence VK1 2-1(1) L23+JK4 (SEQ ID NO:48).
10. A humanised antibody according to claim 9 wherein the residue at, at least one of positions 1, 2, 3, 4, 47, 60 and 70 of the variable domain of the light chain is a donor residue.
11. A humanised antibody according to claim 10 having the light chain variable domain sequence given in SEQ ID NO:20, SEQ ID NO:24 or SEQ ID NO:66.
12. A humanised agonistic antibody according to claim 1 , which binds human PD-1 comprising a light chain wherein the variable domain of the light chain comprises the sequence given in SEQ ID NO:4 for CDR-L1, the sequence given in SEQ ID NO:5 for CDR-L2 and the sequence given in SEQ ID NO:7 for CDR-L3 and the light chain framework region is derived from human sub-group sequence VK3 6-1-(1) A27+JK4 (SEQ ID NO:50).
13. A humanised antibody according to claim 12 wherein the residue at least one of positions 2, 47, 58, 70, 71 and 85 of the variable domain of the light chain is a donor residue.
14. A humanised antibody according to claim 13 having the light chain variable domain sequence given in SEQ ID NO:28.
15. A humanised agonistic antibody according to claim 1 having a heavy chain comprising a sequence selected from the group consisting of: SEQ ID NO:30, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44 and SEQ ID NO:46 and a light chain comprising a sequence selected from the group consisting of SEQ ID NO:20, SEQ ID NO:24, SEQ ID NO:28 and SEQ ID NO:66.
16. A humanised agonistic antibody according to claim 1 having a heavy chain comprising a sequence selected from the group consisting of: SEQ ID NO:46, SEQ ID NO:58, SEQ ID NO:62, SEQ ID NO:76 and SEQ ID NO:80 and a light chain comprising a sequence selected from the group consisting of SEQ ID NO:20, SEQ ID NO:24, SEQ ID NO:28, SEQ ID NO:66 and SEQ ID NO:70.
17. An agonistic antibody molecule according to claim 1 , wherein the antibody molecule is selected from the group consisting of: a complete antibody molecule having full length heavy and light chains or a fragment thereof, such as a Fab, modified Fab′, Fab′, F(ab′) 2 , Fv, VH, VL or scFv fragment.
18. A humanised agonistic antibody according to claim 1 , wherein the variable domain of the light chain comprises a sequence having at least 80% identity or similarity to the light chain variable domain of a light chain comprising a sequence selected from the group consisting of SEQ ID NO:20, SEQ ID NO:24, SEQ ID NO:28 and SEQ ID NO:66; and wherein the variable domain of the heavy chain comprises a sequence having at least 80% identity or similarity to the heavy chain variable domain of a heavy chain comprising a sequence selected from the group consisting of: SEQ ID NO:30, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44 and SEQ ID NO:46.
19. A humanised agonistic antibody according to claim 1 , wherein the variable domain of the light chain comprises a sequence having at least 80% identity or similarity to the light chain variable domain of a light chain comprising a sequence selected from the group consisting of SEQ ID NO: 20, SEQ ID NO:24, SEQ ID NO:28, SEQ ID NO:66 and SEQ ID NO:70; and wherein the variable domain of the heavy chain comprises a sequence having at least 80% identity or similarity to the heavy chain variable domain of a heavy chain comprising a sequence selected from the group consisting of: SEQ ID NO:46, SEQ ID NO:58, SEQ ID NO:62, SEQ ID NO:76 and SEQ ID NO:80.
20. A humanised agonistic antibody according to claim 1 having a binding affinity for isolated human PD-1 (for example human extracellular domain) of less than 5 nM.
21. A pharmaceutical composition comprising an antibody according to claim 1 , in combination with one or more of a pharmaceutically acceptable excipient, diluent or carrier.
22. A pharmaceutical composition according to claim 21 , additionally comprising other active ingredients.
23. A humanised agonistic antibody according to claim 1 , wherein the heavy chain framework region is derived from human sub-group sequence VH 1-2 1-e+JH4 (SEQ ID NO: 54), and the residue at, at least one of, positions 25, 37, 41, 48, 71, 76 and 78 of the variable domain of the heavy chain is a donor residue; or derived from human sub-group sequence VH 1-3 1-46+JH4 (SEQ ID NO: 52), wherein a residue at at least one of positions 25, 37, 41, 48, 71, 73 and 76 of the variable domain of the heavy chain is a donor residue; and the light chain framework region is derived from human sub-group sequence VK1 2-1(1) L23+JK4 (SEQ ID NO:48), and the residue at, at least one of, positions 2, 47, 58, 70, 71 and 85 of the variable domain of the light chain is a donor residue; or derived from human sub-group sequence VK1 2-1(1) L23+JK4 (SEQ ID NO: 50), and the residue at, at least one of, positions 2, 47, 58, 70, 71 and 85 of the variable domain of the light chain is a donor residue.