Anti-TIGIT antibodies
The present invention relates to anti-TIGIT antibodies, as well as use of these antibodies in the treatment of diseases such as cancer and infectious disease.
1. A monoclonal antibody or antigen binding fragment thereof that binds to mature human TIGIT, wherein the antibody and antigen binding fragment thereof comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:88, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:89 and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:90, and wherein the light chain variable region comprises a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:91, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:92, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:93.
2. A monoclonal antibody or antigen binding fragment thereof that binds to mature human TIGIT, wherein the antibody and antigen binding fragment thereof comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:88, a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 134, and a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:90, and wherein the light chain variable region comprises a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO:91, a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO:92, and a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO:93.
3. The monoclonal antibody or antigen binding fragment thereof of claim 2 , wherein the monoclonal antibody and antigen binding fragment thereof comprise:
a. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:128 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:132;
b. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:127 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:130;
c. a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:128 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:133;
d. a heavy chain variable region comprising at least 97% identity to SEQ ID NO:128 and a light chain variable region comprising at least 97% identity to SEQ ID NO: 132, wherein any sequence variations occur in the framework regions of the antibody;
e. a heavy chain variable region comprising at least 97% identity to SEQ ID NO:127 and a light chain variable region comprising at least 97% identity to SEQ ID NO: 130, wherein any sequence variations occur in the framework regions of the antibody; or
f. a heavy chain variable region comprising at least 97% identity to SEQ ID NO:128 and a light chain variable region comprising at least 97% identity to SEQ ID NO: 133, wherein any sequence variations occur in the framework regions of the antibody.
4. The monoclonal antibody or antigen binding fragment thereof of claim 1 , wherein the monoclonal antibody or antigen binding fragment thereof binds to mature human TIGIT with a KD value of 1×10 −9 M to 1×10 −12 M as determined by surface plasmon resonance.
5. The monoclonal antibody or antigen binding fragment thereof of claim 1 , which is a monoclonal antibody comprising two heavy chains and two light chains.
6. The monoclonal antibody or antigen binding fragment thereof of claim 1 , which is a monoclonal antibody, wherein the monoclonal antibody comprises a human IgG1 constant domain and a human kappa constant domain.
7. A composition comprising the monoclonal antibody or antigen binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier or diluent.
8. The composition of claim 7 , further comprising an anti-PD1 monoclonal antibody or an antigen binding fragment thereof.
9. The composition of claim 7 , further comprising an anti-PD1 monoclonal antibody or an antigen binding fragment thereof, wherein the anti-PD1 monoclonal antibody is nivolumab.
10. The composition of claim 7 , further comprising an anti-PD1 monoclonal antibody or an antigen binding fragment thereof, wherein the anti-PD1 monoclonal antibody is pembrolizumab.
11. A monoclonal antibody that binds to mature human TIGIT comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:128 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:132.
12. The monoclonal antibody or antigen binding fragment thereof of claim 3 that is a monoclonal antibody comprising a heavy chain variable region comprising at least 97% identity to SEQ ID NO:128 and a light chain variable region comprising at least 97% identity to SEQ ID NO: 132, wherein any sequence variations occur in the framework regions of the antibody.
13. The monoclonal antibody or antigen binding fragment thereof of claim 2 , wherein the antibody or antigen binding fragment thereof binds to mature human TIGIT with a KD value of 1×10 −9 M to 1×10 −12 M as determined by surface plasmon resonance.
14. The monoclonal antibody or antigen binding fragment thereof of claim 2 , which is a monoclonal antibody comprising two heavy chains and two light chains.
15. The monoclonal antibody or antigen binding fragment thereof of claim 2 , which is a monoclonal antibody, wherein the monoclonal antibody comprises a human IgG1 constant domain and a human kappa constant domain.
16. The monoclonal antibody of claim 15 , wherein the human IgG1 constant domain comprises SEQ ID NO: 86 and the human kappa constant domain comprises SEQ ID NO: 56.
17. The monoclonal antibody of claim 6 , wherein the human IgG1 constant domain comprises SEQ ID NO: 86 and the human kappa constant domain comprises SEQ ID NO: 56.
18. The monoclonal antibody or antigen binding fragment thereof of claim 1 , which is a monoclonal antibody, wherein the monoclonal antibody comprises a human IgG4 constant domain and a human kappa constant domain.
19. The monoclonal antibody or antigen binding fragment thereof of claim 2 , which is a monoclonal antibody, wherein the monoclonal antibody comprises a human IgG4 constant domain and a human kappa constant domain.
20. The monoclonal antibody of claim 18 , wherein the human IgG4 constant domain comprises SEQ ID NO: 55 and the human kappa constant domain comprises SEQ ID NO: 56.
21. The monoclonal antibody of claim 19 , wherein the human IgG4 constant domain comprises SEQ ID NO: 55 and the human kappa constant domain comprises SEQ ID NO: 56.
22. A composition comprising the monoclonal antibody or antigen binding fragment thereof of claim 2 and a pharmaceutically acceptable carrier or diluent.
23. The composition of claim 22 , further comprising an anti-PD1 monoclonal antibody or an antigen binding fragment thereof.
24. The composition of claim 22 further comprising an anti-PD1 monoclonal antibody or an antigen binding fragment thereof, wherein the anti-PD1 monoclonal antibody is nivolumab.
25. The composition of claim 22 , further comprising an anti-PD1 monoclonal antibody or an antigen binding fragment thereof, wherein the anti-PD1 monoclonal antibody is pembrolizumab.
26. A monoclonal antibody which comprises two heavy chains and two light chains, wherein the heavy chains comprise (i) a heavy chain variable region comprising SEQ ID NO: 128 and (ii) an IgG1 constant domain comprising SEQ ID NO: 86, and wherein the light chains comprise (i) a light chain variable region comprising SEQ ID NO: 132 and (ii) a human kappa constant domain comprising SEQ ID NO: 56.
27. A monoclonal antibody which comprises two heavy chains and two light chains, wherein the heavy chains comprise (i) a heavy chain variable region comprising SEQ ID NO: 128 and (ii) an IgG4 constant domain comprising SEQ ID NO: 55, and wherein the light chains comprise (i) a light chain variable region comprising SEQ ID NO: 132 and (ii) a human kappa constant domain comprising SEQ ID NO: 56.
28. A composition comprising (a) a monoclonal antibody which comprises two heavy chains and two light chains, wherein the heavy chains comprise (i) a heavy chain variable region comprising SEQ ID NO: 128 and (ii) an IgG1 constant domain comprising SEQ ID NO: 86, and wherein the light chains comprise (i) a light chain variable region comprising SEQ ID NO: 132 and (ii) a human kappa constant domain comprising SEQ ID NO: 56 and (b) pembrolizumab.
29. A composition comprising (a) a monoclonal antibody which comprises two heavy chains and two light chains, wherein the heavy chains comprise (i) a heavy chain variable region comprising SEQ ID NO: 128 and (ii) an IgG4 constant domain comprising SEQ ID NO: 55, and wherein the light chains comprise (i) a light chain variable region comprising SEQ ID NO: 132 and (ii) a human kappa constant domain comprising SEQ ID NO: 56 and (b) pembrolizumab.
30. The composition of claim 7 , further comprising an anti-PDL-1 monoclonal antibody.
31. The composition of claim 30 , wherein the anti-PDL-1 monoclonal antibody is MPDL3280A.
32. The monoclonal antibody or antigen binding fragment thereof of claim 1 , wherein the monoclonal antibody and antigen binding fragment thereof comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 94 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 95.