IP Library › Granted Patent US 11,021,537

Granted Patent B2

US 11,021,537 · App. 15/968,094 · Granted Jun 1, 2021

Anti-TIGIT antibodies and methods of use thereof

Inventors: Dhan Sidhartha Chand (Woburn, MA); Nicholas Stuart Wilson (San Carlos, CA); Dennis John Underwood (Boston, MA); Benjamin Maxime Morin (Somerville, MA)

Assignee: AGENUS INC.

C07K16/2818 A61K39/395 A61P35/04 C07K16/28 C07K16/2875 C07K16/2878 C07K16/30 G01N33/505 A61K2039/57 C07K2317/24 C07K2317/33 C07K2317/34 C07K2317/52 C07K2317/71 C07K2317/72 C07K2317/73 C07K2317/734 C07K2317/74 C07K2317/76 C07K2317/92 C07K2319/30

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Quick Facts

Patent No.: US 11,021,537
App. No.: 15/968,094
Granted: Jun 1, 2021
Kind: B2

External Links

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Abstract

The instant disclosure provides antibodies that specifically bind to T-cell immunoreceptor with Ig and ITIM domains (TIGIT) (e.g., human TIGIT) and antagonize TIGIT function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

Claims (422)

1. An isolated antibody that specifically binds to human TIGIT, the antibody comprising a heavy chain variable region (VH) comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 9, and a light chain variable region (VL) comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 10.

2. The isolated antibody of claim 1 , wherein the antibody comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs 1, 3, 5, 6, 7, and 8; or 2, 4, 5, 6, 7, and 8, respectively.

3. The isolated antibody of claim 1 , wherein the VH comprises an amino acid sequence that is at least 75% identical to the amino acid sequence of SEQ ID NO: 9.

4. The isolated antibody of claim 3 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 9.

5. The isolated antibody of claim 1 , wherein the VL comprises an amino acid sequence that is at least 75% identical to the amino acid sequence of SEQ ID NO: 10.

6. The isolated antibody of claim 5 , wherein the VL comprises the amino acid of SEQ ID NO: 10.

7. The isolated antibody of claim 1 wherein the VH and VL comprise the amino acid sequences of SEQ ID NOs: 9 and 10, respectively.

8. The isolated antibody of claim 1 , wherein:

(a) the VH comprises an amino acid sequence derived from a human IGHV1 69*01 germline sequence;

(b) the VH comprises an amino acid sequence derived from a human IGHV1 69*06 germline sequence;

(d) the VL comprises an amino acid sequence derived from a human IGLV2 14*01 germline sequence;

(e) the VL comprises an amino acid sequence derived from a human IGLV2 23*02 germline sequence; and/or

(f) the VL comprises an amino acid sequence derived from a human IGLV2 11*01 germline sequence.

9. The isolated antibody of claim 1 , wherein the VH comprises an amino acid region that is at least 75% identical to the amino acid sequence of SEQ ID NO: 34 or 35.

10. The isolated antibody of claim 1 , wherein the VL comprises an amino acid region that is at least 75% identical to the amino acid sequence of any one of SEQ ID NOs: 37-39 and 60.

11. The isolated antibody of claim 1 , wherein the antibody further comprises a heavy chain constant region selected from the group consisting of human IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 .

12. The isolated antibody of claim 11 , wherein the antibody comprises an IgG 1 heavy chain constant region, wherein:

(a) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 19;

(b) the amino acid sequence of the IgG 1 heavy chain constant region comprises an N297A mutation, numbered according to the EU numbering system;

(d) the amino acid sequence of the IgG 1 heavy chain constant region comprises L234F, L235F, and N297A mutations, numbered according to the EU numbering system;

(e) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 21;

(f) the amino acid sequence of the IgG 1 heavy chain constant region comprises S239D and I332E mutations, numbered according to the EU numbering system;

(g) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 22;

(h) the amino acid sequence of the IgG 1 heavy chain constant region comprises S239D, A330L, and I332E mutations, numbered according to the EU numbering system;

(i) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 23;

(j) the amino acid sequence of the IgG 1 heavy chain constant region comprises L235V, F243L, R292P, Y300L, and P396L mutations, numbered according to the EU numbering system;

(k) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 24;

(l) the amino acid sequence of the IgG 1 heavy chain constant region comprises S267E and L328F mutations, numbered according to the EU numbering system;

(m) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 25; or

(n) the IgG 1 heavy chain constant region is afucosylated.

13. The isolated antibody of claim 11 , wherein the antibody comprises an IgG 4 heavy chain constant region, wherein:

(a) the amino acid sequence of the IgG 4 heavy chain constant region comprises an S228P mutation, numbered according to the EU numbering system; and/or

(b) the IgG 4 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 26.

14. The isolated antibody of claim 1 , wherein the antibody comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO: 28.

15. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-18.

16. The isolated antibody of claim 1 , wherein the antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 27.

17. An isolated antibody that specifically binds to human TIGIT, wherein:

(a) a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-18; and/or

(b) a light chain comprising the amino acid sequence of SEQ ID NO: 27.

18. The isolated antibody of claim 17 , wherein the heavy chain and light chain comprise the amino acid sequences of SEQ ID NOs: 11 and 27, respectively.

19. The isolated antibody of claim 1 , wherein:

(a) the antibody is a human antibody;

(b) the antibody is a bispecific antibody;

(d) the antibody preferentially kills regulatory T cells over effector T cells in a population of peripheral blood mononuclear cells (PBMCs) in vitro;

(e) the antibody decreases or inhibits binding of human TIGIT to PVR or PVRL2 relative to the level of binding in the absence of the antibody;

(f) the antibody induces IL-2 and/or IFNγ production by PBMCs stimulated with staphylococcal enterotoxin A (SEA);

(g) the antibody is conjugated to a cytotoxic agent, cytostatic agent, toxin, radionuclide, or detectable label; and/or

(h) the antibody is cross-linked to a second antibody or a fragment thereof.

20. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier or excipient.

21. An isolated polynucleotide encoding the VH and/or VL, or a heavy chain and/or light chain, of the antibody of claim 1 .

22. A vector comprising the polynucleotide of claim 21 .

23. A recombinant host cell comprising the polynucleotide of claim 21 .

24. A recombinant host cell comprising a first polynucleotide encoding the VH, or a heavy chain, of the antibody of claim 1 , and a second polynucleotide encoding the VL, or the light chain, of the antibody of claim 1 .

25. A method of producing an antibody that specifically binds to human TIGIT, or an antigen-binding fragment thereof, the method comprising culturing the host cell of claim 23 such that the polynucleotide is expressed and the antibody, or antigen-binding fragment, is produced.

26. A method of producing an antibody that specifically binds to human TIGIT, or an antigen-binding fragment thereof, the method comprising culturing the host cell of claim 24 such that the first polynucleotide and the second polynucleotide are expressed and the antibody, or antigen-binding fragment, is produced.

27. A method of increasing T cell activation in response to an antigen in a subject, the method comprising administering to the subject an effective amount of the antibody of claim 1 .

28. A method of decreasing or inhibiting Treg activity in response to an antigen in a subject, the method comprising administering to the subject an effective amount of the antibody of claim 1 .

29. A method of increasing NK cell activation in response to an antigen in a subject, the method comprising administering to the subject an effective amount of the antibody of claim 1 .

30. A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of the antibody of claim 1 , optionally wherein the antibody is administered intravenously, subcutaneously, intratumorally, or is delivered to a tumor draining lymph node.

31. A method of treating an infectious disease in a subject, the method comprising administering to the subject an effective amount of the antibody of claim 1 .

32. The pharmaceutical composition of claim 20 , wherein the antibody comprises:

(a) an IgG 1 heavy chain constant region, wherein

(i) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 19,

(ii) the amino acid sequence of the IgG 1 heavy chain constant region comprises an N297A mutation, numbered according to the EU numbering system,

(iii) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 20,

(iv) the amino acid sequence of the IgG 1 heavy chain constant region comprises L234F, L235F, and N297A mutations, numbered according to the EU numbering system,

(v) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 21,

(vi) the amino acid sequence of the IgG 1 heavy chain constant region comprises S239D and I332E mutations, numbered according to the EU numbering system,

(vii) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 22,

(viii) the amino acid sequence of the IgG 1 heavy chain constant region comprises S239D, A330L, and I332E mutations, numbered according to the EU numbering system,

(ix) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 23,

(x) the amino acid sequence of the IgG 1 heavy chain constant region comprises L235V, F243L, R292P, Y300L, and P396L mutations, numbered according to the EU numbering system,

(xi) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 24,

(xii) the amino acid sequence of the IgG 1 heavy chain constant region comprises S267E and L328F mutations, numbered according to the EU numbering system,

(xiii) the IgG 1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 25, or

(xiv) the IgG 1 heavy chain constant region is afucosylated;

(b) an IgG 4 heavy chain constant region, wherein

(i) the amino acid sequence of the IgG 4 heavy chain constant region comprises an S228P mutation, numbered according to the EU numbering system, and/or

(ii) the IgG 4 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 26; or

33. The polynucleotide of claim 21 , wherein the antibody comprises: