Anti-TIM-3 antibodies and methods of use thereof

• US 10,639,368 B2
• Filed: 05/26/2017
• Issued: 05/05/2020
• Est. Priority Date: 05/27/2016
• Status: Active Grant

• Current Assignee: Agenus Inc.
• Original Assignee: Agenus Inc.
• Inventors: van Dijk, Marc, Breous-Nystrom, Ekaterina Vladimirovna, Wilson, Nicholas Stuart, Waight, Jeremy Dale, Underwood, Dennis John
• Primary Examiner(s): Bristol, Lynn A
• Application Number:
  US15/606,148
• Publication Number:
  US 20170368168A1
• Time in Patent Office: 1,075 Days
• Field of Search: 4241381
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/71 Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C07K 2319/55 containing a fusion with a toxin, e.g. diphteria toxin

Abstract

The instant disclosure provides antibodies that specifically bind to TIM-3 (e.g., human TIM-3) and antagonize TIM-3 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

1. An isolated antibody that specifically binds to human TIM-3, the antibody comprising a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2 and CDRH3 and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2 and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences set forth in SEQ ID NOs:

1, 2, 3, 14, 21, and 22;

4, 2, 3, 14, 21, and 22;

5, 2, 3, 14, 21, and 22;

6, 2, 3, 14, 21, and 22;

7, 2, 3, 14, 21, and 22;

8, 2, 3, 14, 21, and 22;

9, 2, 3, 14, 21, and 22;

10, 2, 3, 14, 21, and 22;

11, 2, 3, 14, 21, and 22;

12, 2, 3, 14, 21, and 22;

or 1, 2, 3, 15, 18, and 22, respectively.

2. The isolated antibody of claim 1, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences set forth in SEQ ID NOs:

5, 2, 3, 14, 21, and 22, respectively.

3. The isolated antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

55.

4. The isolated antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs:

24-27 and 29-35.

5. The isolated antibody of claim 1, wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

24-27 and 29-35.

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

56.

7. The isolated antibody of claim 1, wherein the antibody comprises a light chain variable region comprising an amino acid sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs:

36-45 and 47.

8. The isolated antibody of claim 1, wherein the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs:

36-45 and 47.

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

58 or 65.

10. The isolated antibody of claim 1, wherein the heavy chain variable region and the light chain variable region, respectively, comprise the amino acid sequences set forth in SEQ ID NOs:

24 and 36;

24 and 38;

26 and 42;

24 and 42;

24 and 46;

24 and 43;

26 and 43;

26 and 46;

26 and 41;

24 and 41;

25 and 39;

24 and 47;

25 and 40;

26 and 47;

25 and 37;

25 and 45;

25 and 44;

25 and 46;

25 and 42;

25 and 41;

25 and 43;

25 and 47;

27 and 46;

29 and 46;

30 and 46;

31 and 46;

32 and 46;

33 and 46;

34 and 46;

or 35 and 46.

11. The isolated antibody of claim 10, wherein the amino acid sequences of the heavy chain variable region and the light chain variable region, respectively, consist of the amino acid sequences set forth in SEQ ID NOs:

24 and 36;

24 and 38;

26 and 42;

24 and 42;

24 and 46;

24 and 43;

26 and 43;

26 and 46;

26 and 41;

24 and 41;

25 and 39;

24 and 47;

25 and 40;

26 and 47;

25 and 37;

25 and 45;

25 and 44;

25 and 46;

25 and 42;

25 and 41;

25 and 43;

25 and 47;

27 and 46;

29 and 46;

30 and 46;

31 and 46;

32 and 46;

33 and 46;

34 and 46;

or 35 and 46.

12. The isolated antibody of claim 1, comprising a heavy chain and a light chain, wherein the heavy chain and the light chain, respectively, comprise the amino acid sequences set forth in SEQ ID NOs:

58 and 69;

or 65 and 69.

13. The isolated antibody of claim 12, wherein the amino acid sequences of the heavy chain and the light chain, respectively, consist of the amino acid sequences set forth in SEQ ID NOs:

58 and 69;

or 65 and 69.

14. The isolated antibody of any claim 1, wherein the antibody is internalized upon binding to cells expressing human TIM-3.

15. The isolated antibody of claim 1, wherein the antibody comprises a heavy chain constant region selected from the group consisting of human IgG₁, IgG₂, IgG₃, IgG₄, IgA₁, and IgA₂.

16. The isolated antibody of claim 15, wherein the heavy chain constant region is an IgG₁ heavy chain constant region.

17. The isolated antibody of claim 16, wherein the amino acid sequence of the IgG₁ heavy chain constant region comprises a N297A mutation, numbered according to the EU numbering system.

18. The isolated antibody of claim 17, wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO:

72.

19. The isolated antibody of claim 16, wherein the amino acid sequence of the IgG₁ heavy chain constant region comprises a N297Q mutation, numbered according to the EU numbering system.

20. The isolated antibody of claim 16, wherein the IgG₁ heavy chain constant region is non-fucosylated.

21. The isolated antibody of claim 15, wherein the heavy chain constant region is an IgG₄ heavy chain constant region.

22. The isolated antibody of claim 21, wherein the amino acid sequence of the IgG₄ heavy chain constant region comprises a S228P mutation, numbered according to the EU numbering system.

23. The isolated antibody of claim 22, wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO:

74.

24. The isolated antibody of claim 1, wherein the antibody comprises a human kappa or human lamda light chain constant region.

25. The isolated antibody of claim 24, wherein the light chain constant region is a human kappa light chain constant region.

26. The isolated antibody of claim 25, wherein the antibody comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO:

76.

27. The isolated antibody of claim 1, wherein the antibody is a human antibody.

28. The isolated antibody of claim 1, wherein the antibody is antagonistic to human TIM-3.

29. The isolated antibody of claim 1, wherein the antibody deactivates, reduces, or inhibits an activity of human TIM-3.

30. The isolated antibody of claim 1, wherein the antibody inhibits binding of human TIM-3 to phosphatidylserine.

31. The isolated antibody of claim 1 conjugated to a cytotoxic agent, cytostatic agent, toxin, radionuclide, or detectable label.

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