METHODS OF TREATING CANCER USING ANTIBODIES AND MOLECULES THAT BIND TO BTN1A1 OR BTN1A1-LIGANDS

• US 20200131269A1
• Filed: 06/05/2018
• Published: 04/30/2020
• Est. Priority Date: 06/06/2017
• Status: Active Grant

• Current Assignee: STCube, Inc.
• Original Assignee: STCube, Inc.
• Inventors: Yoo, Stephen Sunghan, Chung, Ezra Myung Chul, Bong, Yong-Sik, Kim, Yong-Soo
• Granted Patent: US 11,542,331 B2
• Time in Patent Office: Days
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2815 against CD8
• CPC Class Codes: C07K 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

Provided herein are methods for treating cancer using molecules having an antigen binding fragment that immunospecifically binds to BTN1A1 or a BTN1A1 ligand, such as anti-BTN1A1 antibodies or anti-BTN1A1 ligand antibodies. Also provided herein are BTN1A1 ligands, such as Galectin-1, Galectin-9, Neuropilin-2, and B- and T-Lymphocyte Attenuator.

Claims

1. A molecule comprising an antigen binding fragment that immunospecifically binds to BTN1A1, wherein the molecule inhibits binding of BTN1A1 to a BTN1A1 ligand selected from the group consisting of Galectin-1 (GAL-1), Galectin-9 (GAL-9), NRP-2 (Nrp-2), and B- and T-Lymphocyte Attenuator (BTLA).

2. The molecule of claim 1, wherein the antigen binding fragment immunospecifically binds to BTN1A1 and the molecule inhibits binding of BTN1A1 to GAL-1.

3. The molecule of claim 1 or 2, wherein the antigen binding fragment immunospecifically binds to BTN1A1 and the molecule inhibits binding of BTN1A1 to GAL-9.

4. The molecule of any one of claims 1-3, wherein the antigen binding fragment immunospecifically binds to BTN1A1 and the molecule inhibits binding of BTN1A1 to NRP-2.

5. The molecule of any one of claims 1-4, wherein the antigen-binding fragment immunospecifically binds to BTN1A1 and the molecule inhibits binding of BTN1A1 to BTLA.

6. The molecule of any one of claims 1-5, wherein the antigen binding fragment immunospecifically binds to BTN1A1 and the molecule inhibits binding of BTN1A1 to two or more BN1A1 ligands selected from the group consisting of GAL-1, GAL-9, NRP-2, or BTLA.

7. The molecule of any one of claim 1-7, wherein the antigen binding fragment immunospecifically binds to the extracellular domain (ECD) of BTN1A1.

13. The molecule of any one of claims 1-12, wherein the molecule inhibits binding of the BTN1A1 ligand to BTN1A1 completely.

14. The molecule of any one of claims 1-12, wherein the molecule inhibits at least 1%, at least 3%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of BTN1A1 ligand binding to BTN1A1.

15. The molecule of any one of claims 1-14, wherein the molecule modulates an activity or signaling of BTN1A1 or an activity or signaling of a complex of BTN1A1 and a BTN1A1 ligand, such as GAL-1, GAL-9, NRP-2, or BTLA.

16. The molecule of any one of claims 1-15, wherein the molecule modulates T-cell activity.

17. The molecule of claim 16, wherein the T-cell is a CD8+ T-cell.

18. The molecule of claim 16 or 17, wherein the molecule can increase T-cell activation or T-cell proliferation.

19. The molecule of any one of claims 16-18, wherein the molecule inhibits T-cell apoptosis.

20. The molecule of any one of claims 1-19, wherein the antigen binding fragment preferentially binds glycosylated BTN1A1 over non-glycosylated BTN1A1.

21. The molecule of any one of claims 1-20, wherein the antigen binding fragment preferentially binds dimeric BTN1A1 over monomeric BTN1A1.

22. The molecule of any on of claims 1-21, wherein the antigen-binding fragment immunospecifically binds BTN1A1 or the BTN1A1 ligand with a dissociation constant (K_D) of no more than 1 μ

M.

23. The molecule of any one of claims 1-22, wherein the antigen-binding fragment immunospecifically binds BTN1A1 or the BTN1A1 ligand with a dissociation constant (K_D) of no more than 500 nM, no more than 400 nM, no more than 300 nM, no more than 200 nM, no more than 100 nM, no more than 50 nM, no more than 10 nM, or no more than 5 nM.

24. The molecule of any one of claims 1-23, wherein the antigen binding fragment immunospecifically binds BTN1A1 or the BTN1A1 ligand with a K_D of lower than or equal to the K_D of a BTN1A1-GAL-1 interaction, a BTN1A1-GAL-9 interaction, a BTN1A1-NRP2 interaction or a BTN1A1-BTLA interaction.

25. The molecule of any one of claim 1-24, wherein the antigen binding fragment immunospecifically binds BTN1A1 or the BTN1A1 ligand with a K_D at least 2 times lower, at least 5 times lower, at least 10 times lower, at least 15 times lower, at least 20 times lower, at least 25 times lower, at least 30 times lower, at least 40 times lower, or at last 50 times lower than the K_D of a BTN1A1-GAL-1-1 interaction, a BTN1A1-GAL-9 interaction, a BTN1A1-NRP2 interaction or a BTN1A1-BTLA interaction.

26. The molecule of any one of claims 1-25, wherein the molecule inhibits the binding of the BTN1A1 ligand to BTN1A1 with an IC50 of no more than 1 μ

M.

27. The molecule of any one of claims 1-26, wherein the molecule inhibits the binding of the BTN1A1 ligand to BTN1A1 with an IC50 of no more than 500 nM, no more than 400 nM, no more than 300 nM, no more than 200 nM, no more than 100 nM, no more than 50 nM, no more than 10 nM, or no more than 5 nM.

28. The molecule of any one of claims 1-27, wherein BTN1A1 binding, BTN1A1 ligand binding, or inhibition of BTN1A1 ligand binding to BTN1A1 is analyzed in by co-immunoprecipitation (co-IP), surface plasmon resonance (SPR) assay, β

-galactosidase complementation, or bio-layer interferometry (BLI).

29. The molecule of any one of claims 1-28, wherein the molecule is an antibody.

30. The molecule of claim 29, wherein the antibody is a monoclonal antibody.

31. The molecule of claim 29 or 30, wherein the antibody is a human antibody or a humanized antibody.

32. The molecule of any one of claims 29-31, wherein the antibody is an IgG, IgM, or IgA.

33. The molecule of any one of claims 1-32, wherein the molecule is a Fab′

, a F(ab′

)2, a F(ab′

)3, a monovalent scFv, a bivalent scFv, or a single domain antibody.

34. The molecule of any one of claims 1-33, wherein the molecule is recombinantly produced.

35. A pharmaceutical composition comprising a molecule of any one of claims 1-34, and a pharmaceutically acceptable carrier.

36. The pharmaceutical of claim 35 formulated for parenteral administration.

37. A method of activating T-cells comprising contacting the T-cells with an effective amount of a molecule of any one of claims 1-34, wherein the T-cells are activated through inhibition of BTN1A1 ligand binding to BTN1A1.

38. A method of inhibiting binding of a BTN1A1 ligand to a T-cell expressed BTN1A1, comprising contacting the T-cell with an effective amount of a molecule of any one of claims 1-34, thereby inhibiting binding of the BTN1A1 ligand to the T-cell.

39. The method of claim 37 or 38, wherein the T-cell is a CD8+ cell.

40. The method of any one of claims 37-39, wherein T-cell activation includes (i) increasing T-cell proliferation, (ii) decreasing T-cell apoptosis, or (iii) increasing cytokine production.

41. The method of claim 40, wherein the cytokine is IFNγ

or IL-2.

42. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a molecule of any one of claims 1-34 or a pharmaceutical composition of claim 35 or 36, wherein the molecule inhibits binding of a BTN1A1 ligand to BTN1A1 in the subject.

43. A method of inhibiting BTN1A1 ligand binding to BTN1A1, administering to the subject a therapeutically effective amount of a molecule of any one of claims 1-34 or a pharmaceutical composition of claim 35 or 36, wherein the molecule inhibits binding of a BTN1A1 ligand to BTN1A1 in the subject.

44. The method of claim 42 or 43, wherein administration comprises parenteral administration of the molecule or pharmaceutical composition.

45. The method of any one of claims 42-44 further comprising administering a high-dose radiation therapy to the patient.

46. The method of any one of claims 42-45, wherein the cancer is selected from the group consisting of lung cancer, prostate cancer, pancreas cancer, ovarian cancer, liver cancer, head and neck cancer, breast cancer, and stomach cancer.

47. The method of any one of claims 42-46, wherein the cancer is a lung cancer.

48. The method of any one of claims 42-47, wherein the lung cancer is a non small cell lung cancer (NSCLC).

49. The method of any one of claims 42-48, wherein the NSCLC is squamous NSCLC.

50. The method of any one of claims 42-49, wherein the cancer is an anti-PD-1 therapy or an anti-PD-L1 therapy resistant or refractory cancer.

51. The method of claim 50, wherein the cancer is a breast cancer or a lung cancer.

52. The method of claim 51, wherein the cancer is a mammary carcinoma or a Lewis lung carcinoma.

53. The method of any one of claims 1-52, wherein the molecule is not STC810 or comprises a CDR or VH or VL amino acid sequence of STC810, as described in International Application No. PCT/US16/64436.

8. A molecule comprising an antigen binding fragment that immunospecifically binds to a BTN1A1 ligand selected from the group consisting of GAL-1, GAL-9, NRP-2 and BTLA, wherein the molecule inhibits binding of the BTN1A1 ligand to BTN1A1.

9. The molecule of claim 8, wherein the antigen binding fragment immunospecifically binds to GAL-1 and the molecule inhibits binding of GAL-1 to BTN1A1.

10. The molecule of claim 8, wherein the antigen binding fragment immunospecifically binds to GAL-9 and the molecule inhibits binding of GAL-9 to BTN1A1.

11. The molecule of claim 8, wherein the antigen binding fragment immunospecifically binds to NRP-2 and the molecule inhibits binding of NRP-2 to BTN1A1.

12. The molecule of claim 8, wherein the antigen binding fragment immunospecifically binds to BTLA and the molecule inhibits binding of BTLA to BTN1A1.