ANTIBODY THERAPEUTICS THAT BIND TIM3

• US 20160257758A1
• Filed: 03/04/2016
• Published: 09/08/2016
• Est. Priority Date: 03/06/2015
• Status: Active Grant

• Current Assignee: Sorrento Therapeutics Inc.
• Original Assignee: Sorrento Therapeutics Inc.
• Inventors: Krapf, Irina, Gray, John Dixon, Zhou, Heyue
• Granted Patent: US 9,873,741 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

There is disclosed compositions and methods relating to or derived from anti-TIM3 antibodies. More specifically, there is disclosed fully human antibodies that bind TIM3, TIM3-antibody binding fragments and derivatives of such antibodies, and TIM3-binding polypeptides comprising such fragments. Further still, there is disclosed nucleic acids encoding such antibodies, antibody fragments and derivatives and polypeptides, cells comprising such polynucleotides, methods of making such antibodies, antibody fragments and derivatives and polypeptides, and methods of using such antibodies, antibody fragments and derivatives and polypeptides, including methods of treating a disease.

Claims

1. An isolated fully human anti-TIM3 antibody of an IgG class that binds to a TIM3 epitope, wherein said antibody comprises

a heavy chain variable domain sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, and SEQ ID NO. 69;

and

a light chain variable domain sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, and SEQ ID NO. 70.

2. The fully human antibody of claim 1, wherein the antibody comprises a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2 (TIA1), SEQ ID NO. 3/SEQ ID NO. 4 (TIA5), SEQ ID NO. 5/SEQ ID NO. 6 (TIA6), SEQ ID NO. 7/SEQ ID NO. 8 (TIA7), SEQ ID NO. 9/SEQ ID NO. 10 (TIA9), SEQ ID NO. 11/SEQ ID NO. 12 (TIA10), SEQ ID NO. 13/SEQ ID NO. 14 (TIA11), SEQ ID NO. 15/SEQ ID NO. 16 (TIB1), SEQ ID NO. 17/SEQ ID NO. 18 (TIB2), SEQ ID NO. 19/SEQ ID NO. 20 (TIC1), SEQ ID NO. 21/SEQ ID NO. 22 (TIC2), SEQ ID NO. 23/SEQ ID NO. 24 (TIC4), SEQ ID NO. 25/SEQ ID NO. 26 (TIC5), SEQ ID NO. 27/SEQ ID NO. 28 (TIC8), SEQ ID NO. 29/SEQ ID NO. 30 (TIC10), SEQ ID NO. 31/SEQ ID NO. 32 (TIC11), SEQ ID NO. 33/SEQ ID NO. 34 (TID1), SEQ ID NO. 35/SEQ ID NO. 36 (TID6), SEQ ID NO. 37/SEQ ID NO. 38 (TID10), SEQ ID NO. 39/SEQ ID NO. 40 (TID12), SEQ ID NO. 41/SEQ ID NO. 42 (TIE2), SEQ ID NO. 43/SEQ ID NO. 44 (TIE3), SEQ ID NO. 45/SEQ ID NO. 46 (TIE7), SEQ ID NO. 47/SEQ ID NO. 48 (TIE9), SEQ ID NO. 49/SEQ ID NO. 50 (TIF3), SEQ ID NO. 51/SEQ ID NO. 52 (TIF7), SEQ ID NO. 53/SEQ ID NO. 54 (TIF8), SEQ ID NO. 55/SEQ ID NO. 56 (TIG1), SEQ ID NO. 57/SEQ ID NO. 58 (TIG3), SEQ ID NO. 59/SEQ ID NO. 60 (TIG6), SEQ ID NO. 7/SEQ ID NO. 62 (TIG9), SEQ ID NO. 63/SEQ ID NO. 64 (TIG10), SEQ ID NO. 65/SEQ ID NO. 66 (TIH1), SEQ ID NO. 67/SEQ ID NO. 68 (TIH5), and SEQ ID NO. 69/SEQ ID NO. 70 (TIH11).

3. The fully human antibody of claim 1, wherein the antibody has a K_D of at least 1×

10<sup>−

6</sup>M.

7. A method of treating cancer or an inflammatory or autoimmune disease in a subject in need thereof, the method comprising administering an effective amount of the antibody of claim 1, such that the cancer or autoimmune or inflammatory disease is treated.

8. The method of claim 7, wherein the cancer is selected from the group consisting of ovarian cancer, colon cancer, breast cancer, lung cancer, myelomas, neuroblastic-derived CNS tumors, monocytic leukemias, B-cell derived leukemias, T-cell derived leukemias, B-cell derived lymphomas, T-cell derived lymphomas, and mast cell derived tumors.

9. The method of claim 7, wherein the autoimmune or inflammatory disease is selected from the group consisting of intestinal mucosal inflammation, wasting disease associated with colitis, multiple sclerosis, systemic lupus erythematosus, viral infections, rheumatoid arthritis, osteoarthritis, psoriasis, Crohn'"'"'s disease, and inflammatory bowel disease.

10. The method of claim 7, wherein the antibody comprises a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID NO. 7/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, and SEQ ID NO. 69/SEQ ID NO. 70.

4. An anti-TIM3 fully human antibody fragment comprising a heavy chain variable domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, and SEQ ID NO. 69;

and

a light chain variable domain comprising an amino acid sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, and SEQ ID NO. 70

wherein the fragment is a single chain antibody comprising a peptide linker connecting the heavy and light chain variable domains, or a Fab fragment.

5. The fully human antibody fragment of claim 4, comprising a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID NO. 7/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, and SEQ ID NO. 69/SEQ ID NO. 70.

6. The fully human antibody Fab fragment of claim 4, wherein the antibody has a K_D of at least 1×

10<sup>−

6</sup>M.

11. A method of treating cancer or an inflammatory or autoimmune disease in a subject in need thereof, the method comprising administering an effective amount of the antibody fragment of claim 4, such that the cancer or autoimmune or inflammatory disease is treated.

12. The method of claim 11, wherein the cancer is selected from the group consisting of ovarian cancer, colon cancer, breast cancer, lung cancer, myelomas, neuroblastic-derived CNS tumors, monocytic leukemias, B-cell derived leukemias, T-cell derived leukemias, B-cell derived lymphomas, T-cell derived lymphomas, and mast cell derived tumors.

13. The method of claim 11, wherein the autoimmune or inflammatory disease is selected from the group consisting of intestinal mucosal inflammation, wasting disease associated with colitis, multiple sclerosis, systemic lupus erythematosus, viral infections, rheumatoid arthritis, osteoarthritis, psoriasis, Crohn'"'"'s disease, and inflammatory bowel disease.

14. The method of claim 11, wherein the antibody fragment comprises a heavy chain/light chain variable domain sequence selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID NO. 7/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, and SEQ ID NO. 69/SEQ ID NO. 70.

15. An isolated anti-CD137 antibody, or an antigen-binding fragment thereof,

comprising a heavy chain variable domain comprising complementarity determining regions (CDRs) as set forth in a heavy chain variable domain amino acid sequence selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, and SEQ ID NO. 69;

and

comprising a light chain variable domain comprising CDRs as set forth in a light chain variable region amino acid sequence selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, and SEQ ID NO. 70.

16. The antibody of claim 15, wherein the antibody has CDRs from a heavy/light chain variable domain sequence selected from the group consisting of NO. 1/SEQ ID NO. 2 (TIA1), SEQ ID NO. 3/SEQ ID NO. 4 (TIA5), SEQ ID NO. 5/SEQ ID NO. 6 (TIA6), SEQ ID NO. 7/SEQ ID NO. 8 (TIA7), SEQ ID NO. 9/SEQ ID NO. 10 (TIA9), SEQ ID NO. 11/SEQ ID NO. 12 (TIA10), SEQ ID NO. 13/SEQ ID NO. 14 (TIA11), SEQ ID NO. 15/SEQ ID NO. 16 (TIB1), SEQ ID NO. 17/SEQ ID NO. 18 (TIB2), SEQ ID NO. 19/SEQ ID NO. 20 (TIC1), SEQ ID NO. 21/SEQ ID NO. 22 (TIC2), SEQ ID NO. 23/SEQ ID NO. 24 (TIC4), SEQ ID NO. 25/SEQ ID NO. 26 (TIC5), SEQ ID NO. 27/SEQ ID NO. 28 (TIC8), SEQ ID NO. 29/SEQ ID NO. 30 (TIC10), SEQ ID NO. 31/SEQ ID NO. 32 (TIC11), SEQ ID NO. 33/SEQ ID NO. 34 (TID1), SEQ ID NO. 35/SEQ ID NO. 36 (TID6), SEQ ID NO. 37/SEQ ID NO. 38 (TID10), SEQ ID NO. 39/SEQ ID NO. 40 (TID12), SEQ ID NO. 41/SEQ ID NO. 42 (TIE2), SEQ ID NO. 43/SEQ ID NO. 44 (TIE3), SEQ ID NO. 45/SEQ ID NO. 46 (TIE7), SEQ ID NO. 47/SEQ ID NO. 48 (TIE9), SEQ ID NO. 49/SEQ ID NO. 50 (TIF3), SEQ ID NO. 51/SEQ ID NO. 52 (TIF7), SEQ ID NO. 53/SEQ ID NO. 54 (TIF8), SEQ ID NO. 55/SEQ ID NO. 56 (TIG1), SEQ ID NO. 57/SEQ ID NO. 58 (TIG3), SEQ ID NO. 59/SEQ ID NO. 60 (TIG6), SEQ ID NO. 7/SEQ ID NO. 62 (TIG9), SEQ ID NO. 63/SEQ ID NO. 64 (TIG10), SEQ ID NO. 65/SEQ ID NO. 66 (TIH1), SEQ ID NO. 67/SEQ ID NO. 68 (TIH5), and SEQ ID NO. 69/SEQ ID NO. 70 (TIH11).

17. The antibody, or antigen-binding fragment thereof, of claim 15, which has a K_D of at least 1×

10<sup>−

6</sup>M.

18. A pharmaceutical composition comprising the anti-TIM3 antibody, or antibody fragment of claim 15, and a pharmaceutically acceptable carrier.

19. A method of treating cancer, or an inflammatory or autoimmune disease, in a human subject in need thereof, comprising administering an effective amount of the anti-TIM3 antibody, or antigen-binding fragment thereof, of claim 15 to the subject, such that cancer is treated.

20. The method of claim 19, wherein the cancer is selected from the group consisting of:

ovarian cancer, colon cancer, breast cancer, lung cancer, myelomas, neuroblastic-derived CNS tumors, monocytic leukemias, B-cell derived leukemias, T-cell derived leukemias, B-cell derived lymphomas, T-cell derived lymphomas, and mast cell derived tumors or the autoimmune or inflammatory disease is selected from the group consisting of;

intestinal mucosal inflammation, wasting disease associated with colitis, multiple sclerosis, systemic lupus erythematosus, viral infections, rheumatoid arthritis, osteoarthritis, psoriasis, Crohn'"'"'s disease, and inflammatory bowel disease.