Compounds and methods for treating pain

Patent metadata

Field	Value
Publication number	US-10457728-B2
Application number	US-201715849771-A
Country	US
Kind code	B2
Filing date	Dec 21, 2017
Priority date	Feb 2, 2014
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

This disclosure provides compositions and methods for controlling pain. In particular the disclosure provides a method for controlling pain comprising co-administration of an NGF antagonist and a TNFα antagonist. The NGF antagonist and the TNFα antagonist can be separate molecules or part of a multifunctional polypeptide, e.g., a multispecific binding molecule that comprises an NGF antagonist domain and a TNFα antagonist domain. This disclosure also provides multifunctional polypeptides, e.g., multispecific binding molecules, comprising an NGF antagonist domain, and a TNFα antagonist domain. The method provides improved pain control. Administration of an NGF antagonist and a TNFα antagonist as provided herein can control pain in the subject more effectively than an equivalent amount of the NGF antagonist or the TNFα antagonist administered alone.

First claim

What is claimed is:

1. A binding molecule comprising an NGF antagonist domain and a TNFα antagonist domain, wherein the NGF antagonist domain comprises an anti-NGF antibody or fragment thereof; wherein the TNFα antagonist domain comprises a soluble, TNFα-binding fragment of TNFR-2; wherein the anti-NGF antibody or fragment thereof comprises a VH domain comprising a set of CDRs HCDR1, HCDR2, HCDR3 and a VL domain comprising a set of CDRs LCDR1, LCDR2 and LCDR3, wherein the HCDR1 has the amino acid sequence of SEQ ID NO: 4, the HCDR2 has the amino acid sequence of SEQ ID NO: 5, the HCDR3 has the amino acid sequence of any one of SEQ ID NOs: 6, 11 or 12, the LCDR1 has the amino acid sequence of SEQ ID NO: 8, the LCDR2 has the amino acid sequence of SEQ ID NO: 9, and the LCDR3 has the amino acid sequence of SEQ ID NO: 10; wherein a cysteine is present in the VH domain at the amino acid corresponding to amino acid position 44 of SEQ ID NO: 94; and wherein a cysteine is present in the VL domain at the amino acid corresponding to amino acid position 103 of SEQ ID NO: 95.

2. The binding molecule of claim 1 , wherein the anti-NGF antibody or fragment thereof is an scFv, and wherein the scFv is SS-stabilized.

3. The binding molecule of claim 1 , wherein the TNFα antagonist inhibits binding of TNFα to a TNF receptor (TNFR) on the surface of cells, thereby blocking TNFα activity.

4. The binding molecule of claim 1 , wherein the TNFα antagonist comprises a soluble, TNFα-binding fragment of TNFR-2 fused to an immunoglobulin Fc domain.

5. The binding molecule of claim 4 , wherein the immunoglobulin Fc domain is a human IgG1 Fc domain.

6. The binding molecule of claim 1 , wherein the TNFα antagonist comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 13, or a functional fragment thereof.

7. The binding molecule of claim 1 , wherein the TNFα antagonist comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 13, or a functional fragment thereof.

8. The binding molecule of claim 1 , wherein the TNFα antagonist comprises an amino acid sequence identical to a sequence corresponding to amino acids 1-235 of SEQ ID NO: 13.

9. The binding molecule of claim 8 , wherein the VH domain comprises a VH amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 94; and wherein the VL domain comprises a VL amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 95.

10. The binding molecule of claim 9 , wherein the binding molecule comprises a fusion protein comprising the NGF antagonist fused to the TNFα antagonist through a linker.

11. The binding molecule of claim 10 , wherein the binding molecule comprises a homodimer of the fusion protein.

12. The binding molecule of claim 11 , wherein the TNFα antagonist is a soluble, TNFα-binding fragment of TNFR-2 fused at its carboxy-terminus to an immunoglobulin Fc domain via a linker.

13. The binding molecule of claim 1 , wherein the VH domain comprises a VH amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 94; and wherein the VL domain comprises a VL amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 95.

14. The binding molecule of claim 1 , wherein the VH domain comprises a VH amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 94; and wherein the VL domain comprises a VL amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 95.

15. The binding molecule of claim 1 , wherein the binding molecule comprises a homodimer of a fusion polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17.

16. A pharmaceutical composition comprising the binding molecule of claim 1 , and a pharmaceutically acceptable excipient.

17. A lyophilized composition comprising the binding molecule of claim 1 .

18. A reconstituted lyophilized composition comprising the binding molecule of claim 1 .

19. A kit comprising the binding molecule of claim 1 .

Assignees

• Medimmune Ltd

Inventors

• Schofield Darren
• Sleeman Matthew Alexander
• Chessell Iain Patrick
• Hatcher Jonathan
• Lowe David

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/02

  without antiinflammatory effect · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• C07K2319/35

  containing a fusion for enhanced stability/folding during expression, e.g. fusions with chaperones or thioredoxin · CPC title