# US 11,897,949 B2 · Compounds and methods for treating pain

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- Number: US 11,897,949 B2
- Document ID: US11897949B2
- Status: Granted
- Kind: B2
- Application number: 17/333,291
- Filed: 2021-05-28
- Published: 2021-11-11
- Granted: 2024-02-13
- Earliest claimed: 2014-02-02
- Assignees: MedImmune, LLC
- Applicants: MedImmune Limited
- Inventors: Darren Schofield; Matthew Alexander Sleeman; Iain Patrick Chessell; Jonathan Hatcher; David Lowe
- Web page: https://patentgrep.com/patent/US11897949B2

## CPC

- C07K 16/22: against growth factors {; against growth regulators}
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/02: without antiinflammatory effect
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/48: Nerve growth factor [NGF]
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 14/7151: {for tumor necrosis factor [TNF], for lymphotoxin [LT]}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/31: multispecific
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K 2319/00: Fusion polypeptide
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/32: fusions with soluble part of a cell surface receptor, "decoy receptors"
- C07K 2319/35: containing a fusion for enhanced stability/folding during expression, e.g. fusions with chaperones or thioredoxin
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## 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.

## Claims

### Claim 1

A method for controlling or treating pain in a subject, comprising administering to a subject in need thereof an effective amount of a binding molecule comprising an NGF antagonist domain and a TNFα antagonist domain, wherein the NGF antagonist is an anti-NGF antibody, or antigen-binding 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 comprises the amino acid sequence of SEQ ID NO: 4, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 5, the HCDR3 comprises the amino acid sequence of any one of SEQ ID NOs: 6, 11 or 12, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 8, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 9, and the LCDR3 comprises 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.

### Claim 2 (depends on 1)

The method of claim 1, wherein the anti-NGF antibody or fragment thereof comprises a VH having an amino acid sequence that is at least 90%, 95%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 94 and a VL having an amino acid sequence that is at least 90%, 95%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 95.

### Claim 3 (depends on 1)

The method of claim 1, wherein the NGF antagonist is an anti-NGF scFv fragment.

### Claim 4 (depends on 3)

The method of claim 3, wherein the scFv is SS-stabilized.

### Claim 5 (depends on 1)

The method of claim 1, wherein the TNFα antagonist inhibits binding of TNFα to a TNF receptor (TNFR), thereby blocking TNFα activity.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 6)

The method of claim 6, wherein the immunoglobulin Fc domain is a human IgG1 Fc domain.

### Claim 8 (depends on 1)

The method of claim 1, wherein the TNFα antagonist comprises an amino acid sequence that is at least 90%, 95% or 100% identical to SEQ ID NO: 13, or a functional fragment thereof.

### Claim 9 (depends on 1)

The method of claim 1, wherein the binding molecule comprises a fusion protein that comprises the NGF antagonist fused to the TNFα antagonist through a linker.

### Claim 10 (depends on 9)

The method of claim 9, wherein the binding molecule comprises a homodimer of the fusion protein.

### Claim 11 (depends on 9)

The method of claim 9, wherein the NGF antagonist is an anti-NGF scFv domain and the TNFα antagonist is a soluble, TNFα-binding fragment of TNFR-2 fused at its carboxy-terminus to an immunoglobulin Fc domain.

### Claim 12 (depends on 11)

The method of claim 11, wherein the scFv is fused to the carboxy-terminus of the immunoglobulin Fc domain via a linker.

### Claim 13 (depends on 9)

The method of claim 9, wherein the binding molecule comprises a homodimer of a fusion polypeptide comprising an amino acid sequence that is at least 90%, 95%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 17.

### Claim 14 (depends on 1)

The method of claim 1, wherein the administration is sufficient to prevent, reduce, ameliorate, or eliminate pain in the subject.

### Claim 15 (depends on 1)

The method of claim 1, where in the pain is acute pain, short-term pain, persistent nociceptive pain, neuropathic pain such as persistent or chronic neuropathic pain, or chronic pain such as chronic joint pain.

### Claim 16 (depends on 1)

The method of claim 1, wherein the administration is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70% 80%, 90%, or 100% more effective at controlling pain in the subject than an equivalent amount of the NGF antagonist or the TNFα antagonist administered alone.

### Claim 17 (depends on 1)

The method 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.

### Claim 18 (depends on 1)

The method of claim 1, wherein the NGF antagonist domain comprises an anti-NGF scFv fragment, and the TNFα antagonist domain comprises a soluble, TNFα-binding fragment of TNFR-2; and wherein the anti-NGF scFv fragment comprises, from N-terminus to C-terminus, a VH comprising the amino acid sequence of SEQ ID NO: 94, a 20-amino acid linker sequence (GGGGS)4 (SEQ ID NO: 19), and a VL comprising the amino acid sequence of SEQ ID NO: 95.

### Claim 19 (depends on 18)

The method of claim 18, wherein the binding molecule comprises a homodimer of a fusion polypeptide comprising, from N-terminus to C-terminus:
(i) a TNFα-binding fragment of TNFR-2, a human IgG1Fc domain, a 10-amino-acid linker sequence (GGGGS)2, (SEQ ID NO: 98), a VH comprising the amino acid sequence of SEQ ID NO: 94, a 20-amino acid linker sequence (GGGGS)4 (SEQ ID NO: 19), and a VL comprising the amino acid sequence of SEQ ID NO: 95; or
(ii) a TNFα-binding fragment of TNFR-2 comprising an amino acid sequence identical to a sequence corresponding to amino acids 1-235 of SEQ ID NO: 13, a human IgG1Fc domain, a 10-amino-acid linker sequence (GGGGS)2, (SEQ ID NO: 98), a VH comprising the amino acid sequence of SEQ ID NO: 94, a 20-amino acid linker sequence (GGGGS)4 (SEQ ID NO: 19, and a VL comprising the amino acid sequence of SEQ ID NO: 95.

### Claim 20 (depends on 17)

The method of claim 17, 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.

### Claim 21 (depends on 20)

The method of claim 20, wherein the binding molecule comprises a fusion protein comprising the NGF antagonist fused to the TNFα antagonist through a linker.

### Claim 22 (depends on 21)

The method of claim 21, wherein the binding molecule comprises a homodimer of the fusion protein.

### Claim 23 (depends on 22)

The method of claim 22, 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.