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US-20260125463-A1 - Methods of Using IL-1beta Compounds

US20260125463A1US 20260125463 A1US20260125463 A1US 20260125463A1US-20260125463-A1

Abstract

This invention relates to methods employing IL-1 beta-ligand/IL-1 receptor disrupting compounds, such as IL-1 beta antibodies or IL-1 receptor antibodies, in the treatment and/or prevention of auto-inflammatory syndromes in mammals, particularly humans.

Inventors

  • Hermann Gram
  • Thomas Jung
  • Philip Lowe
  • Trevor Mundel
  • Timothy Wright

Assignees

  • NOVARTIS AG

Dates

Publication Date
20260507
Application Date
20250523

Claims (13)

  1. 1 . A method of treating a disease associated with a mutation in the MEFV gene in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of an IL-1beta antibody comprising: a) an immunoglobulin V H comprising the amino acid sequence set forth as SEQ ID NO: 1 and an immunoglobulin V L comprising the amino acid sequence set forth as SEQ ID NO: 2; or b) the three CDRs of the V H set forth as SEQ ID NO: 1 and the three CDRs of the V L set forth as SEQ ID NO:2.
  2. 2 . (canceled)
  3. 3 . The method according to claim 1 , wherein the three CDRs of SEQ ID NO: 1 comprise the amino acid sequences set forth as SEQ ID NOs: 3-5, and wherein the three CDRs of SEQ ID NO:2 comprise the amino acid sequences set forth as SEQ ID NOs: 6-8.
  4. 4 . The method according to claim 1 , wherein the IL-1beta antibody comprises an antigen binding site comprising: at least one immunoglobulin V H which comprises in sequence hypervariable regions CDR1, CDR2 and CDR3, said CDR1 having the amino acid sequence Val-Tyr-Gly-Met-Asn (SEQ ID NO:3), said CDR2 having the amino acid sequence lle-lle-Trp-Tyr-Asp-Gly-Asp-Asn-Gln-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly (SEQ ID NO:4), and said CDR3 having the amino acid sequence Asp-Leu-Arg-Thr-Gly-Pro (SEQ ID NO:5); and at least one immunoglobulin V L which comprises sequence hypervariable regions CDR1′, CDR2′ and CDR3′, said CDR1′ having the amino acid sequence Arg-Ala-Ser-Gln-Ser-Ile-Gly-Ser-Ser-Leu-His (SEQ ID NO:6) said CDR2′ having the amino acid sequence Ala-Ser-Gln-Ser-Phe-Ser (SEQ ID NO:7), and said CDR3′ having the amino acid sequence His-Gln-Ser-Ser-Ser-Leu-Pro (SEQ ID NO:8).
  5. 5 . The method of claim 1 , wherein the IL-1beta antibody is a human antibody.
  6. 6 . (canceled)
  7. 7 . The method of claim 1 , wherein the IL-1beta antibody is administered to the patient subcutaneously.
  8. 8 . The method of claim 1 , wherein the IL-1beta antibody is administered once every month or less frequently.
  9. 9 . The method of claim 1 , wherein the IL-1beta antibody is administered once every two months or less frequently.
  10. 10 . The method of claim 1 , wherein the IL-1beta antibody is administered once every three months or less frequently.
  11. 11 . The method of claim 1 , wherein the IL-1beta antibody is administered once every four months or less frequently.
  12. 12 . The method of claim 1 , wherein the IL-1beta antibody is ACZ885.
  13. 13 - 20 . (canceled)

Description

The instant application contains a Sequence Listing which has been submitted electronically in html format and is hereby incorporated by reference in its entirety. Said html copy, created on Feb. 27, 2023, is named PAT034610-US-CNT02_SL and is 16,384 bytes in size. This invention relates to a novel use of IL-1β-ligand/IL-1 receptor disrupting compounds (herein referred to as “IL-1beta Compounds”); such as small molecular compounds disrupting IL-1β ligand-IL-1 receptor interaction, IL-1B antibodies or IL-1 receptor antibodies, e.g. IL-1β binding molecules described herein, e.g. antibodies disclosed herein, e.g. IL-1B binding compounds or IL-1 receptor binding compounds, and/or RNA compounds decreasing either IL-1β ligands or IL-1 receptor protein levels, in the treatment and/or prevention of auto-inflammatory syndromes, e.g. Juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and to methods of treating and/or preventing auto-inflammatory syndromes, e.g. Juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome, in mammals, particularly humans. Interleukin-1β (IL-1beta or IL-1β or Interleukin-1β have the same meaning herein) is a potent immuno-modulator which mediates a wide range of immune and inflammatory responses. Inappropriate or excessive production of IL-1 is associated with the pathology of various diseases and disorders, such as septicemia, septic or endotoxic shock, allergies, asthma, bone loss, ischemia, stroke, rheumatoid arthritis and other inflammatory disorders. Antibodies to IL-1β have been proposed for use in the treatment of IL-1 mediated diseases and disorders; see for instance, WO 95/01997 and the discussion in the introduction thereof and WO 02/16436, the content of which is incorporated by reference. In accordance with the present invention, it has now surprisingly been found that IL-1beta Compounds are useful in the prevention and treatment of Auto-Inflammatory Syndromes in patients such as in mammals, particularly humans. Auto-Inflammatory Syndromes according to the inventions are e.g., but not limited to, a group of inherited disorders characterized by recurrent episodes of inflammation, that in contrast to the auto-immune diseases lack high-titer autoantibodies or antigen specific T cells. Furthermore, Auto-inflammatory Syndromes according to the inventions show increased IL-1beta secretion (loss of negative regulatory role of pyrin which seems mutated in said diseases), NFkB activation and impaired leukocyte apoptosis). Auto-inflammatory Syndromes according to the inventions are Muckle-Wells syndromes (MWS), familial cold autoinflammmatory syndrome (FCAS), neonatal-onset mutlisystem inflammatory syndrome (NOMID), chronic infantile neurological, cutaneous, articular (CINCA) syndrome, familial Mediterranean fever (FMF) and/or certain form of juvenile arthritis such as systemic onset idiopathic juvenile arthritis (SOIJA), certain form of juvenile rheumatoid arthritis such as systemic onset idiopathic juvenile rheumatoid arthritis and/or certain form of adult rheumatoid arthritis. Preferably the IL-1beta Compounds are useful in the prevention and treatment of Juvenile rheumatoid arthritis and adult rheumatoid arthritis and/or Muckle Wells Syndrome. In accordance with the particular findings of the present invention, the following embodiments are provided: The present invention concerns compositions and methods for the prevention and treatment of Auto-Inflammatory Syndromes in mammals, including humans. Accordingly, the IL-1beta Compounds are also useful to prepare medicines and medicaments for the treatment of Auto-Inflammatory Syndromes. In a specific aspect, such medicines and medicaments comprise a therapeutically effective amount of IL-1beta Compounds with a pharmaceutically acceptable carrier. In another embodiment, the invention provides the use of an antibody which specifically binds to any of the above or below described polypeptides, e.g. IL-1β ligand or IL-1β receptor, preferably IL-1β ligand, in the prevention and/or treatment of Juvenile rheumatoid arthritis or adult rheumatoid arthritis syndrome and/or other Auto-Inflammatory Syndromes and/or Muckle Wells Syndrome. Optionally, the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody. In one aspect, the present invention concerns an isolated antibody which binds a IL-1β ligand. In another aspect, the antibody inhibits or neutralizes the activity of a IL-1β ligand (an antagonist antibody). In another aspect, the antibody is a monoclonal antibody, which has either a human or nonhuman complementarily determining region (CDR) residues and human framework region (FR) residues. The antibody may be labeled and may be immobilized on a solid support. In a further aspect, the antibody is an antibody fragment, a monoclonal antibody, a single-chain antibody, or an anti-idiotypic antibody. In yet another embodiment, the present invention provides a composition compr