C4BP-based compounds for treating immunological diseases
Inventors
Aran Perramon, Josep M. • RUIZ AVILA, Luis Antonio • ORTIZ SAGRISTA, Jordi • LLUCH LAFUENTE, Nuria
Assignees
Fundacio Privada Institut dInvestigacio Biomedica de Bellvitge IDIBELL • Spherium Biomed SL
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Publication Number
US-12006343-B2
Publication Date
2024-06-11
Expiration Date
Abstract
Compounds for use in the prevention and/or treatment of immunological diseases, particularly rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis, are described, characterized by the subcutaneous administration of isoforms of C4BP lacking the beta chain or polypeptides comprising the CCP6 region of the alpha chain of C4BP no more than once a week or at a dose ranging from 0.24 mg/m2 to 9.99 mg/m2. Pharmaceutical compositions comprising from 0.45 mg to 18.90 mg of these compounds for the prevention and/or treatment of these diseases are also described.
Core Innovation
The patent describes C4BP-based immunomodulatory compounds for prevention or treatment of immune-dysregulation diseases caused by undesired activation of the immune system. The approach increases tolerogenic dendritic cell and/or regulatory T cell populations in a subject in need thereof by administering a C4BP isoform lacking the beta chain.
In the defined isoform, at least one alpha-chain preserves a complement control protein 6 (CCP6) domain. The patent further defines the structure of the C4BP isoform lacking the beta chain by specifying alpha-chains that may be deletion mutants lacking at least one complement control protein (CCP) domain, with preservation of the CCP6 domain.
The patent additionally characterizes subcutaneous administration of the C4BP isoform lacking the beta chain, including administration no more than once per week and low-dose ranges. It provides rationale and supporting examples showing attenuation of proteinuria and improved survival in lupus-prone mouse models compared with intraperitoneal dosing, suppression of dendritic cell maturation markers and IL-12 production, and reduction of arthritis progression in the collagen antibody-induced arthritis (CAIA) model through at least day 12.
Claims Coverage
The document contains two independent claims that cover treatment methods using a beta-chain-lacking C4BP isoform with CCP6 preservation under specified alpha-chain conditions to increase tolerogenic dendritic cell and/or regulatory T cell populations, with subcutaneous administration constraints. Across the independent claims, the inventive features primarily concern the specified C4BP isoform structure and preserved CCP6 domain, and the subcutaneous dose/frequency requirements, with one independent claim also reciting the pharmaceutical composition dosage range.
Beta-chain-lacking C4BP isoform with preserved CCP6 domain
A method comprising administering a C4BP isoform lacking the beta chain wherein if at least one of the alpha-chains forming said isoform is a deletion mutant which lacks at least one complement control protein (CCP) domains, a CCP6 domain is preserved in said alpha-chain.
Subcutaneous low-frequency administration of beta-chain-lacking C4BP isoform
A method wherein said C4BP isoform is administered subcutaneously in a regimen comprising a plurality of administrations and wherein the C4BP isoform is administered no more than once a week.
Subcutaneous low-dose beta-chain-lacking C4BP isoform
A method wherein said C4BP isoform is administered subcutaneously at a dose of from 0.24 mg/m2 to 9.99 mg/m2.
Subcutaneous pharmaceutical composition containing beta-chain-lacking C4BP isoform within a defined amount
A method comprising administering to said subject of a pharmaceutical composition comprising from 0.45 mg to 18.90 mg of a C4BP isoform lacking the beta chain wherein if at least one alpha-chain forming said isoform is a deletion mutant which lacks at least one CCP domain, a CCP6 domain is preserved in said alpha-chain, and wherein the pharmaceutical composition is administered subcutaneously.
Overall, the claim coverage centers on subcutaneous treatment that increases tolerogenic dendritic cell and/or regulatory T cell populations by using a beta-chain-lacking C4BP isoform with preserved CCP6 domain under specified alpha-chain conditions, together with constraints on administration frequency or per-dose/per-composition amounts.
Stated Advantages
Attenuation of proteinuria and improved survival compared with intraperitoneal dosing in lupus-prone mouse models.
Suppression of dendritic cell maturation markers (CD83 and CD86) and IL-12 production.
Reduction of arthritis progression through at least day 12 in the CAIA arthritis model.
Documented Applications
Prevention or treatment of immune-dysregulation diseases caused by undesired activation of the immune system, including systemic lupus erythematosus, lupus nephritis, and rheumatoid arthritis.
CAIA arthritis model reduction of arthritis progression through at least day 12 using subcutaneous C4BP(β−) dosing.
Lupus-prone NZBWF1/NZB-NZW F1 mouse model attenuation of proteinuria and improved survival compared with intraperitoneal dosing.
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