Effective long-term treatment with moss-produced factor H by overcoming the antibody response in a mouse model of C3G

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 7, 2025

Complement-associated disorders are caused by the dysregulation and disbalance of complement system, especially excessive activation. Most drugs that target system designed to inhibit pathway at either proximal or terminal levels. The use a natural regulator such as factor H (FH) could provide superior treatment option restoring balance an overactive system. We recently reported moss-based production analog human FH with optimized glycan profile (CPV-104), which showed in vitro vivo characteristics comparable its counterpart. Here, we follow up our previous work, focusing more detail on time course long-term efficacy CPV-104 FH-deficient ( –/– ) mice. analysis effects following multiple injections into mice was previously hindered immune response, so developed protocol for sustained depletion CD20 + B-cells CD4 T-cells, preventing antibody formation without influencing C3G phenotype. Using this dual-depletion method, were able complete dosing interval experiments mice, administering three different intervals. Repeated administration lastingly resolve C3 deposits, offering additional rationale clinical testing patients. Moreover, novel method has potential adaptation mouse models, allowing doses other therapeutic proteins.

Language: Английский

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Complementing CD20 antibodies’ effector functions

Blood, Journal Year: 2025, Volume and Issue: 145(12), P. 1232 - 1234

Published: March 20, 2025

Language: Английский

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Tissue-targeted regulators of complement for amelioration of human disease: rationale and novel therapeutic strategies

The Journal of Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: April 21, 2025

Abstract The complement system is an essential part of innate immunity, and dysregulated underlying driver in many inflammatory autoimmune diseases. Currently approved complement-focused therapeutics rely on systemic blockade activation, but a major challenge with this approach that components exist high abundance undergo rapid turnover, creating large pharmacologic sink. To improve the arsenal therapies, tissue-targeting has emerged as strategy to re-regulate diseased tissue, while limiting blockade. This approach, which based directing modulators tissues through recognition tissue-fixed activated fragments, tissue-specific epitopes, or injury-associated neoepitopes, potential for enhanced potency durability reduced infection risk. In review, we discuss rationale tissue-targeted strategies taken achieve local regulation, current state preclinical clinical stage therapeutics, future directions.

Language: Английский

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Therapeutic targeting of alternative pathway and C5 but not C5a protects from disease development in a preclinical model of autoimmune blistering dermatosis

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 30, 2025

Introduction Epidermolysis Bullosa Acquisita (EBA) is an autoimmune blistering dermatosis characterized by autoantibodies (AAbs) against type VII collagen (COL7) located at the dermal epidermal junction (DEJ). Local complement activation drives C5a generation associated with neutrophil recruitment and resulting in skin lesions inflammation. Here we tested impact of C5a/C5adesArg, C5 or combined alternative pathway (AP) targeting on disease development inflammation a preclinical mouse model mimicking effector phase EBA. Methods C57BL/6 mice were treated subcutaneously purified rabbit anti-mouse-COL7 IgG presence IgG1 mAbs directed murine C5a/C5adesArg (M031), (mBB5.1), bifunctional protein comprising mBB5.1 fused to active fragment AP inhibitor factor H (M014) isotype control mAb. Formation was evaluated 12 days every other day. On day 12, DEJ separation, AAb C3b deposition infiltration assessed. Results Isotype IgG1-treated developed first 4 peaking 12. Prophylactic treatment either M031 M014 markedly reduced lesions, dermal/epidermal separation recruitment. Surprisingly, AP/C5 inhibition but not C5a/C5adesArg-targeting setting therapeutic treatment. affected Importantly, direct comparison isolated vs. revealed that earlier more pronounced than mBB5.1. Discussion Our findings identify C5/AP as novel option for dermatoses.

Language: Английский

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Towards personalized management of myasthenia gravis phenotypes: From the role of multi-omics to the emerging biomarkers and therapeutic targets

Autoimmunity Reviews, Journal Year: 2024, Volume and Issue: 23(12), P. 103669 - 103669

Published: Oct. 18, 2024

Language: Английский

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Decoding complement: Novel disease insights and therapeutic horizons

European Journal of Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 25, 2024

Language: Английский

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