Academic Journal
Moss-derived recombinant Factor H, CPV-104, effectively antagonizes alternative pathway C3/C5 convertases stabilization by NeFs from patients with primary C3 glomerulopathy.
| Τίτλος: | Moss-derived recombinant Factor H, CPV-104, effectively antagonizes alternative pathway C3/C5 convertases stabilization by NeFs from patients with primary C3 glomerulopathy. |
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| Συγγραφείς: | Imanifard Z; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy., Penati F; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy., Padoa S; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy., Dabrowska-Schlepp P; Department of Nonclinical Development, Eleva GmbH, Freiburg, Germany., Bresin E; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy., Peracchi T; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy., Benigni A; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy., Remuzzi G; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy., Noris M; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy., Donadelli R; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Daccò and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy. |
| Πηγή: | Frontiers in immunology [Front Immunol] 2026 Jul 01; Vol. 17, pp. 1860823. Date of Electronic Publication: 2026 Jul 01 (Print Publication: 2026). |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation] |
| Ιατρικοί όροι (MeSH): | Complement Pathway, Alternative*/drug effects , Complement Factor H*/pharmacology , Complement C3-C5 Convertases*/metabolism , Bryopsida*/metabolism , Glomerulonephritis, Membranoproliferative*/immunology , Glomerulonephritis, Membranoproliferative*/drug therapy , Complement C3 Convertase, Alternative Pathway*/metabolism, Recombinant Proteins/pharmacology ; Complement C3/metabolism ; Complement C3 Nephritic Factor/metabolism ; Humans ; Female |
| Περίληψη: | Background: C3 glomerulopathy (C3G) is a rare kidney disease caused by uncontrolled activation of the complement alternative pathway (AP), frequently driven by nephritic factors (NeFs) that stabilize the AP C3 and C5 convertases. NeFs are detected in up to 80% of patients and exhibit heterogeneous stabilizing activity, contributing to variable degrees of complement dysregulation. Current complement-targeted therapies reduce complement activation but may compromise immune surveillance by blocking key components of the pathway. Supplementation with the physiological AP regulator factor H (FH) represents an alternative strategy aimed at restoring complement homeostasis while preserving essential immune functions. CPV-104 is a fully functional recombinant human FH produced in moss, with optimized glycosylation and improved pharmacokinetics, offering a promising therapeutic approach for C3G. Objectives and Methods: We evaluated the ability of CPV-104 to antagonize NeF-mediated stabilization of the AP C3 convertase (C3bBb) in eight C3G patients enrolled in the Italian MPGN/C3G Registry. Patients were classified as C3NeF+ or C5NeF+ based on properdin dependence in convertase stabilization assays. NeF activity was analyzed using solid-phase assays in which C3bBb decay and formation were assessed in the presence of CPV-104 or serum-derived FH (sd-FH). The impact of CPV-104 ex vivo was tested in fluid-phase assays using patient sera, with Ba (convertase formation) and C3a (convertase activity) measured by ELISA. Results: CPV-104 accelerated decay of NeF-stabilized C3bBb with efficacy comparable to sd-FH. Convertases stabilized by six of eight NeFs were fully dissociated by CPV-104, while two highly potent C3NeFs were partially antagonized. When added during convertase assembly, CPV-104 significantly reduced C3bBb formation in all patients and showed a stronger inhibitory effect than sd-FH. In fluid-phase assays, using patient sera, CPV-104 markedly decreased Ba and C3a generation, with mean inhibition of 68.9% and 51.8%, respectively, and consistently outperformed sd-FH across patient samples. Conclusions: CPV-104 effectively limits both stabilization and formation of AP C3 convertases in NeF-positive C3G, demonstrating superior functional activity compared with sd-FH. By restoring physiological AP regulation rather than broadly inhibiting complement activation, CPV-104 represents a promising and potentially safer therapeutic strategy for NeF-driven C3G and warrants further clinical investigation. (Copyright © 2026 Imanifard, Penati, Padoa, Dabrowska-Schlepp, Bresin, Peracchi, Benigni, Remuzzi, Noris and Donadelli.) |
| Competing Interests: | PD-S was employed by company Eleva GmbH. The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. |
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| Contributed Indexing: | Keywords: C3 glomerulopathy (C3G); C3 nephritic factor (C3NeF); C5 nephritic factor (C5NeF); CPV-104; Factor H (FH); alternative pathway C3/C5 convertases |
| Substance Nomenclature: | 0 (Recombinant Proteins) 80295-65-4 (Complement Factor H) EC 3.4.21.- (Complement C3-C5 Convertases) 0 (Complement C3) EC 3.4.21.47 (Complement C3 Convertase, Alternative Pathway) 0 (Complement C3 Nephritic Factor) |
| Entry Date(s): | Date Created: 20260716 Date Completed: 20260716 Latest Revision: 20260813 |
| Update Code: | 20260814 |
| PubMed Central ID: | PMC13368663 |
| DOI: | 10.3389/fimmu.2026.1860823 |
| PMID: | 42459673 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2026.1860823 |