{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T09:45:22Z","timestamp":1782899122771,"version":"3.54.5"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\u2212targeted 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\u2212104 is a fully functional recombinant human FH produced in moss, with optimized glycosylation and improved pharmacokinetics, offering a promising therapeutic approach for C3G.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives and Methods<\/jats:title>\n                    <jats:p>We evaluated the ability of CPV\u2212104 to antagonize NeF\u2212mediated 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\u2212phase assays in which C3bBb decay and formation were assessed in the presence of CPV\u2212104 or serum\u2212derived FH (sd\u2212FH). The impact of CPV\u2212104 ex vivo was tested in fluid\u2212phase assays using patient sera, with Ba (convertase formation) and C3a (convertase activity) measured by ELISA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CPV\u2212104 accelerated decay of NeF\u2212stabilized C3bBb with efficacy comparable to sd\u2212FH. Convertases stabilized by six of eight NeFs were fully dissociated by CPV\u2212104, while two highly potent C3NeFs were partially antagonized. When added during convertase assembly, CPV\u2212104 significantly reduced C3bBb formation in all patients and showed a stronger inhibitory effect than sd\u2212FH. In fluid\u2212phase assays, using patient sera, CPV\u2212104 markedly decreased Ba and C3a generation, with mean inhibition of 68.9% and 51.8%, respectively, and consistently outperformed sd\u2212FH across patient samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CPV\u2212104 effectively limits both stabilization and formation of AP C3 convertases in NeF\u2212positive C3G, demonstrating superior functional activity compared with sd\u2212FH. By restoring physiological AP regulation rather than broadly inhibiting complement activation, CPV\u2212104 represents a promising and potentially safer therapeutic strategy for NeF\u2212driven C3G and warrants further clinical investigation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1860823","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T08:45:14Z","timestamp":1782895514000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Moss-derived recombinant Factor H, CPV-104, effectively antagonizes alternative pathway C3\/C5 convertases stabilization by NeFs from patients with primary C3 glomerulopathy"],"prefix":"10.3389","volume":"17","author":[{"given":"Zahra","family":"Imanifard","sequence":"first","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2 and Centro 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Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Donadelli","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Clinical Research Center for Rare Diseases Aldo e Cele Dacc\u00f2 and Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso","place":["Bergamo, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-018-0107-2","article-title":"C3 glomerulopathy - understanding a rare complement-driven renal disease","volume":"15","author":"Smith","year":"2019","journal-title":"Nat Rev Nephrol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2024.05.015","article-title":"The role of complement in kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies 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