Author: Frischmuth, Thomas ; Fode, Benjamin ; Schaaf, Andreas ; Niederkrüger, Holger ; Reski, Ralf ; Parsons, Juliana ; Häffner, Karsten ; Zipfel, Peter F ; Hoernstein, Sebastian N W ; Decker, Eva L ; Krieghoff, Nicola ; Koch, Jonas ; Pohl, Martin ; Bohlender, Lennard L ; Michelfelder, Stefan ; Busch, Andreas

Genetic defects in complement regulatory proteins can lead to severe renal diseases, including atypical hemolytic uremic syndrome and C3 glomerulopathies, and age-related macular degeneration. The majority of the mutations found in patients with these diseases affect the glycoprotein complement factor H, the main regulator of the alternative pathway of complement activation. Therapeutic options are limited, and novel treatments, specifically those targeting alternative pathway activation, are highly desirable. Substitution with biologically active factor H could potentially treat a variety of diseases that involve increased alternative pathway activation, but no therapeutic factor H is commercially available. We recently reported the expression of full-length recombinant factor H in moss (Physcomitrella patens). Here, we present the production of an improved moss-derived recombinant human factor H devoid of potentially immunogenic plant–specific sugar residues on proteinN-glycans, yielding approximately 1 mg purified moss–derived human factor H per liter of initialP. patensculture after a multistep purification process. This glycosylation-optimized factor H showed fullin vitrocomplement regulatory activity similar to that of plasma-derived factor H and efficiently blocked LPS-induced alternative pathway activation and hemolysis induced by sera from patients with atypical hemolytic uremic syndrome. Furthermore, injection of moss-derived factor H reduced C3 deposition and increased serum C3 levels in a murine model of C3 glomerulopathy. Thus, we consider moss-produced recombinant human factor H a promising pharmaceutical product for therapeutic intervention in patients suffering from complement dysregulation.

Frontiers in Immunology

Moss-produced human complement factor H with modified glycans has an extended half-life and improved biological activity

Article

Author: Zipfel, Peter F ; Panse, Jens ; Aiello, Sistiana ; Hartmann, Andrea ; Dabrowska-Schlepp, Paulina ; Noris, Marina ; Schaaf, Andreas ; Tschongov, Todor ; Sievert, Christian ; Busch, Andreas ; Häffner, Karsten ; Gastoldi, Sara ; Konwar, Swagata

Most drugs that target the complement system are designed to inhibit the complement pathway at either the proximal or terminal levels. The use of a natural complement regulator such as factor H (FH) could provide a superior treatment option by restoring the balance of an overactive complement system while preserving its normal physiological functions. Until now, the systemic treatment of complement-associated disorders with FH has been deemed unfeasible, primarily due to high production costs, risks related to FH purified from donors’ blood, and the challenging expression of recombinant FH in different host systems. We recently demonstrated that a moss-based expression system can produce high yields of properly folded, fully functional, recombinant FH. However, the half-life of the initial variant (CPV-101) was relatively short. Here we show that the same polypeptide with modified glycosylation (CPV-104) achieves a pharmacokinetic profile comparable to that of native FH derived from human serum. The treatment of FH-deficient mice with CPV-104 significantly improved important efficacy parameters such as the normalization of serum C3 levels and the rapid degradation of C3 deposits in the kidney compared to treatment with CPV-101. Furthermore, CPV-104 showed comparable functionality to serum-derived FH in vitro, as well as similar performance in ex vivo assays involving samples from patients with atypical hemolytic uremic syndrome, C3 glomerulopathy and paroxysomal nocturnal hematuria. CPV-104 – the human FH analog expressed in moss – will therefore allow the treatment of complement-associated human diseases by rebalancing instead of inhibiting the complement cascade.

Frontiers in Neurology

Complement updates in optic neuritis

Review

Author: Guo, Kai ; He, Yuhong ; Xin, Jifu

Optic neuritis (ON) is an inflammatory condition of the optic nerve associated with demyelinating diseases like multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease. The complement system is crucial in ON pathogenesis, driving blood-optic nerve barrier disruption, inflammation, and tissue damage. This review explores the complement activation pathways—classical, alternative, and lectin—and their roles in ON progression. Key proteins such as C3, C5, and terminal pathway components are highlighted as central to disease mechanisms. Recent advances in complement-targeted therapies, including C1q blockers, C3 and C5 inhibitors, show promising results in clinical and preclinical studies. Novel therapies, like anaphylatoxin receptor blockers and recombinant factor H, expand the treatment landscape, while plasma exchange remains vital for severe, corticosteroid-resistant cases. Challenges remain, such as ON heterogeneity, the long-term safety of complement inhibition, and the need for personalized approaches. Future studies should focus on unraveling complement-mediated mechanisms, identifying biomarkers, and refining therapeutic strategies. This review highlights the critical role of complement in ON and the latest therapeutic advances to improve patient outcomes.

100 Deals associated with CPV-104

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Indication	Highest Phase	Country/Location	Organization	Date
C3 glomerulopathy	Preclinical	Germany	Eleva GmbH	11 May 2024

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