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

Abstract

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.

A snapshot of the Physcomitrella N-terminome reveals N-terminal methylation of organellar proteins

“…It has further proven to be a valuable system for proteomics and proteogenomics research due to its easy and axenic culture conditions enabling highly reproducible and even GMP-compliant culture conditions (Sarnighausen et al 2004; Heintz et al 2006; Mueller et al 2014; Hoernstein et al 2016, 2018; Fesenko et al 2019, 2021). Besides broad application in basic research, Physcomitrella is employed as a production platform for recombinant biopharmaceuticals in GMP-compliant bioreactors (Decker and Reski 2020; Ruiz-Molina et al 2021; Tschongov et al 2024). Furthermore, genomic and transcriptomic resources are well established and publicly available (Goodstein et al 2012; Lang et al 2018; Perroud et al 2018; Fernandez-Pozo et al 2020; Bi et al 2024).…”