Department of Internal Medicine IV (Nephrology), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Eleva GmbH, Freiburg, Germany.
Front Immunol. 2024 May 10;15:1383123. doi: 10.3389/fimmu.2024.1383123. eCollection 2024.
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 , as well as similar performance in 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.
大多数靶向补体系统的药物旨在抑制补体途径的近端或末端水平。使用天然补体调节剂（如因子 H [FH]）可以提供一种优越的治疗选择，通过恢复过度活跃的补体系统的平衡，同时保留其正常的生理功能。到目前为止，用 FH 系统性治疗补体相关疾病被认为是不可行的，主要是由于生产成本高、与从供体血液中纯化的 FH 相关的风险以及在不同宿主系统中表达重组 FH 的挑战性。我们最近证明，苔藓基表达系统可以产生大量正确折叠、完全功能的重组 FH。然而，初始变体（CPV-101）的半衰期相对较短。在这里，我们表明，经过糖基化修饰的相同多肽（CPV-104）可以达到与从人血清中获得的天然 FH 相当的药代动力学特征。与 CPV-101 相比，用 CPV-104 治疗 FH 缺陷型小鼠可显著改善重要疗效参数，如血清 C3 水平的正常化和肾脏中 C3 沉积物的快速降解。此外，CPV-104 与血清衍生的 FH 具有相似的功能，并且在涉及来自非典型溶血尿毒症综合征、C3 肾小球病和阵发性夜间血尿患者样本的测定中表现出相似的性能。CPV-104——在苔藓中表达的人 FH 类似物——将通过重新平衡而不是抑制补体级联反应来允许治疗补体相关的人类疾病。
