Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5.

Autor: Adrianna Latuszek, Yashu Liu, Olav Olsen, Randi Foster, Marc Cao, Irena Lovric, Ming Yuan, Nina Liu, Henry Chen, Qian Zhang, Hui Xiao, Carola Springer, George Ehrlich, Vishal Kamat, Ashique Rafique, Ying Hu, Pamela Krueger, Tammy Huang, William Poueymirou, Robert Babb, Michael P Rosconi, Marc W Retter, Gang Chen, Lori Morton, Brian Zambrowicz, Jingtai Cao, Carmelo Romano, William C Olson
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: PLoS ONE, Vol 15, Iss 5, p e0231892 (2020)
Druh dokumentu: article
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0231892
Popis: Complement is a key component of the innate immune system. Inappropriate complement activation underlies the pathophysiology of a variety of diseases. Complement component 5 (C5) is a validated therapeutic target for complement-mediated diseases, but the development of new therapeutics has been limited by a paucity of preclinical models to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of candidate therapies. The present report describes a novel humanized C5 mouse and its utility in evaluating a panel of fully human anti-C5 antibodies. Surprisingly, humanized C5 mice revealed marked differences in clearance rates amongst a panel of anti-C5 antibodies. One antibody, pozelimab (REGN3918), bound C5 and C5 variants with high affinity and potently blocked complement-mediated hemolysis in vitro. In studies conducted in both humanized C5 mice and cynomolgus monkeys, pozelimab demonstrated prolonged PK and durable suppression of hemolytic activity ex vivo. In humanized C5 mice, a switch in dosing from in-house eculizumab to pozelimab was associated with normalization of serum C5 concentrations, sustained suppression of hemolytic activity ex vivo, and no overt toxicity. Our findings demonstrate the value of humanized C5 mice in identifying new therapeutic candidates and treatment options for complement-mediated diseases.
Databáze: Directory of Open Access Journals
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje