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

Adrianna Latuszek,Marc Cao,Vishal Kamat,Ying Hu,Yashu Liu,Gang Chen,Randi Foster,Carmelo Romano,Tammy Huang,William C Olson,Olav Olsen,Irena Lovric,Ashique Rafique,Jingtai Cao,Carola Springer,Robert Babb,Henry Chen,Brian Zambrowicz,Ming Yuan,Pamela Krueger,Lori Morton,William Poueymirou,Qian Zhang,Hui Xiao,Marc W Retter,Nina Liu,G Ehrlich ,Michael Rosconi

doi:10.1371/journal.pone.0231892

Abstract

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.

Highlights

IntroductionRegeneron employees played active roles in all aspects of the research including study design, data collection and analysis, and the preparation and publication of this manuscript
Inhibition of component 5 (C5) is a clinically validated mechanism to treat paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome which are life-threatening orphan diseases characterized by over-activation of terminal complement activity [11,16]
In this study involving humanized C5 mice, we describe the generation and characterization of a fully humanized anti-C5 monoclonal antibody, pozelimab (REGN3918), that binds to human C5 with high affinity, effectively inhibits C5 induced hemolysis and demonstrates prolonged PK/PD profiles

Summary

Introduction

Regeneron employees played active roles in all aspects of the research including study design, data collection and analysis, and the preparation and publication of this manuscript. The complement system is a vital, evolutionarily conserved arm of the innate immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear pathogens from an organism. Activation of complement on pathogen surfaces initiates a cascade of proteolytic events that result in the formation of complement component split products and complexes that act as proinflammatory signals, mediate phagocytosis by opsonization, or induce cell lysis [1,2,3].

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