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

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. OPEN ACCESS Citation: Latuszek A, Liu Y, Olsen O, Foster R, Cao M, Lovric I, et al. (2020) Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5. PLoS ONE 15(5): e0231892. https://doi.org/10.

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

“…Pozelimab is a fully human anti-complement C5, designed for the potential treatment of PNH and CD-55 deficient protein-losing enteropathy (CHAPLE disease) (NCT04209634). The molecule showed to be more potent in decreasing C5 levels and hemolysis in humans and animal models compared to eculizumab and ravulizumab [110], pushing its further investigation for the treatment of PNH and other complement-mediated diseases. Finally, a PEGylated anti-C5 aptamer, avacincaptad pegol sodium (Zimura ® ), is also under active development in a phase 2/3 trial in patients with geographic atrophy secondary to dry age-related macular degeneration (AMD) [111].…”

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

“…This fully humanized antibody against C5 has been shown to suppress C5 levels and hemolysis in human serum and mice models in a more potent manner compared to eculizumab and ravulizumab ( 154 , 155 ). In a Phase 1 study in healthy subjects, pozelimab also showed 70% bioavailability after subcutaneous administration, allowing for more versatile administration options, such as weekly subcutaneous 400 mg administrations after a 15 mg/kg intravenous loading dose ( 156 ).…”

Implication de la cascade du complément dans les formes sévères de COVID-19

“…[44]. D'autres anticorps ciblant la molécule C5, tels que le pozélimab (Regeneron Pharmaceuticals, Inc.) [45], le tésidolumab (Novartis) [46], le crovalimab/SKY59 (Chugai Pharmaceutical/Roche) [47], et l'ABP 959 (Alexion Pharmaceuticals) [48], sont aussi testés dans des essais cliniques pour le traitement de la COVID19.…”