Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart

Inge Walle (), Laura Bracke, Heidi Gytz Olesen, Tonke Bragt, Stéphanie Cadour, Phillip Decker, Giorgia Ciurlia, Erwin Pannecoucke, Emma K. Persson, Olivier Steen, Xinghong Leng, Gregers Rom Andersen, Domenica Gandini and C. Erik Hack
Additional contact information
Inge Walle: argenx
Laura Bracke: argenx
Heidi Gytz Olesen: Department of Molecular Biology and Genetics - Protein Science
Tonke Bragt: Curare Consulting BV
Stéphanie Cadour: argenx
Phillip Decker: argenx
Giorgia Ciurlia: argenx
Erwin Pannecoucke: argenx
Emma K. Persson: argenx
Olivier Steen: argenx
Xinghong Leng: argenx
Gregers Rom Andersen: Department of Molecular Biology and Genetics - Protein Science
Domenica Gandini: argenx
C. Erik Hack: argenx

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Activation of classical and lectin complement pathways contributes to several human diseases. Empasiprubart is a humanized recycling monoclonal antibody that inhibits both pathways by binding to the CCP2 domain of complement factor 2 (C2), an interaction that is dependent on both Ca2+ and pH. Here, we resolve the crystal structure of empasiprubart complexed with C2, providing the molecular basis of its Ca2+ dependency, and report a randomized, double-blind, placebo-controlled trial to assess the safety and tolerability (primary objectives) in addition to pharmacokinetics, pharmacodynamics, and immunogenicity (secondary objectives) of empasiprubart in 78 healthy participants (NCT04532125). A single intravenous (IV) dose of empasiprubart reduces circulating C2 levels by up to 99% and dose-dependently inhibits the classical and lectin pathways. Multiple IV empasiprubart doses reinforce reductions in free C2 levels, which persist until the endpoint of the study at 41 weeks. This prolonged reduction is in line with the empasiprubart elimination half-life (70–88 days). Single and multiple ascending doses of empasiprubart are generally safe and well tolerated. Overall, our results reveal in atomic detail the mechanism of empasiprubart and demonstrate that it is a first-in-class anti-C2 therapeutic antibody for use in complement-mediated diseases.

Date: 2025
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DOI: 10.1038/s41467-025-62925-1

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