ARGX-117, a therapeutic complement inhibiting antibody targeting C2

Area of Science:

• Immunology
• Pharmacology

Background:

• Complement system activation, particularly classical and lectin pathways, contributes to tissue damage in antibody-mediated diseases and ischemia-reperfusion.
• Therapeutic targeting of complement factors is a key strategy for treating these conditions.

Purpose of the Study:

• To characterize ARGX-117, a humanized monoclonal antibody designed to inhibit complement C2.
• To evaluate the mechanism of action, binding characteristics, in vitro efficacy, and pharmacokinetic/pharmacodynamic profile of ARGX-117.

Main Methods:

• In vitro assays to investigate binding to C2 and inhibition of complement activation.
• Complement-mediated cytotoxicity assays using models of autoimmune hemolytic anemia and antibody-mediated rejection.
• Pharmacokinetic/pharmacodynamic study in cynomolgus monkeys to assess C2 reduction and pathway inhibition.

Main Results:

• ARGX-117 binds to the Sushi-2 domain of C2, inhibiting classical and lectin pathway activation upstream of C3.
• The antibody prevents complement-mediated cytotoxicity in vitro and does not inhibit the alternative pathway.
• In cynomolgus monkeys, ARGX-117 demonstrated dose-dependent reduction of C2 and classical pathway activity for at least 7 weeks.

Conclusions:

• ARGX-117 is a potent complement inhibitor targeting both classical and lectin pathways.
• Its unique mechanism spares the alternative pathway, potentially preserving antimicrobial functions.
• ARGX-117 represents a promising therapeutic candidate for complement-mediated diseases.