ARGX-117, a therapeutic complement inhibiting antibody targeting C2

Abstract Background Activation of the classical and lectin pathway of complement may contribute to tissue damage and organ dysfunction of antibody-mediated diseases and ischemia-reperfusion conditions. Complement factors are being considered as targets for therapeutic intervention Objective We here characterize ARGX-117, a humanized inhibitory monoclonal antibody against complement C2. Methods The mode-of-action and binding characteristics of ARGX-117 were investigated in detail. Furthermore, its efficacy was analyzed in in vitro complement cytotoxicity assays. Finally, a PK/PD study was conducted in cynomolgus monkeys. Results Through binding to the Sushi-2 domain of C2, ARGX-117 prevents the formation of the C3 proconvertase, and inhibits classical and lectin pathway activation upstream of C3 activation. As ARGX-117 does not inhibit the alternative pathway it is expected not to affect the antimicrobial activity of this complement pathway. ARGX-117 prevents complement-mediated cytotoxicity in in vitro models for autoimmune hemolytic anemia and antibody-mediated rejection of organ transplants. ARGX-117 exhibits pH- and calcium-dependent target binding and is Fc-engineered to increase affinity at acidic pH to FcRn, and to reduce effector functions. In cynomolgus monkeys, ARGX-117 dose-dependently reduces free C2 levels and classical pathway activity. A two-dose regimen of 80 and 20 mg/kg separated by a week, resulted in profound reduction of classical pathway activity lasting for at least 7 weeks. Conclusion ARGX-117 is a promising new complement inhibitor that is uniquely positioned to target both the classical and lectin pathway while leaving the alternative pathway intact.