ARGX-117, a therapeutic complement inhibiting antibody targeting C2

J Allergy Clin Immunol. 2021 Apr;147(4):1420-1429.e7. doi: 10.1016/j.jaci.2020.08.028. Epub 2020 Sep 11.


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 sought to 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 pharmacokinetic/pharmacodynamic 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 the neonatal Fc receptor, and to reduce effector functions. In cynomolgus monkeys, ARGX-117 dose-dependently reduces free C2 levels and classical pathway activity. A 2-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.

Conclusions: ARGX-117 is a promising new complement inhibitor that is uniquely positioned to target both the classical and lectin pathways while leaving the alternative pathway intact.

Keywords: C2; Complement system; complement inhibitor; monoclonal antibody.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / blood
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / pharmacology*
  • Calcium
  • Complement Activation / drug effects
  • Complement C2 / analysis
  • Complement C2 / antagonists & inhibitors*
  • Complement C2 / metabolism
  • Complement Inactivating Agents / blood
  • Complement Inactivating Agents / pharmacokinetics
  • Complement Inactivating Agents / pharmacology*
  • Epitope Mapping
  • Female
  • Humans
  • Hydrogen-Ion Concentration
  • Macaca fascicularis
  • Male


  • Antibodies, Monoclonal
  • Complement C2
  • Complement Inactivating Agents
  • Calcium