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.
Inge Van de Walle  1 ,  Karen Silence  2 ,  Kevin Budding  3 ,  Liesbeth Van de Ven  2 ,  Kim Dijkxhoorn  3 ,  Elisabeth de Zeeuw  3 ,  Cafer Yildiz  3 ,  Sofie Gabriels  2 ,  Jean-Michel Percier  2 ,  Johanna Wildemann  3 ,  Jan Meeldijk  3 ,  Peter J Simons  4 ,  Louis Boon  4 ,  Linda Cox  4 ,  Rob Holgate  5 ,  Rolf Urbanus  6 ,  Henny G Otten  3 ,  Jeanette H W Leusen  3 ,  Christophe Blanchetot  2 ,  Hans de Haard  2 ,  C Erik Hack  7 ,  Peter Boross  8
Affiliations
  • 1. argenx BVBA, Zwijnaarde, Belgium. Electronic address: [email protected].
  • 2. argenx BVBA, Zwijnaarde, Belgium.
  • 3. Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 4. Bioceros BV, Utrecht, The Netherlands.
  • 5. Antitope Ltd, Cambridge, United Kingdom.
  • 6. Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
  • 7. Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Prothix BV, Leiden, The Netherlands.
  • 8. Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; Prothix BV, Leiden, The Netherlands. Electronic address: [email protected].
PMID: 32926878 DOI: 10.1016/j.jaci.2020.08.028
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 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.
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