ARGX-117, a therapeutic complement inhibiting antibody targeting C2
Van de Walle, Inge; Silence, Karen; Budding, Kevin; Van de Ven, Liesbeth; Dijkxhoorn, Kim; de Zeeuw, Elisabeth; Yildiz, Cafer; Gabriels, Sofie; Percier, Jean-Michel; Wildemann, Johanna; Meeldijk, Jan; Simons, Peter J; Boon, Louis; Cox, Linda; Holgate, Rob; Urbanus, Rolf; Otten, Henny G; Leusen, Jeanette H W; Blanchetot, Christophe; de Haard, Hans; Hack, C Erik; Boross, Peter
(2021) The Journal of Allergy and Clinical Immunology, volume 147, issue 4, pp. 1420 - 1429.e7
(Article)
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
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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.
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Keywords: C2, complement inhibitor, Complement system, monoclonal antibody, Immunology and Allergy, Immunology, Journal Article
ISSN: 0091-6749
Publisher: Mosby Inc.
Note: Funding Information: This work was supported by an LSH Impuls Programme grant from The Life Science and Health —Topconsortium for Knowledge and Innovation and project 40-43100-98-013 from the Dutch Kidney Foundation . Funding Information: This work was supported by an LSH Impuls Programme grant from The Life Science and Health?Topconsortium for Knowledge and Innovation and project 40-43100-98-013 from the Dutch Kidney Foundation. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
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