ARGX-117, a therapeutic complement inhibiting antibody targeting C2 - 05/04/21
, Karen Silence, PhD a, ∗, Kevin Budding, PhD b, ∗, Liesbeth Van de Ven, MSc a, Kim Dijkxhoorn, BSc b, Elisabeth de Zeeuw, MSc b, Cafer Yildiz, BSc b, Sofie Gabriels, BSc a, Jean-Michel Percier, MSc a, Johanna Wildemann, MSc b, Jan Meeldijk, MSc b, Peter J. Simons, PhD d, Louis Boon, PhD d, Linda Cox, MSc d, Rob Holgate, PhD e, Rolf Urbanus, PhD f, g, Henny G. Otten, PhD b, Jeanette H.W. Leusen, PhD b, Christophe Blanchetot, PhD a, Hans de Haard, PhD a, C. Erik Hack, MD, PhD b, c, Peter Boross, PhD b, c, ⁎ 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.
Le texte complet de cet article est disponible en PDF.Key words : Complement system, C2, monoclonal antibody, complement inhibitor
Abbreviations used : ADA, aggIgG, AP, CH50, CP, EC50, FB, FcRn, HRP, LP, PD, PK, RBC, RT, S2, SPR, TBS
Plan
| 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. |
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| Disclosure of conflicts of interest: I. Van de Walle, L. Van de Ven, S. Gabriels, J.-M. Percier, C. Blanchetot, and H. de Haard are employees of and have equity ownership in argenx. K. Silence and C. E. Hack are consultants for argenx. P. J. Simons, L. Cox, and L. Boon are employees of Bioceros BV. P. Boross and C. E. Hack are employees of Prothix BV. R. Holgate is an employee of Antitope/Abzena Ltd. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 4
P. 1420 - avril 2021 Retour au numéro
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