Anti-C2 Antibody ARGX-117 Inhibits Complement in a Disease Model for Multifocal Motor Neuropathy

  • Neurol Neuroimmunol Neuroinflamm. 2021 Nov 10;9(1):e1107. doi: 10.1212/NXI.0000000000001107.
Kevin Budding  1 ,  Lill Eva Johansen  1 ,  Inge Van de Walle  1 ,  Kim Dijkxhoorn  1 ,  Elisabeth de Zeeuw  1 ,  Lauri M Bloemenkamp  1 ,  Jeroen W Bos  1 ,  Marc D Jansen  1 ,  Chantall A D Curial  1 ,  Karen Silence  1 ,  Hans de Haard  1 ,  Christophe Blanchetot  1 ,  Liesbeth Van de Ven  1 ,  Jeanette H W Leusen  1 ,  R Jeroen Pasterkamp  1 ,  Leonard H van den Berg  1 ,  C Erik Hack  1 ,  Peter Boross  1 ,  W Ludo van der Pol  2
Affiliations
  • 1. From the Center for Translational Immunology (K.B., K.D., E.Z., L.M.B., J.H.W.L., C.E.H., P.B.), University Medical Center Utrecht; Department of Neurology and Neurosurgery (L.E.J., L.M.B., J.W.B., M.D.J., C.A.D.C., L.H.B., W.L.P.), University Medical Center Utrecht Brain Center; Department of Translational Neuroscience (L.E.J., L.M.B., R.J.P.), University Medical Center Utrecht Brain Center, Utrecht University; Argenx BVBA, Industriepark-Zwijnaarde 7 (I.W., K.S., H.H., C.B., L.V.), Zwijnaarde, Belgium; and Prothix (C.E.H., P.B.), Leiden, the Netherlands.
  • 2. From the Center for Translational Immunology (K.B., K.D., E.Z., L.M.B., J.H.W.L., C.E.H., P.B.), University Medical Center Utrecht; Department of Neurology and Neurosurgery (L.E.J., L.M.B., J.W.B., M.D.J., C.A.D.C., L.H.B., W.L.P.), University Medical Center Utrecht Brain Center; Department of Translational Neuroscience (L.E.J., L.M.B., R.J.P.), University Medical Center Utrecht Brain Center, Utrecht University; Argenx BVBA, Industriepark-Zwijnaarde 7 (I.W., K.S., H.H., C.B., L.V.), Zwijnaarde, Belgium; and Prothix (C.E.H., P.B.), Leiden, the Netherlands. [email protected].
PMID: 34759020 DOI: 10.1212/NXI.0000000000001107
Abstract

Background and objectives: To determine the role of complement in the disease pathology of multifocal motor neuropathy (MMN), we investigated complement activation, and inhibition, on binding of MMN patient-derived immunoglobulin M (IgM) antibodies in an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model for MMN.

Methods: iPSC-derived MNs were characterized for the expression of complement receptors and membrane-bound regulators, for the binding of circulating IgM anti-GM1 from patients with MMN, and for subsequent fixation of C4 and C3 on incubation with fresh serum. The potency of ARGX-117, a novel inhibitory monoclonal antibody targeting C2, to inhibit fixation of complement was assessed.

Results: iPSC-derived MNs moderately express the Complement Regulatory Proteins CD46 and CD55 and strongly expressed CD59. Furthermore, MNs express C3aR, C5aR, and Complement Receptor 1. IgM anti-GM1 antibodies in serum from patients with MMN bind to MNs and induce C3 and C4 fixation on incubation with fresh serum. ARGX-117 inhibits complement activation downstream of C4 induced by patient-derived anti-GM1 antibodies bound to MNs.

Discussion: Binding of IgM antibodies from patients with MMN to iPSC-derived MNs induces complement activation. By expressing Complement Regulatory Proteins, particularly CD59, MNs are protected against complement-mediated lysis. Yet, because of expressing C3aR, the function of these cells may be affected by complement activation upstream of membrane attack complex formation. ARGX-117 inhibits complement activation upstream of C3 in this disease model for MMN and therefore represents an intervention strategy to prevent harmful effects of complement in MMN.

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