Anti-C2 Antibody ARGX-117 Inhibits Complement in a Disease Model for Multifocal Motor Neuropathy
Budding, Kevin; Johansen, Lill Eva; Van de Walle, Inge; Dijkxhoorn, Kim; de Zeeuw, Elisabeth; Bloemenkamp, Lauri M.; Bos, Jeroen W.; Jansen, Marc D.; Curial, Chantall A.D.; Silence, Karen; de Haard, Hans; Blanchetot, Christophe; Van de Ven, Liesbeth; Leusen, Jeanette H.W.; Pasterkamp, R. Jeroen; van den Berg, Leonard H.; Hack, C. Erik; Boross, Peter; van der Pol, W. Ludo
(2022) Neurology® neuroimmunology & neuroinflammation, volume 9, issue 1, pp. 1 - 11
(Article)
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
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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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Keywords: Antibodies, Monoclonal, Humanized/pharmacology, Cells, Cultured, Complement Activation/immunology, Complement C2/drug effects, Humans, Immunoglobulin M, Induced Pluripotent Stem Cells, Motor Neurons, Polyneuropathies/drug therapy, Clinical Neurology, Neurology, Journal Article
ISSN: 2332-7812
Publisher: Lippincott Williams & Wilkins
Note: Publisher Copyright: © American Academy of Neurology.
(Peer reviewed)