Related Experiment Video
Updated: Oct 13, 2025
Induction of Paralysis and Visual System Injury in Mice by T Cells Specific for Neuromyelitis Optica Autoantigen Aquaporin-4
Published on: August 21, 2017
Anti-C2 Antibody ARGX-117 Inhibits Complement in a Disease Model for Multifocal Motor Neuropathy
Kevin Budding1, Lill Eva Johansen1, Inge Van de Walle1
1From 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.
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.
Insights
Complement activation by patient antibodies drives multifocal motor neuropathy (MMN). A novel antibody, ARGX-117, inhibits this complement pathway, offering a potential therapeutic strategy for MMN.
Area of Science:
- Neuroimmunology
- Complement System Biology
Background:
- Multifocal motor neuropathy (MMN) involves complement system activation.
- Patient-derived immunoglobulin M (IgM) antibodies play a role in MMN pathology.
Purpose of the Study:
- Investigate complement activation in an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model for MMN.
- Assess the inhibitory potential of ARGX-117 on complement fixation.
Main Methods:
- Characterized iPSC-derived MNs for complement receptors and regulators.
- Tested binding of MMN patient IgM anti-GM1 antibodies.
- Assessed C4 and C3 fixation and inhibition by ARGX-117.
Main Results:
- iPSC-derived MNs express complement receptors and regulators, including CD59.
- MMN patient IgM anti-GM1 antibodies bind MNs and activate complement (C4, C3).
- ARGX-117 inhibits complement activation downstream of C4.
Conclusions:
- Complement activation by MMN patient antibodies contributes to disease pathology.
- ARGX-117 effectively inhibits complement activation in an MMN model.
- ARGX-117 represents a potential therapeutic intervention for MMN.
