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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.
Affiliation
  • Budding K; 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 Trans
  • Johansen LE; 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 Trans
  • Van de Walle I; 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 Trans
  • Dijkxhoorn K; 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 Trans
  • de Zeeuw E; 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 Trans
  • Bloemenkamp LM; 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 Trans
  • Bos JW; 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 Trans
  • Jansen MD; 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 Trans
  • Curial CAD; 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 Trans
  • Silence K; 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 Trans
  • de Haard H; 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 Trans
  • Blanchetot C; 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 Trans
  • Van de Ven L; 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 Trans
  • Leusen JHW; 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 Trans
  • Pasterkamp RJ; 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 Trans
  • van den Berg LH; 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 Trans
  • Hack CE; 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 Trans
  • Boross P; 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 Trans
  • van der Pol WL; 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 Trans
Neurol Neuroimmunol Neuroinflamm ; 9(1)2022 01.
Article in En | MEDLINE | ID: mdl-34759020
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Polyneuropathies / Complement C2 / Complement Activation / Antibodies, Monoclonal, Humanized / Motor Neurons Limits: Humans Language: En Journal: Neurol Neuroimmunol Neuroinflamm Year: 2022 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Polyneuropathies / Complement C2 / Complement Activation / Antibodies, Monoclonal, Humanized / Motor Neurons Limits: Humans Language: En Journal: Neurol Neuroimmunol Neuroinflamm Year: 2022 Document type: Article