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C1q-targeted monoclonal antibody prevents complement-dependent cytotoxicity and neuropathology in in vitro and mouse models of neuromyelitis optica

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Abstract

Neuromyelitis optica (NMO) is an autoimmune disorder with inflammatory demyelinating lesions in the central nervous system, particularly in the spinal cord and optic nerve. NMO pathogenesis is thought to involve binding of anti-aquaporin-4 (AQP4) autoantibodies to astrocytes, which causes complement-dependent cytotoxicity (CDC) and downstream inflammation leading to oligodendrocyte and neuronal injury. Vasculocentric deposition of activated complement is a prominent feature of NMO pathology. Here, we show that a neutralizing monoclonal antibody against the C1q protein in the classical complement pathway prevents AQP4 autoantibody-dependent CDC in cell cultures and NMO lesions in ex vivo spinal cord slice cultures and in mice. A monoclonal antibody against human C1q with 11 nM binding affinity prevented CDC caused by NMO patient serum in AQP4-transfected cells and primary astrocyte cultures, and prevented complement-dependent cell-mediated cytotoxicity (CDCC) produced by natural killer cells. The anti-C1q antibody prevented astrocyte damage and demyelination in mouse spinal cord slice cultures exposed to AQP4 autoantibody and human complement. In a mouse model of NMO produced by intracerebral injection of AQP4 autoantibody and human complement, the inflammatory demyelinating lesions were greatly reduced by intracerebral administration of the anti-C1q antibody. These results provide proof-of-concept for C1q-targeted monoclonal antibody therapy in NMO. Targeting of C1q inhibits the classical complement pathway directly and causes secondary inhibition of CDCC and the alternative complement pathway. As C1q-targeted therapy leaves the lectin complement activation pathway largely intact, its side-effect profile is predicted to differ from that of therapies targeting downstream complement proteins.

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Acknowledgments

This work was supported by grants EY13574, EB00415, DK35124, HL73856, DK86125 and DK72517 from the National Institutes of Health, and a grant from the Guthy-Jackson Charitable Foundation. This work was also supported by a sponsored research agreement from Annexon Inc. (Palo Alto, CA, USA). We thank Dr. Jeffrey Bennett (Univ. Colorado Denver, Aurora, CO, USA) for providing recombinant monoclonal NMO antibody and for Accelerated Cure (Waltham, MA, USA) for providing human NMO sera.

Conflict of interest

Drs. Leviten and Rosenthal are employed by Annexon, Inc.

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Authors and Affiliations

  1. Departments of Medicine and Physiology, University of California, 1246 Health Sciences East Tower, San Francisco, CA, 941143-0521, USA

    Puay-Wah Phuan, Hua Zhang, Nithi Asavapanumas, Lukmanee Tradtrantip & A. S. Verkman

  2. Annexon, Inc, Palo Alto, CA, USA

    Michael Leviten & Arnon Rosenthal

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  1. Puay-Wah Phuan
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  2. Hua Zhang
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  6. Lukmanee Tradtrantip
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  7. A. S. Verkman
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Correspondence to A. S. Verkman.

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Phuan, PW., Zhang, H., Asavapanumas, N. et al. C1q-targeted monoclonal antibody prevents complement-dependent cytotoxicity and neuropathology in in vitro and mouse models of neuromyelitis optica. Acta Neuropathol 125, 829–840 (2013). https://doi.org/10.1007/s00401-013-1128-3

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