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.