Potential Therapeutic Benefit of C1-Esterase Inhibitor in Neuromyelitis Optica Evaluated In Vitro and in an Experimental Rat Model

Abstract

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease of the central nervous system in which binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) to astrocytes causes complement-dependent cytotoxicity (CDC) and inflammation resulting in oligodendrocyte and neuronal injury. There is compelling evidence for a central role of complement in NMO pathogenesis. Here, we evaluated the potential of C1-esterase inhibitor (C1-inh) for complement-targeted therapy of NMO. C1-inh is an anti-inflammatory plasma protein with serine protease inhibition activity that has a broad range of biological activities on the contact (kallikrein), coagulation, fibrinolytic and complement systems. C1-inh is approved for therapy of hereditary angioedema (HAE) and has been studied in a small safety trial in acute NMO relapses (NCT 01759602). In vitro assays of NMO-IgG-dependent CDC showed C1-inh inhibition of human and rat complement, but with predicted minimal complement inhibition activity at a dose of 2000 units in humans. Inhibition of complement by C1-inh was potentiated by ∼10-fold by polysulfated macromolecules including heparin and dextran sulfate. In rats, intravenous C1-inh at a dose 30-fold greater than that approved to treat HAE inhibited serum complement activity by <5%, even when supplemented with heparin. Also, high-dose C1-inh did not reduce pathology in a rat model of NMO produced by intracerebral injection of NMO-IgG. Therefore, although C1r and C1s are targets of C1-inh, our in vitro data with human serum and in vivo data in rats suggest that the complement inhibition activity of C1-inh in serum is too low to confer clinical benefit in NMO.

CD55 upregulation in astrocytes by statins as potential therapy for AQP4-IgG seropositive neuromyelitis optica

“…The motivation for this work is the central importance of complement-mediated cytotoxicity in AQP4-IgG seropositive NMO, and the predicted importance, as demonstrated in experimental animal models [15, 17, 18] and by theoretical considerations [37], of complement regulator proteins in modulating complement action on target cells. Though there has been considerable research on complement mechanisms in NMO pathogenesis and on the development and testing of complement-targeted therapeutics [16, 25, 38], there has been relatively little work on complement regulator proteins in NMO. Increasing the expression or activity of complement regulator proteins on target cells is a logical extension of complement inhibitor therapy for NMO, with the potential advantage of avoiding the immunosuppressive actions of global complement inhibition and their concomitant side effects.…”

Neuromyelitis optica spectrum disorders: Emerging therapies

“…Furthermore, nine patients recovered to their pre‐attack neurological conditions, although two required plasmapheresis as an escalation therapy. In a rat model of NMOSD, C1‐esterase inhibitor partially inhibited AQP4‐Ab‐dependent complement‐dependent cytotoxicity (CDC) in vitro , but did not inhibit serum complement activity or reduce inflammatory lesions . These findings show that further investigation is required to explore the mechanism of action of C1‐esterase inhibitor.…”

Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here?

“…A phase Ib clinical trial of the C1-esterase inhibitor Cinryze, which inhibits the C1 complex of the antibody-initiated classical complement pathway, was safe in humans, with no adverse events ( 123 ) (NCT01759602). However, the drug has not been studied further in NMO clinical trials, and a follow-up study in a rat model of NMO concluded that complement inhibition with this drug was too low to reduce pathology and to be of clinical benefit ( 124 ).…”