Targeting the complement system in neuromyelitis optica spectrum disorder

ABSTRACT

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is characterized by central nervous system inflammation and demyelination. In AQP4-IgG seropositive NMOSD, circulating immunoglobulin G (IgG) autoantibodies against astrocyte water channel aquaporin-4 (AQP4) cause tissue injury. Compelling evidence supports a pathogenic role for complement activation following AQP4-IgG binding to AQP4. Clinical studies supported the approval of eculizumab, an inhibitor of C5 cleavage, in AQP4-IgG seropositive NMOSD.

Areas covered

This review covers in vitro, animal models, and human evidence for complement-dependent and complement-independent tissue injury in AQP4-IgG seropositive NMOSD. Complement targets are discussed, including complement proteins, regulators and anaphylatoxin receptors, and corresponding drug candidates.

Expert opinion

Though preclinical data support a central pathogenic role of complement activation in AQP4-IgG seropositive NMOSD, they do not resolve the relative contributions of complement-dependent vs. complement-independent disease mechanisms such as antibody-dependent cellular cytotoxicity, T cell effector mechanisms, and direct AQP4-IgG-induced cellular injury. The best evidence that complement-dependent mechanisms predominate in AQP4-IgG seropositive NMOSD comes from eculizumab clinical data. Various drug candidates targeting distinct complement effector mechanisms may offer improved safety and efficacy. However, notwithstanding the demonstrated efficacy of complement inhibition in AQP4-IgG seropositive NMOSD, the ultimate niche for complement inhibition is not clear given multiple drug options with alternative mechanisms of action.

Abbreviations: AAV2, Adeno-associated virus 2; ADCC, antibody-dependent cellular cytotoxicity; ANCA, antineutrophilic cytoplasmic autoantibody; AQP4, aquaporin-4; AQP4-IgG, AQP4-immunoglobulin G; C1-INH, C1-esterase inhibitor; C3aR, C3a receptor; C4BP, C4 binding protein; C5aR, C5a receptor; CDC, complement-dependent cytotoxicity; CFHR1, complement factor H related 1; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; EndoS, endoglycosidase S; FHL-1, factor-H-like protein 1; GFAP, glial fibrillary acidic protein; Iba-1, ionized calcium-binding adaptor protein-1; IgG, immunoglobulin G; IVIG, intravenous human immunoglobulin G; MAC, membrane attack complex; MBL, maltose-binding lectin; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; NK cell, natural killer cell; NMOSD, neuromyelitis optica spectrum disorder; OAP, orthogonal arrays of particles; PNH, paroxysmal nocturnal hemoglobinuria.

KEYWORDS:

• Aquaporin-4
• astrocyte
• autoimmunity
• complement
• neuroinflammation
• NMOSD

Article highlights

• Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system that can cause significant neurological deficits.

• Pathogenesis of AQP4-IgG seropositive NMOSD involves complement activation produced by binding of AQP4-IgG autoantibodies to AQP4 water channels on astrocytes, which leads to inflammation and demyelination.

• In vitro, animal models and human clinical data support a central role of complement in AQP4-IgG seropositive NMOSD and hence the therapeutic utility of complement inhibition.

• Complement-independent pathogenesis mechanisms may also have a pathogenic role in AQP4-IgG seropositive NMOSD, including antibody-dependent cellular cytotoxicity, AQP4-sensitized T cells, and direct AQP4-IgG-induced astrocyte injury.

• Eculizumab, a humanized monoclonal antibody that binds to C5 and prevents its cleavage, has been approved for treatment of AQP4-IgG seropositive NMOSD.

• Alternative complement-related drugs are in development that target different components of the complement system, complement regulator proteins, and receptors involved in complement effector functions.

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Declaration of interest

A Verkman and L Tradtrantip are named inventors on patents on NMOSD therapeutics, whose rights are owned by the University of California. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors are supported by grant EY13574 from the National Institutes of Health and grants from the Guthy-Jackson Charitable Foundation.