Complement Inhibitor Therapy for Myasthenia Gravis

Front Immunol. 2020 Jun 3:11:917. doi: 10.3389/fimmu.2020.00917. eCollection 2020.

Abstract

Complement activation as a driver of pathology in myasthenia gravis (MG) has been appreciated for decades. The terminal complement component [membrane attack complex (MAC)] is found at the neuromuscular junctions of patients with MG. Animals with experimental autoimmune MG are dependent predominantly on an active complement system to develop weakness. Mice deficient in intrinsic complement regulatory proteins demonstrate a significant increase in the destruction of the neuromuscular junction. As subtypes of MG have been better defined, it has been appreciated that acetylcholine receptor antibody-positive disease is driven by complement activation. Preclinical assessments have confirmed that complement inhibition would be a viable therapeutic approach. Eculizumab, an antibody directed toward the C5 component of complement, was demonstrated to be effective in a Phase 3 trial with subsequent approval by the Federal Drug Administration of the United States and other worldwide regulatory agencies for its use in acetylcholine receptor antibody-positive MG. Second- and third-generation complement inhibitors are in development and approaching pivotal efficacy evaluations. This review will summarize the history and present the state of knowledge of this new therapeutic modality.

Keywords: C5; complement; eculizumab; myasthenia (myasthenia gravis—MG); zilucoplan.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Complement Activation / drug effects*
  • Complement C5 / antagonists & inhibitors*
  • Complement C5 / immunology
  • Complement C5 / metabolism
  • Complement Inactivating Agents / adverse effects
  • Complement Inactivating Agents / therapeutic use*
  • Disease Models, Animal
  • Humans
  • Myasthenia Gravis / drug therapy*
  • Myasthenia Gravis / immunology
  • Myasthenia Gravis / metabolism
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Complement C5
  • Complement Inactivating Agents
  • eculizumab