The indication and effect of complement–targeted medicine

Abstract

Eculizumab is the first drug to be developed and approved as anti–complement therapy for the treatment of paroxysmal nocturnal hemoglobinuria and secondarily for the treatment of atypical hemolytic uremic syndrome, both hematologic diseases associated with the complement system. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of C5 to C5a and C5b by C5 convertase, preventing the generation of the terminal complement complex C5b–9 (membrane attack complex : MAC). Anti–complement therapy has been clinically used in autoantibody– and complement–related neuroimmunological diseases. Anti–acetylcholine receptor antibody–positive (AChR⁺)–generalized myasthenia gravis (gMG) is a disease that could be treated with eculizumab.

AChR autoantibodies are mainly of the IgG1 and IgG3 subtypes ; thus, they are divalent and complement–activating. The binding of these antibodies to AChRs results in the activation of the classical complement pathway, with MAC assembly. The MAC causes local damage to the membrane, resulting in the loss of AChRs ; the damaged postsynaptic membrane shows diminished response to acetylcholine as expressed electrophysiologically by the reduced amplitudes of the endplate potential. The role of the complement system in damage to the neuromuscular junction is supported by experimental animal models of MG. Additionally, evidence showing that functional blockade of C5 protects against severe disease in preclinical studies suggests that complement inhibition might be a potential therapeutic approach for MG. Eculizumab was shown to have efficacy (60% of patients with AchR⁺gMG) and was well tolerated in a 6–month randomized, double–blind, placebo–controlled study (REGAIN). Therefore, it was approved for the treatment of AChR⁺gMG. Approximately 90% of all responders have a good response within 12 weeks after the start of anti–C5 therapy.

There is no consensus on the kind of patients with gMG who are selected to preferentially receive eculizumab, although the indication criteria of eculizumab for AChR⁺gMG includes refractory patients who have a poor response to intravenous immunoglobulin or plasma exchange in Japan. In contrast, practical clinical data have been collected over three years on the market.

Here, we present a review of the role of eculizumab, an anti–complement component C5 therapy in AChR⁺gMG, as well as clinical trial data.