C5 complement inhibitors are therapeutic agents that block the cleavage of complement component 5 (C5), thereby preventing the generation of the inflammatory mediator C5a and the formation of the membrane attack complex.
By inhibiting C5, these drugs preserve upstream complement functions like C3b-mediated opsonization and immune complex clearance while specifically blocking terminal pathway activation.
The mechanism involves binding to C5 to prevent its cleavage by C5 convertases into C5a and C5b.
C5a is a potent anaphylatoxin that activates endothelial and immune cells, while C5b initiates MAC assembly, which can cause cell lysis.
Some C5 inhibitors also interfere with C5b-C6 complex formation, providing dual blockade of terminal pathway activation.
C5 inhibitors include:
Eculizumab (Soliris): a humanized monoclonal antibody administered intravenously, approved for paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD).
Ravulizumab (Ultomiris): a modified version of eculizumab with extended half-life allowing less frequent dosing, approved for PNH, aHUS, gMG, and NMOSD.
Zilucoplan (Zilbrysq): a macrocyclic peptide administered subcutaneously, approved for gMG in anti-AChR antibody-positive adults.
Other agents in development include crovalimab (a long-acting subcutaneous C5 inhibitor) and pozelimab (a fully human anti-C5 antibody with subcutaneous dosing).