Ravulizumab and other complement inhibitors for the treatment of autoimmune disorders

Ravulizumab (ULTOMIRIS™) an intravenous glycoengineered humanized anti-C5 IgG2/4 monoclonal antibody (mAb), is a new FDA-approved treatment for Aquaporin-4-antibody (AQP4-IgG) positive Neuromyelitis Optica Spectrum Disorder (NMOSD). Based on the importance of intermediate and terminal components of the complement cascade during disease pathogenesis, in the last few years, a mAb targeting the C5 complement factor (anti-C5, eculizumab) has already been in use for treating AQP4-IgG positive NMOSD. Ravulizumab acts similarly to eculizumab, binding specifically to the complement protein C5, thereby blocking the generation of the anaphylatoxin C5a and of C5b, which is crucial for generating the membrane attack complex (C5b-9). Here, we discuss the main findings obtained during the phase 3 clinical trial (CHAMPIONNMOSD [NCT0420126]) for ravulizumab and new developments in anti-complement therapy, with other complement inhibitors for the treatment of autoimmune diseases and paroxysmal nocturnal hemoglobinuria (PNH) (zilucoplan, avacopan and, pegcetacoplan). The approval of the new long-acting anti-C5 mAb adds another therapeutic option to the already existing inhibitors of complement currently in use, increasing therapeutic options for inflammatory and autoimmune diseases.