C6

Complement component 6 (C6), a pivotal protein in the complement cascade, is essential for forming the membrane attack complex (MAC). Also termed C6 or complement 6, it binds sequentially with C5b, C7, C8, and multiple C9 molecules to assemble MAC, mediating pathogen lysis or aberrant cell clearance. This process occurs via the terminal complement pathway, intersecting with classical, lectin, and alternative pathways. C6-dependent MAC formation regulates immune defense and inflammatory responses, but dysregulation contributes to tissue damage. Notably, genetic C6 deficiencies are linked to recurrent bacterial infections, particularly Neisseria species, highlighting its critical role in innate immunity. Recent studies also implicate C6 in ischemia-reperfusion injury and neuroinflammatory disorders, expanding its pathophysiological relevance.
Targeting C6 has emerged as a therapeutic strategy for complement-mediated diseases. While anti-C5 agents (e.g., eculizumab) dominate clinical use, C6 inhibition offers potential advantages by blocking terminal MAC assembly without upstream cascade disruption. Preclinical studies demonstrate that anti-C6 monoclonal antibodies reduce pathological MAC deposition in models of age-related macular degeneration and hemolytic uremia. A phase I trial (NCT04833907) recently evaluated a C6-targeting aptamer for paroxysmal nocturnal hemoglobinuria. Challenges persist in balancing efficacy with infection risks, given C6's protective role. Small-molecule inhibitors targeting C6-C7 interaction sites are under exploration, aiming to achieve tissue-specific modulation with improved safety profiles.