eculizumab

Eculizumab binds complement protein C5 with high affinity, preventing its cleavage by C5 convertase into C5a (anaphylatoxin) and C5b (initiates MAC formation). By blocking MAC (C5b-9) assembly, it prevents complement-mediated intravascular hemolysis and cell lysis.

Clinical uses: - Paroxysmal nocturnal hemoglobinuria (PNH): PNH is caused by an acquired mutation in the PIGA gene leading to deficiency of GPI-anchored proteins CD55 and CD59, which normally protect RBCs from complement-mediated lysis. Eculizumab reduces intravascular hemolysis, transfusion requirements, and thrombotic risk in PNH. - Atypical hemolytic uremic syndrome (aHUS): caused by dysregulated complement activation (often due to mutations in complement regulatory proteins like factor H, factor I, or MCP) leading to microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Eculizumab blocks complement-mediated endothelial damage. - Also used in generalized myasthenia gravis (anti-AChR antibody positive) and neuromyelitis optica spectrum disorder (NMOSD).

Key safety consideration: Because complement (particularly the terminal complement pathway) is critical for defense against encapsulated organisms, especially Neisseria meningitidis, patients must receive meningococcal vaccination at least 2 weeks prior to starting therapy, and prophylactic antibiotics may be considered. Increased risk of meningococcal infection is a major boxed warning.

Mechanism relevance for boards: Understanding eculizumab tests knowledge of the complement cascade, GPI-anchored protein deficiency in PNH, and complement dysregulation in aHUS. It's a classic pharmacology-immunology integration question.