ATC Group: L04AJ Complement inhibitors

Avacopan is a selective antagonist of the human complement 5a receptor (C5aR1 or CD88) and competitively inhibits the interaction between C5aR1 and the anaphylatoxin C5a. The specific and selective blockade of C5aR1 by avacopan reduces the pro-inflammatory effects of C5a, which include neutrophil activation, migration, and adherence to sites of small blood vessel inflammation, vascular endothelial cell retraction and permeability.

Eculizumab is a monoclonal antibody, a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab preserves the early components of complement activation that are essential for opsonization of microorganisms and clearance of immune complexes.

Iptacopan binds to Factor B of the alternative complement pathway and regulates the cleavage of C3, generation of downstream effectors, and the amplification of the terminal pathway.

Pegcetacoplan is a symmetrical molecule comprised of two identical pentadecapeptides covalently bound to the ends of a linear 40-kDa PEG molecule. The peptide moieties bind to complement C3 and exert a broad inhibition of the complement cascade. The 40-kDa PEG moiety imparts improved solubility and longer residence time in the body after administration of the medicinal product. It is indicated in the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH) who are anaemic after treatment with a C5 inhibitor.

Ravulizumab is a monoclonal antibody IgG2/4K that specifically binds to the complement protein C5, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the C5b-9. Ravulizumab preserves the early components of complement activation that are essential for opsonisation of microorganisms and clearance of immune complexes. It is indicated in the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH).

Sutimlimab is an IgG, subclass 4 (IgG4) monoclonal antibody (mAb) that inhibits the classical pathway (CP) and specifically binds to complement protein component 1, s subcomponent (C1s), a serine protease that cleaves C4. The activities of the lectin and alternative complement pathways are not inhibited by sutimlimab. Inhibition of the classical complement pathway at the level of C1s prevents deposition of complement opsonins on the surface of red blood cells, resulting in inhibition of haemolysis in patients with CAD.

Zilucoplan is a 15 amino acid, synthetic macrocyclic peptide that inhibits the effects of the complement protein C5 through a dual mechanism of action. It specifically binds to C5, thereby inhibiting its cleavage by the C5 convertase to C5a and C5b, which results in a downregulation of the assembly and cytolytic activity of the membrane attack complex (MAC). Additionally, by binding to the C5b moiety of C5, zilucoplan sterically hinders binding of C5b to C6, which prevents the subsequent assembly and activity of the MAC, should any C5b be formed.