Anticomplement therapy Complement Pathway Alternative Classical Lectin Pathway Initiation Binding of C3b to a surface Antibody-antigen complex Btoinmdianngnoofspelaosnmpaatlheocgtinesn Initial Components C3, Factor B, Factor D C3 Convertase C3b,Bb Effectors C3b C1q,r,s, C4,C2 C4b,2b C3a,C5a MLB, MASP-1, MASP-2, C4,C2 C4b,2b C5b,6,7,8,9 (C5b-9) Phagocytosis Chemotaxis Membrane attack complex Figure 2 The complement system and its effectors. Regulation of the complement system Because the complement system has such a potent ability to cause cellular damage, it is extensively regulated both in the ﬂuid phase and on cell surfaces. We will brieﬂy describe the major complement regulatory proteins. In the classical pathway, one of the main complement regulatory proteins is C1 inhibitor (C1-INH), which binds to the C1r:C1s complex and causes it to dissociate from C1q, thus preventing activation of the complement system. The function of the other major complement regulatory proteins can be categorized under two major activities: (1) breaking up the C3 convertase, termed decay-accelerating activity and (2) cleavage of either C3b or C4b to their inactive forms, iC3b and iC4b, respectively, termed membrane co-factor activity. Proteins with decay-accelerating activity which regulate the classical pathway include C4-binding protein (C4bp), complement receptor 1 (CR1), and decay-accelerating factor (DAF) or CD55. Proteins with decay-accelerating activity which regulate the alternative pathway include CR1, factor H (FH), and DAF (Figure 1). All membrane co-factor activity relies on the function of a serine protease known as factor I (FI). Factor I, in turn, requires at least one of several potential co-factors to degrade C3b and C4b. For the classical pathway, proteins with membrane co-factor activity include C4bp, CR1, and membrane co-factor protein (MCP), while those for the alternative pathway are CR1, FH, and MCP. Another important regulatory protein is CD59, also known as protectin. CD59 prevents formation of the C5b-9 Biologics:Targets & Therapy 2008:2(4) complex (MAC) on cell surfaces and is highly expressed on cell membranes throughout the body. Development of complement inhibitors The ﬁrst complement inhibitor described in the scientiﬁc literature was cobra venom factor (CVF). The anticomplement activity of cobra venom was described by Flexner and Noguchi in 1903 (Flexner and Noguchi 1903). It was not until the late 1960’s and early 1970’s that the component of cobra venom responsible for its anticomplement activity was recognized (Gewurz et al 1967; Maillard and Zarco 1968; Cochrane et al 1970; Phillips 1970; Muller-Eberhard and Fjellstrom 1971). CVF binds to mammalian FB in plasma and after cleavage of FB by FD, a stable, soluble C3 convertase is produced, the CVF-Bb complex (Cooper 1973). The CVF-Bb complex consumes C3 in the plasma very efﬁciently; in fact, a single injection of CVF can completely eliminate complement activity for 24–72 hours in certain animal models (Morgan and Harris 2003). One of the ﬁrst synthetic molecules to be developed for anticomplement therapy was nafamastat mesilate, also known as FUT-175. This molecule inhibits C1r, C1s, C3 convertase, C5 convertase, and FD (Fujii and Hitomi 1981; Inagi et al 1991). Nafamastat mesilate is not entirely complement-speciﬁc, however, and can inhibit several other plasma proteases (Hitomi and Fujii 1982). Using phage display random peptide libraries, several com- plement inhibitors have been discovered. Compstatin, which 673