Kulkarni and Afshar-Kharghan is composed of only 13 amino acid residues, binds to C3 and inhibits its cleavage by C3 convertase (Sahu et al 1996). Molecules blocking C1q in vitro have also been obtained from random peptide libraries (Roos et al 2001). Interestingly, heparin has long been known to possess anticomplement properties (Weiler et al 1978). Its effects include binding to and subsequent inactivation of C1, inhibition of MAC assembly, and blockage of the formation of C3 convertase (Baker et al 1975; Hughes-Jones and Gardner 1978; Almeda et al 1983; Weiler 1983). Another category of complement inhibitors is recombinant proteins that are engineered using genes encoding membrane complement regulatory proteins. These recombinant proteins have been genetically modiﬁed to make them soluble so that they inhibit complement activation in the ﬂuid phase. One of the ﬁrst recombinant complement inhibitors was soluble CR1 (sCR1), also known as TP10. Weisman et al developed this molecule, which comprises the entire extracellular domain of CR1, and showed that it inhibited formation of C3 and C5 convertases in vivo (Weisman et al 1990a, 1990b). Soluble recombinant MCP and DAF have also been developed and have been shown to inhibit complement both in vitro and in vivo (Moran et al 1992; Christiansen et al 1996). A hybrid molecule named complement activation blocker-2 (CAB-2) was designed by fusing the functional domains of MCP and DAF (Higgins et al 1997). In vitro CAB-2 was shown to inhibit complement activation (Kroshus et al 2000). Another logical approach to inhibition of the complement system is to use a blocking antibody against one of the many interacting complement proteins. N19-8, the ﬁrst anticomplement monoclonal blocking antibody developed, was shown to block C5 cleavage in vitro (Wurzner et al 1991). Subsequently, a second antibody to human C5, termed h5G1.1, was developed (Kroshus et al 1995). This molecule was modiﬁed to have only single-chain Fv fragments but still retain full antiC5 activity (Thomas et al 1996). Using recombinant DNA technologies, investigators became able to combine complement-binding antibodies to inhibitory domains of complement regulatory proteins. There are two different ways in which these hybrid molecules have been designed. One way is to use the Fab portion (the antigen- binding fraction) of the antibody to direct the molecule toward a particular cell membrane component, while the Fc portion (the constant fraction) is the soluble complement regulator itself. Two examples of hybrid molecules created in this way are antidansyl Fab arms fused with either CD59 or DAF (Zhang et al 1999, 2001). Both fusion proteins were able to avidly bind to dansyl-labeled Chinese hamster ovary 674 cells. Another way to fuse antibody fragments to soluble complement inhibitors is to use the complement inhibitors themselves as the Fab arms of the molecule and to use the normal Fc portion of the antibody to keep the molecules in the circulation longer (Pugsley 2001). One downside to this approach is reduced activity of the hybrid molecule as compared to a pure soluble complement inhibitor, perhaps due to a steric hindrance (Harris et al 2002). Complement inhibition as therapy for disease The possibility of complement inhibition as therapy for various disease states has been studied in organ transplantation, ischemia-reperfusion injury, coronary artery disease, myocardial infarction, stroke, infection, cancer, immunosuppression, paroxysmal nocturnal hematuria, glomerulonephritis, rheumatoid arthritis, and acute respiratory distress syndrome, and has also been used in the coating of extracorporeal circuits in cardiopulmonary bypass and dialysis (Table 1). Any possible beneﬁt from inhibiting the complement system should be balanced with potential side effects, such as an increased susceptibility to infection with encapsulated bacteria, Neisseria meningitidis in particular, and autoimmune diseases caused by decreased clearance of immune complexes. In this review, we will focus on anticomplement therapy in paroxysmal nocturnal hemoglobinuria, glomerulonephritis, coronary artery disease, myocardial infarction, and cardiac surgery requiring cardiopulmonary bypass. Paroxysmal nocturnal hemoglobinuria Overview and pathophysiology Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder due to an acquired somatic mutation in the X-linked phosphatidylinositol glycan complementation class A (PIG-A) gene, which leads to a partial or com- plete deﬁciency of all proteins which are usually linked to the cell membrane via a glycosyl phosphatidylinositol (GPI) anchor (Takeda et al 1993; Bessler et al 1994). DAF and CD59, complement regulatory proteins, are two GPI-anchored molecules; therefore, PNH cells have a deﬁ- ciency of DAF and/or CD59 on their cell membrane and are more susceptible to destruction by complement. The proportion of normal stem cells and PNH stem cells in any one patient can vary, but PNH cells usually constitute the majority of hematopoietic cells (Richards et al 2007). The clinical features of PNH include intravascular hemolysis, bone marrow failure, and a predisposition to thrombosis Biologics:Targets & Therapy 2008:2(4)