Complement is an intricate key element of the innate immune system. Being part of the first line of defense, it is mobilized rapidly to the expense of specificity. This lack of specificity necessitates a high degree of control which is revealed by its structure of a complex cascade of consecutive creation of complement components by highly regulated proteolytic steps.
The complement system has been demonstrated to be involved in the pathogenesis of numerous diseases, some of them serious, life-threatening conditions. The pathological effect can be caused by deficient activity as a result of genetically lack of a complement component or as a result of decreased synthesis or consumption of complement components. The destructive effect can also be caused by the opposite mechanism, i.e. increased activity causing tissue damage and aseptic inflammatory processes. Pharmacological regulation of complement activity has been the focus of intense research over the last few years. One result has been the development of an inhibitor of the C5 convertase.
C5 convertase is a serine protease that cleaves complement factor C5. The enzyme can either be formed by complement components from the classical/lectin pathways or from the alternative pathway. The cleavage of C5 is the last enzymatic step in the complement activation cascade resulting in the formation of two biologically important fragments, C5a and C5b. Both fragments play vital roles in killing microorganisms. C5a, the smaller fragment, is a potent anaphylatoxin mediating inflammatory responses by stimulation of neutrophils and phagocytes. C5b initiates the formation of the membrane attack complex (MAC, C5b-9) which results in the lysis of bacteria, cells and other pathogens.
Specific inhibition of C5 activation would preserve the immune clearance and opsonization functions of complement which depend on C3b, but it would prevent the generation of both C5a and C5b-9. Recent approaches in blocking complement activation include inhibitory anti-C5 antibodies. The most noted is the commercial drug antibody Eculizimab (trade name Soliris) produced by Alexion Pharmaceutical Inc, Cheshire, Connecticut, USA. Eculizumab is a humanized monoclonal antibody, derived from the murine antibody m5G1.1 constructed from an IgG2/4 kappa immunoglobulin comprised of human constant regions and murine complementarity-determining regions (CDRs) grafted onto human framework light- and heavy-chain variable regions. The antibody has been extensively modified to minimize immunogenicity and prevent pro-inflammatory responses. The molecular mechanism of Eculizumab is believed to prevent C5 to become a C5 convertase.
Clinically, Eculizumab is presently approved for treatment of paroxysmal nocturnal hemoglobinuria, PNH (FDA 2007, EMA 2007) and atypical hemolytic uremic syndrome, aHUS (FDA 2011, EMA 2011). The drug is also currently investigated for other clinical indications.
PNH is a rare blood disorder with high morbidity and mortality with a prevalence of about 13 per million. The disease is caused by a deficiency of a complement inhibitory protein, CD59, which normally blocks the formation of the MAC on the erythrocytes, thereby preventing hemolysis. The pathophysiology of PNH is directly linked to the complement-mediated destruction of the susceptible PNH red blood cells, which results in intravascular hemolysis, the primary clinical manifestation in all PNH patients.
aHUS is a very rare, life-threatening, progressive disease. In most cases it is caused by chronic, uncontrolled activation of the complement system often due to mutations in complement regulatory proteins such as factor H or factor I. The disease is characterized by systemic thrombotic microangiopathy (TMA), which is the formation of blood clots in small blood vessels throughout the body, which can lead to stroke, heart attack, kidney failure, and death. TMA is caused by excessive activation of complement resulting in platelet activation, damage to endothelial cells, activation of white blood cells, decreased platelet count, hemolysis, and damage to a number of different organs such as the kidneys, liver, and pancreas.
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