Complement system was discovered in 19th century as a part of immune system responsible for tissue repair and homeostasis, thereby providing first line of defense against multiple infections. This complete process is in association with a complex and highly regulated assembly of proteins which involve several soluble and surface-bound complement components, including receptors and regulators, which are majorly generated by the liver. These proteins interact with multiple immune cells and complement the action of antibodies, which are in turn responsible for killing the infectious agents.
Pathways involved in Complement Activation
Multiple components are involved in the pathway, including nine central components (C1 to C9), activation products (such as C3a and C3b), regulators and inhibitors (such as Factor H and C4BP), and proteases and enzymes (such as Factor B). Further, the complement system can be activated by three distinct pathways-
Classical Pathway: It involves complement components C1, C2 and C4 and is initiated when antigen-antibody complexes bind the recognition moiety, C1q, causing the related proteases, C1r and C1s, to activate.
Lectin Pathway: It is initiated when antigen-antibody complexes bind to bacterial sugars, lectins such as mannose binding lectin (MBL), ficolins or collectins.
Alternative Pathway: It involves various factors such as B, D, H and I. It is initiated when complement component C3b (generated from the activation pathways or non-specific sources) bind to Factor B.
All the three complement pathways converge at C3 activation, resulting in cleavage of C5. The anaphylatoxins C3a and C5a are generated during this process, and C5 cleavage initiates the terminal complement pathway which culminates in the formation of the membrane attack complex (MAC).
Consequences of a Dysregulated Complement System
Excessive activation and inadequate regulation of the complement system may lead to inflammatory events that exacerbate clinical complications such as tissue damage, organ failure, and, in severe case, death.
Need for Next Generation Complement Therapeutics
Complement system has a role in the pathophysiology of many diseases, driving pathology in some cases and amplifying or worsening the inflammatory and destructive effects of non-complement disease triggers in others. As a result, anti-complement medications have been developed for the inhibition or modulation of complement system and are recognized as a promising therapeutic approach for the treatment of associated diseases. The next generation complement therapeutics have been grouped into five categories based on the mechanism of action. These include complement components inhibitors, enhancers of regulatory protein activity and receptor antagonists.
Future of Next Generation Complement Therapeutics
Driven by encouraging clinical research efforts, new pharma entrants, broadening of disease focus, and a rising desire to get beyond C5 with some innovative ways, the complement therapeutics are expected to capture a significant share in the pharmaceutical market with more drug candidates getting approved and marketed over the coming decade.
Since the complement system is a complicated and multidimensional system, many different therapeutic targets, for a variety of disease indications such as paroxysmal nocturnal hemoglobinuria, hereditary angioedema, kidney diseases and several others are likely to be discovered in the future. The main focus is to develop innovative therapies with reduced cost and increased safety.
For more details on this emerging domain, check out the following report: