The Complement System as a Therapeutic Target: New Insights into Health

Posted by Janice on November 2nd, 2021

The complement system consists of a group of nearly 60 proteins that are found in the blood plasma or on the surface of some cells. The complement system is well known for its role in innate immunity and in the maintenance of tissue homeostasis, providing a first line of defense against infection and playing a key role in flagging apoptotic cells and debris for disposal. The complement system can be activated by pathogens or a pathogen-bound antibody. Complement activation results in opsonization of pathogens and their removal by phagocytes, as well as cell lysis.

The activation of complement system is known to occur through three different pathways: the classical pathway, the alternate pathway, and the lectin pathway. These pathways depend on different molecules for their initiation, but they converge to generate the same set of effector molecules. All three activation pathways lead to the production of C3 convertase, which activates C3 creating C3a and C3b, the latter of which is an opsonin that binds to the surface of pathogens. Each pathway has its own initiator and regulators, but all three pathways converge at C3 and lead to the formation of the membrane attack complex (MAC). The MAC formed on a target (e.g. a bacterium) rapidly kills the bacterium without the help of immune cells.

Complement also contributes to pathogenesis of many diseases. Normally, complement is a system that fine-tunes the balance between inhibition and amplification, maintaining homeostasis in vivo. However, inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement deficiency and loss-of-function mutations in complement components are the underlying causes of the pathophysiology of many diseases. Studies have shown that dysregulation of the complement system promotes cancer progression.

Therefore, the multiple roles of complement in diseases make it an attractive target for therapeutic intervention. Therapeutic strategies for complement immunomodulation include blocking the activation pathways and developing specific complement inhibitors. Complement inhibitors, inhibitory monoclonal antibodies and receptor inhibitors have been developed to block complement effects and thus re-establish the balance and homeostasis.

Currently, only a few rare diseases are allowed to be treated clinically with complement-targeted therapies. For example, paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder characterized by hemolytic anemia, bone marrow failure, and thrombosis. Selective inhibition of C5 using monoclonal antibodies (mAb) has been considered a promising therapeutic option for many years.

C5a, one of the cleavage products, is produced by complement system activation. Whilst C5a is a potent mediator of immune and inflammatory processes, excessive production or inadequate regulation of C5a has been implicated in the pathogenesis of numerous immuno-inflammatory diseases.Studies have shown that the blockade of C5a or its receptor C5aR inhibits the development of sepsis and markedly improves survival in animal models. Thus, C5a has been recognized as a key factor in the pathogenesis of sepsis. Moreover, the C5a antibodies have been shown to be effective in preclinical studies in animal models of sepsis.

The field of complement inhibition has become a therapeutic area of increasing interest. Compared with conventional drugs, complement inhibitors may be one of the best options for the treatment of autoimmune diseases.The present research has elucidated the regulatory mechanisms of the complement system and demonstrated how the bio-pathway machinery maintains the balance between activation and inhibition. Further studies are expected to contribute to the development of therapeutic approaches targeting the complement system.