Immunotherapeutics

The complement system is one of the major constituents of innate immunity, capable not only of killing microbes but also to perform opsonization and guidance of adaptive immunity as well as to scavenge cellular debris, thus limiting the risk of autoimmune events. For a long time the complement was considered a scientifically interesting system with limited physiological relevance. Such view dramatically changed during the last thirty years as direct or indirect involvement of the complement system has been reported in most human diseases. Practical therapeutic approaches employ either complement stimulation, for better eradication of microbes and tumor cells, or inhibition, in case of complement-driven autoimmune events. Recent insights on the role of complement in maintenance of body homeostasis, metabolism, mobilization of regulatory T cells, angiogenesis and interference with intracellular signaling, together with molecular insights of complement activation by antibodies, opened new avenues for effective complement-based immunotherapy.

Complement is considered as an effector mechanism of the first anticancer monoclonal antibody (rituximab) approved for clinical use more than 20 years ago. Since then, new generations of complement-activating drugs have been invented and dozens of candidates are now being tested in ongoing clinical trials. Reports on synergistic effects of complement modulators and immune checkpoint inhibitors give prospect for new therapeutic strategies in cancer therapy. First approved complement inhibitor eculizumab is highly efficient in treatment of atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Similarly C3, factor B and factor D inhibitors hold promise in blocking undesired complement activation in numerous pathogenic conditions. The fact that markers of complement activation are found in rheumatic, inflammatory, neurodegenerative and metabolic diseases underline the implications of complement in the pathogenesis of these disorders and opens the way for potential therapeutic intervention.
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Allied Journal of Medical Research
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