John D. Lambris

Dimitrios C. Mastellos

Edimara S. Reis

The complement system is a multi-tasking gatekeeper of innate immunity thatintricately interacts with other key defense systems, such as the endothelial barrier,contact activation and coagulation systems, in maintaining tissue immunosurveillanceand homeostasis. Its rapid and forceful activation in the bloodstream not onlyensures the effective containment of microbial infections through potent cytolyticmechanisms, but also alerts the adaptive immune compartment to ensure the mountingof a proper humoral immune response against foreign antigens. However, there isa lurking ‘dark side’ that can lead complement astray, fueling a self-perpetuatingvicious cycle of inflammation, exuberant immune activation and irreversible tissueinjury that collectively exacerbate both acute and chronic pathologies. Indeed,complement dysregulation or excessive activation have been widely recognized askey pathogenic drivers in a wide spectrum of inflammatory or immune-mediateddiseases. Targeted modulation of the complement system at various points ofthe cascade has revealed promising therapeutic targets for ameliorating diseasescores in a number of conditions ranging from ocular, neurodegenerative andthromboinflammatory disorders, to cancer, periodontal diseases, chronic hemolyticanemias, ischemia-reperfusion organ injury, antibody-mediated transplant rejectionand hemodialysis-triggered inflammation. Elegant pre-clinical studies employing a diversified toolbox of highly specificcomplement inhibitors in rodent or primate models of disease have opened newavenues of therapeutic exploration by providing proof of concept for the therapeuticefficacy of complement modulation. At the same time, the clinical experience gainedduring this last decade with the sole complement-specific drug currently in the clinic,eculizumab, has rekindled the interest of biopharmaceutical companies in developingnew and potent complement therapeutics for complement-driven diseases. In this respect, the complement field is witnessing a new surge of clinical trialsthat are evaluating the safety, PK/PD profile and clinical efficacy of promising drugcandidates in a number of clinical conditions driven by complement imbalance orover-activation.

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