Vilobelimab

The complement system is a critical innate immune response against pathogens. Activation of the complement cascade results in proteolytic cleavage of the complement factor C5, generating C5a and C5b. C5a is a potent anaphylatoxin that binds to the C5a receptor to initiate an inflammatory cascade. The C5a/C5aR1 signalling pathway promotes enhanced vascular permeability, coagulation, proinflammatory cytokine release, and recruitment and activation of neutrophils and other myeloid cells. Ultimately, C5a also initiates neutrophil-driven tissue damage. Complement activation and high levels of C5a have been implicated in various inflammatory conditions, such as septic shock, antineutrophilic cytoplasmic antibody (ANCA) vasculitis, and viral infections such as avian influenza A (H7N9) virus infection and Coronavirus disease (COVID-19).

The complement system can be activated through three pathways: classical, lectin, and alternative pathways. The lectin pathway is triggered by binding of either mannose-binding lectin protein (MBL) or ficolin to pathogens, such as bacterial or fungal carbohydrate structures and proteins. Experimental studies suggest that the SARS-CoV-2 virus nucleocapsid protein can bind to the mannan-binding lectin serine protease 2, thereby activating the downstream complement pathway and generating C5a. Because high levels of C5a have been identified in patients with severe COVID-19, C5a was suggested as a key mediator of acute respiratory distress syndrome and thrombotic microangiopathy associated with COVID-19. Vilobelimab is a chimeric monoclonal IgG4-kappa antibody that binds to complement factor 5a (C5a) with a dissociation constant of 9.6pM and blocks its interaction with the C5a receptor.