A Targeted Blockade of Terminal C5a Is Critical to Management of Sepsis and Acute Respiratory Distress Syndrome: The Mechanism of Action of Vilobelimab

Abstract

Vilobelimab, a first-in-class, human-mouse chimeric immunoglobulin G4 (IgG4) kappa monoclonal antibody, targets human complement component 5a (C5a) in plasma. Unlike upstream complement inhibitors, vilobelimab does not inhibit the generation of the membrane attack complex (C5b-9), necessary to mitigate certain infections. C5a is a strong anaphylatoxin and chemotactic agent that plays an essential role in both innate and adaptive immunity. Elevated levels of C5a have been associated with pathologic processes, including sepsis and inflammatory respiratory disorders such as acute respiratory distress syndrome (ARDS). Blocking C5a with vilobelimab has shown therapeutic promise. A randomized, multicenter placebo-controlled Phase III study of vilobelimab in patients with severe COVID-19 (PANAMO) found that patients treated with vilobelimab had a significantly lower risk of death by day 28 and 60. Based on this study, the United States Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Gohibic^® (vilobelimab) injection for the treatment of COVID-19 in hospitalized adults when initiated within 48 h of receiving invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO). In January 2025, the European Commission (EC) granted marketing authorization for Gohibic^® (vilobelimab) for the treatment of adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced ARDS who are receiving systemic corticosteroids as part of standard of care and receiving IMV with or without ECMO. Herein, we review the mechanism of action of vilobelimab in selectively inhibiting C5a-induced inflammation, outlining its bench-to-bedside development from the fundamental biology of the complement system and preclinical evidence through to the clinical data demonstrating its life-saving potential in the management of COVID-19-induced ARDS.

Keywords: C5; C5a; C5b; acute respiratory distress syndrome; complement; extrinsic pathway; mechanism; membrane attack complex; sepsis; vilobelimab.

Figure 1

Complement activation pathways and the mechanism of action of vilobelimab. Classical, lectin, and alternative complement activation pathways converge on the generation of active complement split products and the MAC. In this pathway, C5 convertases bind via the MG7 domain of C5, cleaving C5 into its components, C5a and C5b. The extrinsic pathway represents an additional route of complement activation. In this pathway, proteolytic enzymes such as thrombin or plasmin bind to and cleave C5 at or near its scissile bond, to generate C5a. Overactivation of C5a amplifies the innate immune response, contributing to cytokine storm, tissue damage, and multi-organ dysfunction. Vilobelimab blocks C5a generated through both the extrinsic pathway as well as conventional complement pathways, interrupting this inflammatory cascade, while also allowing C5b to be generated as part of MAC formation. By interrupting the inflammatory cascade (X), vilobelimab presumably decreases coagulation, NET formation, ROS generation, granular enzymes release, vascular injury, the cytokine storm, and tissue injury. MAC graphic adapted from Serna et al. [29] licensed by CC BY 4.0. MAC, membrane attack complex; NETs, neutrophil extracellular traps; ROS, reactive oxygen species.

Figure 2

C5a as a central amplifier of inflammation. C5a is a potent pro-inflammatory mediator that activates neutrophils and other immune cells such as monocytes and macrophages. It drives the release of ROS, granular enzymes, NETs, and promotes coagulation, increased vascular permeability, endothelial adhesion, and angiogenesis. CCL, CC motif chemokine ligand; CXCL, CXC motif chemokine ligand; HMGB, high-mobility group box; IL, interleukin; NET, neutrophil extracellular trap; PGE, prostaglandin E; Th, T helper; TNF, tumor necrosis factor [28,34,35,36,37,38,39,40].