Bezlotoxumab

C. difficile infections are caused by two exotoxins, toxin A and toxin B. Exotoxins are believed to bind to cell surface receptors expressed on colonocytes and are internalized via endocytosis. This process is followed by the acidification of the endosome, leading to a conformation change of the toxin, allowing for the transport of the endosome, autocleavage of the toxin via a cysteine protease domain, and the release of glucosyltransferase domain (GTD) from the endosome to the host cell cytoplasm. GTD glucosylates and inactivates small GTPases, such as Rac and Rho, critical for maintaining the actin cytoskeleton, cell adhesion, epithelial permeability, and other cellular function and homeostasis processes. Exotoxins eventually induce apoptosis and cell loss. Endotoxins also promote the release of proinflammatory mediators that recruit neutrophils and macrophages to the injury site, further aggravating the gut injury and damage. C. difficile infections are associated with a high risk of recurrence.

Bezlotoxumab binds to C. difficile toxin B and neutralizes it. According to the findings of surface plasmon resonance analysis, bezlotoxumab binds to the toxin via two epitopes in the C-terminal CROP domain of the toxin, partially blocking the putative receptor binding pockets and preventing it from binding to host cell receptors. Bezlotoxumab does not bind to C. difficile toxin A.