Ansuvimab

Zaire ebolavirus (Ebola virus, EBOV) is one of six species within the Ebolavirus genus, which itself is one of six genera within the Filoviridae family. Infection with pathogenic filoviruses such as EBOV in humans can result in hemorrhagic fever with very high fatality rates (25-90%). Following infection, a variable latency period of ~2-21 days occurs before the onset of symptoms, which are vague at first, including fatigue, fever, aches, myalgia, and gastrointestinal complaints, but that progress in severe disease to both internal and external bleeding, multiorgan failure, secondary infections, meningoencephalitis, hypotension, and shock. The pathogenesis of EBOV is poorly understood but is thought to be multifactorial: immune suppression, cytokine dysregulation, vascular dysfunction, and abnormal coagulation.

EBOV is a non-segmented negative-sense RNA virus whose genome comprises seven genes, including the GP1,2 glycoprotein involved in host cell entry and subsequent viral escape into the cytoplasm. GP1,2 binds to one of several possible host receptors such as various lectins and TYRO3 receptor tyrosine kinases, β1 integrins, the asialoglycoprotein receptor, human folate receptor-α, and TIM1. Following internalization into endolysosomes by macropinocytosis, GP1,2 is cleaved by host cathepsins into a fusion-competent form termed GPCL, which subsequently binds the Niemann-Pick C1 protein (NPC1) to induce fusion of the host endolysosomal and viral membranes that releases the viral nucleocapsids into the host cytoplasm.

The EBOV GP is a class I fusion protein comprising GP1 and GP2 subunits, transcribed as a single gene and proteolytically processed into individual subunits linked by disulphide bonds; three subunit heterodimers subsequently associate to form the mature chalice-shaped GP1,2. Ansuvimab (formerly mAb114) is a fully human IgG1 monoclonal antibody (mAb) derived from an Ebola virus disease (EVD) survivor from the 1995 Kikwit EBOV outbreak 11 years after infection that binds to GP1,2 over a region encompassing both the glycan cap and GP1 core, although the glycan cap is dispensable for binding. Furthermore, structural studies reveal that ansuvimab binds to regions of the GP1 core thought to be important for GPCL interaction with NPC1 and blocks NPC1-GP interactions in vitro. Further in vitro studies revealed that ansuvimab exhibits strong GP binding (EC50 of 0.02 μg/mL), the ability to neutralize GP-expressing lentiviral particles (IC50 of 0.09 μg/mL), and strong antibody-dependent cell-mediated cytotoxicity (ADCC) at concentrations of 0.03 μg/mL. Hence, the proposed ansuvimab mechanism of action is through direct blockage of EBOV endolysosome escape and ADCC-mediated killing of EBOV-infected cells.