Ansuvimab (Ebanga)

概览

Ansuvimab is a fully human monoclonal IgG1 antibody directed against the GP1,2 surface protein of Zaire ebolavirus that is an effective treatment for Ebola virus disease.

作用机制

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 GP glycoprotein involved in host cell entry and subsequent viral escape into the cytoplasm. GP 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, GP is cleaved by host cathepsins into a fusion-competent form termed GP, 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 GP and GP 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 GP. 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 GP over a region encompassing both the glycan cap and GP core, although the glycan cap is dispensable for binding. Furthermore, structural studies reveal that ansuvimab binds to regions of the GP core thought to be important for GP interaction with NPC1 and blocks NPC1-GP interactions in vitro. Further in vitro studies revealed that ansuvimab exhibits strong GP binding (EC of 0.02 μg/mL), the ability to neutralize GP-expressing lentiviral particles (IC 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.

适应症

Ansuvimab is indicated for the treatment of Zaire ebolavirus infection in adult and pediatric patients, including neonates born to a mother who tests positive for Zaire ebolavirus by RT-PCR. Ansuvimab has not been shown to be effective against other species within the Ebolavirus and Marburgvirus genera; factors such as the possible emergence of resistant strains suggest local information on circulating Zaire ebolavirus strains should be consulted before initiating treatment.

• Ebola Virus Disease