Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates

Abstract

BackgroundFor most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases.MethodsIn this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses.ResultsOf the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent.ConclusionsThis antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.

Analysis of a Therapeutic Antibody Cocktail Reveals Determinants for Cooperative and Broad Ebolavirus Neutralization

“…MBP134 AF is a two-antibody cocktail with pan-ebolavirus activity that demonstrated efficacy in NHPs . REGN-EB3 is a three-antibody cocktail (Pascal et al, 2018), and mAb114 is a single mAb that is specific to the receptor binding site of the GP (Corti et al, 2016a)-both are monospecific to EBOV. REGN-EB3 and mAb114 were recently assessed in the field in the DRC outbreak of human EVD, and early treatment was associated with reduction of the mortality rate to 6% with REGN-EB3 or to 11% with mAb114 (Nature News, 2019).…”

Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection

“…Also included were ZMapp (Qiu et al, 2014), KZ52 (Maruyama et al, 1999), and other published and unpublished mAbs (Bornholdt et al, 2016a; Flyak et al, 2016; Fusco et al, 2015; Holtsberg et al, 2015; Keck et al, 2015; Koellhoffer et al, 2012; Pascal et al, 2018; Qiu et al, 2012b; Takada et al, 2003; Wilson et al, 2000). The study results describe relationships between epitopes recognized on EBOV GP and antibody functions and inform strategies for recognition and development of effective antibody-based therapeutics to treat infection.…”

A Two-Antibody Pan-Ebolavirus Cocktail Confers Broad Therapeutic Protection in Ferrets and Nonhuman Primates

“…Of the five ebolaviruses known to infect humans, EBOV, SUDV, and BDBV have caused outbreaks with case-fatality rates up to 90% in the last decade (Burk et al, 2016). Although several therapeutic products are in clinical development for the treatment of Ebola virus disease (EVD), no medical countermeasures to SUDV or BDBV have progressed beyond proof-of-concept studies (Corti et al, 2016; Mire et al, 2013; Pascal et al, 2018; Qiu et al, 2014; Thi et al., 2016). To address this unmet public health need, we developed a two-antibody cocktail, MBP134 AF , with demonstrable activity against all known ebolaviruses ( companion report, Wec et al ), including the “pre-emergent” agent Bombali virus recently discovered in molossid bats in Sierra Leone (Goldstein et al, 2018).…”