Convergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies.

Charles D Murin,Lauren E Williamson,Edgar Davidson,Benjamin J Doranz,Alexander Bukreyev,Natalia Kuzmina,Philipp A Ilinykh,Xiaoli Shen,Aubrey L Bryan,Jeffrey Copps,James E Crowe,Andrew B Ward,Andrew I Flyak,Jessica F Bruhn,Tanwee Alkutkar,Kai Huang,Pavlo Gilchuk

doi:10.1016/j.celrep.2021.108984

Abstract

SUMMARYAntibodies that target the glycan cap epitope on the ebolavirus glycoprotein (GP) are common in the adaptive response of survivors. A subset is known to be broadly neutralizing, but the details of their epitopes and basis for neutralization are not well understood. Here, we present cryoelectron microscopy (cryo-EM) structures of diverse glycan cap antibodies that variably synergize with GP base-binding antibodies. These structures describe a conserved site of vulnerability that anchors the mucin-like domains (MLDs) to the glycan cap, which we call the MLD anchor and cradle. Antibodies that bind to the MLD cradle share common features, including use of IGHV1–69 and IGHJ6 germline genes, which exploit hydrophobic residues and form β-hairpin structures to mimic the MLD anchor, disrupt MLD attachment, destabilize GP quaternary structure, and block cleavage events required for receptor binding. Our results provide a molecular basis for ebolavirus neutralization by broadly reactive glycan cap antibodies.

Highlights

There is mounting evidence that protection from filovirus infection can be achieved through use of monoclonal antibodies that target the glycoprotein (GP) surface (Bornholdt et al, 2019; Brannan et al, 2019; Mire et al, 2017; Qiu et al, 2014; Saphire et al, 2018b)
REGN-EB3 is only effective against EBOV; a pan-EBOV therapeutic agent that recognizes multiple EBOVs that cause severe disease in humans and major outbreaks, including Bundibugyo ebolavirus (BDBV) and Sudan ebolavirus (SUDV), would be ideal, given the unpredictability of EBOV outbreaks
We chose previously isolated antibodies based on properties similar to the synergistic glycan cap monoclonal antibodies (mAbs) EBOV-548, including (1) synergy with EBOV-520 and/or EBOV-515, (2) broad reactivity and neutralization, (3) long CDRH3 loops, (4) cross-reactivity with sGP, and/or (5) protection in vivo

Summary

Introduction

There is mounting evidence that protection from filovirus infection can be achieved through use of monoclonal antibodies (mAbs) that target the glycoprotein (GP) surface (Bornholdt et al, 2019; Brannan et al, 2019; Mire et al, 2017; Qiu et al, 2014; Saphire et al, 2018b). Several structures of antigen-antibody complexes indicate that antibodies can access nearly any region on the surface of GPs (Flyak et al, 2015, 2018; Gilchuk et al, 2018; Milligan et al, 2019; Murin et al, 2018, 2019; Pallesen et al, 2016; Pascal et al, 2018; Saphire et al, 2018a; Wec et al, 2017; West et al, 2018; Zhao et al, 2017) Such antibodies have utility as post-exposure therapeutic agents when used in combination, such as the tri-mAb cocktail REGN-EB3, which has demonstrated high efficacy in animal models (Pascal et al, 2018) and in a clinical trial carried out during a recent ebolavirus (EBOV) outbreak (Mulangu et al, 2019). The antibody 13C6, which is included in the antibody cocktail ZMapp, targets

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