The authors were interested in the structural features that determine the broad-spectrum activity of broadly neutralising anti-ebolavirus antibodies (Abs) that act outside of the internal fusion loop epitope. They examined the structure of a broadly neutralising human monoclonal Ab (mAb), ADI-15946, that was identified in a human survivor of the 2013-2016 outbreak. The crystal structure of ADI-15946, when in complex with cleaved Ebolavirus glycoprotein (EBOV GPCL), found that the binding of the mAb structurally mimics the conserved interaction between the EBOV GP core and its glycan cap β17-β18 loop to inhibit infection. They found that both endosomal proteolysis of EBOV GP and the binding of the mAb, FVM09, displace this loop, increasing the exposure of ADI-15946’s conserved epitope, and enhancing neutralisation. The authors were also able to map the paratope of ADI-15946, thereby explaining the reduced activity of the antibody against Sudan virus. This allowed for rational, structure-guided engineering to enhance the antibody’s binding and neutralisation of Sudan virus whilst retaining its parental activity against EBOV and Bundibugyo virus.
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