Structural Basis of Broad Ebolavirus Neutralization by a Human Survivor Antibody

West, B. R.; Wec, A. Z.; Moyer, C. L.; Fusco, M. L.; Illinykh, P. A.; Huang, K.; James, R.; Herbert, A.; Hui, S.; Wirchnianski, A. S.; Goodwin, E.; Aman, M. J.; Walker, L. M.; Dye, J. M.; Bukreyev, A.; Chandran, K.; Saphire, E. O.

doi:10.1101/394502

bioRxiv · 10.1101/394502

Structural Basis of Broad Ebolavirus Neutralization by a Human Survivor Antibody

West, B. R.·Wec, A. Z.·Moyer, C. L.·Fusco, M. L.·Illinykh, P. A.·Huang, K.·James, R.·Herbert, A.·Hui, S.·Wirchnianski, A. S.·Goodwin, E.·Aman, M. J.·Walker, L. M.·Dye, J. M.·Bukreyev, A.·Chandran, K.·Saphire, E. O.

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Abstract

The structural features that govern broad-spectrum activity of broadly neutralizing, anti-ebolavirus antibodies (Abs) are currently unknown. Here we describe the first structure of a broadly neutralizing human Ab, ADI-15946, in complex with cleaved Ebola virus glycoprotein (EBOV GPCL). We find that ADI-15946 employs structural mimicry of a conserved interaction between the GP core and the glycan cap {beta}17-{beta}18 loop to inhibit infection. Both endosomal proteolysis of EBOV GP and binding of monoclonal Ab (mAb) FVM09 displace this loop, increase exposure of ADI-15946s conserved epitope and potentiate neutralization. Our work also illuminated the determinants of ADI-15946s reduced activity against Sudan virus (SUDV), and enabled rational, structure-guided engineering to enhance binding and neutralization against SUDV while retaining the parental breadth of activity.\n\nOne Sentence SummaryThe first crystal structure of a broadly active antibody against surface glycoproteins of ebolaviruses identifies a highly conserved epitope beneath the glycan cap and highlights the molecular requirements for broad ebolavirus neutralization.

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West, B. R., Wec, A. Z., Moyer, C. L., Fusco, M. L., Illinykh, P. A., Huang, K., James, R., Herbert, A., Hui, S., Wirchnianski, A. S., Goodwin, E., Aman, M. J., Walker, L. M., Dye, J. M., Bukreyev, A., Chandran, K., Saphire, E. O.. 2018-08-19. Structural Basis of Broad Ebolavirus Neutralization by a Human Survivor Antibody. https://doi.org/10.1101/394502

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