Structural constraints link differences in neutralization potency of human anti-Eastern equine encephalitis virus monoclonal antibodies

• DOI: 10.1073/pnas.2213690120
• Publication Date: 2023-03-24T18:12:19Z
• Authors: Lauren E. Williamson; Abhishek Bandyopa...; Kevin Bailey; Devika Sirohi; Thomas Klose; Justin G. Julander; Richard J. Kuhn; James E. Crowe
• Keywords: Paratope; Epitope mapping; Conformational epitope

Selection and development of monoclonal antibody (mAb) therapeutics against pathogenic viruses depends on certain functional characteristics. Neutralization potency, or the half-maximal inhibitory concentration (IC50) values, is an important characteristic candidate therapeutic antibodies. Structural insights into bases neutralization potency differences between antiviral neutralizing mAbs are lacking. In this report, we present cryo-electron microscopy (EM) reconstructions three anti-Eastern equine encephalitis virus (EEEV) human targeting overlapping epitopes E2 protein, with greater than 20-fold in their respective IC50 values. From our structural biophysical analyses, identify several constraints that contribute to observed potencies. Cryo-EM EEEV complex these Fab fragments reveal dictate intravirion intervirion cross-linking glycoprotein spikes by IgG counterparts as a mechanism neutralization. Additionally, describe critical features for recognition including epitope-paratope interaction surface, occupancy, kinetic on-rate binding protein. Each constraint contributes extent inhibition blockade entry, fusion, and/or egress. These findings provide potencies antibodies, which help inform rational design principles vaccines antibodies all icosahedral viruses.