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TitleStructural constraints link differences in neutralization potency of human anti-Eastern equine encephalitis virus monoclonal antibodies.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 120, Issue 13, Page e2213690120, Year 2023
Publish dateMar 28, 2023
AuthorsLauren E Williamson / Abhishek Bandyopadhyay / Kevin Bailey / Devika Sirohi / Thomas Klose / Justin G Julander / Richard J Kuhn / James E Crowe /
PubMed AbstractSelection and development of monoclonal antibody (mAb) therapeutics against pathogenic viruses depends on certain functional characteristics. Neutralization potency, or the half-maximal inhibitory ...Selection and development of monoclonal antibody (mAb) therapeutics against pathogenic viruses depends on certain functional characteristics. Neutralization potency, or the half-maximal inhibitory concentration (IC) values, is an important characteristic of candidate therapeutic antibodies. Structural insights into the bases of neutralization potency differences between antiviral neutralizing mAbs are lacking. In this report, we present cryo-electron microscopy (EM) reconstructions of three anti-Eastern equine encephalitis virus (EEEV) neutralizing human mAbs targeting overlapping epitopes on the E2 protein, with greater than 20-fold differences in their respective IC values. From our structural and biophysical analyses, we identify several constraints that contribute to the observed differences in the neutralization potencies. Cryo-EM reconstructions of EEEV in complex with these Fab fragments reveal structural constraints that dictate intravirion or intervirion cross-linking of glycoprotein spikes by their IgG counterparts as a mechanism of neutralization. Additionally, we describe critical features for the recognition of EEEV by these mAbs including the epitope-paratope interaction surface, occupancy, and kinetic differences in on-rate for binding to the E2 protein. Each constraint contributes to the extent of EEEV inhibition for blockade of virus entry, fusion, and/or egress. These findings provide structural and biophysical insights into the differences in mechanism and neutralization potencies of these antibodies, which help inform rational design principles for candidate vaccines and therapeutic antibodies for all icosahedral viruses.
External linksProc Natl Acad Sci U S A / PubMed:36961925 / PubMed Central
MethodsEM (single particle)
Resolution5.2 - 6.6 Å
Structure data

26945

7v0n

EMDB-26945, PDB-7v0n:
Cryo-EM structure of SINV/EEEV in complex with Fab fragment of a moderately/weakly neutralizing human antibody IgG-21
Method: EM (single particle) / Resolution: 5.9 Å

26946

7v0o

EMDB-26946, PDB-7v0o:
Cryo-EM structure of SINV/EEEV in complex with Fab fragment of a moderately/weakly neutralizing human antibody IgG-94
Method: EM (single particle) / Resolution: 6.6 Å

26947

7v0p

EMDB-26947, PDB-7v0p:
Cryo-EM structure of SINV/EEEV in complex with Fab fragment of a potently neutralizing human antibody IgG-106
Method: EM (single particle) / Resolution: 5.2 Å

Source
  • eastern equine encephalitis virus
  • homo sapiens (human)
KeywordsVIRUS/IMMUNE SYSTEM / cryo-EM / single particle / virus neutralization / inter virion crosslink / aggregation / VIRUS-IMMUNE SYSTEM complex / inter-virion crosslink / intra-virion crosslink

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