Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane

Nat Commun. 2025 Feb 3;16(1):1293. doi: 10.1038/s41467-025-56452-2.

Abstract

Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP1,2) are the standard of care for Ebola virus disease (EVD). Anti-GP1,2 mAbs targeting the stalk and membrane proximal external region (MPER) potently neutralize EBOV in vitro and are protective in a mouse model of EVD. However, their neutralization mechanism is poorly understood because they target a GP1,2 epitope that has evaded structural characterization. Using X-ray crystallography and cryo-electron tomography of mAb 3A6 complexed with its stalk-MPER epitope, we reveal a previously undescribed mechanism in which 3A6 binds to a conformation of GP1,2 that is lifted from the virion membrane. We further show that in both domestic guinea pig and rhesus monkey EVD models, 3A6 provides therapeutic benefit at high-viremia advanced disease stages and at the lowest dose yet demonstrated for any anti-EBOV mAb-based monotherapy. The findings reported here can guide design of next-generation highly potent anti-EBOV therapeutics and vaccines.

MeSH terms

  • Animals
  • Antibodies, Monoclonal* / immunology
  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / therapeutic use
  • Antibodies, Viral* / immunology
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Ebolavirus* / immunology
  • Epitopes / immunology
  • Female
  • Guinea Pigs
  • Hemorrhagic Fever, Ebola* / immunology
  • Hemorrhagic Fever, Ebola* / prevention & control
  • Hemorrhagic Fever, Ebola* / virology
  • Humans
  • Macaca mulatta*
  • Mice
  • Viral Envelope Proteins / chemistry
  • Viral Envelope Proteins / immunology
  • Viral Envelope Proteins / metabolism
  • Viremia / immunology
  • Virion* / immunology
  • Virion* / metabolism

Substances

  • Antibodies, Monoclonal
  • Antibodies, Viral
  • Epitopes
  • Viral Envelope Proteins
  • Antibodies, Neutralizing
  • envelope glycoprotein, Ebola virus