A "Trojan horse" bispecific-antibody strategy for broad protection against ebolaviruses

Science. 2016 Oct 21;354(6310):350-354. doi: 10.1126/science.aag3267. Epub 2016 Sep 8.

Abstract

There is an urgent need for monoclonal antibody (mAb) therapies that broadly protect against Ebola virus and other filoviruses. The conserved, essential interaction between the filovirus glycoprotein, GP, and its entry receptor Niemann-Pick C1 (NPC1) provides an attractive target for such mAbs but is shielded by multiple mechanisms, including physical sequestration in late endosomes. Here, we describe a bispecific-antibody strategy to target this interaction, in which mAbs specific for NPC1 or the GP receptor-binding site are coupled to a mAb against a conserved, surface-exposed GP epitope. Bispecific antibodies, but not parent mAbs, neutralized all known ebolaviruses by coopting viral particles themselves for endosomal delivery and conferred postexposure protection against multiple ebolaviruses in mice. Such "Trojan horse" bispecific antibodies have potential as broad antifilovirus immunotherapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / immunology*
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology*
  • Antibodies, Viral / immunology*
  • Binding Sites / immunology
  • Carrier Proteins / immunology*
  • Cell Line, Tumor
  • Ebolavirus / immunology*
  • Endosomes / virology
  • Hemorrhagic Fever, Ebola / prevention & control*
  • Hemorrhagic Fever, Ebola / therapy
  • Humans
  • Immunotherapy / methods
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Receptors, Virus / immunology*
  • Viral Envelope Proteins / immunology*
  • Virus Internalization

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • Receptors, Virus
  • Viral Envelope Proteins
  • envelope glycoprotein, Ebola virus