Synthetic Antibodies With a Human Framework That Protect Mice From Lethal Sudan Ebolavirus Challenge

ACS Chem Biol. 2014 Oct 17;9(10):2263-73. doi: 10.1021/cb5006454. Epub 2014 Aug 26.

Abstract

The ebolaviruses cause severe and rapidly progressing hemorrhagic fever. There are five ebolavirus species; although much is known about Zaire ebolavirus (EBOV) and its neutralization by antibodies, little is known about Sudan ebolavirus (SUDV), which is emerging with increasing frequency. Here we describe monoclonal antibodies containing a human framework that potently inhibit infection by SUDV and protect mice from lethal challenge. The murine antibody 16F6, which binds the SUDV envelope glycoprotein (GP), served as the starting point for design. Sequence and structural alignment revealed similarities between 16F6 and YADS1, a synthetic antibody with a humanized scaffold. A focused phage library was constructed and screened to impart 16F6-like recognition properties onto the YADS1 scaffold. A panel of 17 antibodies were characterized and found to have a range of neutralization potentials against a pseudotype virus infection model. Neutralization correlated with GP binding as determined by ELISA. Two of these clones, E10 and F4, potently inhibited authentic SUDV and conferred protection and memory immunity in mice from lethal SUDV challenge. E10 and F4 were further shown to bind to the same epitope on GP as 16F6 with comparable affinities. These antibodies represent strong immunotherapeutic candidates for treatment of SUDV infection.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies / administration & dosage*
  • Antibodies / chemistry
  • Antibodies / immunology
  • Antibodies, Neutralizing / chemistry
  • Antibodies, Neutralizing / immunology*
  • Antigens, Viral / chemistry
  • Antigens, Viral / immunology*
  • Ebolavirus / immunology
  • Ebolavirus / pathogenicity*
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / immunology
  • Female
  • Hemorrhagic Fever, Ebola / immunology
  • Hemorrhagic Fever, Ebola / prevention & control*
  • Hemorrhagic Fever, Ebola / virology
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Peptide Library
  • Protein Conformation
  • Receptors, Interferon / physiology*
  • Sequence Homology, Amino Acid
  • Sudan
  • Viral Envelope Proteins / immunology*

Substances

  • Antibodies
  • Antibodies, Neutralizing
  • Antigens, Viral
  • Epitopes
  • Peptide Library
  • Receptors, Interferon
  • Viral Envelope Proteins