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Asymmetric and non-stoichiometric glycoprotein recognition by two distinct antibodies results in broad protection against ebolaviruses

Journal Article · · Cell
 [1];  [2];  [3];  [4];  [4];  [5];  [6];  [6];  [6];  [6];  [2];  [7];  [7];  [1];  [1];  [1];  [8];  [8];  [9];  [10] more »;  [10];  [11];  [7];  [4];  [6];  [10];  [2];  [12] « less
  1. La Jolla Institute for Immunology (LJI), CA (United States)
  2. Emory Univ., Atlanta, GA (United States)
  3. La Jolla Institute for Immunology (LJI), CA (United States); The Scripps Research Inst., La Jolla, CA (United States)
  4. University of Texas Medical Branch, Galveston, TX (United States); Galveston National Laboratory, TX (United States)
  5. Univ. of Wisconsin, Madison, WI (United States)
  6. Galveston National Laboratory, TX (United States); University of Texas Medical Branch, Galveston, TX (United States)
  7. US Army Research Institute for Infectious Disease, Frederick, MD (United States)
  8. Zalgen Labs, Germantown, MD (United States)
  9. Frederick National Laboratory for Cancer Research, MD (United States)
  10. National Institutes of Health (NIH), Frederick, MD (United States)
  11. Univ. of Wisconsin, Madison, WI (United States); Univ. of Tokyo (Japan)
  12. La Jolla Institute for Immunology (LJI), CA (United States); Univ. of California, San Diego, CA (United States)
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Several ebolaviruses cause outbreaks of severe disease. Vaccines and monoclonal antibody cocktails are available to treat Ebola virus (EBOV) infections, but not Sudan virus (SUDV) or other ebolaviruses. Current cocktails contain antibodies that cross-react with the secreted soluble glycoprotein (sGP) that absorbs virus-neutralizing antibodies. By sorting memory B cells from EBOV infection survivors, we isolated two broadly reactive anti-GP monoclonal antibodies, 1C3 and 1C11, that potently neutralize, protect rodents from disease, and lack sGP cross-reactivity. Both antibodies recognize quaternary epitopes in trimeric ebolavirus GP. 1C11 bridges adjacent protomers via the fusion loop. 1C3 has a tripartite epitope in the center of the trimer apex. One 1C3 antigen-binding fragment anchors simultaneously to the three receptor-binding sites in the GP trimer, and separate 1C3 paratope regions interact differently with identical residues on the three protomers. A cocktail of both antibodies completely protected nonhuman primates from EBOV and SUDV infections, indicating their potential clinical value.

Research Organization:
SLAC National Accelerator Laboratory, Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-76SF00515
OSTI ID:
1981561
Journal Information:
Cell, Journal Name: Cell Journal Issue: 6 Vol. 185; ISSN 0092-8674
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Bundibugyo virus
Ebola virus
Sudan virus
antibody therapeutic
cryo-EM
ebolavirus
medical countermeasure
monoclonal antibody
nonhuman primate