@article{08197500f2a24638b6e64106697cf37b,
title = "Pan-ebolavirus protective therapy by two multifunctional human antibodies",
abstract = "Ebolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum and are ineffective against ebolaviruses other than Ebola virus (EBOV), including medically important Bundibugyo (BDBV) and Sudan (SUDV) viruses. Here, we report the development of a therapeutic cocktail comprising two broadly neutralizing human antibodies, rEBOV-515 and rEBOV-442, that recognize non-overlapping sites on the ebolavirus glycoprotein (GP). Antibodies in the cocktail exhibited synergistic neutralizing activity, resisted viral escape, and possessed differing requirements for their Fc-regions for optimal in vivo activities. The cocktail protected non-human primates from ebolavirus disease caused by EBOV, BDBV, or SUDV with high therapeutic effectiveness. High-resolution structures of the cocktail antibodies in complex with GP revealed the molecular determinants for neutralization breadth and potency. This study provides advanced preclinical data to support clinical development of this cocktail for pan-ebolavirus therapy.",
keywords = "Ebolavirus, antibody therapeutics, ebolavirus infection, epitope mapping, glycoprotein, neutralizing antibodies, viral antibodies",
author = "Pavlo Gilchuk and Murin, {Charles D.} and Cross, {Robert W.} and Ilinykh, {Philipp A.} and Kai Huang and Natalia Kuzmina and Viktoriya Borisevich and Agans, {Krystle N.} and Geisbert, {Joan B.} and Zost, {Seth J.} and Nargi, {Rachel S.} and Sutton, {Rachel E.} and Naveenchandra Suryadevara and Bombardi, {Robin G.} and Carnahan, {Robert H.} and Alexander Bukreyev and Geisbert, {Thomas W.} and Ward, {Andrew B.} and Crowe, {James E.}",
note = "Funding Information: We thank D. Deer for technical assistance with NHP studies. We thank George K. Lewis, Robin Flinko, and Chiara Orlandi for providing target cell line and protocols for RFADCC assay. The Jurkat-EBOV GP cell line was a kind gift from C. Davis and R. Ahmed. This work was supported by NIH ( U19 AI109711 to J.E.C. and A.B., U19 AI142785 to J.E.C. and T.W.G., and U19 AI109762 to A.B.W.), HHS ( HHSN272201400058C to J.E.C.), and DTRA ( HDTRA1-13-1-0034 to J.E.C. and A.B.). J.E.C. is a recipient of the 2019 Future Insight Prize from Merck KGaA , which supported this work with a grant. The project was supported by The Vanderbilt Institute for Clinical and Translational Research (VICTR) funded by the National Center for Advancing Translational Sciences (NCATS) Clinical Translational Science Award (CTSA) Program ( 5UL1TR002243-03 ). Work in BSL-4 and ABSL-4 was supported by NIH ( 5UC7AI094660-07 ) and by the Animal Resource Center of the Galveston National Laboratory . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Funding Information: We thank D. Deer for technical assistance with NHP studies. We thank George K. Lewis, Robin Flinko, and Chiara Orlandi for providing target cell line and protocols for RFADCC assay. The Jurkat-EBOV GP cell line was a kind gift from C. Davis and R. Ahmed. This work was supported by NIH (U19 AI109711 to J.E.C. and A.B. U19 AI142785 to J.E.C. and T.W.G. and U19 AI109762 to A.B.W.), HHS (HHSN272201400058C to J.E.C.), and DTRA (HDTRA1-13-1-0034 to J.E.C. and A.B.). J.E.C. is a recipient of the 2019 Future Insight Prize from Merck KGaA, which supported this work with a grant. The project was supported by The Vanderbilt Institute for Clinical and Translational Research (VICTR) funded by the National Center for Advancing Translational Sciences (NCATS) Clinical Translational Science Award (CTSA) Program (5UL1TR002243-03). Work in BSL-4 and ABSL-4 was supported by NIH (5UC7AI094660-07) and by the Animal Resource Center of the Galveston National Laboratory. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. P.G. C.D.M. R.W.C. R.H.C. A.B. T.W.G. A.B.W. and J.E.C. planned the studies. P.G. C.D.M. R.W.C. P.A.I. K.H. V.B. K.N.A. J.B.G. N.K. T.A. R.S.N. R.E.S. N.S. S.J.Z. and R.G.B. conducted experiments. P.G. C.D.M. R.W.C. A.B. T.W.G. A.B.W. and J.E.C. interpreted the studies. P.G. C.D.M. and J.E.C. wrote the first draft of the paper. A.B. T.W.G. A.B.W, and J.E.C. obtained funding. All authors reviewed, edited, and approved the paper. J.E.C. has served as a consultant for Eli Lilly, GlaxoSmithKline and Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines, and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received unrelated sponsored research agreements from Takeda Vaccines, IDBiologics, and AstraZeneca. Vanderbilt University has applied for patents concerning ebolavirus antibodies that are related to this work. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = oct,
day = "28",
doi = "10.1016/j.cell.2021.09.035",
language = "English (US)",
volume = "184",
pages = "5593--5607.e18",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "22",
}