@article{81d451a9d90d44acb2e6b45e3188c6d3,
title = "A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in cynomolgus macaques",
abstract = "Background: Human monoclonal antibody (mAb) treatments are promising for COVID-19 prevention or therapy. The pre-exposure prophylactic efficacy of neutralizing antibodies that are engineered with mutations to extend their persistence in human serum and the neutralizing antibody titer in serum required for protection against SARS-CoV-2 infection remain poorly characterized. Methods: The Fc region of two neutralizing mAbs (COV2-2130 and COV2-2381) targeting non-overlapping epitopes on the receptor binding domain of SARS-CoV-2 spike protein was engineered to extend their persistence in humans and reduce interactions with Fc gamma receptors. We assessed protection by individual antibodies or a combination of the two antibodies (designated ADM03820) given prophylactically by an intravenous or intramuscular route in a non-human primate (NHP) model of SARS-CoV-2 infection. Findings: Passive transfer of individual mAbs or ADM03820 conferred virological protection in the NHP respiratory tract in a dose-dependent manner, and ADM03820 potently neutralized SARS-CoV-2 variants of concern in vitro. We defined a protective serum-neutralizing antibody titer and concentration in NHPs for passively transferred human antibodies that acted by direct viral neutralization. Conclusions: In summary, we demonstrate that neutralizing antibodies with extended half-life and lacking Fc-mediated effector functions are efficient for pre-exposure prophylaxis of SARS-CoV-2 infection in NHPs. These results support clinical development of ADM03820 for COVID-19 prevention. Funding: This research was supported by a contract from the JPEO-CBRND (W911QY-20-9-003, 20-05); the Joint Sciences and Technology Office and Joint Program Executive Office (MCDC-16-01-002 JSTO, JPEO); a DARPA grant (HR0011-18-2-0001); an NIH grant (R01 AI157155); and the 2019 Future Insight Prize from Merck KGaA.",
keywords = "Pre-clinical research, SARS-CoV-2, aerosol, antibody therapeutics, cynomolgus macaques, human monoclonal antibody, neutralizing antibodies",
author = "Cobb, {Ronald R.} and Joseph Nkolola and Pavlo Gilchuk and Abishek Chandrashekar and Jingyou Yu and House, {Robert V.} and Earnhart, {Christopher G.} and Dorsey, {Nicole M.} and Hopkins, {Svetlana A.} and Snow, {Doris M.} and Chen, {Rita E.} and VanBlargan, {Laura A.} and Manuel Hechenblaickner and Brian Hoppe and Laura Collins and Tomic, {Milan T.} and Nonet, {Genevieve H.} and Kyal Hackett and Slaughter, {James C.} and Lewis, {Mark G.} and Hanne Andersen and Anthony Cook and Diamond, {Michael S.} and Carnahan, {Robert H.} and Barouch, {Dan H.} and Crowe, {James E.}",
note = "Funding Information: We thank E. Bondzie, N. Mercado, V. Giffin, D. Hope, and F. Nampanya for their assistance. This research was supported by the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND), contract number W911QY-20-9-003, 20-05; the Joint Sciences and Technology Office and Joint Program Executive Office, contract number MCDC-16-01-002 JSTO, JPEO; Defense Advanced Research Projects Agency (DARPA) grant HR0011-18-2-0001; and National Institutes of Health (NIH) grant R01 AI157155. J.E.C. is a recipient of the 2019 Future Insight Prize from Merck KGaA. The content is solely the responsibility of the authors and does not represent the official views of the US government or other sponsors. R.R.C. M.S.D. R.H.C. D.H.B. and J.E.C. planned the studies. J.N. P.G. A.C. J.Y. R.V.H. C.G.E. N.M.D. S.A.H. D.M.S. R.E.C. L.A.V. M.H. B.H. L.C. M.T.T. G.H.N. K.H. J.C.S. M.L. H.A. A.C. and D.H.B. conducted experiments, analyzed data, and interpreted the results. J.C.S. and P.G. performed and oversaw the statistical analysis. D.H.B. and P.G. had unrestricted access to all the data in the paper. J.E.C, M.S.D. and D.H.B. obtained funding. R.R.C. J.N. P.G. and J.E.C. wrote the first draft of the paper, with the other authors providing editorial comments. All authors agreed to submit the manuscript, read and approved the final draft, and take full responsibility for its content, including the accuracy of the data. R.R.C. R.V.H. D.M.S. M.H. B.H. L.C. G.H.N. M.T.T. and K.H. are employees of Ology Bioservices. C.G.E. and N.M.D. are employees of the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense for the US Department of Defense (JPEO-CBRND). S.A.H. is an employee of Logistics Management Institute (LMI), performing technical contract support for JPEO-CBRND. J.E.C. has served as a consultant for Luna Innovations, is a member of the scientific advisory board of Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from Takeda, IDBiologics, and AstraZeneca. Vanderbilt University has applied for patents related to antibodies studied in this paper. M.S.D. is a consultant for InBios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and is on the scientific advisory boards of Moderna and Immunome. The laboratory of M.S.D. has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions. Funding Information: R.R.C., R.V.H., D.M.S., M.H., B.H., L.C., G.H.N., M.T.T., and K.H. are employees of Ology Bioservices. C.G.E. and N.M.D. are employees of the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense for the US Department of Defense (JPEO-CBRND). S.A.H. is an employee of Logistics Management Institute (LMI), performing technical contract support for JPEO-CBRND. J.E.C. has served as a consultant for Luna Innovations, is a member of the scientific advisory board of Meissa Vaccines, and is founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from Takeda, IDBiologics, and AstraZeneca. Vanderbilt University has applied for patents related to antibodies studied in this paper. M.S.D. is a consultant for InBios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation and is on the scientific advisory boards of Moderna and Immunome. The laboratory of M.S.D. has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions. Funding Information: We thank E. Bondzie, N. Mercado, V. Giffin, D. Hope, and F. Nampanya for their assistance. This research was supported by the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) , contract number W911QY-20-9-003, 20-05 ; the Joint Sciences and Technology Office and Joint Program Executive Office , contract number MCDC-16-01-002 JSTO, JPEO; Defense Advanced Research Projects Agency (DARPA) grant HR0011-18-2-0001 ; and National Institutes of Health (NIH) grant R01 AI157155 . J.E.C. is a recipient of the 2019 Future Insight Prize from Merck KGaA. The content is solely the responsibility of the authors and does not represent the official views of the US government or other sponsors. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = mar,
day = "11",
doi = "10.1016/j.medj.2022.01.004",
language = "English",
volume = "3",
pages = "188--203.e4",
journal = "Med",
issn = "2666-6359",
number = "3",
}