A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in cynomolgus macaques

Ronald R. Cobb, Joseph Nkolola, Pavlo Gilchuk, Abishek Chandrashekar, Jingyou Yu, Robert V. House, Christopher G. Earnhart, Nicole M. Dorsey, Svetlana A. Hopkins, Doris M. Snow, Rita E. Chen, Laura A. VanBlargan, Manuel Hechenblaickner, Brian Hoppe, Laura Collins, Milan T. Tomic, Genevieve H. Nonet, Kyal Hackett, James C. Slaughter, Mark G. LewisHanne Andersen, Anthony Cook, Michael S. Diamond, Robert H. Carnahan, Dan H. Barouch, James E. Crowe

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Pages (from-to)188-203.e4
JournalMed
Volume3
Issue number3
DOIs
StatePublished - Mar 11 2022

Keywords

  • Pre-clinical research
  • SARS-CoV-2
  • aerosol
  • antibody therapeutics
  • cynomolgus macaques
  • human monoclonal antibody
  • neutralizing antibodies

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