Potent neutralization of SARS-CoV-2 by human antibody heavy-chain variable domains isolated from a large library with a new stable scaffold
Zehua Sun,
Chuan Chen,
Wei Li,
David R. Martinez,
Aleksandra Drelich,
Du-San Baek,
Xianglei Liu,
John W. Mellors,
Chien-Te Tseng,
Ralph S. Baric,
Dimiter S. Dimitrov
Affiliations
Zehua Sun
Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
Chuan Chen
Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
Wei Li
Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
David R. Martinez
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Aleksandra Drelich
Department of Microbiology & Immunology, Centers for Biodefense and Emerging Diseases, Galveston National Laboratory, Galveston, TX, USA
Du-San Baek
Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
Xianglei Liu
Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
John W. Mellors
Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
Chien-Te Tseng
Department of Microbiology & Immunology, Centers for Biodefense and Emerging Diseases, Galveston National Laboratory, Galveston, TX, USA
Ralph S. Baric
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Dimiter S. Dimitrov
Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA
Effective therapies are urgently needed for COVID-19. Here we describe the identification of a new stable human immunoglobulin G1 heavy-chain variable (VH) domain scaffold that was used for the construction of a large library, lCAT6, of engineered human VHs. This library was panned against the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. Two VH domains (VH ab6 and VH m397) were selected and fused to Fc for increased half-life in circulation. The VH-Fc ab6 and m397 specifically neutralized SARS-CoV-2 with high potencies (50% neutralization at 0.35 µg/ml and 1.5 µg/ml, respectively) as measured by two independent replication-competent virus neutralization assays. Ab6 and m397 competed with ACE2 for binding to RBD, suggesting a competitive mechanism of virus neutralization. These VH domains may have potential applications for prophylaxis and therapy of COVID-19 alone or in combination, as well as for diagnosis and as tools for research.
