High Potency of a Bivalent Human V H Domain in SARS-CoV-2 Animal Models

Wei Li; Alexandra Schäfer; Swarali S Kulkarni; Xianglei Liu; David R Martinez; Chuan Chen; Zehua Sun; Sarah R Leist; Aleksandra Drelich; Liyong Zhang; Marcin L Ura; Alison Berezuk; Sagar Chittori; Karoline Leopold; Dhiraj Mannar; Shanti S Srivastava; Xing Zhu; Eric C Peterson; Chien-Te Tseng; John W Mellors; Darryl Falzarano; Sriram Subramaniam; Ralph S Baric; Dimiter S Dimitrov

doi:10.1016/j.cell.2020.09.007

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High Potency of a Bivalent Human V H Domain in SARS-CoV-2 Animal Models

Journal article

Open access

Peer reviewed

High Potency of a Bivalent Human V H Domain in SARS-CoV-2 Animal Models

Wei Li, Alexandra Schäfer, Swarali S Kulkarni, Xianglei Liu, David R Martinez, Chuan Chen, Zehua Sun, Sarah R Leist, Aleksandra Drelich, Liyong Zhang, …

Cell, Vol.183(2), p.429

2020-10-15

DOI: https://doi.org/10.1016/j.cell.2020.09.007

PMID: 32941803

Abstract

Pandemics

Coronavirus Infections - drug therapy

Humans

Immunoglobulin Variable Region - chemistry

Pneumonia, Viral - drug therapy

Immunoglobulin Heavy Chains - chemistry

Antibodies, Neutralizing - ultrastructure

Immunoglobulin Variable Region - immunology

Peptide Library

COVID-19

Antibodies, Neutralizing - immunology

Immunoglobulin Fc Fragments - immunology

Immunoglobulin Variable Region - ultrastructure

Peptidyl-Dipeptidase A - metabolism

Protein Domains

Female

Immunoglobulin Variable Region - administration & dosage

Antibodies, Viral - administration & dosage

Immunoglobulin Heavy Chains - immunology

Cricetinae

Spike Glycoprotein, Coronavirus - genetics

Spike Glycoprotein, Coronavirus - metabolism

Antibody Affinity

Angiotensin-Converting Enzyme 2

Animals

Antibodies, Viral - ultrastructure

Antibodies, Viral - chemistry

Antibodies, Viral - immunology

Immunoglobulin Heavy Chains - ultrastructure

Mice

Mice, Inbred BALB C

Mutation

Spike Glycoprotein, Coronavirus - chemistry

Immunoglobulin Heavy Chains - administration & dosage

Spike Glycoprotein, Coronavirus - ultrastructure

Novel COVID-19 therapeutics are urgently needed. We generated a phage-displayed human antibody V domain library from which we identified a high-affinity V binder ab8. Bivalent V , V -Fc ab8, bound with high avidity to membrane-associated S glycoprotein and to mutants found in patients. It potently neutralized mouse-adapted SARS-CoV-2 in wild-type mice at a dose as low as 2 mg/kg and exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection, possibly enhanced by its relatively small size. Electron microscopy combined with scanning mutagenesis identified ab8 interactions with all three S protomers and showed how ab8 neutralized the virus by directly interfering with ACE2 binding. V -Fc ab8 did not aggregate and did not bind to 5,300 human membrane-associated proteins. The potent neutralization activity of V -Fc ab8 combined with good developability properties and cross-reactivity to SARS-CoV-2 mutants provide a strong rationale for its evaluation as a COVID-19 therapeutic.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.104 Virology - General; 1.104.1353 Coronavirus
Web Of Science research areas: Biochemistry & Molecular Biology; Cell Biology
ESI research areas: Molecular Biology & Genetics

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Title: High Potency of a Bivalent Human V H Domain in SARS-CoV-2 Animal Models
Creators: Wei Li - Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA. Electronic address: liwei171@pitt.edu
Alexandra Schäfer - Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 3109 Michael Hooker Research Center, Chapel Hill, NC 27599, USA
Swarali S Kulkarni - Vaccine and Infectious Disease Organization-International Vaccine Centre, and the Department of Veterinary Microbiology, University of Saskatchewan, 117 Veterinary Road, Saskatoon, SK S7N 5E3, Canada
Xianglei Liu - Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA
David R Martinez - Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 3109 Michael Hooker Research Center, Chapel Hill, NC 27599, USA
Chuan Chen - Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA
Zehua Sun - Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA
Sarah R Leist - Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 3109 Michael Hooker Research Center, Chapel Hill, NC 27599, USA
Aleksandra Drelich - Department of Microbiology and Immunology, Centers for Biodefense and Emerging Diseases, Galveston National Laboratory, 301 University Blvd., Galveston, TX 77550, USA
Liyong Zhang - Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA
Marcin L Ura - Abound Bio, 1401 Forbes Ave., Pittsburgh, PA 15219, USA
Alison Berezuk - Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
Sagar Chittori - Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
Karoline Leopold - Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
Dhiraj Mannar - Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
Shanti S Srivastava - Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
Xing Zhu - Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
Eric C Peterson - Abound Bio, 1401 Forbes Ave., Pittsburgh, PA 15219, USA
Chien-Te Tseng - Department of Microbiology and Immunology, Centers for Biodefense and Emerging Diseases, Galveston National Laboratory, 301 University Blvd., Galveston, TX 77550, USA
John W Mellors - Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA; Abound Bio, 1401 Forbes Ave., Pittsburgh, PA 15219, USA
Darryl Falzarano - Vaccine and Infectious Disease Organization-International Vaccine Centre, and the Department of Veterinary Microbiology, University of Saskatchewan, 117 Veterinary Road, Saskatoon, SK S7N 5E3, Canada
Sriram Subramaniam - Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
Ralph S Baric - Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 3109 Michael Hooker Research Center, Chapel Hill, NC 27599, USA
Dimiter S Dimitrov - Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA; Abound Bio, 1401 Forbes Ave., Pittsburgh, PA 15219, USA. Electronic address: mit666666@pitt.edu
Publication Details: Cell, Vol.183(2), p.429
Grant note: R01 AI132178 / NIAID NIH HHS R01 AI108197 / NIAID NIH HHS P30 CA016086 / NCI NIH HHS F32 AI152296 / NIAID NIH HHS T32 AI007151 / NIAID NIH HHS
Academic Unit: Miller School of Medicine; Sylvester Comprehensive Cancer Center; UMMG Department of Ophthalmology; UMMG Dept of Neurological Surgery
Language: English
Resource Type: Journal article
PMID: 32941803
Record Identifier: 991031600202902976