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High Potency of a Bivalent Human VH Domain in SARS-CoV-2 Animal Models.
Li, Wei; Schäfer, Alexandra; Kulkarni, Swarali S; Liu, Xianglei; Martinez, David R; Chen, Chuan; Sun, Zehua; Leist, Sarah R; Drelich, Aleksandra; Zhang, Liyong; Ura, Marcin L; Berezuk, Alison; Chittori, Sagar; Leopold, Karoline; Mannar, Dhiraj; Srivastava, Shanti S; Zhu, Xing; Peterson, Eric C; Tseng, Chien-Te; Mellors, John W; Falzarano, Darryl; Subramaniam, Sriram; Baric, Ralph S; Dimitrov, Dimiter S.
  • Li W; 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.
  • Schäfer A; Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 3109 Michael Hooker Research Center, Chapel Hill, NC 27599, USA.
  • Kulkarni SS; 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.
  • Liu X; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA.
  • Martinez DR; Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 3109 Michael Hooker Research Center, Chapel Hill, NC 27599, USA.
  • Chen C; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA.
  • Sun Z; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA.
  • Leist SR; Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 3109 Michael Hooker Research Center, Chapel Hill, NC 27599, USA.
  • Drelich A; Department of Microbiology and Immunology, Centers for Biodefense and Emerging Diseases, Galveston National Laboratory, 301 University Blvd., Galveston, TX 77550, USA.
  • Zhang L; Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA.
  • Ura ML; Abound Bio, 1401 Forbes Ave., Pittsburgh, PA 15219, USA.
  • Berezuk A; Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Chittori S; Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Leopold K; Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Mannar D; Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Srivastava SS; Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Zhu X; Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Peterson EC; Abound Bio, 1401 Forbes Ave., Pittsburgh, PA 15219, USA.
  • Tseng CT; Department of Microbiology and Immunology, Centers for Biodefense and Emerging Diseases, Galveston National Laboratory, 301 University Blvd., Galveston, TX 77550, USA.
  • Mellors JW; 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.
  • Falzarano D; 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.
  • Subramaniam S; Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Baric RS; Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 3109 Michael Hooker Research Center, Chapel Hill, NC 27599, USA.
  • Dimitrov DS; 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.
Cell ; 183(2): 429-441.e16, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-878393
ABSTRACT
Novel COVID-19 therapeutics are urgently needed. We generated a phage-displayed human antibody VH domain library from which we identified a high-affinity VH binder ab8. Bivalent VH, VH-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. VH-Fc ab8 did not aggregate and did not bind to 5,300 human membrane-associated proteins. The potent neutralization activity of VH-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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Immunoglobulin Variable Region / Immunoglobulin Heavy Chains / Coronavirus Infections / Peptide Library Type of study: Experimental Studies / Randomized controlled trials Language: English Journal: Cell Year: 2020 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Immunoglobulin Variable Region / Immunoglobulin Heavy Chains / Coronavirus Infections / Peptide Library Type of study: Experimental Studies / Randomized controlled trials Language: English Journal: Cell Year: 2020 Document Type: Article