High Potency of a Bivalent Human VH Domain in SARS-CoV-2 Animal Models
Authors: Shanti S Srivastava
Xing Zhu
Aleksandra Drelich
Xianglei Liu
Ralph S Baric
Swarali S Kulkarni
Chien-Te Tseng
Sagar Chittori
John W Mellors
Marcin L Ura
Sarah R Leist
Liyong Zhang
Zehua Sun
David R Martinez
Dimiter S Dimitrov
Sriram Subramaniam
Eric C Peterson
Dhiraj Mannar
Darryl Falzarano
Chuan Chen
Alexandra Schäfer
Wei Li
Alison Berezuk
Karoline Leopold
Journal: Cell (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: SARS-CoV-2; electron microscopy; human V(H) antibody domain; mouse and hamster models; virus neutralization.
Affiliations: 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: ., Department of Epidemiology, University of North Carolina at Chapel Hill, 135 Dauer Drive, 3109 Michael Hooker Research Center, Chapel Hill, NC 27599, USA., 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., Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, 3550 Terrace St., Pittsburgh, PA 15261, USA., Department of Microbiology and Immunology, Centers for Biodefense and Emerging Diseases, Galveston National Laboratory, 301 University Blvd., Galveston, TX 77550, USA., Abound Bio, 1401 Forbes Ave., Pittsburgh, PA 15219, USA., Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada., 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., 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: .

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. 

Retracted: No

PubPeer comments:
 The COI disclosure reads as follows: u201c**DECLARATION OF INTERESTS**. Wei Li, Chuan Chen, Zehua Sun, John W. Mellors and Dimiter S. Dimitrov are co-inventors of a patent, filed on March 12 by the University of Pittsburgh, related to ab8 described in this paper.u201d According to articles about this paper, [here] for example, u201cAbound Bio, a UPMC backed company, has been formed to license Ab8 for worldwide development.u201d And according to [this site] , two of the authors founded Abound Bio: u201cFounded by two successful leaders in the therapeutic antibody space, John Mellors, MD, and Dimiter Dimitrov, PhD, ScD, Abound Bio has a unique approach to antibody library development selection and engineering of candidate therapeutics, specifically researching immunotherapies for infectious diseases and cancer of unmet medical need.u201d Should the COI disclosure more clearly disclose the potential commercial ties of the authors, or is it implied because of the statement that a patent was filed? , 
 yes, it is implied because of the patent statement. thanks! ,