Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2

Shion A. Lim; Josef A. Gramespacher; Katarina Pance; Nicholas J. Rettko; Paige Solomon; Jing Jin; Irene Lui; Susanna K. Elledge; Jia Liu; Colton J. Bracken; Graham Simmons; Xin X. Zhou; Kevin K. Leung; James A. Wells

doi:10.1080/19420862.2021.1893426

mAbs (Jan 2021)

Bispecific VH/Fab antibodies targeting neutralizing and non-neutralizing Spike epitopes demonstrate enhanced potency against SARS-CoV-2

Shion A. Lim,
Josef A. Gramespacher,
Katarina Pance,
Nicholas J. Rettko,
Paige Solomon,
Jing Jin,
Irene Lui,
Susanna K. Elledge,
Jia Liu,
Colton J. Bracken,
Graham Simmons,
Xin X. Zhou,
Kevin K. Leung,
James A. Wells

Affiliations

Shion A. Lim: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
Josef A. Gramespacher: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
Katarina Pance: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
Nicholas J. Rettko: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
Paige Solomon: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
Jing Jin: Vitalant Research Institute and Department of Laboratory Medicine, University of California San Francisco, University of California San Francisco, California, USA
Irene Lui: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
Susanna K. Elledge: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
Jia Liu: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
Colton J. Bracken: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
Graham Simmons: Vitalant Research Institute and Department of Laboratory Medicine, University of California San Francisco, University of California San Francisco, California, USA
Xin X. Zhou: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
Kevin K. Leung: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
James A. Wells: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA

DOI: https://doi.org/10.1080/19420862.2021.1893426
Journal volume & issue: Vol. 13, no. 1

Abstract

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Numerous neutralizing antibodies that target SARS-CoV-2 have been reported, and most directly block binding of the viral Spike receptor-binding domain (RBD) to angiotensin-converting enzyme II (ACE2). Here, we deliberately exploit non-neutralizing RBD antibodies, showing they can dramatically assist in neutralization when linked to neutralizing binders. We identified antigen-binding fragments (Fabs) by phage display that bind RBD, but do not block ACE2 or neutralize virus as IgGs. When these non-neutralizing Fabs were assembled into bispecific VH/Fab IgGs with a neutralizing VH domain, we observed a ~ 25-fold potency improvement in neutralizing SARS-CoV-2 compared to the mono-specific bi-valent VH-Fc alone or the cocktail of the VH-Fc and IgG. This effect was epitope-dependent, reflecting the unique geometry of the bispecific antibody toward Spike. Our results show that a bispecific antibody that combines both neutralizing and non-neutralizing epitopes on Spike-RBD is a promising and rapid engineering strategy to improve the potency of SARS-CoV-2 antibodies.

Published in mAbs

ISSN: 1942-0862 (Print); 1942-0870 (Online)
Publisher: Taylor & Francis Group
Country of publisher: United Kingdom
LCC subjects: Medicine: Therapeutics. Pharmacology; Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: https://www.tandfonline.com/journals/kmab

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