Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain

Rajeshwer S Sankhala; Vincent Dussupt; Wei-Hung Chen; Hongjun Bai; Elizabeth J Martinez; Jaime L Jensen; Phyllis A Rees; Agnes Hajduczki; William C Chang; Misook Choe; Lianying Yan; Spencer L Sterling; Isabella Swafford; Caitlin Kuklis; Sandrine Soman; Jocelyn King; Courtney Corbitt; Michelle Zemil; Caroline E Peterson; Letzibeth Mendez-Rivera; Samantha M Townsley; Gina C Donofrio; Kerri G Lal; Ursula Tran; Ethan C Green; Clayton Smith; Natalia de Val; Eric D Laing; Christopher C Broder; Jeffrey R Currier; Gregory D Gromowski; Lindsay Wieczorek; Morgane Rolland; Dominic Paquin-Proulx; Dewald van Dyk; Zachary Britton; Saravanan Rajan; Yueh Ming Loo; Patrick M McTamney; Mark T Esser; Victoria R Polonis; Nelson L Michael; Shelly J Krebs; Kayvon Modjarrad; M Gordon Joyce

doi:10.1016/j.str.2023.11.015

Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain

Structure. 2024 Feb 1;32(2):131-147.e7. doi: 10.1016/j.str.2023.11.015. Epub 2023 Dec 28.

Authors

Rajeshwer S Sankhala¹, Vincent Dussupt², Wei-Hung Chen¹, Hongjun Bai², Elizabeth J Martinez¹, Jaime L Jensen¹, Phyllis A Rees¹, Agnes Hajduczki¹, William C Chang¹, Misook Choe¹, Lianying Yan³, Spencer L Sterling³, Isabella Swafford⁴, Caitlin Kuklis⁵, Sandrine Soman⁵, Jocelyn King⁵, Courtney Corbitt⁵, Michelle Zemil⁴, Caroline E Peterson¹, Letzibeth Mendez-Rivera⁴, Samantha M Townsley⁴, Gina C Donofrio⁴, Kerri G Lal², Ursula Tran⁴, Ethan C Green³, Clayton Smith⁶, Natalia de Val⁶, Eric D Laing³, Christopher C Broder³, Jeffrey R Currier⁵, Gregory D Gromowski⁵, Lindsay Wieczorek⁴, Morgane Rolland², Dominic Paquin-Proulx⁴, Dewald van Dyk⁷, Zachary Britton⁷, Saravanan Rajan⁷, Yueh Ming Loo⁸, Patrick M McTamney⁸, Mark T Esser⁸, Victoria R Polonis⁹, Nelson L Michael¹⁰, Shelly J Krebs¹¹, Kayvon Modjarrad¹², M Gordon Joyce¹³

Affiliations

¹ Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
² Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
³ Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD, USA.
⁴ U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
⁵ Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁶ Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA; Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA.
⁷ Antibody Discovery and Protein Engineering (ADPE), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
⁸ Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
⁹ U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
¹⁰ Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
¹¹ Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA. Electronic address: skrebs@hivresearch.org.
¹² Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
¹³ Emerging Infectious Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA. Electronic address: gjoyce@eidresearch.org.

PMID: 38157856
DOI: 10.1016/j.str.2023.11.015

Abstract

Given the continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs), immunotherapeutics that target conserved epitopes on the spike (S) glycoprotein have therapeutic advantages. Here, we report the crystal structure of the SARS-CoV-2 S receptor-binding domain (RBD) at 1.95 Å and describe flexibility and distinct conformations of the angiotensin-converting enzyme 2 (ACE2)-binding site. We identify a set of SARS-CoV-2-reactive monoclonal antibodies (mAbs) with broad RBD cross-reactivity including SARS-CoV-2 Omicron subvariants, SARS-CoV-1, and other sarbecoviruses and determine the crystal structures of mAb-RBD complexes with Ab246 and CR3022 mAbs targeting the class IV site, WRAIR-2134, which binds the recently designated class V epitope, and WRAIR-2123, the class I ACE2-binding site. The broad reactivity of class IV and V mAbs to conserved regions of SARS-CoV-2 VoCs and other sarbecovirus provides a framework for long-term immunotherapeutic development strategies.

MeSH terms

Angiotensin-Converting Enzyme 2 / metabolism
Antibodies, Neutralizing / chemistry
Antibodies, Viral / chemistry
Binding Sites
COVID-19*
Epitopes
Humans
SARS-CoV-2* / metabolism

Substances

Angiotensin-Converting Enzyme 2
Antibodies, Neutralizing
Antibodies, Viral
Epitopes