A broadly neutralizing monoclonal antibody overcomes the mutational landscape of emerging SARS-CoV-2 variants of concern

Hilal Ahmad Parray; Naveen Narayanan; Sonal Garg; Zaigham Abbas Rizvi; Tripti Shrivastava; Sachin Kushwaha; Janmejay Singh; Praveenkumar Murugavelu; Anbalagan Anantharaj; Farha Mehdi; Nisha Raj; Shivam Singh; Jyotsna Dandotiya; Asha Lukose; Deepti Jamwal; Sandeep Kumar; Adarsh K Chiranjivi; Samridhi Dhyani; Nitesh Mishra; Sanjeev Kumar; Kamini Jakhar; Sudipta Sonar; Anil Kumar Panchal; Manas Ranjan Tripathy; Shirlie Roy Chowdhury; Shubbir Ahmed; Sweety Samal; Shailendra Mani; Sankar Bhattacharyya; Supratik Das; Subrata Sinha; Kalpana Luthra; Gaurav Batra; Devinder Sehgal; Guruprasad R Medigeshi; Chandresh Sharma; Amit Awasthi; Pramod Kumar Garg; Deepak T Nair; Rajesh Kumar

doi:10.1371/journal.ppat.1010994

A broadly neutralizing monoclonal antibody overcomes the mutational landscape of emerging SARS-CoV-2 variants of concern

PLoS Pathog. 2022 Dec 12;18(12):e1010994. doi: 10.1371/journal.ppat.1010994. eCollection 2022 Dec.

Authors

Hilal Ahmad Parray¹, Naveen Narayanan², Sonal Garg¹, Zaigham Abbas Rizvi¹, Tripti Shrivastava¹, Sachin Kushwaha³, Janmejay Singh¹, Praveenkumar Murugavelu¹, Anbalagan Anantharaj¹, Farha Mehdi¹, Nisha Raj¹, Shivam Singh¹, Jyotsna Dandotiya¹, Asha Lukose¹, Deepti Jamwal¹, Sandeep Kumar¹, Adarsh K Chiranjivi¹, Samridhi Dhyani¹, Nitesh Mishra⁴, Sanjeev Kumar⁵, Kamini Jakhar¹, Sudipta Sonar¹, Anil Kumar Panchal¹, Manas Ranjan Tripathy¹, Shirlie Roy Chowdhury¹, Shubbir Ahmed¹, Sweety Samal¹, Shailendra Mani¹, Sankar Bhattacharyya¹, Supratik Das¹, Subrata Sinha⁴, Kalpana Luthra⁴, Gaurav Batra¹, Devinder Sehgal³, Guruprasad R Medigeshi¹, Chandresh Sharma¹, Amit Awasthi¹, Pramod Kumar Garg¹, Deepak T Nair², Rajesh Kumar¹

Affiliations

¹ Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India.
² Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India.
³ National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
⁴ Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
⁵ ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.

Abstract

The emergence of new variants of SARS-CoV-2 necessitates unremitting efforts to discover novel therapeutic monoclonal antibodies (mAbs). Here, we report an extremely potent mAb named P4A2 that can neutralize all the circulating variants of concern (VOCs) with high efficiency, including the highly transmissible Omicron. The crystal structure of the P4A2 Fab:RBD complex revealed that the residues of the RBD that interact with P4A2 are a part of the ACE2-receptor-binding motif and are not mutated in any of the VOCs. The pan coronavirus pseudotyped neutralization assay confirmed that the P4A2 mAb is specific for SARS-CoV-2 and its VOCs. Passive administration of P4A2 to K18-hACE2 transgenic mice conferred protection, both prophylactically and therapeutically, against challenge with VOCs. Overall, our data shows that, the P4A2 mAb has immense therapeutic potential to neutralize the current circulating VOCs. Due to the overlap between the P4A2 epitope and ACE2 binding site on spike-RBD, P4A2 may also be highly effective against a number of future variants.

Copyright: © 2022 Parray et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2* / chemistry
Animals
Antibodies, Monoclonal / therapeutic use
Antibodies, Neutralizing* / therapeutic use
Antibodies, Viral / therapeutic use
COVID-19* / immunology
COVID-19* / therapy
Humans
Mice
Mice, Transgenic
Neutralization Tests
SARS-CoV-2* / genetics
SARS-CoV-2* / immunology
Spike Glycoprotein, Coronavirus / genetics

Substances

Angiotensin-Converting Enzyme 2
Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Supplementary concepts

SARS-CoV-2 variants

Grants and funding

The work for isolation and characterization of mAbs was supported by the Translational Health Science and Technology Institute Intramural grant (Grant No. THSTI-T001 to RK) and GIISER South Asia grant from Bill and Melinda Gates Foundation, Seattle, USA (Grant No. Investment INV-030592 to PKG). Intramural funds from the Regional Centre for Biotechnology (RCB) were utilized for structural work in this study (Grant No. RCB- C01001 to DTN). THSTI and RCB are funded by the Department of Biotechnology, Ministry of Science and Technology, Government of India. Data collection at the ESRF was supported by the ESRF Access Program of the Department of Biotechnology (Grant No. BT/PR36150/INF/22/214/2020). Animal studies work was supported by financial support from BIRAC (Grant No. BT/CS0054/05/21 to AA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.