Bispecific Antibodies Provide Broad Neutralization of Emerging Beta-coronaviruses by Targeting ACE2 and Viral Spikes

Overview

Journal Emerg Microbes Infect

Specialty Infectious Diseases

Date 2024 Sep 11

PMID 39258934

Authors

Minghui Li

Chaoyue Zhao

Jialu Shi

Xun Wang

Yuanchen Liu

Xiaoyu Zhao

Guonan Cai

Hin Chu

Pengfei Wang

Affiliations

Soon will be listed here.

Abstract

Human coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2 have recurrently emerged as significant pathogens, causing severe respiratory illnesses and presenting challenges to monoclonal antibody therapeutics due to their rapid evolution, particularly the diverse variants of SARS-CoV-2. In this study, we utilized "Knob-into-Hole" and "IgG-scFv" technologies to engineer bispecific antibodies (bsAbs) that target both the viral receptor and spike protein, enhancing their neutralization breadth and potency. Our bsAbs, combining anti-SARS-CoV-2 or anti-MERS-CoV antibodies with an anti-ACE2 antibody, demonstrated effective neutralization across a range of SARS-CoV-2 variants, SARS-CoV and MERS-CoV in both pseudovirus and authentic virus assays. Notably, the "IgG-scFv" bsAbs format exhibited superior binding and neutralization capabilities compared to the "Knob-into-Hole" configurations. The most effective of these, "IgG-scFv" H11B11_m336, displayed exceptional neutralization potency against a panel of 24 pseudotyped Beta-Coronaviruses, with IC values ranging from 0.001-0.183 μg/mL. Overall, our findings underscore the potential of bsAbs as an effective strategy to meet the immediate challenges posed by existing and emerging pathogens, thereby enhancing global pandemic preparedness.

References

Park Y, De Marco A, Starr T, Liu Z, Pinto D, Walls A . Antibody-mediated broad sarbecovirus neutralization through ACE2 molecular mimicry. Science. 2022; 375(6579):449-454. PMC: 9400459. DOI: 10.1126/science.abm8143. View

Cerutti G, Guo Y, Wang P, Nair M, Wang M, Huang Y . Neutralizing antibody 5-7 defines a distinct site of vulnerability in SARS-CoV-2 spike N-terminal domain. Cell Rep. 2021; 37(5):109928. PMC: 8519878. DOI: 10.1016/j.celrep.2021.109928. View

van der Velden Y, Villaudy J, Rijnstra E, van der Linden C, Vink M, Schermer E . Diverse HIV-1 escape pathways from broadly neutralizing antibody PGDM1400 in humanized mice. MAbs. 2020; 12(1):1845908. PMC: 7755169. DOI: 10.1080/19420862.2020.1845908. View

Westendorf K, Zentelis S, Wang L, Foster D, Vaillancourt P, Wiggin M . LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants. Cell Rep. 2022; 39(7):110812. PMC: 9035363. DOI: 10.1016/j.celrep.2022.110812. View

Tegally H, Moir M, Everatt J, Giovanetti M, Scheepers C, Wilkinson E . Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa. Nat Med. 2022; 28(9):1785-1790. PMC: 9499863. DOI: 10.1038/s41591-022-01911-2. View

Hui D, Zumla A . Severe Acute Respiratory Syndrome: Historical, Epidemiologic, and Clinical Features. Infect Dis Clin North Am. 2019; 33(4):869-889. PMC: 7127569. DOI: 10.1016/j.idc.2019.07.001. View

Ju B, Zhang Q, Ge J, Wang R, Sun J, Ge X . Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature. 2020; 584(7819):115-119. DOI: 10.1038/s41586-020-2380-z. View

Bian H, Zheng Z, Wei D, Wen A, Zhang Z, Lian J . Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial. Signal Transduct Target Ther. 2021; 6(1):194. PMC: 8127508. DOI: 10.1038/s41392-021-00603-6. View

Zost S, Gilchuk P, Case J, Binshtein E, Chen R, Nkolola J . Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature. 2020; 584(7821):443-449. PMC: 7584396. DOI: 10.1038/s41586-020-2548-6. View

10.

Zhao X, Qiu T, Huang X, Mao Q, Wang Y, Qiao R . Potent and broadly neutralizing antibodies against sarbecoviruses induced by sequential COVID-19 vaccination. Cell Discov. 2024; 10(1):14. PMC: 10847457. DOI: 10.1038/s41421-024-00648-1. View

11.

Huang Y, Yu J, Lanzi A, Yao X, Andrews C, Tsai L . Engineered Bispecific Antibodies with Exquisite HIV-1-Neutralizing Activity. Cell. 2016; 165(7):1621-1631. PMC: 4972332. DOI: 10.1016/j.cell.2016.05.024. View

12.

Sun X, Yi C, Zhu Y, Ding L, Xia S, Chen X . Neutralization mechanism of a human antibody with pan-coronavirus reactivity including SARS-CoV-2. Nat Microbiol. 2022; 7(7):1063-1074. DOI: 10.1038/s41564-022-01155-3. View

13.

Radic L, Sliepen K, Yin V, Brinkkemper M, Capella-Pujol J, Schriek A . Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses. iScience. 2023; 26(4):106540. PMC: 10065043. DOI: 10.1016/j.isci.2023.106540. View

14.

Wang Y, Zhang X, Ma Y, Wang Y, Zhan W, Zheng Q . Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies. Cell Discov. 2022; 8(1):104. PMC: 9540141. DOI: 10.1038/s41421-022-00463-6. View

15.

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

16.

Low J, Jerak J, Tortorici M, McCallum M, Pinto D, Cassotta A . ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies. Science. 2022; 377(6607):735-742. PMC: 9348755. DOI: 10.1126/science.abq2679. View

17.

John O, Olabode O, Lucero-Prisno Iii D, Adebimpe O, Singh A . XBB.1.16 Omicron subvariant rise to a variant of interest: Implications for global alertness and preparedness. J Taibah Univ Med Sci. 2023; 18(6):1285-1287. PMC: 10203986. DOI: 10.1016/j.jtumed.2023.05.013. View

18.

Pinto D, Park Y, Beltramello M, Walls A, Tortorici M, Bianchi S . Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody. Nature. 2020; 583(7815):290-295. DOI: 10.1038/s41586-020-2349-y. View

19.

Caskey M, Klein F, Lorenzi J, Seaman M, West Jr A, Buckley N . Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015; 522(7557):487-91. PMC: 4890714. DOI: 10.1038/nature14411. View

20.

Zhou P, Yuan M, Song G, Beutler N, Shaabani N, Huang D . A human antibody reveals a conserved site on beta-coronavirus spike proteins and confers protection against SARS-CoV-2 infection. Sci Transl Med. 2022; 14(637):eabi9215. PMC: 8939767. DOI: 10.1126/scitranslmed.abi9215. View