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The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody

Conrad E.Z. Chan, Shirley G.K. Seah, De Hoe Chye, Shane Massey, Maricela Torres, Angeline P.C. Lim, Steven K.K. Wong, Jacklyn J.Y. Neo, Pui San Wong, Jie Hui Lim, Gary S.L. Loh, Dong Ling Wang, Jerome D. Boyd-Kirkup, Siyu Guan, Dipti Thakkar, Guo Hui Teo, Kiren Purushotorman, Paul E. Hutchinson, Barnaby E. Young, David C. Lye, Jenny G. Low, Paul A. MacAry, Hannes Hentze, Venkateshan S. Prativadibhayankara, Kantharaj Ethirajulu, Damian O’Connell, Jason Comer, Chien-Te K. Tseng, Alan D.T. Barrett, Piers J. Ingram, Trevor Brasel, Brendon J. Hanson
doi: https://doi.org/10.1101/2020.10.26.355107
Conrad E.Z. Chan
1Biological Defence Programme, DSO National Laboratories, Singapore
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  • For correspondence: hbrendon@dso.org.sg trbrasel@utmb.edu p.ingram@hummingbirdbio.com cenzuo@dso.org.sg
Shirley G.K. Seah
1Biological Defence Programme, DSO National Laboratories, Singapore
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De Hoe Chye
1Biological Defence Programme, DSO National Laboratories, Singapore
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Shane Massey
2Department of Microbiology & Immunology and Office of Regulated Nonclinical Studies, University of Texas Medical Branch, Galveston, TX, USA
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Maricela Torres
2Department of Microbiology & Immunology and Office of Regulated Nonclinical Studies, University of Texas Medical Branch, Galveston, TX, USA
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Angeline P.C. Lim
1Biological Defence Programme, DSO National Laboratories, Singapore
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Steven K.K. Wong
1Biological Defence Programme, DSO National Laboratories, Singapore
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Jacklyn J.Y. Neo
1Biological Defence Programme, DSO National Laboratories, Singapore
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Pui San Wong
1Biological Defence Programme, DSO National Laboratories, Singapore
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Jie Hui Lim
1Biological Defence Programme, DSO National Laboratories, Singapore
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Gary S.L. Loh
1Biological Defence Programme, DSO National Laboratories, Singapore
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Dong Ling Wang
1Biological Defence Programme, DSO National Laboratories, Singapore
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Jerome D. Boyd-Kirkup
3Hummingbird Bioscience, Singapore
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Siyu Guan
3Hummingbird Bioscience, Singapore
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Dipti Thakkar
3Hummingbird Bioscience, Singapore
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Guo Hui Teo
4Life Science Institute, National University of Singapore, Singapore
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Kiren Purushotorman
4Life Science Institute, National University of Singapore, Singapore
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Paul E. Hutchinson
4Life Science Institute, National University of Singapore, Singapore
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Barnaby E. Young
5National Centre for Infectious Diseases, Singapore
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David C. Lye
5National Centre for Infectious Diseases, Singapore
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Jenny G. Low
6Singapore General Hospital, Singapore
7Programme in Emerging Infectious Disease, Duke-National University of Singapore Medical School
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Paul A. MacAry
8Department of Microbiology & Immunology, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Hannes Hentze
9Experimental Drug Development Centre, Therapeutics Development, A*STAR Research Entities (ARES), Singapore
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Venkateshan S. Prativadibhayankara
9Experimental Drug Development Centre, Therapeutics Development, A*STAR Research Entities (ARES), Singapore
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Kantharaj Ethirajulu
9Experimental Drug Development Centre, Therapeutics Development, A*STAR Research Entities (ARES), Singapore
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Damian O’Connell
9Experimental Drug Development Centre, Therapeutics Development, A*STAR Research Entities (ARES), Singapore
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Jason Comer
2Department of Microbiology & Immunology and Office of Regulated Nonclinical Studies, University of Texas Medical Branch, Galveston, TX, USA
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Chien-Te K. Tseng
10Department of Microbiology & Immunology and Center of Biodefense and Emerging Disease, University of Texas Medical Branch, Galveston, TX, USA
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Alan D.T. Barrett
11Department of Pathology and Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA
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Piers J. Ingram
3Hummingbird Bioscience, Singapore
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  • For correspondence: hbrendon@dso.org.sg trbrasel@utmb.edu p.ingram@hummingbirdbio.com cenzuo@dso.org.sg
Trevor Brasel
2Department of Microbiology & Immunology and Office of Regulated Nonclinical Studies, University of Texas Medical Branch, Galveston, TX, USA
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  • For correspondence: hbrendon@dso.org.sg trbrasel@utmb.edu p.ingram@hummingbirdbio.com cenzuo@dso.org.sg
Brendon J. Hanson
1Biological Defence Programme, DSO National Laboratories, Singapore
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  • For correspondence: hbrendon@dso.org.sg trbrasel@utmb.edu p.ingram@hummingbirdbio.com cenzuo@dso.org.sg
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Abstract

SARS-CoV-2-neutralizing antibodies are promising therapeutics for COVID-19. However, little is known about the mechanisms of action of these antibodies or their effective dosing windows. We report the discovery and development of SC31, a potent SARS-CoV-2 neutralizing IgG1 antibody, originally isolated from a convalescent patient at day 27 after the onset of symptoms. Neutralization occurs via a binding epitope that maps within the ACE2 interface of the SARS-CoV-2 Spike protein, conserved across all common circulating SARS-CoV-2 mutants. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, SC31 demonstrated potent survival benefit by dramatically reducing viral load concomitant with attenuated pro-inflammatory responses linked to severe systemic disease, such as IL-6. Comparison with a Fc-null LALA variant of SC31 demonstrated that optimal therapeutic efficacy of SC31 requires intact Fc-mediated effector functions that can further induce an IFNγ-driven anti-viral immune response. Dose-dependent efficacy for SC31 was observed down to 5mg/kg when dosed before the activation of lung inflammatory responses. Importantly, despite FcγR binding, no evidence of antibody dependent enhancement was observed with the Fc-competent SC31 even at sub-therapeutic doses. Therapeutic efficacy was confirmed in SARS-CoV-2-infected hamsters, where SC31 again significantly reduced viral load, decreased lung lesions and inhibited progression to severe disease manifestations. This study underlines the potential for significant COVID-19 patient benefit for the SC31 antibody that justifies rapid advancement to the clinic, as well as highlighting the importance of appropriate mechanistic and functional studies during development.

One Sentence Summary Anti-SARS-CoV-2 IgG1 antibody SC31 controls infection in vivo by blocking SP:ACE2 binding and triggering a Fc-mediated anti-viral response.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody
Conrad E.Z. Chan, Shirley G.K. Seah, De Hoe Chye, Shane Massey, Maricela Torres, Angeline P.C. Lim, Steven K.K. Wong, Jacklyn J.Y. Neo, Pui San Wong, Jie Hui Lim, Gary S.L. Loh, Dong Ling Wang, Jerome D. Boyd-Kirkup, Siyu Guan, Dipti Thakkar, Guo Hui Teo, Kiren Purushotorman, Paul E. Hutchinson, Barnaby E. Young, David C. Lye, Jenny G. Low, Paul A. MacAry, Hannes Hentze, Venkateshan S. Prativadibhayankara, Kantharaj Ethirajulu, Damian O’Connell, Jason Comer, Chien-Te K. Tseng, Alan D.T. Barrett, Piers J. Ingram, Trevor Brasel, Brendon J. Hanson
bioRxiv 2020.10.26.355107; doi: https://doi.org/10.1101/2020.10.26.355107
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The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody
Conrad E.Z. Chan, Shirley G.K. Seah, De Hoe Chye, Shane Massey, Maricela Torres, Angeline P.C. Lim, Steven K.K. Wong, Jacklyn J.Y. Neo, Pui San Wong, Jie Hui Lim, Gary S.L. Loh, Dong Ling Wang, Jerome D. Boyd-Kirkup, Siyu Guan, Dipti Thakkar, Guo Hui Teo, Kiren Purushotorman, Paul E. Hutchinson, Barnaby E. Young, David C. Lye, Jenny G. Low, Paul A. MacAry, Hannes Hentze, Venkateshan S. Prativadibhayankara, Kantharaj Ethirajulu, Damian O’Connell, Jason Comer, Chien-Te K. Tseng, Alan D.T. Barrett, Piers J. Ingram, Trevor Brasel, Brendon J. Hanson
bioRxiv 2020.10.26.355107; doi: https://doi.org/10.1101/2020.10.26.355107

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