Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2

Phillip Pymm; Samuel J. Redmond; Olan Dolezal; Francesca Mordant; Ester Lopez; James P. Cooney; Kathryn C. Davidson; Ebene R. Haycroft; Chee Wah Tan; Rebecca Seneviratna; Samantha L. Grimley; Damian F.J. Purcell; Stephen J. Kent; Adam K. Wheatley; Lin Fa Wang; Andrew Leis; Alisa Glukhova; Marc Pellegrini; Amy W. Chung; Kanta Subbarao; Adam P. Uldrich; Wai Hong Tham; Dale I. Godfrey; Nicholas A. Gherardin

doi:10.1016/j.isci.2022.105259

Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2

Phillip Pymm, Samuel J. Redmond, Olan Dolezal, Francesca Mordant, Ester Lopez, James P. Cooney, Kathryn C. Davidson, Ebene R. Haycroft, Chee Wah Tan, Rebecca Seneviratna, Samantha L. Grimley, Damian F.J. Purcell, Stephen J. Kent, Adam K. Wheatley, Lin Fa Wang, Andrew Leis, Alisa Glukhova, Marc Pellegrini, Amy W. Chung, Kanta SubbaraoAdam P. Uldrich, Wai Hong Tham, Dale I. Godfrey^*, Nicholas A. Gherardin^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

7 Citations (Scopus)

Abstract

The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.

Original language	English
Article number	105259
Number of pages	27
Journal	iScience
Volume	25
Issue number	11
DOIs	https://doi.org/10.1016/j.isci.2022.105259
Publication status	Published - 18 Nov 2022
Externally published	Yes

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Pymm, P., Redmond, S. J., Dolezal, O., Mordant, F., Lopez, E., Cooney, J. P., Davidson, K. C., Haycroft, E. R., Tan, C. W., Seneviratna, R., Grimley, S. L., Purcell, D. F. J., Kent, S. J., Wheatley, A. K., Wang, L. F., Leis, A., Glukhova, A., Pellegrini, M., Chung, A. W., ... Gherardin, N. A. (2022). Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2. iScience, 25(11), Article 105259. https://doi.org/10.1016/j.isci.2022.105259

@article{3322ebb29e8f48fca03dc0fa0c91e298,

title = "Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2",

abstract = "The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.",

keywords = "Immunology, microbiology, structural biology",

author = "Phillip Pymm and Redmond, {Samuel J.} and Olan Dolezal and Francesca Mordant and Ester Lopez and Cooney, {James P.} and Davidson, {Kathryn C.} and Haycroft, {Ebene R.} and Tan, {Chee Wah} and Rebecca Seneviratna and Grimley, {Samantha L.} and Purcell, {Damian F.J.} and Kent, {Stephen J.} and Wheatley, {Adam K.} and Wang, {Lin Fa} and Andrew Leis and Alisa Glukhova and Marc Pellegrini and Chung, {Amy W.} and Kanta Subbarao and Uldrich, {Adam P.} and Tham, {Wai Hong} and Godfrey, {Dale I.} and Gherardin, {Nicholas A.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = nov,

day = "18",

doi = "10.1016/j.isci.2022.105259",

language = "English",

volume = "25",

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Pymm, P, Redmond, SJ, Dolezal, O, Mordant, F, Lopez, E, Cooney, JP, Davidson, KC, Haycroft, ER, Tan, CW, Seneviratna, R, Grimley, SL, Purcell, DFJ, Kent, SJ, Wheatley, AK, Wang, LF, Leis, A, Glukhova, A, Pellegrini, M, Chung, AW, Subbarao, K, Uldrich, AP, Tham, WH, Godfrey, DI & Gherardin, NA 2022, 'Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2', iScience, vol. 25, no. 11, 105259. https://doi.org/10.1016/j.isci.2022.105259

TY - JOUR

T1 - Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2

AU - Pymm, Phillip

AU - Redmond, Samuel J.

AU - Dolezal, Olan

AU - Mordant, Francesca

AU - Lopez, Ester

AU - Cooney, James P.

AU - Davidson, Kathryn C.

AU - Haycroft, Ebene R.

AU - Tan, Chee Wah

AU - Seneviratna, Rebecca

AU - Grimley, Samantha L.

AU - Purcell, Damian F.J.

AU - Kent, Stephen J.

AU - Wheatley, Adam K.

AU - Wang, Lin Fa

AU - Leis, Andrew

AU - Glukhova, Alisa

AU - Pellegrini, Marc

AU - Chung, Amy W.

AU - Subbarao, Kanta

AU - Uldrich, Adam P.

AU - Tham, Wai Hong

AU - Godfrey, Dale I.

AU - Gherardin, Nicholas A.

PY - 2022/11/18

Y1 - 2022/11/18

N2 - The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.

AB - The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.

KW - Immunology

KW - microbiology

KW - structural biology

UR - http://www.scopus.com/inward/record.url?scp=85140254512&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2022.105259

DO - 10.1016/j.isci.2022.105259

M3 - Article

AN - SCOPUS:85140254512

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 11

M1 - 105259

ER -

Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2

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