Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity

Wei Hung Chen; Agnes Hajduczki; Elizabeth J. Martinez; Hongjun Bai; Hanover Matz; Thomas M. Hill; Eric Lewitus; William C. Chang; Layla Dawit; Caroline E. Peterson; Phyllis A. Rees; Adelola B. Ajayi; Emily S. Golub; Isabella Swafford; Vincent Dussupt; Sapna David; Sandra V. Mayer; Sandrine Soman; Caitlin Kuklis; Courtney Corbitt; Jocelyn King; Misook Choe; Rajeshwer S. Sankhala; Paul V. Thomas; Michelle Zemil; Lindsay Wieczorek; Tricia Hart; Debora Duso; Larry Kummer; Lianying Yan; Spencer L. Sterling; Eric D. Laing; Christopher C. Broder; Jazmean K. Williams; Edgar Davidson; Benjamin J. Doranz; Shelly J. Krebs; Victoria R. Polonis; Dominic Paquin-Proulx; Morgane Rolland; William W. Reiley; Gregory D. Gromowski; Kayvon Modjarrad; Helen Dooley; M. Gordon Joyce

doi:10.1038/s41467-023-36106-x

Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity

Wei Hung Chen, Agnes Hajduczki, Elizabeth J. Martinez, Hongjun Bai, Hanover Matz, Thomas M. Hill, Eric Lewitus, William C. Chang, Layla Dawit, Caroline E. Peterson, Phyllis A. Rees, Adelola B. Ajayi, Emily S. Golub, Isabella Swafford, Vincent Dussupt, Sapna David, Sandra V. Mayer, Sandrine Soman, Caitlin Kuklis, Courtney CorbittJocelyn King, Misook Choe, Rajeshwer S. Sankhala, Paul V. Thomas, Michelle Zemil, Lindsay Wieczorek, Tricia Hart, Debora Duso, Larry Kummer, Lianying Yan, Spencer L. Sterling, Eric D. Laing, Christopher C. Broder, Jazmean K. Williams, Edgar Davidson, Benjamin J. Doranz, Shelly J. Krebs, Victoria R. Polonis, Dominic Paquin-Proulx, Morgane Rolland, William W. Reiley, Gregory D. Gromowski, Kayvon Modjarrad, Helen Dooley^*, M. Gordon Joyce^*

^*Corresponding author for this work

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

26 Scopus citations

Abstract

Despite rapid and ongoing vaccine and therapeutic development, SARS-CoV-2 continues to evolve and evade, presenting a need for next-generation diverse therapeutic modalities. Here we show that nurse sharks immunized with SARS-CoV-2 recombinant receptor binding domain (RBD), RBD-ferritin (RFN), or spike protein ferritin nanoparticle (SpFN) immunogens elicit a set of new antigen receptor antibody (IgNAR) molecules that target two non-overlapping conserved epitopes on the spike RBD. Representative shark antibody variable NAR-Fc chimeras (ShAbs) targeting either of the two epitopes mediate cell-effector functions, with high affinity to all SARS-CoV-2 viral variants of concern, including the divergent Omicron strains. The ShAbs potently cross-neutralize SARS-CoV-2 WA-1, Alpha, Beta, Delta, Omicron BA.1 and BA.5, and SARS-CoV-1 pseudoviruses, and confer protection against SARS-CoV-2 challenge in the K18-hACE2 transgenic mouse model. Structural definition of the RBD-ShAb01-ShAb02 complex enabled design and production of multi-specific nanobodies with enhanced neutralization capacity, and picomolar affinity to divergent sarbecovirus clade 1a, 1b and 2 RBD molecules. These shark nanobodies represent potent immunotherapeutics both for current use, and future sarbecovirus pandemic preparation.

Original language	English
Article number	580
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-36106-x
State	Published - Dec 2023
Externally published	Yes

Access to Document

10.1038/s41467-023-36106-x

Cite this

Chen, W. H., Hajduczki, A., Martinez, E. J., Bai, H., Matz, H., Hill, T. M., Lewitus, E., Chang, W. C., Dawit, L., Peterson, C. E., Rees, P. A., Ajayi, A. B., Golub, E. S., Swafford, I., Dussupt, V., David, S., Mayer, S. V., Soman, S., Kuklis, C., ... Joyce, M. G. (2023). Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity. Nature Communications, 14(1), Article 580. https://doi.org/10.1038/s41467-023-36106-x

@article{1bceef15100e438c8d8abd131cac0393,

title = "Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity",

abstract = "Despite rapid and ongoing vaccine and therapeutic development, SARS-CoV-2 continues to evolve and evade, presenting a need for next-generation diverse therapeutic modalities. Here we show that nurse sharks immunized with SARS-CoV-2 recombinant receptor binding domain (RBD), RBD-ferritin (RFN), or spike protein ferritin nanoparticle (SpFN) immunogens elicit a set of new antigen receptor antibody (IgNAR) molecules that target two non-overlapping conserved epitopes on the spike RBD. Representative shark antibody variable NAR-Fc chimeras (ShAbs) targeting either of the two epitopes mediate cell-effector functions, with high affinity to all SARS-CoV-2 viral variants of concern, including the divergent Omicron strains. The ShAbs potently cross-neutralize SARS-CoV-2 WA-1, Alpha, Beta, Delta, Omicron BA.1 and BA.5, and SARS-CoV-1 pseudoviruses, and confer protection against SARS-CoV-2 challenge in the K18-hACE2 transgenic mouse model. Structural definition of the RBD-ShAb01-ShAb02 complex enabled design and production of multi-specific nanobodies with enhanced neutralization capacity, and picomolar affinity to divergent sarbecovirus clade 1a, 1b and 2 RBD molecules. These shark nanobodies represent potent immunotherapeutics both for current use, and future sarbecovirus pandemic preparation.",

author = "Chen, {Wei Hung} and Agnes Hajduczki and Martinez, {Elizabeth J.} and Hongjun Bai and Hanover Matz and Hill, {Thomas M.} and Eric Lewitus and Chang, {William C.} and Layla Dawit and Peterson, {Caroline E.} and Rees, {Phyllis A.} and Ajayi, {Adelola B.} and Golub, {Emily S.} and Isabella Swafford and Vincent Dussupt and Sapna David and Mayer, {Sandra V.} and Sandrine Soman and Caitlin Kuklis and Courtney Corbitt and Jocelyn King and Misook Choe and Sankhala, {Rajeshwer S.} and Thomas, {Paul V.} and Michelle Zemil and Lindsay Wieczorek and Tricia Hart and Debora Duso and Larry Kummer and Lianying Yan and Sterling, {Spencer L.} and Laing, {Eric D.} and Broder, {Christopher C.} and Williams, {Jazmean K.} and Edgar Davidson and Doranz, {Benjamin J.} and Krebs, {Shelly J.} and Polonis, {Victoria R.} and Dominic Paquin-Proulx and Morgane Rolland and Reiley, {William W.} and Gromowski, {Gregory D.} and Kayvon Modjarrad and Helen Dooley and Joyce, {M. Gordon}",

note = "Publisher Copyright: {\textcopyright} 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-36106-x",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

number = "1",

}

Chen, WH, Hajduczki, A, Martinez, EJ, Bai, H, Matz, H, Hill, TM, Lewitus, E, Chang, WC, Dawit, L, Peterson, CE, Rees, PA, Ajayi, AB, Golub, ES, Swafford, I, Dussupt, V, David, S, Mayer, SV, Soman, S, Kuklis, C, Corbitt, C, King, J, Choe, M, Sankhala, RS, Thomas, PV, Zemil, M, Wieczorek, L, Hart, T, Duso, D, Kummer, L, Yan, L, Sterling, SL, Laing, ED , Broder, CC, Williams, JK, Davidson, E, Doranz, BJ, Krebs, SJ, Polonis, VR, Paquin-Proulx, D, Rolland, M, Reiley, WW, Gromowski, GD, Modjarrad, K, Dooley, H & Joyce, MG 2023, 'Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity', Nature Communications, vol. 14, no. 1, 580. https://doi.org/10.1038/s41467-023-36106-x

TY - JOUR

T1 - Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity

AU - Chen, Wei Hung

AU - Hajduczki, Agnes

AU - Martinez, Elizabeth J.

AU - Bai, Hongjun

AU - Matz, Hanover

AU - Hill, Thomas M.

AU - Lewitus, Eric

AU - Chang, William C.

AU - Dawit, Layla

AU - Peterson, Caroline E.

AU - Rees, Phyllis A.

AU - Ajayi, Adelola B.

AU - Golub, Emily S.

AU - Swafford, Isabella

AU - Dussupt, Vincent

AU - David, Sapna

AU - Mayer, Sandra V.

AU - Soman, Sandrine

AU - Kuklis, Caitlin

AU - Corbitt, Courtney

AU - King, Jocelyn

AU - Choe, Misook

AU - Sankhala, Rajeshwer S.

AU - Thomas, Paul V.

AU - Zemil, Michelle

AU - Wieczorek, Lindsay

AU - Hart, Tricia

AU - Duso, Debora

AU - Kummer, Larry

AU - Yan, Lianying

AU - Sterling, Spencer L.

AU - Laing, Eric D.

AU - Broder, Christopher C.

AU - Williams, Jazmean K.

AU - Davidson, Edgar

AU - Doranz, Benjamin J.

AU - Krebs, Shelly J.

AU - Polonis, Victoria R.

AU - Paquin-Proulx, Dominic

AU - Rolland, Morgane

AU - Reiley, William W.

AU - Gromowski, Gregory D.

AU - Modjarrad, Kayvon

AU - Dooley, Helen

AU - Joyce, M. Gordon

PY - 2023/12

Y1 - 2023/12

N2 - Despite rapid and ongoing vaccine and therapeutic development, SARS-CoV-2 continues to evolve and evade, presenting a need for next-generation diverse therapeutic modalities. Here we show that nurse sharks immunized with SARS-CoV-2 recombinant receptor binding domain (RBD), RBD-ferritin (RFN), or spike protein ferritin nanoparticle (SpFN) immunogens elicit a set of new antigen receptor antibody (IgNAR) molecules that target two non-overlapping conserved epitopes on the spike RBD. Representative shark antibody variable NAR-Fc chimeras (ShAbs) targeting either of the two epitopes mediate cell-effector functions, with high affinity to all SARS-CoV-2 viral variants of concern, including the divergent Omicron strains. The ShAbs potently cross-neutralize SARS-CoV-2 WA-1, Alpha, Beta, Delta, Omicron BA.1 and BA.5, and SARS-CoV-1 pseudoviruses, and confer protection against SARS-CoV-2 challenge in the K18-hACE2 transgenic mouse model. Structural definition of the RBD-ShAb01-ShAb02 complex enabled design and production of multi-specific nanobodies with enhanced neutralization capacity, and picomolar affinity to divergent sarbecovirus clade 1a, 1b and 2 RBD molecules. These shark nanobodies represent potent immunotherapeutics both for current use, and future sarbecovirus pandemic preparation.

AB - Despite rapid and ongoing vaccine and therapeutic development, SARS-CoV-2 continues to evolve and evade, presenting a need for next-generation diverse therapeutic modalities. Here we show that nurse sharks immunized with SARS-CoV-2 recombinant receptor binding domain (RBD), RBD-ferritin (RFN), or spike protein ferritin nanoparticle (SpFN) immunogens elicit a set of new antigen receptor antibody (IgNAR) molecules that target two non-overlapping conserved epitopes on the spike RBD. Representative shark antibody variable NAR-Fc chimeras (ShAbs) targeting either of the two epitopes mediate cell-effector functions, with high affinity to all SARS-CoV-2 viral variants of concern, including the divergent Omicron strains. The ShAbs potently cross-neutralize SARS-CoV-2 WA-1, Alpha, Beta, Delta, Omicron BA.1 and BA.5, and SARS-CoV-1 pseudoviruses, and confer protection against SARS-CoV-2 challenge in the K18-hACE2 transgenic mouse model. Structural definition of the RBD-ShAb01-ShAb02 complex enabled design and production of multi-specific nanobodies with enhanced neutralization capacity, and picomolar affinity to divergent sarbecovirus clade 1a, 1b and 2 RBD molecules. These shark nanobodies represent potent immunotherapeutics both for current use, and future sarbecovirus pandemic preparation.

UR - http://www.scopus.com/inward/record.url?scp=85147452625&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-36106-x

DO - 10.1038/s41467-023-36106-x

M3 - Article

C2 - 36737435

AN - SCOPUS:85147452625

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 580

ER -