Unleashing the Power of Shark Variable Single Domains (VNARs): Broadly Neutralizing Tools for Combating SARS-CoV-2

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2023 Sep 27

PMID 37753081

Authors

Olivia Cabanillas-Bernal

Blanca J Valdovinos-Navarro

Karla E Cervantes-Luevano

Noemi Sanchez-Campos

Alexei F Licea-Navarro

Affiliations

Soon will be listed here.

Abstract

The pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated a joint global effort to develop vaccines and other treatments that could mitigate the negative effects and the rapid spread of the virus. Single-domain antibodies derived from various sources, including cartilaginous fish, camelids, and humans, have gained attention as promising therapeutic tools against coronavirus disease 2019. Shark-derived variable new antigen receptors (VNARs) have emerged as the smallest naturally occurring antigen-binding molecules. Here, we compile and review recent published studies on VNARs with the capacity to recognize and/or neutralize SARS-CoV-2. We found a close balance between the use of natural immune libraries and synthetic VNAR libraries for the screening against SARS-CoV-2, with phage display being the preferred display technology for the selection of VNARs against this virus. In addition, we discuss potential modifications and engineering strategies employed to improve the neutralization potential of VNARs, such as exploring fusion with the Fc domain of human Immunoglobulin G (IgG) to increase avidity and therapeutic potential. This research highlights the potential of VNARs as powerful molecular tools in the fight against infectious diseases.

References

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H . Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020; 395(10224):565-574. PMC: 7159086. DOI: 10.1016/S0140-6736(20)30251-8. View

Wei L, Wang M, Xiang H, Jiang Y, Gong J, Su D . Bamboo Shark as a Small Animal Model for Single Domain Antibody Production. Front Bioeng Biotechnol. 2021; 9:792111. PMC: 8692893. DOI: 10.3389/fbioe.2021.792111. View

Zielonka S, Weber N, Becker S, Doerner A, Christmann A, Christmann C . Shark Attack: high affinity binding proteins derived from shark vNAR domains by stepwise in vitro affinity maturation. J Biotechnol. 2014; 191:236-45. DOI: 10.1016/j.jbiotec.2014.04.023. View

Steven J, Muller M, Carvalho M, Ubah O, Kovaleva M, Donohoe G . Maturation of a Humanized Shark VNAR Domain to Improve Its Biophysical Properties to Facilitate Clinical Development. Front Immunol. 2017; 8:1361. PMC: 5660122. DOI: 10.3389/fimmu.2017.01361. View

Dooley H, Stanfield R, Brady R, Flajnik M . First molecular and biochemical analysis of in vivo affinity maturation in an ectothermic vertebrate. Proc Natl Acad Sci U S A. 2006; 103(6):1846-51. PMC: 1413636. DOI: 10.1073/pnas.0508341103. View

Tortorici M, Beltramello M, Lempp F, Pinto D, Dang H, Rosen L . Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms. Science. 2020; 370(6519):950-957. PMC: 7857395. DOI: 10.1126/science.abe3354. View

Duenas S, Escalante T, Gasperin-Bulbarela J, Bernaldez-Sarabia J, Cervantes-Luevano K, Jimenez S . Chimeric Peptides from and with Antigen-Binding Capacity: A Conotoxin Scaffold to Create Non-Natural Antibodies (NoNaBodies). Toxins (Basel). 2023; 15(4). PMC: 10141372. DOI: 10.3390/toxins15040269. View

Feng B, Chen Z, Sun J, Xu T, Wang Q, Yi H . A Class of Shark-Derived Single-Domain Antibodies can Broadly Neutralize SARS-Related Coronaviruses and the Structural Basis of Neutralization and Omicron Escape. Small Methods. 2022; 6(7):e2200387. PMC: 9347709. DOI: 10.1002/smtd.202200387. View

Schoof M, Faust B, Saunders R, Sangwan S, Rezelj V, Hoppe N . An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike. Science. 2020; 370(6523):1473-1479. PMC: 7857409. DOI: 10.1126/science.abe3255. View

10.

Terry J, Anderson L, Scherman M, McAlister C, Perera R, Schountz T . Development of a SARS-CoV-2 nucleocapsid specific monoclonal antibody. Virology. 2021; 558:28-37. PMC: 7849420. DOI: 10.1016/j.virol.2021.01.003. View

11.

HAMERS-CASTERMAN C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, Songa E . Naturally occurring antibodies devoid of light chains. Nature. 1993; 363(6428):446-8. DOI: 10.1038/363446a0. View

12.

Chakraborty C, Sharma A, Bhattacharya M, Agoramoorthy G, Lee S . The Drug Repurposing for COVID-19 Clinical Trials Provide Very Effective Therapeutic Combinations: Lessons Learned From Major Clinical Studies. Front Pharmacol. 2021; 12:704205. PMC: 8636940. DOI: 10.3389/fphar.2021.704205. View

13.

Sadoff J, Gray G, Vandebosch A, Cardenas V, Shukarev G, Grinsztejn B . Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N Engl J Med. 2021; 384(23):2187-2201. PMC: 8220996. DOI: 10.1056/NEJMoa2101544. View

14.

Jankowitz R, Joyce J, Jacobs S . Anaphylaxis after administration of ibritumomab tiuxetan for follicular non-hodgkin lymphoma. Clin Nucl Med. 2008; 33(2):94-6. DOI: 10.1097/RLU.0b013e31815ef825. View

15.

Roux K, Greenberg A, Greene L, Strelets L, Avila D, McKinney E . Structural analysis of the nurse shark (new) antigen receptor (NAR): molecular convergence of NAR and unusual mammalian immunoglobulins. Proc Natl Acad Sci U S A. 1998; 95(20):11804-9. PMC: 21721. DOI: 10.1073/pnas.95.20.11804. View

16.

Camacho-Villegas T, Mata-Gonzalez M, Garcia-Ubbelohd W, Nunez-Garcia L, Elosua C, Paniagua-Solis J . Intraocular Penetration of a vNAR: In Vivo and In Vitro VEGF Neutralization. Mar Drugs. 2018; 16(4). PMC: 5923400. DOI: 10.3390/md16040113. View

17.

Matz H, Dooley H . Shark IgNAR-derived binding domains as potential diagnostic and therapeutic agents. Dev Comp Immunol. 2018; 90:100-107. DOI: 10.1016/j.dci.2018.09.007. View

18.

Liu L, Wang P, Nair M, Yu J, Rapp M, Wang Q . Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature. 2020; 584(7821):450-456. DOI: 10.1038/s41586-020-2571-7. View

19.

DeNardo G, Bradt B, Mirick G, DeNardo S . Human antiglobulin response to foreign antibodies: therapeutic benefit?. Cancer Immunol Immunother. 2003; 52(5):309-16. PMC: 11034264. DOI: 10.1007/s00262-002-0350-y. View

20.

Fernandez-Quintero M, Fischer A, Kokot J, Waibl F, Seidler C, Liedl K . The influence of antibody humanization on shark variable domain (VNAR) binding site ensembles. Front Immunol. 2022; 13:953917. PMC: 9514858. DOI: 10.3389/fimmu.2022.953917. View