2022 / 04

DOI: 10.47183/mes.2022.049

ORIGINAL RESEARCH

Neutralizing antibody creation technologies: case of SARS-CoV-2

Baklaushev VP1,2,3, Samoilova EM1,2, Kuznetsova SM1, Ermolaeva EV2, Yusubalieva GM1,2, Kalsin VA1,2, Lipatova AV2, Troitsky AV1
About authors

1 Federal Scientific and Clinical Center of Specialized Types of Medical Care and Medical Technologies, Federal Medical Biological Agency of Russia, Moscow, Russia

2 Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia

3 Research Institute of Pulmonology, Federal Medical Biological Agency of Russia, Moscow, Russia

Correspondence should be addressed: Vladimir P. Baklaushev
Orexovyj bul'var, 28, g. Moscow, 115682, Russia; ur.abmf-cknf@pv.vehsualkab

About paper

Funding: the study was supported financially by the Ministry of Science and Higher Education of the Russian Federation (contract #075-15-2021-1086, contract #RF----193021X0015, 15.IP.21.0015).

Received: 2022-11-29 Accepted: 2022-12-20 Published online: 2022-12-30
|
  1. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975; 256 (5517): 495–7.
  2. Frenzel A, Kügler J, Helmsing S, Meier D, Schirrmann T, Hust M, et al. Designing human antibodies by phage display. Transfus Med Hemother. 2017; 44 (5): 312–8.
  3. Emmons C, Hunsicker LG. Muromonab-CD3 (Orthoclone OKT3): the first monoclonal antibody approved for therapeutic use. Iowa Med. 1987; 77 (2): 78–82.
  4. Presta LG. Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv Drug Deliv Rev. 2006; 58: 640–56.
  5. Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science. 1985; 228: 1315–7.
  6. McCafferty J, Griffiths AD, Winter G, Chiswell DJ. Phage antibodies: filamentous phage displaying antibody variable domains. Nature. 1990; 348 (6301): 552–4.
  7. Ledsgaard L, Ljungars A, Rimbault C, Sørensen CV, Tulika T, Wade J, et al. Advances in antibody phage display technology. Drug Discov. Today. 2022; 27 (8): 2151–69.
  8. Gorchakov AA, Kulemzin SV, Guselnikov SV, Baranov KO, Belovezhets TN, Mechetina LV, et al. Isolation of a panel of ultrapotent human antibodies neutralizing SARS-CoV-2 and viral variants of concern. Cell Discov. 2021; 7 (1): 96.
  9. Baklaushev VP, Kulemzin SV, Gorchakov АА, Lesnyak VN, Yusubalieva GM, Sotnikova AG. COVID-19. Aetiology, pathogenesis, diagnosis and treatment. Journal of Clinical Practice. 2020; 11 (1): 7–20.
  10. Coronavirus disease (COVID-19) pandemic. World Health Organization. 2021. Available from: https://www.who.int/ emergencies/diseases/novel-coronavirus-2019.
  11. Baklaushev VP, Yusubalieva GM, Bychinin MV, Yusubalieva SM, Kalsin VA, Troickij AV. Racional'naya strategiya podderzhaniya protivovirusnogo immuniteta k novym variantam SARS-CoV-2. Klinicheskaya praktika. 2022; 13 (3): 43–55. Russian.
  12. Synowiec A, Szczepański A, Barreto-Duran E, Lie LK, Pyrc K. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a systemic infection. Clin Microbiol Rev. 2021; 34: e00133–20.
  13. Hoogenboom HR. Overview of antibody phage-display technology and its applications. Methods Mol Biol. 2002; 178: 1–37.
  14. Hanes J, Plückthun A. In vitro selection and evolution of functional proteins by using ribosome display. Proc Natl Acad Sci U S A. 1997; 94 (10): 4937–42.
  15. Boder ET, Wittrup KD. Yeast surface display for screening combinatorial polypeptide libraries. Nat Biotechnol. 1997; 15 (6): 553–7.
  16. Beerli RR, Bauer M, Buser RB, Gwerder M, Muntwiler S, Maurer P, et al. Isolation of human monoclonal antibodies by mammalian cell display. Proc Natl Acad Sci U S A. 2008; 105 (38): 14336–41.
  17. Hoet RM, Cohen EH, Kent RB, Rookey K, Schoonbroodt S, Hogan S, et al. Generation of high-affinity human antibodies by combining donor-derived and synthetic complementarity-determining-region diversity. Nat Biotechnol. 2005; 23: 344–8.
  18. Vaughan TJ, Williams AJ, Pritchard K, Osbourn JK, Pope AR, Earnshaw JC, et al. Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library. Nat Biotechnol. 1996; 14: 309–14.
  19. Chan CE, Chan AH, Lim AP, Hanson BJ. Comparison of the efficiency of antibody selection from semi-synthetic scFv and non-immune Fab phage display libraries against protein targets for rapid development of diagnostic immunoassays. J Immunol Methods. 201; 373 (1–2): 79–88.
  20. Li K, Zettlitz KA, Lipianskaya J, Zhou Y, Marks JD, Mallick P, et al. A fully human scFv phage display library for rapid antibody fragment reformatting. Protein Eng Des Sel. 2015; 28 (10): 307–16.
  21. Burton DR, Pyati J, Koduri R, Sharp SJ, Thornton GB, Parren PW, et al. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science. 1994; 266 (5187): 1024–7.
  22. Maynard JA, Maassen CB, Leppla SH, Brasky K, Patterson JL, Iverson BL, et al. Protection against anthrax toxin by recombinant antibody fragments correlates with antigen affinity. Nat Biotechnol. 2002; 20 (6): 597–601.
  23. Matveev AL, Kozlova IV, Stronin OV, Khlusevich YA, Doroshchenko EK, Baykov IK, et al. Post-exposure administration of chimeric antibody protects mice against European, Siberian, and FarEastern subtypes of tick-borne encephalitis virus. PLoS One. 2019; 14 (4): e0215075.
  24. Ferrara F, Erasmus MF, D'Angelo S, Leal-Lopes C, Teixeira AA, Choudhary A, et al. A pandemic-enabled comparison of discovery platforms demonstrates a naïve antibody library can match the best immune-sourced antibodies. Nat Commun. 2022; 13 (1): 462.
  25. Tillib SV. Perspektivy ispol'zovaniya odnodomennyx antitel v biomedicine. Molekulyarnaya biologiya. 2020; 54 (3): 362–73.
  26. Iezzi ME, Policastro L, Werbajh S, Podhajcer O, Canziani GA. Single-domain antibodies and the promise of modular targeting in cancer imaging and treatment. Front Immunol. 2018; 9: 273.
  27. Vincke C, Loris R, Saerens D, Martinez-Rodriguez S, Muyldermans S, Conrath K. General strategy to humanize a camelid single-domain antibody and identification of a universal humanized nanobody scaffold. J Biol Chem. 2009; 284 (5): 3273–84.
  28. De Genst E, Silence K, Decanniere K, Conrath K, Loris R, Kinne J, et al. Molecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies. Proc Natl Acad Sci U S A. 2006; 103 (12): 4586–91.
  29. Muyldermans S. Applications of nanobodies. Annu Rev Anim Biosci. 2021; 9: 401–21.
  30. Zavrtanik U, Lukan J, Loris R, Lah J, Hadži S. Structural basis of epitope recognition by heavy-chain camelid antibodies. J Mol Biol. 2018; 430 (21): 4369–86.
  31. Schoof M, Faust B, Saunders RA, Sangwan S, Rezelj V, Hoppe N, et al. An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike. Science. 2020; 370 (6523): 1473–9.
  32. Van der Linden RH, Frenken LG, de Geus B, Harmsen MM, Ruuls RC, Stok W, et al. Comparison of physical chemical properties of llama VHH antibody fragments and mouse monoclonal antibodies. Biochim Biophys Acta. 1999; 1431 (1): 37–46.
  33. Jovčevska I, Muyldermans S. The therapeutic potential of nanobodies. BioDrugs. 2020; 34 (1): 11–26.
  34. Muyldermans S. Nanobodies: natural single-domain antibodies. Annu Rev Biochem. 2013; 82: 775–97.
  35. Van Roy M, Ververken C, Beirnaert E, Hoefman S, Kolkman J, Vierboom M, et al. The preclinical pharmacology of the high affinity anti-IL-6R Nanobody® ALX-0061 supports its clinical development in rheumatoid arthritis. Arthritis Res Ther. 2015; 17 (1): 135.
  36. Ishiwatari-Ogata C, Kyuuma M, Ogata H, Yamakawa M, Iwata K, Ochi M, et al. Ozoralizumab, a humanized anti-TNFα NANOBODY® Compound, exhibits efficacy not only at the onset of arthritis in a human TNF transgenic mouse but also during secondary failure of administration of an anti-TNFα IgG. Front Immunol. 2022; 13: 853008.
  37. Van Faassen H, Ryan S, Henry KA, Raphael S, Yang Q, Rossotti MA, et al. Serum albumin-binding VH Hs with variable pH sensitivities enable tailored half-life extension of biologics. FASEB J. 2020; 34 (6): 8155–71.
  38. Saerens D, Ghassabeh GH, Muyldermans S. Single-domain antibodies as building blocks for novel therapeutics. Curr Opin Pharmacol. 2008; 8 (5): 600–8.
  39. Godakova SA, Noskov AN, Vinogradova ID, Ugriumova GA, Solovyev AI, Esmagambetov IB, et al. Camelid VHHs fused to human Fc fragments provide long term protection against botulinum neurotoxin A in mice. Toxins (Basel). 2019; 11 (8): 464.
  40. Günaydın G, Yu S, Gräslund T, Hammarström L, Marcotte H. Fusion of the mouse IgG1 Fc domain to the VHH fragment (ARP1) enhances protection in a mouse model of rotavirus. Sci Rep. 2016; 6: 30171.
  41. Detalle L, Stohr T, Palomo C, Piedra PA, Gilbert BE, Mas V, et al. Generation and characterization of ALX-0171, a potent novel therapeutic nanobody for the treatment of respiratory syncytial virus infection. antimicrob agents chemother. 2015; 60 (1): 6–13.
  42. Stalin Raj V, Okba NMA, Gutierrez-Alvarez J, Drabek D, van Dieren B, Widagdo W, et al. Chimeric camel/human heavy-chain antibodies protect against MERS-CoV infection. Sci Adv. 2018; 4 (8): eaas9667.
  43. Hufton SE, Risley P, Ball CR, Major D, Engelhardt OG, Poole S. The breadth of cross sub-type neutralisation activity of a single domain antibody to influenza hemagglutinin can be increased by antibody valency. PLoS One. 2014; 9 (8): e103294.
  44. Ibañez LI, De Filette M, Hultberg A, Verrips T, Temperton N, Weiss RA, et al. Nanobodies with in vitro neutralizing activity protect mice against H5N1 influenza virus infection. J Infect Dis. 2011; 203 (8): 1063–72.
  45. Laursen NS, Friesen RHE, Zhu X, Jongeneelen M, Blokland S, Vermond J, et al. Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin. Science. 2018; 362 (6414): 598–602
  46. McMahon C, Baier AS, Pascolutti R, Wegrecki M, Zheng S, Ong JX, et al. Yeast surface display platform for rapid discovery of conformationally selective nanobodies. Nat Struct Mol Biol. 2018; 25 (3): 289–96.
  47. Favorskaya IA, Shcheblyakov DV, Esmagambetov IB, Dolzhikova IV, Alekseeva IA, Korobkova AI, et al. Single-Domain Antibodies Efficiently Neutralize SARS-CoV-2 Variants of Concern. Front Immunol. 2022; 13: 822159.
  48. Wrapp D, De Vlieger D, Corbett KS, Torres GM, Wang N, Van Breedam W, et al. Structural basis for potent neutralization of betacoronaviruses by single-domain camelid antibodies. Cell. 2020; 181 (5): 1004–15.e15.
  49. Chen F, Liu Z, Jiang F. Prospects of Neutralizing Nanobodies Against SARS-CoV-2. Front Immunol. 2021; 12: 690742.
  50. Pedrioli, A, Oxenius, A. Single B cell technologies for monoclonal antibody discovery. Trends Immunol. 2021; 42: 1143–58.
  51. Lee EC, Liang Q, Ali H, Bayliss L, Beasley A, Bloomfield-Gerdes T, et al. Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery. Nat Biotechnol. 2014; 32 (4): 356–63.
  52. Gérard A, Woolfe A, Mottet G, Reichen M, Castrillon C, Menrath V, et al. High-throughput single-cell activity-based screening and sequencing of antibodies using droplet microfluidics. Nat Biotechnol. 2020; 38 (6): 715–21.
  53. Scheid JF, Mouquet H, Feldhahn N, Seaman MS, Velinzon K, Pietzsch J, et al. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature. 2009; 458 (7238): 636–40.
  54. McCoy LE, Burton DR. Identification and specificity of broadly neutralizing antibodies against HIV. Immunol Rev. 2017; 275 (1): 11–20.
  55. Macagno A, Bernasconi NL, Vanzetta F, Dander E, Sarasini A, Revello MG, et al. Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex. J Virol. 2010; 84 (2): 1005–13.
  56. Wang Q, Michailidis E, Yu Y, Wang Z, Hurley AM, Oren DA, et al. A combination of human broadly neutralizing antibodies against hepatitis B virus HBsAg with distinct epitopes suppresses escape mutations. Cell Host Microbe. 2020; 28 (2): 335–49.e6.
  57. Hartley GE, Edwards ESJ, Aui PM, Varese N, Stojanovic S, McMahon J, et al. Rapid generation of durable B cell memory to SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 and convalescence. Sci Immunol. 2020; 5 (54): eabf8891.
  58. Hansen J, Baum A, Pascal KE, Russo V, Giordano S, Wloga E, et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science. 2020; 369 (6506): 1010–4.
  59. Brouwer PJM, Caniels TG, van der Straten K, Snitselaar JL, Aldon Y, Bangaru S, et al. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science. 2020; 369 (6504): 643–50.
  60. Zost SJ, Gilchuk P, Case JB, Binshtein E, Chen RE, Nkolola JP, et al. Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature. 2020; 584 (7821): 443–9.
  61. Tanno H, McDaniel JR, Stevens CA, Voss WN, Li J, Durrett R, et al. A facile technology for the high-throughput sequencing of the paired VH:VL and TCRβ:TCRα repertoires. Sci Adv. 2020; 6 (17): eaay9093.
  62. Setliff I, Shiakolas AR, Pilewski KA, Murji AA, Mapengo RE, Janowska K, et al. High-throughput mapping of B cell receptor sequences to antigen specificity. Cell. 2019; 179 (7): 1636–46.e15.
  63. Gupta A, Gonzalez-Rojas Y, Juarez E, Crespo Casal M, Moya J, Falci DR, et al. Early treatment for covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab. N Engl J Med. 2021; 385 (21): 1941–50.
  64. Loo YM, McTamney PM, Arends RH, Abram ME, Aksyuk AA, Diallo S, et al. The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans. Sci Transl Med. 2022; 14 (635): eabl8124.
  65. Vishwakarma P, Vattekatte AM, Shinada N, Diharce J, Martins C, Cadet F, et al. VHH structural modelling approaches: a critical review. Int J Mol Sci. 2022; 23 (7): 3721.
  66. Senior AW, Evans R, Jumper J, Kirkpatrick J, Sifre L, Green T, et al. Improved protein structure prediction using potentials from deep learning. Nature. 2020; 577: 706–10.
  67. Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021; 596 (7873): 583–9.
  68. Schritt D, Li S, Rozewicki J, Katoh K, Yamashita K, Volkmuth W, et al. Repertoire Builder: high-throughput structural modeling of B and T cell receptors. Mol Sys. Des Eng. 2019; 4: 761–8.
  69. Xu Z, Davila A, Wilamowski J, Teraguchi S, Standley DM. Improved antibody-specific epitope prediction using AlphaFold and AbAdapt. Chembiochem. 2022; 23 (18): e202200303.
  70. Abanades B, Georges G, Bujotzek A, Deane CM. ABlooper: fast accurate antibody CDR loop structure prediction with accuracy estimation. Bioinformatics. 2022; 38 (7): 1877–80. DOI: 10.1093/ bioinformatics/btac016.
  71. Ruffolo JA, Sulam J, Gray JJ. Antibody structure prediction using interpretable deep learning. Patterns (NY). 2021; 3 (2): 100406. DOI: 10.1016/j.patter.2021.100406. PMID: 35199061; PMCID: PMC8848015.
  72. Cohen T, Halfon M, Schneidman-Duhovny D. NanoNet: Rapid and accurate end-to-end nanobody modeling by deep learning. Front Immunol. 2022; 13: 958584. DOI: 10.3389/fimmu.2022.958584.
  73. Sun D, Sang Z, Kim YJ, Xiang Y, Cohen T, Belford AK, et al. Potent neutralizing nanobodies resist convergent circulating variants of SARS-CoV-2 by targeting diverse and conserved epitopes. Nat Commun. 2021; 12: 4676.