Skip to main content
Log in

Molecular engineering of nanobodies as tools in allergology: diagnostics and beyond

  • review
  • Published:
Allergo Journal International Aims and scope Submit manuscript

Summary

Background

Molecular technologies have paved the way to improved understanding of allergic diseases in many ways, ranging from molecular allergens to tailor-made tools for analytical, diagnostic, and therapeutic purposes. Engineering of such molecules has become a mainstay in most biotechnical and biomedical areas. A not so new kid on the block is the nanobody, a single-domain antibody obtained from primarily camelid species. Despite their large promise and potential, it took nanobodies a long time to also enter the stage in allergology.

Methods

This review summarizes the state of the art and the feasibility of engineering nanobody-based tools for applications in allergology.

Results

In recent years, nanobodies with specificity for allergens have been increasingly generated. In parallel, their molecular engineering has enabled the development of derivatives that offer many advantages compared to standard antibody approaches. Hence, different application forms of nanobody-based molecules have been developed and reported in proof-of-concept studies.

Discussion

Recent studies give a first glimpse of the future possibilities of nanobody technologies in a complex system such as allergic diseases. It has become clear that the simplicity of the approaches as compared to regular antibody technologies will both broaden and deepen the scope of applications in allergology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AIT:

allergen immunotherapy

BAT:

basophil activation test

CCD:

cross-reactive carbohydrate determinants

CDR:

complementarity-determining region

HBV:

honeybee venom

HCAbs:

heavy chain-only antibodies

HEK:

human embryonic kidney

HSA:

human serum albumin

IgE:

immunoglobulin E

MAT:

mast cell activation test

nb-hIgE:

nanobody-based human IgE

PTM:

post-translational modification

RSV:

respiratory syncytial virus

scFv:

single-chain antibody fragment

sdabs:

single-domain antibodies

sIgE:

specific IgE

tIgE:

total IgE

VH:

Heavy-chain variable domain

VHH:

single variable domain

YSD:

yeast surface display

References

  1. Finkelman FD, Boyce JA, Vercelli D, Rothenberg ME. Key advances in mechanisms of asthma, allergy, and immunology in 2009. J Allergy Clin Immunol. 2010;125:312–8.

    Article  CAS  PubMed  Google Scholar 

  2. Chang TW. The pharmacological basis of anti-IgE therapy. Nat Biotechnol. 2000;18:157–62.

    Article  CAS  PubMed  Google Scholar 

  3. Gould HJ, Sutton BJ. IgE in allergy and asthma today. Nat Rev Immunol. 2008;8:205–17.

    Article  CAS  PubMed  Google Scholar 

  4. Clement MJ, Fortune A, Phalipon A, Marcel-Peyre V, Simenel C, Imberty A, et al. Toward a better understanding of the basis of the molecular mimicry of polysaccharide antigens by peptides: the example of Shigella flexneri 5a. J Biol Chem. 2006;281:2317–32.

    Article  CAS  PubMed  Google Scholar 

  5. Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, Songa EB, et al. Naturally occurring antibodies devoid of light chains. Nature. 1993;363:446–8.

    Article  CAS  PubMed  Google Scholar 

  6. Ward ES, Gussow D, Griffiths AD, Jones PT, Winter G. Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli. Nature. 1989;341:544–6.

    Article  CAS  PubMed  Google Scholar 

  7. Konning D, Zielonka S, Grzeschik J, Empting M, Valldorf B, Krah S, et al. Camelid and shark single domain antibodies: structural features and therapeutic potential. Curr Opin Struct Biol. 2016;45:10–6.

    Article  PubMed  Google Scholar 

  8. Platts-Mills TA, Hilger C, Jappe U, van Hage M, Gadermaier G, Spillner E, et al. Carbohydrate epitopes currently recognized as targets for IgE antibodies. Allergy. 2021;76:2383–94.

    Article  CAS  PubMed  Google Scholar 

  9. Pons L, Chery C, Romano A, Namour F, Artesani MC, Gueant JL. The 18 kDa peanut oleosin is a candidate allergen for IgE-mediated reactions to peanuts. Allergy. 2002;57(72):88–93.

    Article  PubMed  Google Scholar 

  10. Blank S, Seismann H, Michel Y, McIntyre M, Cifuentes L, Braren I, et al. Api m 10, a genuine A. mellifera venom allergen, is clinically relevant but underrepresented in therapeutic extracts. Allergy. 2011;66:1322–9.

    Article  CAS  PubMed  Google Scholar 

  11. Frick M, Fischer J, Helbling A, Rueff F, Wieczorek D, Ollert M, et al. Predominant Api m 10 sensitization as risk factor for treatment failure in honey bee venom immunotherapy. J Allergy Clin Immunol. 2016;138:1663–1671.e9.

    Article  CAS  PubMed  Google Scholar 

  12. Santos AF, Alpan O, Hoffmann HJ. Basophil activation test: mechanisms and considerations for use in clinical trials and clinical practice. Allergy. 2021;76:2420–32.

    Article  CAS  PubMed  Google Scholar 

  13. Erdmann SM, Sachs B, Schmidt A, Merk HF, Scheiner O, Moll-Slodowy S, et al. In vitro analysis of birch-pollen-associated food allergy by use of recombinant allergens in the basophil activation test. Int Arch Allergy Immunol. 2005;136:230–8.

    Article  CAS  PubMed  Google Scholar 

  14. Bahri R, Custovic A, Korosec P, Tsoumani M, Barron M, Wu J, et al. Mast cell activation test in the diagnosis of allergic disease and anaphylaxis. J Allergy Clin Immunol. 2018;142:485–96.e16.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Eberlein B, Krischan L, Darsow U, Ollert M, Ring J. Double positivity to bee and wasp venom: improved diagnostic procedure by recombinant allergen-based IgE testing and basophil activation test including data about cross-reactive carbohydrate determinants. J Allergy Clin Immunol. 2012;130:155–61.

    Article  CAS  PubMed  Google Scholar 

  16. Vos B, Kohler J, Muller S, Stretz E, Rueff F, Jakob T. Spiking venom with rVes v 5 improves sensitivity of IgE detection in patients with allergy to Vespula venom. J Allergy Clin Immunol. 2013;131:1225–7.e1.

    Article  CAS  PubMed  Google Scholar 

  17. Vachova M, Panzner P, Kopac P, Bidovec Stojkovic U, Korosec P. Routine clinical utility of honeybee venom allergen components. J Allergy Clin Immunol Pract. 2018;6:2121–2123.e1.

    Article  PubMed  Google Scholar 

  18. Prenner C, Mach L, Glossl J, Marz L. The antigenicity of the carbohydrate moiety of an insect glycoprotein, honey-bee (Apis mellifera) venom phospholipase A2. The role of alpha 1,3-fucosylation of the asparagine-bound N‑acetylglucosamine. Biochem J. 1992;284(2):377–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Wojtalewicz N, Goseberg S, Kabrodt K, Schellenberg I. Six years of INSTAND e. V. sIgE proficiency testing: an evaluation of in vitro allergy diagnostics. Allergo J Int. 2017;26:43–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Wojtalewicz N, Kabrodt K, Goseberg S, Schellenberg I. Evaluation of the manufacturer-dependent differences in specific immunoglobulin E results for indoor allergens. Ann Allergy Asthma Immunol. 2018;121:490–5.

    Article  CAS  PubMed  Google Scholar 

  21. Thorpe SJ, Heath A, Fox B, Patel D, Egner W. The 3rd international standard for serum IgE: international collaborative study to evaluate a candidate preparation. Clin Chem Lab Med. 2014;52:1283–9.

    Article  CAS  PubMed  Google Scholar 

  22. Braren I, Blank S, Seismann H, Deckers S, Ollert M, Grunwald T, et al. Generation of human monoclonal allergen-specific IgE and IgG antibodies from synthetic antibody libraries. Clin Chem. 2007;53:837–44.

    Article  CAS  PubMed  Google Scholar 

  23. Offermann N, Plum M, Hubner U, Rathloff K, Braren I, Fooke M, et al. Human serum substitution by artificial sera of scalable allergen reactivity based on polyclonal antibodies and chimeras of human FcgammaRI and IgE domains. Allergy. 2016;71:1794–9.

    Article  CAS  PubMed  Google Scholar 

  24. Wood RA, Segall N, Ahlstedt S, Williams PB. Accuracy of IgE antibody laboratory results. Ann Allergy Asthma Immunol. 2007;99:34–41.

    Article  PubMed  Google Scholar 

  25. Smith SA, Chruszcz M, Chapman MD, Pomes A. Human monoclonal IgE antibodies‑a major milestone in allergy. Curr Allergy Asthma Rep. 2023;23:53–65.

    Article  CAS  PubMed  Google Scholar 

  26. Schuurman J, Perdok GJ, Lourens TE, Parren PW, Chapman MD, Aalberse RC. Production of a mouse/human chimeric IgE monoclonal antibody to the house dust mite allergen Der p 2 and its use for the absolute quantification of allergen-specific IgE. J Allergy Clin Immunol. 1997;99:545–50.

    Article  CAS  PubMed  Google Scholar 

  27. Furtado PB, McElveen JE, Gough L, Armour KL, Clark MR, Sewell HF, et al. The production and characterisation of a chimaeric human IgE antibody, recognising the major mite allergen Der p 1, and its chimaeric human IgG1 anti-idiotype. Mol Pathol. 2002;55:315–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Lu CS, Hung AF, Lin CJ, Chen JB, Chen C, Shiung YY, et al. Generating allergen-specific human IgEs for immunoassays by employing human epsilon gene knockin mice. Allergy. 2015;70:384–90.

    Article  CAS  PubMed  Google Scholar 

  29. Steinberger P, Kraft D, Valenta R. Construction of a combinatorial IgE library from an allergic patient. Isolation and characterization of human IgE Fabs with specificity for the major timothy grass pollen allergen, Phl p 5. J Biol Chem. 1996;271:10967–72.

    Article  CAS  PubMed  Google Scholar 

  30. Jakobsen CG, Bodtger U, Kristensen P, Poulsen LK, Roggen EL. Isolation of high-affinity human IgE and IgG antibodies recognising bet v 1 and humicola lanuginosa lipase from combinatorial phage libraries. Mol Immunol. 2004;41:941–53.

    Article  CAS  PubMed  Google Scholar 

  31. Hecker J, Diethers A, Schulz D, Sabri A, Plum M, Michel Y, et al. An IgE epitope of Bet v 1 and fagales PR10 proteins as defined by a human monoclonal IgE. Allergy. 2012;67:1530–7.

    Article  CAS  PubMed  Google Scholar 

  32. Hecker J, Diethers A, Etzold S, Seismann H, Michel Y, Plum M, et al. Generation and epitope analysis of human monoclonal antibody isotypes with specificity for the Timothy grass major allergen Phl p 5a. Mol Immunol. 2011;48:1236–44.

    Article  CAS  PubMed  Google Scholar 

  33. Croote D, Darmanis S, Nadeau KC, Quake SR. High-affinity allergen-specific human antibodies cloned from single IgE B cell transcriptomes. Science. 2018;362:1306–9.

    Article  CAS  PubMed  Google Scholar 

  34. Wurth MA, Hadadianpour A, Horvath DJ, Daniel J, Bogdan O, Goleniewska K, et al. Human IgE mAbs define variability in commercial Aspergillus extract allergen composition. JCI Insight. 2018;3(20):e123387. https://doi.org/10.1172/jci.insight.123387.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Aagaard JB, Sivelle C, Fischer M, Byskov K, Laursen NS, Pfutzner W, et al. Nanobody-based human antibody formats act as IgE surrogate in hymenoptera venom allergy. Allergy. 2022;77:2859–62.

    Article  CAS  PubMed  Google Scholar 

  36. Muyldermans S. Nanobodies: natural single-domain antibodies. Annu Rev Biochem. 2013;82:775–97.

    Article  CAS  PubMed  Google Scholar 

  37. Zavrtanik U, Lukan J, Loris R, Lah J, Hadzi S. Structural basis of epitope recognition by heavy-chain camelid antibodies. J Mol Biol. 2018;430:4369–86.

    Article  CAS  PubMed  Google Scholar 

  38. 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;103:4586–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Mitchell LS, Colwell LJ. Comparative analysis of nanobody sequence and structure data. Proteins. 2018;86:697–706.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Harmsen MM, De Haard HJ. Properties, production, and applications of camelid single-domain antibody fragments. Appl Microbiol Biotechnol. 2007;77:13–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Muyldermans S. A guide to: generation and design of nanobodies. FEBS J. 2021;288:2084–102.

    Article  CAS  PubMed  Google Scholar 

  42. 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;25:289–96.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Moutel S, Bery N, Bernard V, Keller L, Lemesre E, de Marco A, et al. NaLi-H1: A universal synthetic library of humanized nanobodies providing highly functional antibodies and intrabodies. Elife. 2016;5:e16228.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Zimmermann I, Egloff P, Hutter CAJ, Kuhn BT, Brauer P, Newstead S, et al. Generation of synthetic nanobodies against delicate proteins. Nat Protoc. 2020;15:1707–41.

    Article  CAS  PubMed  Google Scholar 

  45. Smith GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science. 1985;228:1315–7.

    Article  CAS  PubMed  Google Scholar 

  46. Crameri R, Walter G. Selective enrichment and high-throughput screening of phage surface-displayed cDNA libraries from complex allergenic systems. Comb Chem High Throughput Screen. 1999;2:63–72.

    Article  CAS  PubMed  Google Scholar 

  47. Boder ET, Wittrup KD. Yeast surface display for screening combinatorial polypeptide libraries. Nat Biotechnol. 1997;15:553–7.

    Article  CAS  PubMed  Google Scholar 

  48. Ryckaert S, Pardon E, Steyaert J, Callewaert N. Isolation of antigen-binding camelid heavy chain antibody fragments (nanobodies) from an immune library displayed on the surface of Pichia pastoris. J Biotechnol. 2010;145:93–8.

    Article  CAS  PubMed  Google Scholar 

  49. Sivelle C, Sierocki R, Ferreira-Pinto K, Simon S, Maillere B, Nozach H. Fab is the most efficient format to express functional antibodies by yeast surface display. mAbs. 2018;10:720–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Kang BH, Lax BM, Wittrup KD. Yeast surface display for protein engineering: library generation, screening, and affinity maturation. Methods Mol Biol. 2022;2491:29–62.

    Article  PubMed  Google Scholar 

  51. Chen X, Gentili M, Hacohen N, Regev A. A cell-free nanobody engineering platform rapidly generates SARS-CoV‑2 neutralizing nanobodies. Nat Commun. 2021;12:5506.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Koide A, Tereshko V, Uysal S, Margalef K, Kossiakoff AA, Koide S. Exploring the capacity of minimalist protein interfaces: interface energetics and affinity maturation to picomolar KD of a single-domain antibody with a flat paratope. J Mol Biol. 2007;373:941–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Yau KY, Dubuc G, Li S, Hirama T, Mackenzie CR, Jermutus L, et al. Affinity maturation of a V(H)H by mutational hotspot randomization. J Immunol Methods. 2005;297:213–24.

    Article  CAS  PubMed  Google Scholar 

  54. Chen X, Zaro JL, Shen WC. Fusion protein linkers: property, design and functionality. Adv Drug Deliv Rev. 2013;65:1357–69.

    Article  CAS  PubMed  Google Scholar 

  55. Conrath KE, Lauwereys M, Wyns L, Muyldermans S. Camel single-domain antibodies as modular building units in bispecific and bivalent antibody constructs. J Biol Chem. 2001;276:7346–50.

    Article  CAS  Google Scholar 

  56. Djender S, Schneider A, Beugnet A, Crepin R, Desrumeaux KE, Romani C, et al. Bacterial cytoplasm as an effective cell compartment for producing functional VHH-based affinity reagents and camelidae IgG-like recombinant antibodies. Microb Cell Fact. 2014;13:140.

    Article  PubMed Central  PubMed  Google Scholar 

  57. Shen ZL, Xiang YF, Vergara S, Chen AP, Xiao ZY, Santiago U, et al. A resource of high-quality and versatile nanobodies for drug delivery. Iscience. 2021;24(9):103014. https://doi.org/10.1016/j.isci.2021.103014.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Ridgway JBB, Presta LG, Carter P. ‘Knobs-into-holes’ engineering of antibody C(H)3 domains for heavy chain heterodimerization. Protein Eng. 1996;9:617–21.

    Article  CAS  PubMed  Google Scholar 

  59. De Nardis C, Hendriks LJA, Poirier E, Arvinte T, Gros P, Bakker ABH, et al. A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G(1). J Biol Chem. 2017;292:14706–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. de Marco A. Recombinant expression of nanobodies and nanobody-derived immunoreagents. Protein Expr Purif. 2020;172:105645.

    Article  PubMed Central  PubMed  Google Scholar 

  61. Akiba H, Tamura H, Kiyoshi M, Yanaka S, Sugase K, Caaveiro JMM, et al. Structural and thermodynamic basis for the recognition of the substrate-binding cleft on hen egg lysozyme by a single-domain antibody. Sci Rep. 2019;9:15481.

    Article  PubMed Central  PubMed  Google Scholar 

  62. Chen F, Ma H, Li Y, Wang H, Samad A, Zhou J, et al. Screening of nanobody specific for peanut major allergen Ara h 3 by phage display. J Agric Food Chem. 2019;67:11219–29.

    Article  CAS  PubMed  Google Scholar 

  63. Hu Y, Wu S, Wang Y, Lin J, Sun Y, Zhang C, et al. Unbiased immunization strategy yielding specific nanobodies against macadamia allergen of Vicilin-like protein for immunoassay development. J Agric Food Chem. 2021;69:5178–88.

    Article  CAS  PubMed  Google Scholar 

  64. Hu Y, Zhang C, Yang F, Lin J, Wang Y, Wu S, et al. Selection of specific nanobodies against lupine allergen Lup an 1 for immunoassay development. Foods. 2021;10(10):2428.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Zettl I, Ivanova T, Strobl MR, Weichwald C, Goryainova O, Khan E, et al. Isolation of nanobodies with potential to reduce patients IgE binding to Bet v 1 (68/100 characters). Allergy. 2022;77(6):1751–60. https://doi.org/10.1111/all.15191.

    Article  CAS  PubMed  Google Scholar 

  66. Aagaard JB, Fischer M, Lober J, Neumann FB, Allahverdi D, Sivelle C, et al. Extract-shaped immune repertoires as source for nanobody-based human IgE in grass pollen allergy. Mol Biotechnol. 2023; https://doi.org/10.1007/s12033-023-00664-8.

    Article  PubMed  Google Scholar 

  67. Matricardi PM, Kleine-Tebbe J, Hoffmann HJ, Valenta R, Hilger C, Hofmaier S, et al. EAACI molecular allergology user’s guide. Pediatr Allergy Immunol. 2016;27(23):1–250.

    Article  PubMed  Google Scholar 

  68. Korosec P, Valenta R, Mittermann I, Celesnik N, Erzen R, Zidarn M, et al. Low sensitivity of commercially available rApi m 1 for diagnosis of honeybee venom allergy. J Allergy Clin Immunol. 2011;128:671–3.

    Article  CAS  PubMed  Google Scholar 

  69. Schrautzer C, Bokanovic D, Hemmer W, Lang R, Hawranek T, Schwarz I, et al. Sensitivity and specificity of hymenoptera allergen components depend on the diagnostic assay employed. J Allergy Clin Immunol. 2016;137:1603–5.

    Article  CAS  PubMed  Google Scholar 

  70. 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. 2016;60:6–13.

    Article  CAS  PubMed  Google Scholar 

  71. Khaled AQ, Sana Y, Abdulrahman R, Raida K, Sami AH. Blocking of histamine release and IgE binding to FcepsilonRI on human basophils by antibodies produced in camels. Allergy Asthma Immunol Res. 2015;7:583–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Jabs F, Plum M, Laursen NS, Jensen RK, Molgaard B, Miehe M, et al. Trapping IgE in a closed conformation by mimicking CD23 binding prevents and disrupts Fc epsilon RI interaction. Nat Commun. 2018;9(1):7. https://doi.org/10.1038/s41467-017-02312-7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Orengo JM, Radin AR, Kamat V, Badithe A, Ben LH, Bennett BL, et al. Treating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement. Nat Commun. 2018;9:1421.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Shamji MH, Singh I, Layhadi JA, Ito C, Karamani A, Kouser L, et al. Passive prophylactic administration with a single dose of anti-Fel d 1 monoclonal antibodies REGN1908-1909 in cat allergen-induced allergic rhinitis - a randomized, double-blind, placebo-controlled clinical trial. Am J Respir Crit Care Med. 2021;204:23–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Gevaert P, De Craemer J, De Ruyck N, Rottey S, de Hoon J, Hellings PW, et al. Novel antibody cocktail targeting Bet v 1 rapidly and sustainably treats birch allergy symptoms in a phase 1 study. J Allergy Clin Immunol. 2022;149:189–99.

    Article  CAS  PubMed  Google Scholar 

  76. Zettl I, Ivanova T, Zghaebi M, Rutovskaya MV, Ellinger I, Goryainova O, et al. Generation of high affinity ICAM-1-specific nanobodies and evaluation of their suitability for allergy treatment. Front Immunol. 2022;13:1022418. https://doi.org/10.3389/fimmu.2022.1022418.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Figures 1a, 2 and 3 were created with BioRender.com.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Edzard Spillner.

Ethics declarations

Conflict of interest

J. Baunvig Aagaard, A.-S. Ravn Ballegaard, P. Ommen Andersen and E. Spillner declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baunvig Aagaard, J., Ravn Ballegaard, AS., Ommen Andersen, P. et al. Molecular engineering of nanobodies as tools in allergology: diagnostics and beyond. Allergo J Int 32, 240–250 (2023). https://doi.org/10.1007/s40629-023-00261-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40629-023-00261-w

Navigation