Abstract
Antibodies are widely used as versatile biological tools in cancer therapeutics. In radiopharmaceutical therapy, they have been extensively exploited as vehicles for the delivery of cytotoxic radionuclide payloads for killing tumor cells. However, their success has been impeded by high toxicity profiles due to their long circulatory half-life, which produces high radiation doses to healthy non-target tissues. This issue has prompted the development of smaller engineered antibody fragments that bind to the same epitopes as their parent antibodies but with increased pharmacokinetic profiles, deeper tumor penetration, and better safety profiles. Antibody fragments have produced promising results as vectors for radiopharmaceutical therapy, with an approved fragment-based radiotherapeutic in China and an increasing number of ongoing clinical trials. Nonetheless, concerns surrounding the stability, unfavorable tissue distribution, and reduced binding affinity of radiolabeled antibody fragments have inhibited their widespread application in radiopharmaceutical therapy. In response, a great deal of effort has been dedicated to optimize the pharmacokinetics of antibody fragments (especially reducing their retention in the kidneys) and improving the radiochemical techniques used to synthesize them. In this chapter, we explore the application of antibody fragments for radiopharmaceutical therapy, their methods of production, and their potential for clinical translation.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Wong KJ, Baidoo KE, Nayak TK, Garmestani K, Brechbiel MW, Milenic DE. In vitro and in vivo pre-clinical analysis of a F(ab′)2 fragment of panitumumab for molecular imaging and therapy of HER1-positive cancers. EJNMMI Res. 2011;1(1):1–15.
Alibakhshi A, Abarghooi Kahaki F, Ahangarzadeh S, Yaghoobi H, Yarian F, Arezumand R, et al. Targeted cancer therapy through antibody fragments-decorated nanomedicines. J Control Release. 2017;268:323–34.
Tiller KE, Tessier PM. Advances in antibody design. Annu Rev Biomed Eng. 2015;17:191–216.
Liu L. Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins. Protein Cell. 2018;9(1):15–32.
Maloth KN, Velpula N, Ugrappa S, Kodangal S. Radioisotopes: an overview. Int J Case Rep Image. 2014;5(9):604.
Dekempeneer Y, Keyaerts M, Krasniqi A, Puttemans J, Muyldermans S, Lahoutte T, et al. Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle. Expert Opin Biol Ther. 2016;16(8):1035–47. https://doi.org/10.1080/14712598.2016.1185412.
Carter LM, Poty S, Sharma SK, Lewis JS. Preclinical optimization of antibody-based radiopharmaceuticals for cancer imaging and radionuclide therapy—model, vector, and radionuclide selection. J Labelled Comp Radiopharm. 2018;61(9):611–35.
D’Huyvetter M, Xavier C, Caveliers V, Lahoutte T, Muyldermans S, Devoogdt N. Radiolabeled nanobodies as theranostic tools in targeted radionuclide therapy of cancer. Expert Opin Drug Deliv. 2014;11(12):1939–54.
D’Huyvetter M, Aerts A, Xavier C, Vaneycken I, Devoogdt N, Gijs M, et al. Development of 177Lu-nanobodies for radioimmunotherapy of HER2-positive breast cancer: evaluation of different bifunctional chelators. Contrast Media Mol Imaging. 2012;7(2):254–64.
Navarro L, Berdal M, Chérel M, Pecorari F, Gestin JF, Guérard F. Prosthetic groups for radioiodination and astatination of peptides and proteins: a comparative study of five potential bioorthogonal labeling strategies. Bioorg Med Chem. 2019;27(1):167–74.
Bartholomä MD. Radioimmunotherapy of solid tumors: approaches on the verge of clinical application. J Labelled Comp Radiopharm. 2018;61(9):715–26.
Debie P, Lafont C, Defrise M, Hansen I, van Willigen DM, van Leeuwen FWB, et al. Size and affinity kinetics of nanobodies influence targeting and penetration of solid tumours. J Control Release. 2020;317:34–42.
Bates A, Power CA. David vs. Goliath: the structure, function, and clinical prospects of antibody fragments. Antibodies. 2019;8(2):28.
Xenaki KT, Oliveira S, van Bergen en Henegouwen PMP. Antibody or antibody fragments: implications for molecular imaging and targeted therapy of solid tumors. Front Immunol. 2017;8:1287.
Kholodenko RV, Kalinovsky DV, Doronin II, Ponomarev ED, Kholodenko IV. Antibody fragments as potential biopharmaceuticals for cancer therapy: success and limitations. Curr Med Chem. 2019;26(3):396–426.
Alonso MartÃnez LM, Xiques Castillo A, Calzada Falcón VN, Pérez-Malo Cruz M, Leyva Montaña R, Zamora Barrabà M, et al. Development of 90Y-DOTA-nimotuzumab Fab fragment for radioimmunotherapy. J Radioanal Nucl Chem. 2014;302(1):49–56.
Chitneni SK, Koumarianou E, Vaidyanathan G, Zalutsky MR. Observations on the effects of residualization and dehalogenation on the utility of N-succinimidyl ester acylation agents for radioiodination of the internalizing antibody trastuzumab. Molecules. 2019;24(21):3907.
D’Huyvetter M, De Vos J, Xavier C, Pruszynski M, Sterckx YGJ, Massa S, et al. 131I-labeled anti-HER2 camelid sdAb as a theranostic tool in cancer treatment. Clin Cancer Res. 2017;23(21):6616–28.
Massa S, Xavier C, Muyldermans S, Devoogdt N. Emerging site-specific bioconjugation strategies for radioimmunotracer development. Expert Opin Drug Deliv. 2016;13(8):1149–63.
Kitten O, Martineau P. Antibody alternative formats: antibody fragments and new frameworks. Medecine/Sciences. 2019;35(12):1092–7.
Chen ZN, Mi L, Xu J, Song F, Zhang Q, Zhang Z, et al. Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials. Int J Radiat Oncol Biol Phys. 2006;65(2):435–44.
Rondon A, Rouanet J, Degoul F. Radioimmunotherapy in oncology: overview of the last decade clinical trials. Cancers. 2021;13(21):5570.
Grünberg J, Novak-Hofer I, Honer M, Zimmermann K, Knogler K, Bläuenstein P, et al. In vivo evaluation of177Lu- and 67/64Cu-labeled recombinant fragments of antibody chCE7 for radioimmunotherapy and PET imaging of L1-CAM-positive tumors. Clin Cancer Res. 2005;11(14):5112–20.
Haylock AK, Nilvebrant J, Mortensen A, Velikyan I, Nestor M, Falk R. Generation and evaluation of antibody agents for molecular imaging of CD44v6-expressing cancers. Oncotarget. 2017;8(39):65152–70.
Tsai WTK, Wu AM. Aligning physics and physiology: engineering antibodies for radionuclide delivery. J Labelled Comp Radiopharm. 2018;61(9):693–714.
Olafsen T, Wu AM. Antibody vectors for imaging. Semin Nucl Med. 2010;40(3):167–81.
Pandit-Taskar N, O’Donoghue JA, Ruan S, Lyashchenko SK, Carrasquillo JA, Heller G, et al. First-in-human imaging with 89Zr-Df-IAB2M anti-PSMA minibody in patients with metastatic prostate cancer: pharmacokinetics, biodistribution, dosimetry, and lesion uptake. J Nucl Med. 2016;57(12):1858–64.
Hamers-Casterman C, Atarhouch T, Muyldermans S, Robinson G, Hammers C, Songa EB, et al. Naturally occurring antibodies devoid of light chains. Nature. 1993;363(6428):446–8.
Piramoon M, Khodadust F, Jalal S. BBA - reviews on cancer radiolabeled nanobodies for tumor targeting : from bioengineering to imaging and therapy. BBA – Rev Cancer. 1875;2021(2):188529.
Muyldermans S. A guide to: generation and design of nanobodies. FEBS J. 2021;288(7):2084–102.
Keyaerts M, Xavier C, Heemskerk J, Devoogdt N, Everaert H, Ackaert C, et al. Phase i study of 68Ga-HER2-Nanobody for PET/CT assessment of HER2 expression in breast carcinoma. J Nucl Med. 2016;57(1):27–33.
D’Huyvetter M, De Vos J, Caveliers V, Vaneycken I, Heemskerk J, Duhoux FP, et al. Phase I trial of 131I-GMIB-anti-HER2-VHH1, a new promising candidate for HER2-targeted radionuclide therapy in breast cancer patients. J Nucl Med. 2021;62(8):1097–105.
Tchouate Gainkam LO, Caveliers V, Devoogdt N, Vanhove C, Xavier C, Boerman O, et al. Localization, mechanism and reduction of renal retention of technetium-99m labeled epidermal growth factor receptor-specific nanobody in mice. Contrast Media Mol Imaging. 2011;6(2):85–92.
Chigoho DM, Bridoux J, Hernot S. Reducing the renal retention of low- to moderate-molecular-weight radiopharmaceuticals. Curr Opin Chem Biol. 2021;63:219–28.
D’Huyvetter M, Vincke C, Xavier C, Aerts A, Impens N, Baatout S, et al. Targeted radionuclide therapy with a 177Lu-labeled anti-HER2 nanobody. Theranostics. 2014;4(7):708–20.
Harmand TJ, Islam A, Pishesha N, Ploegh HL. Nanobodies as: in vivo, non-invasive, imaging agents. RSC Chem Biol. 2021;2(3):685–701.
Arslan M, Karadağ D, Kalyoncu S. Protein engineering approaches for antibody fragments: directed evolution and rational design approaches. Turk J Biol. 2019;43(1):1–12.
Ferrer-Miralles N, Domingo-EspÃn J, Corchero J, Vázquez E, Villaverde A. Microbial factories for recombinant pharmaceuticals. Microb Cell Factories. 2009;8:1–8.
Gaciarz A, Khatri NK, Velez-Suberbie ML, Saaranen MJ, Uchida Y, Keshavarz-Moore E, et al. Efficient soluble expression of disulfide bonded proteins in the cytoplasm of Escherichia coli in fed-batch fermentations on chemically defined minimal media. Microb Cell Factories. 2017;16(1):1–12.
Spadiut O, Capone S, Krainer F, Glieder A, Herwig C. Microbials for the production of monoclonal antibodies and antibody fragments. Trends Biotechnol. 2014;32(1):54–60.
Rodrigo G, Gruvegård M, Van Alstine JM. Antibody fragments and their purification by protein L affinity chromatography. Antibodies. 2015;4(3):259–77.
Vaneycken I, Devoogdt N, Van Gassen N, Vincke C, Xavier C, Wernery U, et al. Preclinical screening of anti-HER2 nanobodies for molecular imaging of breast cancer. FASEB J. 2011;25(7):2433–46.
Xavier C, Vaneycken I, D’Huyvetter M, Heemskerk J, Keyaerts M, Vincke C, et al. Synthesis, preclinical validation, dosimetry, and toxicity of 68Ga-NOTA-anti-HER2 nanobodies for iPET imaging of HER2 receptor expression in cancer. J Nucl Med. 2013;54(5):776–84.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Funeh, C.N., Asiabi, P., D’Huyvetter, M., Devoogdt, N. (2023). Case Study #3: Antibody Fragments in Radiopharmaceutical Therapy. In: Bodei, L., Lewis, J.S., Zeglis, B.M. (eds) Radiopharmaceutical Therapy. Springer, Cham. https://doi.org/10.1007/978-3-031-39005-0_12
Download citation
DOI: https://doi.org/10.1007/978-3-031-39005-0_12
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-39004-3
Online ISBN: 978-3-031-39005-0
eBook Packages: Biomedical and Life Sciences