Immunologische Tracerentwicklung mit Nanobodies

Zusammenfassung

Nanobodies sind die antigenbindenden Fragmente eines speziellen Antikörperformats, welches zum Beispiel in Kameliden vorkommt. Die Größe, Struktur und Beschaffenheit von Nanobodies bringen viele Vorteile mit sich, wodurch sie als exzellente Vehikel für die Entwicklung von Radiotracern in der nuklearmedizinischen Bildgebung und Therapie von großem Wert sind. Zu diesem Zweck werden die entsprechenden Radiohalogene oder Radiometalle auf unterschiedliche Art und Weise selektiv oder unselektiv an der Peptidkette des Nanobody’s angebracht. Die indirekte Radiohalogenierung mittels prosthetischer Gruppen und die Postmarkierung von bereits eingebrachten Chelatoren mit Radiometallen sind die bevorzugten Markierungsstrategien. Am häufigsten erfolgt die Tracerentwicklung über den His₆-Tag mit ^99mTc-Tricarbonyl. Präklinisch und auch zum Teil klinisch konnte die Eignung von verschiedenen nanobodybasierten Tracern bereits gezeigt werden.

Abstract

Nanobodies are the antigen-binding fragments of a special antibody format, which for example can be found in camelids. The size, structure and nature of nanobodies implies many advantages, by which they are of great value as excellent vehicles for the development of radiotracers in nuclear medical imaging and therapy. For this purpose, the appropriate radiohalogens or radiometals are attached in different ways selectively or unselectively to the peptide chain of the nanobody. The indirect radiohalogenation by means of prosthetic groups and the post-labeling of already introduced chelators with radiometals are the preferred labeling strategies. Most commonly, the tracer development takes place through the His₆-tag with ^99mTc-tricarbonyl. Preclinically and also in parts clinically, the suitability of different nanobody-based tracers could already be demonstrated.

Schlüsselwörter

Nanobody - Radiohalogene - Radiometalle - Bildgebung - Therapie

Keywords

Nanobody - radiohalogens - radiometals - imaging - therapy

Publication History

Article published online:
01 March 2024

• Literatur

• 1 Vosjan MJWD, Vercammen J, Kolkman JA. et al. Nanobodies targeting the hepatocyte growth factor: potential new drugs for molecular cancer therapy. Mol Cancer Ther 2012; 11: 1017-1025
• 2 Hamers-Casterman C, Atarhouch T, Muyldermans S. et al. Naturally occurring antibodies devoid of light chains. Nature 1993; 363: 446-448
• 3 Harmsen MM, de Haard HJ. Properties, production, and applications of camelid single-domain antibody fragments. Appl Microbiol Biotechnol 2007; 77: 13-22
• 4 Kijanka M, Dorresteijn B, Oliveira S. et al. Nanobody-based cancer therapy of solid tumors. Nanomedicine (Lond) 2015; 10: 161-174
• 5 Pardon E, Laeremans T, Triest S. et al. A general protocol for the generation of Nanobodies for structural biology. Nat Protoc 2014; 9: 674-693
• 6 de Genst E, Silence K, Decanniere K. et al. Molecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies. Proc Natl Acad Sci U S A 2006; 103: 4586-4591
• 7 Stijlemans B, Conrath K, Cortez-Retamozo V. et al. Efficient targeting of conserved cryptic epitopes of infectious agents by single domain antibodies. African trypanosomes as paradigm. J Biol Chem 2004; 279: 1256-1261
• 8 Gutfilen B, Souza SA, Valentini G. Copper-64: a real theranostic agent. Drug Des Devel Ther 2018; 12: 3235-3245
• 9 Fu R, Carroll L, Yahioglu G. et al. Antibody Fragment and Affibody ImmunoPET Imaging Agents: Radiolabelling Strategies and Applications. ChemMedChem 2018; 13: 2466-2478
• 10 Zhu M, Zhang J, Yang M. et al. In vitro and in vivo study on the treatment of non-small cell lung cancer with radionuclide labeled PD-L1 nanobody. J Cancer Res Clin Oncol 2023; 149: 8429-8442
• 11 Pruszynski M, Koumarianou E, Vaidyanathan G. et al. Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody. Nucl Med Biol 2013; 40: 52-59
• 12 Xavier C, Blykers A, Vaneycken I. et al. (18)F-nanobody for PET imaging of HER2 overexpressing tumors. Nucl Med Biol 2016; 43: 247-252
• 13 Debie P, Devoogdt N, Hernot S. Targeted Nanobody-Based Molecular Tracers for Nuclear Imaging and Image-Guided Surgery. Antibodies (Basel) 2019; 8: 12
• 14 D'Huyvetter M, Aerts A, Xavier C. et al. Development of 177Lu-nanobodies for radioimmunotherapy of HER2-positive breast cancer: evaluation of different bifunctional chelators. Contrast Media Mol Imaging 2012; 7: 254-264
• 15 Cleeren F, Lecina J, Ahamed M. et al. Al18F-Labeling Of Heat-Sensitive Biomolecules for Positron Emission Tomography Imaging. Theranostics 2017; 7: 2924-2939
• 16 Gao H, Wu Y, Shi J. et al. Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy. J Immunother Cancer 2020; 8: e001156
• 17 Massa S, Xavier C, Muyldermans S. et al. Emerging site-specific bioconjugation strategies for radioimmunotracer development. Expert Opin Drug Deliv 2016; 13: 1149-1163
• 18 Huang L, Tchouate Gainkam LO, Caveliers V. et al. SPECT imaging with 99mTc-labeled EGFR-specific nanobody for in vivo monitoring of EGFR expression. Mol Imaging Biol 2008; 10: 167-175
• 19 Chakravarty R, Goel S, Cai W. Nanobody: the "magic bullet" for molecular imaging?. Theranostics 2014; 4: 386-398
• 20 Tchouate Gainkam LO, Caveliers V, Devoogdt N. 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: 85-92
• 21 Cortez-Retamozo V, Lahoutte T, Caveliers V. et al. 99mTc-Labeled Nanobodies: A New Type of Targeted Probes for Imaging Antigen Expression. CRP 2008; 1: 37-41
• 22 Keyaerts M, Xavier C, Heemskerk J. et al. Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma. J Nucl Med 2016; 57: 27-33
• 23 Lecocq Q, de Vlaeminck Y, Hanssens H. et al. Theranostics in immuno-oncology using nanobody derivatives. Theranostics 2019; 9: 7772-7791
• 24 Hrynchak I, Santos L, Falcão A. et al. Nanobody-Based Theranostic Agents for HER2-Positive Breast Cancer: Radiolabeling Strategies. Int J Mol Sci 2021; 22: 10745
• 25 Klarenbeek A, El Mazouari K, Desmyter A. et al. Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform. MAbs 2015; 7: 693-706
• 26 Vincke C, Loris R, Saerens D. et al. General strategy to humanize a camelid single-domain antibody and identification of a universal humanized nanobody scaffold. J Biol Chem 2009; 284: 3273-3284
• 27 Yang EY, Shah K. Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics. Front Oncol 2020; 10: 1182
• 28 Conrath K, Vincke C, Stijlemans B. et al. Antigen binding and solubility effects upon the veneering of a camel VHH in framework-2 to mimic a VH. J Mol Biol 2005; 350: 112-125
• 29 Ladenson RC, Crimmins DL, Landt Y. et al. Isolation and characterization of a thermally stable recombinant anti-caffeine heavy-chain antibody fragment. Anal Chem 2006; 78: 4501-4508
• 30 Arbabi-Ghahroudi M, Tanha J, MacKenzie R. Prokaryotic expression of antibodies. Cancer Metastasis Rev 2005; 24: 501-519