Theranostics 2023; 13(1):355-373. doi:10.7150/thno.77560 This issue Cite

Research Paper

Size-advantage of monovalent nanobodies against the macrophage mannose receptor for deep tumor penetration and tumor-associated macrophage targeting

Marco Erreni1,2✉, Francesca D'Autilia1, Roberta Avigni3, Evangelia Bolli4,5, Sana M. Arnouk4,5, Kiavash Movahedi4,5, Pieterjan Debie6, Achille Anselmo3, Raffaella Parente1, Cécile Vincke4,5, Fijs W.B. van Leeuwen7, Paola Allavena2,3, Cecilia Garlanda2,3, Alberto Mantovani2,3,8, Andrea Doni1, Sophie Hernot6*, Jo A. Van Ginderachter4,5✉*

1. Unit of Advanced Optical Microscopy, IRCCS Humanitas Research Hospital -, via Manzoni 56, 20089 Rozzano, Milan, Italy.
2. Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy.
3. IRCCS Humanitas Research Hospital -, via Manzoni 56, 20089 Rozzano, Milan, Italy.
4. Cellular and Molecular Immunology Lab, Vrije Universiteit Brussel, Brussels, Belgium (Pleinlaan 2, 1050 Brussels).
5. Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium.
6. Laboratory for In vivo Cellular and Molecular Imaging (ICMI-BEFY/MIMA), Vrije Universiteit Brussel, Brussels, Belgium (Laarbeeklaan 103, 1090 Brussels).
7. Leiden University Medical Center, Interventional Molecular Imaging Laboratory, Albinusdreef 2 2333 ZA Leiden.
8. The William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK.
* Equal contribution

Citation:
Erreni M, D'Autilia F, Avigni R, Bolli E, Arnouk SM, Movahedi K, Debie P, Anselmo A, Parente R, Vincke C, van Leeuwen FWB, Allavena P, Garlanda C, Mantovani A, Doni A, Hernot S, Van Ginderachter JA. Size-advantage of monovalent nanobodies against the macrophage mannose receptor for deep tumor penetration and tumor-associated macrophage targeting. Theranostics 2023; 13(1):355-373. doi:10.7150/thno.77560. https://www.thno.org/v13p0355.htm
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Abstract

Graphic abstract

Rationale: Nanobodies (Nbs) have emerged as an elegant alternative to the use of conventional monoclonal antibodies in cancer therapy, but a detailed microscopic insight into the in vivo pharmacokinetics of different Nb formats in tumor-bearers is lacking. This is especially relevant for the recognition and targeting of pro-tumoral tumor-associated macrophages (TAMs), which may be located in less penetrable tumor regions.

Methods: We employed anti-Macrophage Mannose Receptor (MMR) Nbs, in a monovalent (m) or bivalent (biv) format, to assess in vivo TAM targeting. Intravital and confocal microscopy were used to analyse the blood clearance rate and targeting kinetics of anti-MMR Nbs in tumor tissue, healthy muscle tissue and liver. Fluorescence Molecular Tomography was applied to confirm anti-MMR Nb accumulation in the primary tumor and in metastatic lesions.

Results: Intravital microscopy demonstrated significant differences in the blood clearance rate and macrophage targeting kinetics of (m) and (biv)anti-MMR Nbs, both in tumoral and extra-tumoral tissue. Importantly, (m)anti-MMR Nbs are superior in reaching tissue macrophages, an advantage that is especially prominent in tumor tissue. The administration of a molar excess of unlabelled (biv)anti-MMR Nbs increased the (m)anti-MMR Nb bioavailability and impacted on its macrophage targeting kinetics, preventing their accumulation in extra-tumoral tissue (especially in the liver) but only partially influencing their interaction with TAMs. Finally, anti-MMR Nb administration not only allowed the visualization of TAMs in primary tumors, but also at a distant metastatic site.

Conclusions: These data describe, for the first time, a microscopic analysis of (m) and (biv)anti-MMR Nb pharmacokinetics in tumor and healthy tissues. The concepts proposed in this study provide important knowledge for the future use of Nbs as diagnostic and therapeutic agents, especially for the targeting of tumor-infiltrating immune cells.

Keywords: tumor-associated macrophage targeting, macrophage mannose receptor, single-domain antibody, intravital microscopy, pharmacokinetics


Citation styles

APA
Erreni, M., D'Autilia, F., Avigni, R., Bolli, E., Arnouk, S.M., Movahedi, K., Debie, P., Anselmo, A., Parente, R., Vincke, C., van Leeuwen, F.W.B., Allavena, P., Garlanda, C., Mantovani, A., Doni, A., Hernot, S., Van Ginderachter, J.A. (2023). Size-advantage of monovalent nanobodies against the macrophage mannose receptor for deep tumor penetration and tumor-associated macrophage targeting. Theranostics, 13(1), 355-373. https://doi.org/10.7150/thno.77560.

ACS
Erreni, M.; D'Autilia, F.; Avigni, R.; Bolli, E.; Arnouk, S.M.; Movahedi, K.; Debie, P.; Anselmo, A.; Parente, R.; Vincke, C.; van Leeuwen, F.W.B.; Allavena, P.; Garlanda, C.; Mantovani, A.; Doni, A.; Hernot, S.; Van Ginderachter, J.A. Size-advantage of monovalent nanobodies against the macrophage mannose receptor for deep tumor penetration and tumor-associated macrophage targeting. Theranostics 2023, 13 (1), 355-373. DOI: 10.7150/thno.77560.

NLM
Erreni M, D'Autilia F, Avigni R, Bolli E, Arnouk SM, Movahedi K, Debie P, Anselmo A, Parente R, Vincke C, van Leeuwen FWB, Allavena P, Garlanda C, Mantovani A, Doni A, Hernot S, Van Ginderachter JA. Size-advantage of monovalent nanobodies against the macrophage mannose receptor for deep tumor penetration and tumor-associated macrophage targeting. Theranostics 2023; 13(1):355-373. doi:10.7150/thno.77560. https://www.thno.org/v13p0355.htm

CSE
Erreni M, D'Autilia F, Avigni R, Bolli E, Arnouk SM, Movahedi K, Debie P, Anselmo A, Parente R, Vincke C, van Leeuwen FWB, Allavena P, Garlanda C, Mantovani A, Doni A, Hernot S, Van Ginderachter JA. 2023. Size-advantage of monovalent nanobodies against the macrophage mannose receptor for deep tumor penetration and tumor-associated macrophage targeting. Theranostics. 13(1):355-373.

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