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

Marco Erreni, Francesca D'Autilia, Roberta Avigni, Evangelia Bolli, Sana M Arnouk, Kiavash Movahedi, Pieterjan Debie, Achille Anselmo, Raffaella Parente, Cécile Vincke, Fijs W B van Leeuwen, Paola Allavena, Cecilia Garlanda, Alberto Mantovani, Andrea Doni, Sophie Hernot, Jo A Van Ginderachter

Onderzoeksoutput: Articlepeer review

5 Citaten (Scopus)
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Samenvatting

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.
Originele taal-2English
Pagina's (van-tot)355-373
Aantal pagina's19
TijdschriftTheranostics
Volume13
Nummer van het tijdschrift1
DOI's
StatusPublished - 1 jan 2023

Keywords

  • intravital microscopy
  • Macrophage mannose receptor (MMR)
  • Pharmacokinetics
  • single-domain antibody
  • tumor-associated macrophage targeting

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