Article Dans Une Revue Journal of Controlled Release Année : 2025

Novel single-domain antibodies targeting a unique transferrin receptor 1 epitope for cross-species delivery of drugs in the central nervous system

Romy Cohen
  • Fonction : Auteur
Diane Beuzelin
  • Fonction : Auteur
Aude Faucon
  • Fonction : Auteur
Karima Abouzid
  • Fonction : Auteur
Gersande Godefroy
Maxime Masse
  • Fonction : Auteur
Yasmine Mechioukhi
  • Fonction : Auteur
Ingrid Julien-Gau
  • Fonction : Auteur
Cléa Boursery
  • Fonction : Auteur
Christophe Fraisier
  • Fonction : Auteur
Karine Varini
  • Fonction : Auteur
Morgane Thomas
  • Fonction : Auteur
Guillaume Jacquot
  • Fonction : Auteur
Bastien Serrano
  • Fonction : Auteur
Andréa Romette
  • Fonction : Auteur
Gauthier Dangla Pélissier
Magali Godard
  • Fonction : Auteur
Jamal Temsamani
  • Fonction : Auteur

Résumé

The blood-brain barrier (BBB) is a major obstacle for delivering therapeutic agents to the central nervous system (CNS), posing significant challenges for treating neurological disorders. Among current strategies to improve brain drug exposure, hijacking physiological pathways involved in receptor-mediated transcytosis has emerged as a promising strategy. While targeting transferrin receptor 1 (TfR1) is widely explored, many TfR1- antibodies lack cross-species reactivity, limiting translational development. In the present study, we identified and characterized camelid-derived single-domain antibodies (VHHs) with robust cross-reactivity to rodent, rhesus monkey, and human TfR1. Epitope mapping of the VHH revealed a novel binding site at the interface of the TfR1 dimer. When fused to a human IgG1 Fc domain, these VHHs, as monomers or homodimers, were efficiently internalized by engineered CHO cells and brain endothelial cells expressing TfR1 from different species. Systemic administration of VHH-Fc constructs in mice demonstrated significantly improved brain uptake compared to irrelevant controls. Functional delivery was confirmed using neurotensin-induced hypothermia, and we established correlations between in vivo effects and binding properties determined by surface plasmon resonance. Notably, efficient BBB transcytosis was associated with intermediate affinity and rapid dissociation rates. Engineered variants maintained favorable cross-species binding, including similar affinities to human and nonhuman primate TfR1, facilitating translational studies. The cross-reactive anti-TfR1 VHHs we developed offer a versatile and modular platform for CNS drug delivery and hold promise as molecular shuttles for transporting therapeutic agents across the BBB. Our work establishes a robust foundation for developing next generation brain-targeted biotherapeutics, including peptides, enzyme replacement therapies, antibody-based treatments for neurodegenerative diseases, and oligonucleotide delivery for CNS disorders, enabling seamless translation from preclinical to clinical applications.

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Dates et versions

hal-05340484 , version 1 (05-11-2025)

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Marion David, Romy Cohen, Diane Beuzelin, Géraldine Ferracci, Marina Cresci, et al.. Novel single-domain antibodies targeting a unique transferrin receptor 1 epitope for cross-species delivery of drugs in the central nervous system. Journal of Controlled Release, 2025, 388, pp.114344. ⟨10.1016/j.jconrel.2025.114344⟩. ⟨hal-05340484⟩
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