Abstract
Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. Nevertheless, numerous neurological diseases and brain pathologies, including cancer, result in BBB leakiness favoring single-domain antibodies uptake into the CNS. Some single-domain antibodies have been reported to naturally cross the BBB. In addition, different strategies and methods to deliver both nanobodies and VNARs into the brain parenchyma can be exploited when the BBB is intact. These include device-based and physicochemical disruption of the BBB, receptor and adsorptive-mediated transcytosis, somatic gene transfer, and the use of carriers/shuttles such as cell-penetrating peptides, liposomes, extracellular vesicles, and nanoparticles. Approaches based on single-domain antibodies are reaching the clinic for other diseases. Several tailoring methods can be followed to favor the transport of nanobodies and VNARs to the CNS, avoiding the limitations imposed by the BBB to fulfill their therapeutic, diagnostic, and theragnostic promises for the benefit of patients suffering from CNS pathologies.
Highlights
Single-domain antibodies constitute an attractive alternative to conventional monoclonal antibodies
While several recent reviews have explored the different ways single-domain antibodies reach the brain [4,5,6], mainly through transcytosis, the present report reviews the up-to-date status of current literature on the transport of nanobodies through the brain barrier barrier (BBB), providing an additional overview of coadjutant methods to deliver nanobodies to the brain parenchyma and discussing several strategies that could be applied to direct nanobodies towards the BBB, as well as some of the potential challenges to be addressed for clinical translation
To human Fc domain (TXB2-hFc) targets TfR1 with high affinity and cross-species reactivTargeting transferrin receptors at the BBB improves the uptake of immunoliposomes ity
Summary
Single-domain antibodies constitute an attractive alternative to conventional monoclonal antibodies. Microglia and the endfeet of astrocytes constitute the microenvironment ronment which supports and communicates with the vessel components of the neurovascular unit. Permeability of the BBB is limited to receptor-specific ligands or molecules, which show both lipophilic solubility and a MW smaller than 400 Da, hindering therapeutic concentrations in the brain [28]. The neonatal Fc receptor (FcRn) located at the brain microvascular endothelium actively mediates the reverse transcytosis of IgG from the brain to blood across the BBB [32,33].
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