Transportation of Single-Domain Antibodies through the Blood–Brain Barrier

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.

Central Nervous System Delivery of Antibodies and Their Single-Domain Antibodies and Variable Fragment Derivatives with Focus on Intranasal Nose to Brain Administration

“…Several drug delivery strategies have been introduced to cross the BBB: a paracellular route or passive diffusion by disruption of the BBB, a transcellular route by enhancing transcytosis using molecular BBB shuttles or direct delivery bypassing the BBB with intrathecal, intraventricular or intranasal delivery [ 143 , 144 , 145 ]. While nanobodies have been often discussed in relation to crossing the BBB, the number of experimental validations is rather low.…”

Diagnosis of Glioblastoma by Immuno-Positron Emission Tomography

“…Various molecular mechanisms for the transportation of nanobodies through the Blood–Brain Barrier (BBB) have been extensively described and include adsorptive and receptor-mediated transcytosis, somatic gene transfer, and the use of carriers or shuttles such as cell-penetrating peptides, extracellular vesicles, liposomes, and nanoparticles as well as device-based and physicochemical disruption of the BBB [ 143 , 144 , 145 , 146 ].…”

“…The development of nanobody-based radiotracers for the non-invasive diagnosis of glioblastoma by immuno-PET may also involve some potential challenges. First, suboptimal imaging of glioblastoma may be achieved due to the low penetration of nanobodies through the BBB [ 184 ], although some nanobodies have shown their potential to access the brain parenchyma [ 143 ]. Second, the administration of nanobodies with theragnostic potential may elicit immunogenic responses.…”

“…In contrast to conventional antibodies, nanobody-based immuno-PET probes may launch a novel era for the diagnosis of glioblastoma. Various molecular mechanisms for the transportation of nanobodies through the BBB have been extensively described [ 143 , 144 , 145 , 146 ] ( Figure 6 ). Receptor-mediated transcytosis performs the movement of receptor ligands (e.g., transferrin, lactoferrin) across the BBB by a specific affinity-dependent unidirectional transport [ 147 , 148 ].…”

Galectins in Glioma: Current Roles in Cancer Progression and Future Directions for Improving Treatment

“…Because of their small size, not surprisingly, a number of teams have recently studied whether Nbs can cross the BBB and whether they could be used for the treatment of brain diseases. The results are very encouraging and have shown that Nbs can reach the brain via the BBB either directly, via receptor-mediated transcytosis, or indirectly, using, for example, various forms of carriers, including nanoparticles or liposomes [ 141 , 142 ]. We also better understand why some Nbs are more efficient at crossing the BBB.…”