Abstract
Passive immunotherapy, i.e., treatment with therapeutic antibodies, has been increasingly used over the last decade in several diseases such as cancers or inflammation. However, these proteins have some limitations that single-domain antibodies could potentially solve. One of the main issues of conventional antibodies is their limited brain penetration because of the blood–brain barrier (BBB). In this review, we aim at exploring the different options single-domain antibodies (sDAbs) such as variable domain of heavy-chain antibodies (VHHs) and variable new antigen receptors (VNARs) have already taken to reach the brain allowing them to be used as therapeutic, diagnosis or transporter tools.
Highlights
Monoclonal antibodies have been of common use for several years for the treatment of several diseases such as cancers or inflammation
The object of the present review is to summarize the state of the art regarding brain exposure of single-domain antibodies with a focus on variable domain of heavy-chain antibodies (VHHs) and variable new antigen receptors (VNARs)
Even though we show in the previous section that several single-domain antibodies (sDAbs) have demonstrated enhanced brain exposure, no VHH or VNAR are presently in clinical development in a Central Nervous System (CNS) application except for one VHH currently in phase II development [77] in breast cancer brain metastasis
Summary
Monoclonal antibodies have been of common use for several years for the treatment of several diseases such as cancers or inflammation. These proteins have specific properties making them unique tools They have a high identity rate with mouse and human variable domain of conventional antibodies heavy chain (VH) around 80% [13], and, even if they come from a different species than the one treated, they are weakly immunogenic in mice [14,15]. Even though VNAR are lacking one CDR, they can still recognize numerous antigens thanks to a higher variability in CDR1 and a longer CDR3 [35] These characteristics make them the smallest antibodies with a molecular weight of only 12 kDa. VHHs and VNARs small sizes allow them to be good candidates as therapeutics, diagnostics and transporters. This small size allows them to reach buried epitopes, facilitating the discovery of mouse–human cross-species reactive sDAbs, a feature not always accessible with conventional IgGs [36]
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