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Review
. 2015:55:613-31.
doi: 10.1146/annurev-pharmtox-010814-124852. Epub 2014 Oct 8.

Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier

Jason M Lajoie  1 , Eric V Shusta
Affiliations
Review

Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier

Jason M Lajoie et al. Annu Rev Pharmacol Toxicol. 2015.

Abstract

Biologics are an emerging class of medicines with substantial promise to treat neurological disorders such as Alzheimer's disease, stroke, and multiple sclerosis. However, the blood-brain barrier (BBB) presents a formidable obstacle that appreciably limits brain uptake and hence the therapeutic potential of biologics following intravenous administration. One promising strategy for overcoming the BBB to deliver biologics is the targeting of endogenous receptor-mediated transport (RMT) systems that employ vesicular trafficking to transport ligands across the BBB endothelium. If a biologic is modified with an appropriate targeting ligand, it can gain improved access to the brain via RMT. Various RMT-targeting strategies have been developed over the past 20 years, and this review explores exciting recent advances, emphasizing studies that show brain targeting in vivo.

Keywords: antibody; biologics; blood-brain barrier; insulin receptor; low density lipoprotein receptor; receptor-mediated transport; transferrin receptor.

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Figures

Figure 1
Figure 1
Endogenous BBB transport routes: (a) Paracellular diffusion of hydrophilic molecules is restricted by the tight junctions formed between adjacent endothelial cells. (b) Small molecules such as glucose, amino acids, and nucleotides gain access to the brain via carrier-mediated transport (CMT). Stereo- and size-selective proteins expressed at both the apical and basolateral plasma membrane mediate the transport of these molecules into the brain. (c) Drug efflux pumps are expressed at the apical plasma membrane and recognize a wide array of ligands including many pharmaceutical compounds. Efflux pumps contribute to the observed barrier properties of the BBB via recognition and removal of unwanted substances from the endothelial cells. (d) Cationic serum proteins can gain access to the brain via adsorptive-mediated transport (AMT). This involves the non-specific adsorption of proteins to negatively charged domains on the apical plasma membrane and subsequent transcytosis. (e) Several proteins gain access to the brain via receptor-mediated transport (RMT). Receptors on the apical plasma membrane recognize and bind to blood-borne ligands with subsequent transcytosis across the endothelial cells and release into the brain.
Figure 2
Figure 2
(a) Schematic of the BBB RMT mechanism: (i) Initially, a protein ligand or an RMT-targeting therapeutic binds to a specific receptor on the apical plasma membrane. (ii) Subsequently the membrane invaginates to form an intracellular vesicle through endocytosis. Once inside the cell, the vesicle containing receptor-ligand complexes can be trafficked to various destinations. (iii) In some cases, the vesicle is recycled back to the apical plasma membrane. (iv) Alternatively, vesicles can be shuttled to the basolateral plasma membrane where fusion with the membrane and release of vesicular contents is termed transcytosis. (v) Vesicles can also be sent to the lysosome for degradation of their contents. An RMT-targeting antibody binding to and trafficking with a transmembrane receptor is shown as an example of the mechanism by which RMT-targeting vectors gain access to the brain. (b) Constructs and binding affinity of the various anti-TfR antibodies engineered to improve BBB transcytosis.
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