Receptor–mediated transcytosis of macromolecules across the blood–brain barrier

ABSTRACT

Introduction

The blood–brain barrier (BBB) restricts brain access of virtually all macromolecules. Receptor-mediated transcytosis (RMT) is one strategy toward their brain delivery. In this strategy, targeting ligands conjugated to therapeutic payload or decorating particles containing the payload interact with targets on brain capillary endothelial cells (BCEC), triggering internalization, trafficking, and release from BCEC.

Areas covered

RMT at the BBB has leveraged multiple formats of macromolecules and large particles. Interactions between those and BCEC have been studied primarily using antibodies, with findings applicable to the design of larger particles. BBB-penetrant constructs have also been identified in screening campaigns and directed evolution, and subsequently found to interact with RMT targets. In addition, BCEC targeted by constructs incorporating genomic payload can be made to produce therapeutic proteins.

Expert opinion

While targeting may not be strictly necessary to reach a therapeutic effect for all macromolecules, it can improve a molecule’s BBB transport, exposing it to the entire brain parenchyma and enhancing its effect. Constructs with better BCEC transcytosis may be designed rationally, leveraging knowledge about BCEC trafficking, and found in screening campaigns, where this knowledge can reduce the search space and improve iterative refinement. Identification of new targets may also help generate BBB-crossing constructs.

KEYWORDS:

• Blood–brain barrier
• endocytosis
• receptor-mediated transcytosis
• targeting
• trafficking
• macromolecules
• particles

Article highlights

• Receptor-mediated transcytosis (RMT) can enhance transport of macromolecules and larger particles across brain capillary endothelial cells (BCEC).

• Various factors relevant to targets as well as to constructs have been found to affect RMT within BCEC.

• New constructs can be designed rationally or found in large screening or directed evolution campaigns that can leverage findings about RMT mechanisms.

• BCEC targeted by constructs incorporating genomic payload can also be made to produce and secrete therapeutics.

• This box summarizes key points contained in the article.

Declaration of interest

H Baghirov is employed by Roche. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

H Baghirov thanks all researchers whose work inspired him to think about BBB transport.

Additional information

Funding

This paper was not funded.