Strategies to identify, engineer, and validate antibodies targeting blood–brain barrier receptor-mediated transcytosis systems for CNS drug delivery

ABSTRACT

Introduction

Numerous therapeutics for neurological diseases have been developed, but many have failed in clinical trials in part due to limited brain bioavailability, mainly stemming from inefficient transport through the blood–brain barrier (BBB). One potential approach to noninvasive, BBB-targeted drug delivery to the brain is the use of engineered antibodies as delivery vehicles that can transport conjugated drug cargo across the BBB and into the brain via receptor-mediated transcytosis (RMT). Effective development of these RMT targeting systems includes novel target discovery, along with antibody engineering and subsequent validation.

Areas covered

This review focuses on both known and emerging RMT systems, targeting antibody properties in relation to BBB trafficking, and antibody validation strategies.

Expert opinion

Clinical development of known RMT targeting systems and identification of novel BBB RMT targets will be complementary strategies for overcoming the BBB in central nervous system (CNS) disease treatment. The search for new RMT targets with higher brain specificity and enriched expression in the brain has given rise to some new targets which may offer unique benefits. It is our opinion that the expansion of BBB RMT system identification, along with targeting molecule engineering and validation strategies, will substantially contribute to the treatment of a wide range of neurological diseases.

KEYWORDS:

• Receptor-mediated transcytosis
• blood–brain barrier
• drug delivery
• antibody
• screening
• engineering

Article highlights

• Rapid advancement in the development of blood–brain barrier (BBB) receptor-mediated transcytosis (RMT) targeting antibodies, including multiple that are in human clinical trials, suggests the potential for new treatments for neurological diseases.

• A remaining need for the field of BBB RMT-mediated brain drug delivery is the discovery of novel targets with enhanced brain specificity and higher delivery capacity including in the aged and diseased brain.

• Screening approaches can help identify antibodies and receptors that might not be identified using ‘omics’ approaches.

• Different RMT systems and their targeting antibodies will have different optimal affinity and valency properties.

• Validation of the brain uptake of an RMT targeting antibody is crucial and oftentimes requires additional pharmacodynamic studies for comprehensive evaluation.

Declaration of interest

EV Shusta holds patents for several antibodies with BBB targeting potential.

Reviewer disclosures

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

Acknowledgments

All figures were created with BioRender.com.

Additional information

Funding

This work was funded in part by National Institutes of Health grant NS118028.