Targeted transport of biotherapeutics at the blood-brain barrier

ABSTRACT

Introduction

The treatment of neurological diseases is significantly hampered by the lack of available therapeutics. A major restraint for the development of drugs is denoted by the presence of the blood-brain barrier (BBB), which precludes the transfer of biotherapeutics to the brain due to size restraints.

Areas covered

Novel optimism for transfer of biotherapeutics to the brain has been generated via development of targeted therapeutics to nutrient transporters expressed by brain capillary endothelial cells (BCECs). Targeting approaches with antibodies acting as biological drug carriers allow for proteins and genetic material to enter the brain, and qualified therapy using targeted proteins for protein replacement has been observed in preclinical models and now emerging in the clinic. Viral vectors denote an alternative for protein delivery to the brain by uptake and transduction of BCECs, or by transport through the BBB leading to neuronal transduction.

Expert opinion

The breaching of the BBB to large molecules has opened for treatment of diseases in the brain. A sturdier understanding of how biotherapeutics undergo transport through the BBB and how successful transport into the brain can be monitored is required to further improve the translation from successful preclinical studies to the clinic.

KEYWORDS:

• Antibody
• blood-brain barrier
• brain capillary endothelial cell
• CD98
• nanobody
• targeting
• transferrin receptor
• viral gene therapy

Article highlights

• The blood-brain barrier (BBB) prevents the entry of modern-days biotherapeutics unless specialized in design.

• Targeting biotherapeutics to nutrient transporters expressed by brain capillary endothelial cells (BCECs) allow for cellular uptake and transcellular transport with release into the brain.

• Targeting approaches involve antibodies weakened in affinity or avidity, which transport therapeutic proteins and siRNA. Other approaches involve BBB-targeted, unconjugated antibodies that undergo transport into the brain and directly engage with unwanted proteins.

• BBB targeted nanobodies sized approximately one tenth of an antibody denote an interesting alternative to targeted antibodies with lower manufacturing costs and an interesting pharmacokinetic profile.

• Viral vectors are alternatives for protein delivery to the brain by uptake and transduction of BCECs, or to neurons and glia subsequent to viral vector transport across the BBB.

• The understanding of how biotherapeutics like proteins, including therapeutic antibodies, and viral vectors undergo transport through BCECs and how this can be monitored in the brain need further optimization to success.

Declaration of interests

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Acknowledgments

Some of the most recent results obtained and described by the authors were generated by generous grants from the Danish Research Council (Grant no. 1030-00474B), the Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery (Grant no. R155-2013-14113), and Scleroseforeningen [Grant no. A41926].

Additional information

Funding

This paper was not funded.