Engineering antibody and protein therapeutics to cross the blood–brain barrier

Abstract

Diseases in the central nervous system (CNS) are often difficult to treat. Antibody and protein-based therapeutics hold huge promises in CNS disease treatment. However, proteins are restricted from entering the CNS by the blood–brain barrier (BBB). To achieve enhanced BBB crossing, antibody-based carriers have been developed by utilizing the endogenous macromolecule transportation pathway known as receptor-mediated transcytosis (RMT). In this report, we first provided an overall review on key CNS diseases and the most promising antibody or protein-based therapeutics approved or in clinical trials. The CNS diseases covered include glioblastoma (GBM), Alzheimer’s disease (AD), Parkinson’s disease (PD), and Lysosomal storage diseases (LSDs). We then reviewed the platforms that are being explored to increase macromolecule brain entry to combat CNS diseases. Highlights include targeting the transferrin receptor (TfR) and insulin receptor (InsR) for enhancing macromolecule therapeutics brain entry. Case studies were discussed in detail to illustrate key parameters in creating and evaluating a successful brain penetrating protein therapeutic. Finally, we analyzed lessons learned from past experiences and provided perspective on future engineering of novel delivery vehicles for antibody and protein-based therapies for CNS diseases. Statement of Significance: Beyond simply reviewing previous state-of-the-art in antibody delivery crossing the BBB, we summarized a comprehensive list of design tips to generate successful bispecific BBB-crossing antibodies.

A pivotal decade for bispecific antibodies?

“…Finally, given the versatility of bsAbs and the potential to mediate completely novel MOAs, the field of bsAbs is poised to see novel emerging approaches and candidates enter the clinic, hopefully providing pivotal data in the years to come, both in oncology and in non-oncology indications, including applications in infection/virology, autoimmunity, metabolism, neurology and ophthalmology. These novel concepts include different approaches as described recently, 5 including the development of: 1) effector cell engagers different from TCEs, engaging, e.g., myeloid, NK or γδ-T cells, 96–98 2) in situ assembly concepts to specifically activate bsAbs on dual target-expressing cells 99 , 100 or in the tumor microenvironment, 101 3) PROTAC-like approaches resulting in internalization and degradation of membrane proteins, 102 4) antibody-based cytokine mimetics to trigger cytokine receptors, 103 , 104 and 5) unique solutions for delivery of bsAbs beyond barriers such as the blood-brain-barrier, 105 which may have applications for the treatment of neurodegenerative and other diseases. 106 …”

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

“…Other prominent examples of receptor-mediated transcytosis in mammals includes transferrin, insulin, leptin, and Fc receptors that transport immunoglobulins across the BBB. 31…”

Constitutive knockout of interleukin-6 ameliorates memory deficits and entorhinal astrocytosis in the MRL/lpr mouse model of neuropsychiatric lupus

“…Prior to such trials, CNS bioavailability of systemically-administered therapies which inhibit IL-6 must be assessed. For example, monoclonal antibody delivery to the CNS can be limited by the brain barriers [ 111 ]. Intravenously delivered tocilizumab showed likely sub-therapeutic, although detectable, levels in the brain during pre-clinical testing [ 112 ].…”

“…However, the increased presence of intrathecal antibodies and potential breakdown of the blood–brain and blood-CSF barriers [ 7 , 10 , 62 ] indicate that higher tocilizumab concentrations are possible in the brains of NPSLE patients. Additionally, techniques which optimize monoclonal antibody delivery to the brain tissue are rapidly advancing [ 111 ].…”