In its Brain Targeting Program, a Wyss team led by Founding Director Donald Ingber, M.D., Ph.D. and Staff Program Lead James Gorman, M.D., Ph.D. is developing improved approaches to target drugs and diagnostics to the brain. Leveraging the human blood-brain barrier (BBB) Chip technology developed by Ingber’s team, combined with advanced antibody R&D capabilities, the Program is developing next-generation human antibody shuttles specific for known and potential novel BBB transport proteins. By performing state-of-the-art proteomic and transcriptomic investigations of human endothelial cells from the brain microvasculature and other organs, they also aim to identify proteins that are preferentially enriched on the blood-exposed endothelial surface of the BBB. These BBB-enriched proteins will be tested as new candidate targets for improved brain targeting. The program is collaborating with multiple pharma companies in a pre-competitive arrangement, and aims to make the technologies available non-exclusively.
The BBB tightly controls the transport of essential nutrients into the brain and shields it from unwanted substances and pathogens circulating in the blood stream. Importantly, it is also the major obstacle preventing more than 98% of life-saving drugs including chemical compounds, peptides, and therapeutic antibodies from being efficiently delivered to the brain. Most chemical and protein drugs do not cross the BBB, and the majority of those that do cross are actively pumped back into the blood stream. Some receptors on the brain microvasculature that undergo receptor-mediated endocytosis have been shown to transport proteins that bind them across the BBB in a process known as “transcytosis.” Antibodies that bind these receptors and transport payloads across the BBB have been termed “shuttles,” and the receptors themselves “shuttle targets.”
Due to species differences, in vivo models in organisms such as mice and non-human primates are challenging for the development of shuttles to transport drugs across the human BBB. For example, shuttles directed to human shuttle targets often do not cross-react with their mouse counterparts. Non-human primate experimentation is costly, raises ethical issues, and does not adequately predict brain targeting in humans. To complement these animal models, diverse in vitro models have been developed to study drug transport across the human BBB. While some previous in vitro models have been partially successful in mimicking the BBB’s physical barrier and transport functions, all have had features that limited their usefulness as drug development platforms.
Ingber’s team has developed a next-generation in vitro model of the human BBB with enhanced functionalities by combining their microfluidic Organ-On-Chip culture technology with induced pluripotent stem cell (iPS) cell technology and a developmentally-inspired differentiation program.
iPS cells developed into endothelial cells in low-oxygen conditions that emulate the development of the brain’s microvasculature in the normal human BBB, together with normal support cells, form an exceptionally tightly organized in vitro BBB when exposed to fluidic shear forces in the device. In the enhanced human BBB Chip Assay, key endothelial barrier and transport functions are more reflective of those in vivo and the BBB remains stable for at least 14 days, which is far beyond the capabilities of previous in vitro human BBB models. Using this system, the team has developed a highly sensitive and well-controlled transcytosis assay which it is exploiting to select and engineer improved antibody shuttles. In addition, it can be personalized by using various normal and patient-derived iPS cells to capture natural and disease-associated variances in antibody transcytosis and other transport functions.
The Brain Targeting Program efforts can provide companies with a unique set of tools to test and improve BBB transport of proprietary drug compounds, a panel of validated human antibodies for use as therapeutic shuttles, and unique targets for development of improved shuttles. The Wyss Institute is actively pursuing collaborations to advance the Brain Targeting Program, to expand knowledge of BBB transport, and to further validate the predictive capabilities of the BBB Chip Assay.