Nandini Kashyap of Cambridge Healthtech Institute recently spoke with Dr. Danica Stanimirovic of National Research Council of Canada about challenges and opportunities in the delivering therapies across the blood brain barrier to treat CNS diseases, and where the industry is headed in coming years. Dr. Stanimirovic is the keynote speaker at the 5th Annual Blood-Brain Barrier which is taking place on June 19-20, 2019 in Boston, MA where she will be delivering her talk on “Blood-Brain Barrier-Crossing Single-Domain Antibodies Targeting IGF1R: Mechanism of Action and Preclinical Assessment”. This conference is being organized as part of the 18th Annual World Preclinical Congress which runs from June 17-20, 2019 in Boston, MA.

KEYNOTE PRESENTATION: Blood-Brain Barrier-Crossing Single-Domain Antibodies Targeting IGF1R: Mechanism of Action and Preclinical Assessment

Stanimirovic_DanicaDanica Stanimirovic, MD, PhD, Director, Translational Bioscience Department, Human Health Therapeutics Portfolio, National Research Council of Canada

Insulin growth factor 1 (IGF1) is transported across the blood-brain barrier (BBB) via a receptor-mediated transcytosis. To exploit IGF1 transcytosis route for therapeutic delivery across the BBB, single-domain antibodies (sdAb) selective for IGF1 receptor (IGF1R) were raised and optimized for binding affinity, biophysical properties, receptor binding epitopes, and species cross-reactivity. Enhanced cargo delivery across the BBB (including peptides, antibodies, enzymes and nanocarriers) was demonstrated in vitro and in animal models.

SPEAKER BIO

Danica Stanimirovic, MD, PhD, Director, Translational Bioscience Department, Human Health Therapeutics Portfolio, National Research Council of Canada

Danica Stanimirovic manages a portfolio of R&D projects in partnership with academia, Canadian and international biopharma companies, aimed at developing, de-risking and advancing antibody-based therapeutics through preclinical development. She leads the NRC’s Therapeutics beyond Brain Barriers Program, focused on biologic and gene therapies for neurological diseases. Adjunct Professor at the Department of Cellular and Molecular Medicine, University of Ottawa, a founding member of the International Brain Barriers Society, and member of Scientific Advisory Boards of biotechnology companies and large international R&D initiatives (e.g., EU Innovative Medicines Initiative), she has been the recipient of several Canadian and international awards. She was trained in cerebrovascular research at the National Institutes of Health, USA. She has authored over 170 manuscripts and 20 patents in the field of integrative neuroscience, innovative biologics and drug delivery across the blood-brain barrier.

Can you tell us about yourself, your role and how you started working in BBB field?

The subject of the blood-brain barrier emerged as the key focus during my formative years when I studied stroke and brain trauma, where barrier disruption contributes to life-threatening brain swelling. I had the opportunity to learn from and work with the pioneers in the field of cerebral vascular biology and the blood-brain barrier at the University of Belgrade and subsequently at the NINDS, including Dr. Maria Spatz, who established the first BBB model using cultures of human brain endothelial cells. I have subsequently established a neurobiology program of R&D at the National Research Council of Canada, which has subsequently become recognized for its unique offering in the field of models and technologies for brain delivery of therapeutics. The program works in collaboration with Canadian and international companies to develop neurotherapeutics through pre-clinical studies and has a strong focus on biotherapeutics, including antibody and gene therapies.

What are the major obstacles in your field of research?

Developing therapeutics for brain disease is among the most challenging and costly in health research. The human brain is a very complex and evolved organ which we have only just started to decipher with the help of advanced imaging technologies; diseases affecting the brain are often chronic and degenerative or caused by specific gene mutations. Unfortunately, most of our research and pre-clinical studies are done in rodents – mouse brains are >2000-fold smaller and much less complex than a human’s; therefore ‘translating’ findings to humans is difficult. And, of course, there is the blood-brain barrier that shields the brain from foreign substances, and this includes therapeutics administered into the bloodstream. Finding ways to non-invasively deliver biotherapeutics across the blood-brain barrier, in sufficient amounts to produce therapeutic effect, is a major challenge in the field. Currently, the prevailing approach is to co-opt the natural blood-brain barrier transporters that supply the brain with essential nutrients. Antibodies against these transporters could be used to ‘shuttle’ therapeutic cargos across the BBB. A few BBB transporters have been tested so far, with promising results, but also many caveats. The field is still in search of an ‘ideal’ BBB transport system, with abundance and efficiency of transport suitable for many therapeutic applications.

How much of your work has led to translation to the clinic?

The concept of receptor-mediated transcytosis across the blood-brain barrier still awaits proof of concept in clinical trials. Two BBB carriers have entered clinical trials, but results still remain inconclusive. One of the technologies originating from the NRC, a single domain antibody FC5, is in late-stage preclinical development by the Canadian company Kalgene Pharmaceuticals Inc., as a BBB-delivery arm for a therapeutic that targets Alzheimer’s disease.

Why have you chosen to speak at 5th Annual Blood-Brain Barrier and what are you looking forward to at 2019 gathering?

The conference, now in its 5th iteration, is gaining recognition as a valuable networking event where industry and academia can interact productively and learn about advances and the development progress of various concepts and technologies for CNS delivery of therapeutics.

What can the audience expect from your talk?

My talk will provide an outline of key principles of RMT-mediated transport across the BBB and will focus specifically on the development and preclinical evaluation of a new class of BBB carrier antibodies against IGF1R.

Please share some closing remarks or comments

A better understanding of BBB molecular make-up and physiology, in conjunction with advances in imaging, will lead to a pipeline of more selective and optimized BBB carriers that will be deployed to improve the efficacy of biotherapeutics for the CNS. I am hopeful that the field will be able to learn from clinical failures and implement BBB delivery strategies as an essential component of de-risking and improving success.