Dr. Danica Stanimirovic, Program Leader, Therapeutics Beyond Brain Barriers, presenting carrier molecules that can deliver biologics to the brain at Biotransfer 2014 in Toronto


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Video of Dr. Danica Stanimirovic, Program Leader, Therapeutics Beyond Brain Barriers, presenting carrier molecules that can deliver biologics to the brain at Biotransfer 2014 in Toronto.


(On screen: Presentation - Blood-brain barrier carriers: A platform for (bio)therapeutic delivery to CNS targets. Danica Stanimirovic. Human Health Therapeutics Portfolio. National Research Council of Canada)

Thank you, Bernard. Thank you, everybody. I'm going to present today a set of platform technology for delivering biotherapeutics across the blood-brain barrier to central nervous system targets.

(On screen: Presentation slide - Market and Drivers)

So to set the stage, here are just a few notions about why we are doing this. Obviously, Bernard mentioned that biologics are now the fastest-growing segment of pharma market. There is increased interest in CNS indications that's driven by growing markets in this field as well as aging population and very high cost burden of these diseases.

(On screen: Presentation slide - Opportunity: Delivery of Biologics to CNS targets)

So we are trying to seize the opportunity to expand biologics to CNS indications. With this, we would open large CNS markets to biologics therapies, and those will facilitate commercialization for high-burden diseases of these therapies. However, there is a significant challenge to this goal, and that is that biologics cannot cross into CNS because of the blood-brain barrier.

(On screen: Presentation slide - Challenge: Biologics cannot cross the BBB)

So currently this is done mostly. . .delivery of biologics is done mostly by neurosurgical treatments aided by some advanced imaging technologies. This is some of the list, including a osmotic blood-brain barrier disruption, intrathecal infusion, focused ultrasound. However, there are deficiencies to these techniques, including some of them are invasive. They have side effects. They require hospitalization and very expensive imaging setup. They are not really applicable to large patient populations. So they're very unique techniques that have lots of disadvantages.

(On screen: Presentation slide - Non-invasive BBB delivery)

So for noninvasive blood-brain barrier delivery, the kind of technologies are using specific receptors that are expressed on the surface of blood-brain barrier endothelial cells that naturally deliver large molecules into the brain for its metabolic function. So these are transferrin receptor, for example, insulin receptor, and LRP receptor. Some antibodies have been developed against these receptors. However, because of their wide distribution and participation in very important physiological functions, these are not ideal. Some on-target toxicity has been reported for these molecules.

(On screen: Presentation slide - NRC's Technology)

So NRC technology contains a pipeline of blood-brain barrier delivery carriers and also novel targets to deliver biologics to the CNS. We also complement these pipeline technologies with very unique expertise, blood-brain barrier models and methods, cerebrovascular biomarkers, and some internal pipeline of blood-brain barrier-enabled biologics.

(On screen: Presentation slide - NRC's BBB Carriers: Single-Domain Antibodies)

So NRC blood-brain barrier carriers are single-domain antibodies. These are antibody fragments that are a tenth of the size of normal antibody. They are monomeric, modular, customizable, have excellent developability, and can be easily optimized for multiple applications.

(On screen: Presentation slide - NRC BBB Carriers)

So these carriers originate from humanized camelid single-domain antibodies. They were isolated by either phenotypic screening in various blood-brain barrier models or by raising single-domain antibodies against specific targets expressed on brain endothelial cells. We also have a pipeline of fully human domain antibodies. So now with this pipeline of carriers, we can start building some very innovative designs of biologics and, in particular, bi-specific antibodies by combining single-domain antibody blood-brain barrier carriers and then therapeutic molecules in various formats.

(On screen: Presentation slide - Demonstration)

Here we have some ideas or some molecules that we have produced by specific antibody area, but also antibody-drug conjugates. So here is just one demonstration of the technology, in which we have the antibody, therapeutic antibody, that is fused with one of the blood-brain barrier carriers coming from single-domain antibodies in blue. Then the same therapeutic antibody that's fused with control VHH with control single-domain antibody that does not cross the blood-brain barrier. So when we inject this into animals and look at a pharmacological behavior of these antibodies, we can see that they behave very similarly in serum. They have essentially the same pharmacokinetics. But when you look at the CSF, you can see that only the antibody that has been functionalized with blood-brain barrier carrier shows very increased and high levels in CSF. So from similar from these and similar studies, we now know that using blood-brain barrier carriers we can increase brain exposure by 15 to 25-fold and also increase the potency of our therapeutic antibodies by 30-fold.

(On screen: Presentation slide - Technology Exploitation: Business Model)

So our business model for exploiting this technology has two thrusts. One is co-development, where we work with a partner to functionalize their lead therapeutic with our NRC blood-brain barrier carriers, and then support for the development, validation, and characterization of this fused molecule using our proprietary techniques and methods. We also offer incremental support, and that is essentially evaluation of blood-brain barrier penetration of various partners' molecules, using some of our test models. So NRC blood-brain barrier carriers are available for non-exclusive licensing and also for collaborative co-development with partners.

(On screen: Presentation slide - Readiness Status)

So in terms of readiness status, these carriers have already been licensed to several partners and are being developed for therapeutic applications in various disease areas and also using various biological-type molecules such as therapeutic antibodies, therapeutic peptides, and therapeutic enzymes. In some cases, some earlier-stage technologies are still in the process of optimization, and sometimes this is also done with partners.

(On screen: Presentation slide - Targeted industries)

So the technology . . .with this technology, we are targeting biopharma with CNS therapeutics pipeline, biopharma that has therapeutic pipeline, and biologics that's not originally intended for CNS applications but can be repurposed for CNS, drug delivery companies, and also CROs.

(On screen: Presentation slide - NRC Technology Advantage)

So in summary, NRC technology advantages in this field includes a pipeline of antibody fragment, blood-brain barrier carriers that are highly modular building blocks for unique biologics. We also have quite good expertise in engineering, affinity optimization, and further development of fused molecules. We also work with new blood-brain barrier targets that have higher selectivity, better toxicity profile, and we can tailor the modes of delivery depending on desired therapeutic effects.

(On screen: Presentation slide - Intellectual Property)

We have a very large patent portfolio covering this technology.

(On screen: Presentation - Danica Stanimirovic. Director, HHT Translational Bioscience Department Lead, Therapeutics Beyond Brain Barriers Program. 613-993-3730. Danica.Stanimirovic@nrc.gc.ca. Stacey Nunes, Client Relations. 613-993-9212. Stacey.Nunes@nrc.gc.ca.

If you are interested in discussing this further, these are our contacts. You can talk to me or Stacey Nunes, our client relationship leader.