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