The blood-brain barrier (BBB) maintains essential brain homeostasis, but as a result can impede delivery of new therapies. Antibodies and new drugs hold promise for treating brain diseases and disorders; however, their utility is often limited by poor
penetration across the BBB. The inaugural Blood-Brain Barrier conference will bring together experts from industry and academia to brainstorm ideas and share new research on topics such as the BBB at sites of pathology, preclinical
models, tools and strategies for understanding and prediction of brain penetration, and imaging in BBB studies. The conference will also feature case studies and updates from the industry on topics such as antibody delivery and vector-mediated transport
The annual conference will feature stimulating discussions and a friendly place to network with peers. We invite you to present a talk, a poster, or to attend to learn from and network with the leading experts from around the globe.
Wednesday, June 10
7:00 am Registration and Morning Coffee
8:00 Chairperson’s Opening Remarks
Margareta Hammarlund-Udenaes, Ph.D., Professor, Translational PK/PD, Department of Pharmaceutical Biosciences, Uppsala University
8:05 KEYNOTE PRESENTATION: REGULATION OF THE BLOOD-BRAIN BARRIER IN HEALTH AND DISEASE
Richard Daneman, Ph.D., Assistant Professor, University of California, San Francisco
The blood-brain barrier (BBB) is crucial to ensure proper neuronal function and protect the CNS from injury and disease. We have used genomic, genetic and molecular approach to elucidate the cellular and molecular mechanisms that regulate the formation
of the BBB as well as the mechanisms that lead to its dysfunction during disease.
8:35 Targeting Vascular Dysfunction to Improve CNS Health
Robert D. Bell, Ph.D., Principal Scientist, Neurovascular Biology Lab Head, Pfizer, Inc.
The vascular system plays an integral role in maintaining central nervous system (CNS) health. Both systemic circulatory changes and alterations directly within the BBB have been suggested to contribute to both the onset and progression of several neurological
conditions. In addition, emerging evidence suggests that vascular risk factors including hypertension, diabetes, obesity, atherosclerosis, metabolic syndrome, and stroke can negatively impact BBB function. The relationship between systemic vasculature
and BBB in health and disease will be reviewed.
9:05 Cancer-Derived Extracellular Vesicles Promote Brain Metastasis
Naoomi Tominaga, Ph.D., Researcher, Divison of Molecular and Cellular Medicine, National Cancer Center, Japan
Brain metastasis is an important cause of mortality in breast cancer patients. A key event during brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB), which consists of the endothelium and surrounding cells. Transfer
of extracellular vesicles (EVs) derived from the cancer cells represents a novel mechanism of communication between cancer cells and normal cells. Here, we show that breast cancer–derived EVs promote brain metastasis by destruction of BBB.
9:35 Do We Always Need to Cross the Blood-Brain Barrier?
Lois A. Lampson, Ph.D., Associate Professor of Neurosurgery, Brigham & Women’s Hospital / Harvard
The BBB does not always impede therapy for the brain. Migratory cells, including immune effector cells, can enter, and their activity can be modulated before they enter. Some agents work from outside the brain: systemic antibody can prevent entry
of drugs or pathogens, or even draw material out of the brain. Differences between the BBB at sites of pathology vs. normal brain can help to concentrate therapy at target sites.
10:05 Coffee Break in the Exhibit Hall with Poster Viewing
10:50 Human Pluripotent Stem Cell Modeling of the Blood-Brain Barrier
Eric V. Shusta, Ph.D., Professor, Chemical and Biological Engineering, University of Wisconsin, Madison
A renewable source of human BBB endothelium could prove enabling for brain research and pharmaceutical development. We demonstrate that endothelial cells generated from human pluripotent stem cells (hPSCs) can be specified to possess many BBB attributes,
including well-organized tight junctions, polarized efflux transport, and nutrient transporter expression. Importantly, hPSC-derived BBB endothelial cells also respond to cues provided by other cells of the neurovascular unit such as human pericytes,
astrocytes and neurons to generate very tight barrier properties.
11:20 FEATURED PRESENTATION: DELIVERY OF SMALL AND LARGER DRUGS ACROSS THE BBB – TO MEASURE IS TO KNOW
Ph.D., Professor, Translational PK/PD, Department of Pharmaceutical Biosciences, Uppsala University
Methods for measuring delivery of drugs across the BBB are now available to accommodate the unbound, active moiety, thereby providing important information on success rate of compounds for CNS action. The talk will include discussions on the
factors needed to be taken into consideration and methods of choice, as well as new information on regional differences in BBB transport and brain distribution. Quantitative results on nanocarrier delivery will also be discussed.
11:50 Imaging and Detection of Nitric Oxide in the Brain by EPR and NMR
Lawrence Berliner, Ph.D., Professor of Chemistry and Biochemistry, Chemistry and Biochemistry, University of Denver; Emeritus, Ohio State University
In a septic rat, NO complexes with the lipophilic Fe(II)-chelate spin trap, N,N-diethyl-dithiocarbamate (DETC), in the brain. The in-vivo L-band EPR spectrum confirms [(DETC)2 – Fe(II)-NO]. The radical distribution was ‘visualized’
by MR images displaying significantly enhanced contrast where the NO was generated (called the MRI ‘spin-trapping’).The NO complex was more stable in vivo and a more effective MRI contrast agent than other stable nitrogen containing
radicals, such as aminoxyl radicals.
12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:00 Refreshment Break in the Exhibit Hall with Poster Viewing
1:30 Chairperson’s Remarks
Richard Daneman, Ph.D., Assistant Professor, University of California, San Francisco
1:35 MRI-Guided Focused Ultrasound Activated Stem Cell Facilitated Blood-Brain Barrier Opening
King C. Li, M.D., FRCP(C), MBA, Senior Associate Dean for Clinical and Translational Research, Professor and Chair,
Department of Radiology, Wake Forest School of Medicine
The objective of this project is to create a remote-controllable stem cell-based strategy to allow us to open up the blood-brain barrier at the time and place of our choosing. Drugs and therapeutic agents up to at least 300 nm in size can be delivered
through the blood-brain barrier using this technology. This novel paradigm utilizing image-guided focused ultrasound and stem cells can potentially be applied to all diseases that affect the central nervous system.
2:05 New Blood-Brain Barrier Shuttles: Phenotypic Screens and Targeted Proteomics
Danica Stanimirovic, Ph.D., Director, Translational Bioscience, Human Health Therapeutics
Portfolio, National Research Council of Canada
The blood-brain barrier (BBB) expresses a myriad of receptors and transporters at its luminal surface, yet only a handful of targets have been used to develop molecular Trojan horses for brain delivery of large molecules. We have identified novel
receptor-ligand pairs as brain delivery platforms using workflows that combine `function-first` screening of antibody display libraries and targeted proteomics to understand their trafficking mechanisms across the BBB.
2:35 Paracellular Portal to the CNS: Are Macromolecules Permitted?
Pankaj Karande, Ph.D., Assistant Professor, Department of Chemical & Biological Engineering, Center
for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute
Delivery of macromolecules into the central nervous system (CNS) is a formidable challenge. The paracellular route has long been considered an exclusive pathway for entry of small water soluble molecules and ions but it can serve as an attractive
portal for delivery of proteins, polypeptides, and enzymes. We will discuss our recent discovery of short peptide vectors, PEPDARTs, that specifically target the paracellular pathway into the CNS for delivery of macromolecular cargo.
3:05 CNS Uptake of Large Molecules and Peptides: PK Profile and Applications to Drug Discovery & Development
Sara Belli, Ph.D., DMPK Project Leader, Pharmaceutical Sciences/p-RED, Roche Innovation Center Basel
Large molecules have great potential as CNS therapeutics since they are able to mimick function of endogenous neuropeptides, reducing expression of disease-related genes or clearing pathological protein aggregates. Developing novel, effective,
and safe drugs for CNS diseases is hindered by blood–brain barrier reducing distribution of large molecules candidates to brain. Herein, an overview on current knowledge with examples of brain targeting approaches will be given focusing
on PK and PKPD profiling.
3:35 Understanding Antibody Penetration through Blood-Brain Barrier using Cell Fractionation and Quantitative Proteomics
Arsalan Haqqani, Ph.D., Research Officer, Human Health Therapeutics Portfolio, National Research Council
Better understanding of mechanism(s) of antibody penetration through BBB is needed to deliver therapies into the CNS. We describe a multiplexed quantitative method, involving endosome fractionation and label-free targeted mass spectrometry,
to track and quantify BBB-crossing antibodies in various intracellular compartments of brain endothelial cells. The results show that the method has a potential to quantitatively compare the trafficking of multiple BBB-crossing antibodies,
providing an insight into mechanism and antibody characteristics that favor their BBB transcytosis.
4:05 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 PLENARY KEYNOTE PANEL
6:00 Welcome Reception in the Exhibit Hall with Poster Viewing
7:00 Close of Day
Thursday, June 11
7:30 am Interactive Breakout Discussion Groups with Continental Breakfast
Each discussion group in this session is led by a moderator/s who ensures focused conversations around key issues. Attendees join a specific group and the small, informal setting facilitates sharing of ideas and active networking.
TABLE 12: How can we best exploit the BBB to concentrate therapy at a target site?
Moderator: Lois A. Lampson, Ph.D., Associate Professor of Neurosurgery, Brigham & Women’s Hospital / Harvard Medical School
The BBB is plastic. It differs at sites of pathology, as compared to normal brain. This brainstorming session will ask: How and when can this difference be exploited for localized delivery of drugs or antibodies?
- Specific examples for when the BBB is already permissive, and no further "opening" is needed.
- Specific examples for when the BBB is not normal, but not open enough.
- Specific ideas about how to increase BBB opening, but only at sites of pathology.
TABLE 13: Brain Uptake of Large Molecules: How/What to Optimize
Moderator: Sara Belli, Ph.D., DMPK Project Leader, Pharmaceutical Sciences/p-RED, Roche Innovation Center Basel
- The weakest point in CNS drug research? Would say the identification of the efficacious brain concentration to target in man.
- In vitro studies for optimizing brain uptake of large molecules: is nothing available?
- In vivo studies for optimizing brain uptake of large molecules: do animal data predict sufficiently well CNS disposition in man? How to assess this?
TABLE 14: Dynamics of the BBB
Moderator: Richard Daneman, Ph.D., Assistant Professor, University of California, San Francisco
- How does the BBB respond to stimuli?
- How do changes of the BBB affect environment of the CNS
- How is the BBB different between different people?
8:35 Chairperson’s Remarks
Lois A. Lampson, Ph.D., Associate Professor of Neurosurgery, Brigham & Women’s Hospital / Harvard Medical School
8:45 BBB Disruption and Drug Delivery in Neurodegenerative Disease
Nga Bien-Ly, Ph.D., Postdoctoral Fellow, Dept. of Neuroscience, Genentech, Inc.
It is generally believed that the BBB is disrupted in many neurodegenerative diseases thus suggesting that drug delivery is enhanced as a consequence of BBB leakage. We set out to determine the extent of BBB disruption in mouse models of neurodegeneration,
focusing on antibody permeability and Alzheimer’s disease, by assessing the differences in brain uptake of control and transferrin receptor (TfR) bispecific antibodies. These results will aid in determining the necessity of developing
improved drug delivery methods for the treatment of neurodegenerative diseases.
9:15 Engineering Lysosomal Enzyme Therapeutics for the Brain as IgG Fusion Proteins that Penetrate the Blood-Brain Barrier
Ruben Boado, Ph.D., Vice President, Research & Development, ArmaGen Technologies, Inc.
BBB-penetration of enzyme therapeutics is enabled by re-engineering recombinant enzyme as IgG fusion proteins, wherein the IgG transport domain targets a specific endogenous receptor-mediated transporter within BBB, such as the human insulin
receptor (HIR). The therapeutic domain of the IgG fusion protein exerts the pharmacological effect in brain once across BBB. Several bi-functional IgG-fusion proteins have been engineered using a genetically engineered monoclonal antibody
directed to the BBB HIR as the transport domain. First in human trials are planned for 2015.
9:45 FEATURED PRESENTATION: OPEN THE BLOOD BRAIN BARRIER GATE FOR BIOLOGICS
Per-Ola Freskgard, Ph.D., Vice Director and Senior Leader,
Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd.
Although biotherapeutics have vast potential for treating brain disorders, their use has been limited due to low exposure across the blood-brain barrier (BBB). This talk will describe a Brain Shuttle technology, which can be engineered
into a standard therapeutic antibody or other modalities for successful BBB transport. These findings will have major implications for the development of biologics-based treatment of brain disorders.
10:15 Selected Poster Presentation I: Canonical Wnt Pathway Modulation Impacts Brain Endothelial Cell Response to Hypoxic Stress
Shyanne Page, Graduate Student, Texas Tech University Health Sciences Center, Dept. of Pharmaceutical Sciences, School of Pharmacy
Stroke is a leading cause of death and morbidity, yet we suffer from lack of stroke neuroprotective drugs. We speculate that identifying novel drug candidates capable of protecting the blood-brain barrier function may help improve stroke outcome
in patients. Using the human induced pluripotent stem cell (iPSC) model developed by Shusta and colleagues, we assessed the ability of these cells to respond to hypoxia/ischemia and evaluated the ability of Wnt/b-catenin activation as
a vasculoprotective pathway.
10:30 Selected Poster Presentation II: Leukocyte-Endothelial Interactions at the Blood-Brain Barrier Studied in Fully-Human Flow-Based In Vitro Models Incorporating Microfluidics
Birgit Obermeier, Ph.D., Postdoctoral Scientist, Neuroimmunology Research, Biogen
In many neurological diseases, dysregulated immune cell infiltration across the BBB is a crucial event in pathogenesis. To decipher mechanisms of leukocyte-endothelial interactions and to study how to manipulate this process for therapeutic
applications, we use in vitro models of the human BBB in the setting of inflammation. Our models include co-culture of cells of the neurovascular unit, account for shear forces in macro- and microfluidic platforms, and allow live cell
imaging of leukocyte trafficking under flow in real time.
10:45 Coffee Break in the Exhibit Hall with Poster Viewing
11:30 Use of a Camelid VHH to Engineer Blood-Brain Barrier Crossing Bispecific
Graham K. Farrington, Ph.D., Director, Chemical & Molecular Therapeutics, Biological
Drug Discovery, Biogen
We have engineered a llama single domain VHH antibody FC5 into mono- and bi-valent proteins fused to a huFc. Upon IV injection in rats up to a 30-fold higher brain exposure was observed compared to control. Upon IV dosing in a Hargreaves model
of inflammatory pain up to a 60-fold increase in pharmacological potency was observed. The study demonstrates that modular incorporation of FC5 as the BBB-carrier arm in bi-specific antibodies or antibody-drug conjugates offers an avenue
to develop pharmacologically active biotherapeutics for CNS indications.
12:00 pm Blood-Brain Barrier (BBB) Penetrating Dual Specific Binding Proteins for Treating Brain and Neurological Diseases
Denise Karaoglu Hanzatian, Ph.D., Principal Research Scientist, Biologics
Discovery, AbbVie Bioresearch Center, Abbvie
12:30 Close of Conference