Cambridge Healthtech Institute’s Inaugural Advancing CNS Biotherapeutics and Crossing the Blood-Brain Barrier conference strives to bring you the hottest topics and biggest opportunities in discovering and developing highly efficacious
therapeutic agents against CNS disorders and innovative strategies for delivering therapies across the blood-brain barrier (BBB). This new meeting will brainstorm ideas and share new research on topics such as the biologics for CNS targets and biomarkers,
brain cancer, neurodegeneration, neuroinflammation, neuroimmunology, alteration of CNS/BBB barriers due to injury or disease, preclinical models, neuroimaging, tools for prediction of brain penetration, and updates from the industry on topics such
as antibody delivery and vector-mediated transport across BBB.
This conference will feature stimulating discussions and a friendly place to network with peers. We invite you to present a poster, or to attend to learn from and network with the leading experts from around the globe.
Final Agenda
SUNDAY, JANUARY 7
4:00 - 6:00 pm Pre-Conference Registration
MONDAY, JANUARY 8
7:00 am Registration and Morning Coffee
9:00 Welcome by Conference Organizer
Nandini Kashyap, Conference Director, Cambridge Healthtech Institute
9:05 Chairperson’s Opening Remarks
Per-Ola Freskgard, Ph.D., Vice Director and Senior Leader, Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd.
9:10 Efficient and Safe Biologics for Diseases of CNS
Per-Ola Freskgard, Ph.D., Vice Director and Senior Leader, Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd.
Technologies to overcome the blood brain barrier have received significant attention. However, whether the technology being used harbors safety limitations to drug development is not entirely clear. Here, I present the Brain Shuttle-mAb (BS-mAb) technology
and investigate the role of Fc effector function in vitro and in vivo. The approach I describe for an amyloid-beta antibody can be applied to any existing therapeutic antibodies. The approach could have a transforming impact
of the development of a new generation of therapies for neurological and psychiatric indications
9:50 Clearance of Beta-amyloid is Facilitated by Apolipoprotein E and Circulating High-density Lipoproteins in Bioengineered Human Vessels
Jerome Robert, Ph.D., Pathology and Laboratory Medicine, Djavad Mowafaghian Centre
for Brain Health, University of British Columbia
Amyloid plaques, consisting of deposited beta-amyloid (Aβ), are a neuropathological hallmark of Alzheimer’s Disease (AD). Cerebral vessels play a major role in AD, as Aβ is cleared from the brain by pathways involving the cerebrovasculature,
most AD patients have cerebrovascular amyloid (cerebral amyloid angiopathy (CAA), and cardiovascular risk factors increase dementia risk. Here we present a notable advance in vascular tissue engineering by generating the first functional 3-
dimensioinal model of CAA in bioengineered human vessels. We show that lipoproteins including brain (apoE) and circulating (high-density lipoprotein) synergize to facilitate Aβ transport across bioengineered human cerebral vessels. These
lipoproteins facilitate Aβ42 transport more efficiently than Aβ40, consistent with Aβ40 being the primary species that accumulates in CAA. Moreover, apoE4 is less effective than apoE2 in promoting Aβ transport, also consistent
with the well-established role of apoE4 in Aβ deposition in AD. .
10:20 Networking Coffee Break
10:45 Biologics That Already Benefit the Brain: Lessons, Mysteries, Surprises
Lois A. Lampson, Ph.D., Formerly Associate Professor of Neurosurgery, Brigham
& Women’s Hospital/Harvard Medical School
Biologics that already benefit the brain include monoclonal antibodies for MS, brain metastases, and models of AD and other tauopathies. Lessons include the value of indirect effects, often involving migratory cells, with the antibody itself not
crossing the BBB. Mysteries include the final effector mechanism, and the state and role of the BBB. Surprises include unorthodox specificities, such as anti-tumor antibodies that also attack normal cells.
11:15 New Targets and Biomarkers for CNS Disorders and Diseases
Servio H. Ramirez, Ph.D., Associate Professor, Pathology and Laboratory Medicine,
Lewis Katz School of Medicine, Temple University
Extracellular microvesicles (EVs) have emerged as a novel biological phenomenon, released by virtually every cell type in the body. We have identified that brain endothelial derived EVs contain key constituents of the BBB. Our recent discoveries
suggest that BBB de-stabilization during neuroinflammation triggers brain endothelial EV release which facilitates BBB breach. Thus, I will introduce concepts that could help us understand EV significance in vascular remodeling and utility
as biomarkers.
11:45 PANEL DISCUSSION: Challenges and Opportunities in Discovery and Development of New CNS and BBB Therapies
Moderator:
Lois A. Lampson, Ph.D., Formerly Associate Professor of Neurosurgery, Brigham & Women’s Hospital/Harvard Medical School
Panelists:
Per-Ola Freskgard, Ph.D., Vice Director and Senior Leader, Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd.
Jerome Robert, PhD, Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia
Servio Ramirez, Ph.D., Associate Professor, Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University
12:15 pm Enjoy Lunch on Your Own
2:00 Chairperson’s Remarks
Torben Moos, M.D., Ph.D., DMSc, Professor, Medicine and Health Technology, Aalborg University
2:05 Brain Penetrating IgG Fusion Proteins: From Genetic Engineering to Clinical Trials in Lysosomal Storage Disorders
Ruben Boado, Ph.D., Vice President, Research & Development/Co-Founder, ArmaGen, Inc.
Lysosomal enzymes, such as iduronase (IDUA) and sulfatases, are large molecule drugs that do not cross the blood-brain barrier (BBB). The BBB-penetration of enzyme therapeutics is enabled by re-engineering the recombinant enzyme as bi-functional
IgG fusion proteins, wherein the IgG domain targets a specific endogenous receptor-mediated transporter system within the BBB, such as the human insulin receptor (HIR). The enzyme therapeutic domain of the fusion protein exerts the pharmacological
effect in brain once across the BBB. Several brain penetrating IgG-LSD fusion proteins have been engineered and validated. First in human proof of concept Phase II clinical trial in LSD is in progress.
2:35 Deliverable Biologics at the Blood-Brain Barrier
Torben Moos, M.D., Ph.D., DMSc, Professor, Medicine and Health Technology, Aalborg
University
My presentation will cover the concepts of the blood-brain barrier (BBB) with emphasis on macromolecular transport. I will cover the restraints and probable avenues for transport of biologics through the BBB. I will place emphasis on transport
of proteins with therapeutic potential. This will include targeted uptake at the BBB, the potential of induced gene therapy to the BBB, and hypotheses on further release of biologics into the brain.
3:05 Transition to BuzZ Sessions
3:15 BuzZ Sessions with Refreshments
Join your peers and colleagues for interactive roundtable discussions.
4:30 Delivery across the BBB, Utilizing Single-Domain Antibodies and a New Receptor-Mediated Transcytosis Pathway
Kristin Kemmerich, Ph.D., Head, Antibody Generation Section, National
Research Council Canada
The blood-brain barrier (BBB) regulates brain homeostasis and provides protection against pathogens and other molecules, but it also restricts the effective delivery of biotherapeutics into the CNS. Here we characterize an unexplored receptor-mediated
transcytosis pathway to deliver biologics to the brain. We developed specific single-domain antibodies that can carry payload across the BBB and assessed these in vitro and in vivo to allow for PK/PD modeling.
5:00 Development of Highly Efficient BBB Transport of Antibodies to the CNS Using in vivo Phage Display with Single Domain VNAR to the Transferrin Receptor
Frank S. Walsh, Ph.D., CEO, Ossianix
Antibody-based molecules do not cross the BBB in amounts required for therapeutic efficacy. Receptor-mediated transporters in the luminal membrane of brain capillary endothelium offer an approach for the delivery of therapeutics to the brain.
Using a combination of in vitro and in vivo phage display technology, we isolated a panel of cross species binders to the transferrin receptor 1 (TfR1) from synthetic
single domain VNAR libraries. At therapeutic (2 mg/kg) doses delivered by tail vein injection, high levels (>5% brain/plasma ratio) of the bispecific antibodies were found in the brain after 18 hours.
5:30 Blood-Brain Barrier Penetrating Dual Specific Binding Proteins for Treating Brain and Neurological Diseases
Kangwen Deng, Ph.D., Senior Scientist, Biologics, AbbVie
Blood-brain barrier (BBB), which consists mainly of specialized brain capillary endothelial cells, is a physical and physiological barrier that controls very efficiently and selectively the entry of compounds from blood into the CNS, and protects
nervous tissue from harmful substances and infectious agents present in circulating blood. While naturally protective, the BBB provides a challenge for drug development as most of the small organic molecule drugs and nearly all biologic
therapeutics do not cross the BBB to therapeutically relevant concentrations. Here, we will describe the generation and expression of DVD-Ig proteins which are capable of binding specific disease targets in the brain. The levels and localization
of DVD-Ig proteins, which were injected systemically, were assessed by two orthogonal methods. Results showing the uptake, retention as well as the elevated functional activity of DVD-Ig proteins in the brain will be demonstrated.
6:
00 - 7:15 Welcome Reception in the Exhibit Hall with Poster Viewing
7:15 Close of Day
TUESDAY, JANUARY 9
8:00 am Registration and Morning Coffee
8:30 Chairperson’s Remarks
Miroslaw Janowski, M.D., Ph.D., Associate Professor, Radiology, Johns Hopkins University
8:35 Extremely Fast Clinical MRI for Predicting and Real-Time Monitoring of Intra-Arterial Opening of the Blood-Brain Barrier
Miroslaw Janowski, M.D., Ph.D., Associate Professor,
Radiology, Johns Hopkins University
MRI guidance enables opening of the blood-brain barrier (BBB) using intra-arterial route in a predicted and precise fashion. However, the monitoring of the process of BBB opening was difficult, as the real-time EPI MRI pulse sequence
was not capable of visualizing the marker of BBB permeability. Here, we show that extreme speed of MRI reconstruction using the new GPU set-up allows turning other pulse sequences into real-time mode and visualize the process
of BBB opening.
9:05 Nanobodies to Cross the Blood-Brain Barrier
Yessica Wouters, Researcher, VIB & KU Leuven Center for Brain & Disease Research
9:50 Coffee Break in the Exhibit Hall with Poster Viewing
11:00 The Blood Meningeal Barrier (BMB) Orchestrates the Development of Neuroinflammatory Responses
Jorge Iván Alvarez, Ph.D., Assistant Professor,
Department of Pathobiology, University of Pennsylvania
To address how CNS endothelium drives neuroinflammation, we established a novel human model of the BMB and BBB. We found that the BMB immunological fingerprint induces a proinflammatory phenotype on migrating lymphocytes and promotes
B cell aggregates that mirror their distribution within the meningeal compartment during multiple sclerosis. Our findings highlight the heterogeneity of the CNS vascular beds, how they regulate leukocyte function and demonstrate
that the BMB niche is more conducive to promote neuroinflammation.
11:30 Intranasal Administration as a Method to Target Therapeutics to the CNS
Jeffrey Lochhead, Ph.D., Research Assistant Professor,
Department of Pharmacology, University of Arizona
12:00 pm Close of Advancing CNS Biotherapeutics and Crossing the Blood-Brain Barrier Conference