BioCenturyInnovations070915

STRATEGY
THE PRIORITY OF
PROXIMITY
By Lauren Martz, Staff Writer
Following on two years of success with its four innovation centers,
Johnson & Johnson is expanding its hub-and-spoke model for
identifying and developing external early stage innovations to new
regions. Among the 17 deals announced last month by Johnson &
Johnson Innovation, the pharma’s early stage collaboration unit, three
are designed to extend the company’s reach into research institutions
in Europe and Canada.
One is a partnership with the Karolinska Institute to form a Nordic
innovation hub. The other two are broad collaborations that grant
J&J access to more early stage technology: a drug discovery deal with
the Lead Discovery Center GmbH (LDC) that spans Germany, and
an extended and expanded collaboration with MaRS Innovation in
Toronto to support emerging science projects in Ontario.
A fourth deal out of the 17 involves a partnership with the University
of Queensland and UniQuest Pty. Ltd. in Australia to identify drugs
against a new target for ankylosing spondlyitis. (See "Australian
Innovations", page 2)
"Great science is just as likely to come from outside the company as it
is to come from inside," said Melinda Richter, head of J&J Innovation's
JLABS network. "We do know that at least half of the revenue from
pharma comes from external innovations, so we're agnostic to where
the technology comes from."
In 2013, J&J Innovation opened its first innovation center in London,
and it has since created three more centers in San Francisco, Boston
and Shanghai. Each center is responsible for coordinating all early
stage investments and collaborations within its broad geographic
range, and has the ability to make local deals.
"The innovation centers are hotspots for life science innovation
where senior technology people from J&J are allocated from across
the different sectors of the company to interact with the scientific
community and make different forms of deals to promote development
of new technology, create new spinout companies or in-license
technology into J&J for development," said Robert Urban, head of
Johnson & Johnson Innovation, Boston.
JULY 9, 2015
COVER STORY
1 THE PRIORITY OF PROXIMITY
J&J Innovation is forming research hubs in Europe and
Canada to stimulate biotech growth and expand its
access to academic innovations.
STRATEGY
6 GSK AIMS HIGHER IN GENETICS
GSK has launched the Altius Institute to help it employ
information about gene regulation for improving target
selection.
PRODUCT R&D
9 DOWNSTREAM WITHOUT A NET
Modiquest has spun out Citryll to develop therapeutic
antibodies against citrullinated proteins that may
have advantages over PAD inhibitors in treating
autoimmune diseases.
TARGETS & MECHANISMS
11 SORTING OUT α-SYNUCLEIN
Two studies show how different forms of α-synuclein
might initiate and propagate Parkinson's disease in the
brain, pointing to new therapeutic possibilities.
15 TOP TRANSLATIONAL TARGETS, 2013-14
The most frequently cited targets from selected
disease areas, as published in The Distillery from
2013-2014.
DISTILLERY
16 THERAPEUTICS
Antagonizing CXCL12-CXCR4 signaling for T-ALL;
BMP9 for PAH; griselimycin-based DnaN inhibitor for
tuberculosis; and more...
23 TECHNIQUES
Delayed remyelination mouse model of MS; spatially
and temporally controlled CRISPR gene editing;
gadolinium nanoparticle-based MRI agent for GBM;
and more...

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STRATEGY
According to Johan Verbeeck, senior director of partnership
management at Johnson & Johnson Innovation, London,
the types of deals that the innovation centers make range
from simple equity investments to biotech options. "We need
flexibility to make deals so that we don't miss out on a piece of
science," he said. "The common goal of all of our deals is to find
a way to translate early stage research to assets worth further
pursuing. The last thing you will find is a deal template."
Urban noted that J&J Innovation has already made over 200
investments through its innovation centers. Now, the company
wants to build on that with further ties to academics, and sees
the new alliances as “spokes” extending out from its innovation
hubs.
"Each innovation center covers a very large geographic range,
and we are strong believers in the value of proximity to science,
including both entrepreneurs and academics," said Verbeeck.
"We said that if our original model was successful, we would
begin to open satellite offices to achieve greater proximity to
the work. Our new hub in the Nordics is a way to expand our
network in Europe."
NORDIC INNOVATION
The Nordic innovation hub at Karolinska gives the pharma
broad access to the institute's network of researchers.
Under the terms of the deal, J&J Innovation partnered with
Karolinska Institutet Holding AB, the institute's holding
company that enables technology commercialization. J&J has
formed a satellite office at the Karolinska Institute to scout for
new technologies, which is affiliated with the London innovation
center.
STRATEGY
AUSTRALIAN INNOVATIONS
Broad collaborations to access external innovations are
only one of the types of deals announced last month by J&J
Innovations. The company is also forming disease-focused
researchpartnerships,includingacollaborationwithUniQuest
Pty. Ltd., the technology transfer and commercialization
company associated with the University of Queensland, to
develop small molecules for ankylosing spondylitis.
Current treatments for the disease — which is a form of
arthritis affecting the joints of the spine — include NSAIDs
and biologics such as tumor necrosis factor (TNF) α inhibitors
to treat the pain and inflammation.
According to Bruce Wyse, business development manager
at the University of Queensland, those therapeutics are not
effective for all patients and they only address the symptoms,
not the cause of disease. The goal of new therapies is to stop
disease progression.
The deal was struck between Johnson & Johnson’s Janssen
CilagPty.Ltd.subsidiaryandUniQuest,toidentify,developand
commercialize small molecule modulators of an undisclosed
target. Janssen selected UniQuest based on a promising
new target identified by a University of Queensland team
led by Matt Brown, director of the University of Queensland
Dementia Institute. As the university’s commercialization
company, UniQuest is facilitating the deal with Janssen.
Under the terms of the three-year deal, UniQuest and
University of Queensland researchers will identify small
molecule candidates against the target using assays and
disease models, and will develop the molecules through
lead optimization. Mark Ashton, senior director of health
at UniQuest, told BioCentury that Janssen will be providing
financial support during this phase, and Wyse added that
Janssen will also provide drug development guidance during
the process.
Janssen has exclusive rights to develop and commercialize
resulting molecules.
According to Wyse, the researchers also have data supporting
a role for the target in other inflammatory diseases including
psoriasis and inflammatory bowel disease (IBD). UniQuest is
not disclosing whether therapeutics developed for the other
indications are also included in the deal.
The deal is the third major research collaboration between
Janssen and UniQuest. In 2012, the partners joined up to
develop pain therapeutics using components of spider venom.
The next year, Janssen Biotech Inc. partnered with Uniquest
spinout Dendright Pty. Ltd. to develop immunotherapy for
rheumatoid arthritis (RA).
— Lauren Martz

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STRATEGY
According to Alexander von Gabain, deputy vice chancellor for
innovation and commercial outreach at Karolinska, J&J signed
the deal with the holding company, rather than the institute
itself, to avoid conflicts of interest.
"Karolinska Institutet Holding AB is daughter of Karolinska
and our commercialization vehicle, enabling the university
to take part in business incubation, seed investment and
equity ownership regarding technology transfer and spin-
off companies" he said. "Through this partnership, J&J is also
aiming to provide seed investments for proof of concepts of early
translational projects and to support start-ups and advanced
spin-offs with venture capital to further facilitate the innovation
activity at Karolinska."
Within the deal, J&J will supply to researchers from Karolinska
and the Nordic region, industry knowledge, coaching and
investments to develop new ideas into assets.
Both Verbeeck and von Gabain noted that the primary goal of
the partnership is to improve the biotechnology landscape and
stimulate company formation in the region.
"Having satellite offices like this one is the way that we support
the life science ecosystem," said Verbeeck. "A healthy life science
ecosystem benefits everyone."
He added that J&J believes investing in the overall ecosystem
will pay dividends in the long run because that is where its
products have come from in the past. "It benefits us to create a
biotech sector with a good understanding of J&J," he said.
J&J Innovation already had several research collaborations
with Karolinska and selected the institute because of the depth
of science and the institute's influence in the Nordic region,
Verbeeck said.
"Karolinska is interconnected within Scandinavia and also
reaches out beyond the region with relationships with leading
European partner universities and academic institutions," von
Gabain told BioCentury. He added that Karolinska also has
global alliances with U.S. and Far East-based health care and
research institutions. "We think we are an attractive partner for
J&J because interesting projects from other institutions that may
be translated may come to the attention of the company just by
being at or linked to the campus and utilizing our networks."
He added that the structure of the deal allows both partners to
take advantage of the whole network of research in the Nordic
region.
"Within the blue chip group of big pharmas, many still take the
traditional approach to external innovation," von Gabain said.
"They look for a publication that pops out of a university that
could be important for a product, approach the university and
try to make a very specific deal on the discovery.”
By contrast, he said, J&J’s strategy allows for deals that might not
have been expected at the outset. “If you restrict partnerships to
only a very narrow focus, you might miss out on the innovation
opportunities that can come from a more open innovation
environment."
TRANSLATION AT KAROLINSKA
The collaboration aligns not only with J&J’s strategy, but is
equally important to Karolinska’s new translational drive.
Since von Gabain joined the institute last September, his aim
has been to foster innovation by disseminating knowledge
and education about how to translate early stage research and
entrepreneurship throughout the entire organization.
He told BioCentury that the J&J partnership is one of the first
steps towards implementing that goal.
The deal centers around J&J’s five primary therapeutic areas:
cardiovascular and metabolic diseases, immunology, infectious
diseases and vaccines, neuroscience, and oncology. In addition,
J&J is open to supporting projects related to its medical device
and consumer product businesses.
"We do know that at least half of the revenue from
pharma comes from external innovations, so we're
agnostic to where the technology comes from."
Melinda Richter, Johnson & Johnson

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For Karolinska, those areas represent many of its primary
research areas, and it hopes to follow it up with more deals with
other industry partners.
“Hopefully this won’t be the only deal of that kind. We can’t play
with 10 companies, but the hope is that in a year and a half, we
will have two or three such pharma partners that complement
each other in their appetite for various disease areas,” said von
Gabain.
"With all of our deals, we stay focused on our strategic areas
because this not only helps us develop our programs but also
allows us to evaluate external science because we have the
internal expertise to do so," said Verbeeck.
The collaboration is set for three years, but Karolinska and J&J
Innovation both expect that it will extend beyond that initial
time frame.
OTHER NEW DEALS
J&J Innovation's collaborations with LDC and MaRS Innovation
also fall into its strategy of extending the company’s reach
beyond its innovation centers.
LDC is a compound validation and screening center in Europe
that the Max Planck Institute for Infection Biology spun out in
2008.
"The Lead Discovery Center is a unique construct in Europe,"
said Verbeeck. "A lot of universities deal with the same issue
of how to validate novel targets and screen against the targets
for leads. The LDC helps them figure that out, which creates
an advantage for translation and commercialization of the
research."
The goal of the J&J alliance is to accelerate drug discovery
initiatives that come out of academic institutions within LDC's
network of academic researchers at Max Planck Institutes and
the Helmholtz Association. The structure of the collaboration
allows J&J Innovation to select projects from the academic
network within its five therapeutic areas and allows the partners
to create individual deals around each project.
“Similar to the Karolinska deal, this is all about the network. The
collaboration spans a lot of research in an attractive life science
cluster. It is just another reflection of our priority for proximity,”
said Verbeeck.
He added: "We set this up to give us access to potential novel
targets at German institutions, and we can either work with
LDC to validate and screen against those targets, or they can
screen on our behalf. The goal is to bring the new targets to
proof of concept in animals, and then we can decide whether
to bring the technology to the innovation centers for further
investment and development."
J&J Innovation expanded its collaboration with MaRS
Innovation to increase access to technology in Toronto
and elsewhere in Ontario. Unlike the European deals, this
collaboration is managed by the innovation center in Boston.
The expansion builds on a previous relationship between
J&J Innovation and MaRS Innovation that resulted in three
partnered projects: one for improving cardiac surgery outcomes;
a second using biomarkers to detect depression; and a third
focused on diagnosis of gestational diabetes.
Those three projects were selected as part of MaRS Innovation's
Framework Fund. Projects supported by the fund are chosen
by MaRS Innovation and an industry partner, and the partners
each contribute equal funding. The amount of funding per
project varies based on the research needs. J&J Innovation has
first right to negotiate technology resulting from its Framework
Fund projects.
The expanded agreement allows the partners to develop a
second cohort of projects under the Framework Fund. The
partners are already looking for new projects, but the number
of new projects they will take on is not set. MaRS Innovation
is not disclosing the amount of funding available to the second
cohort of projects.
MaRS Innovations has also partnered with J&J's Janssen R&D
LLC subsidiary in the Neuroscience Catalyst consortium, which
received a C$1 million ($0.79 million) investment from the
Government of Ontario's Ministry of Research and Innovation
last month, raising the consortium's total funding to C$3.7
million ($2.9 million). Members of the consortium include the
"We said that if our original model
was successful, we would begin
to open satellite offices to achieve
greater proximity to the work. We are
now looking to expand our network in
Europe."
Johan Verbeeck, Johnson & Johnson

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University of Toronto, Evotec AG and the Ontario Centres of
Excellence (OCE).
The consortium, which was launched last September, is selecting
early stage research projects focused on identifying new
therapeutics for Alzheimer's disease (AD) and mood disorders.
"Unlike our Framework Fund projects, the Neuroscience
Catalyst projects are still precompetitive and there is no IP to
be addressed," said MaRS Innovation CEO Rafi Hofstein. "Once
these precompetitive projects are developed, we could move
them into the fund."
"Through our Innovation Center Network, we've made it easier
to get in touch with the right person at J&J," said Verbeeck. "This
greatly facilitates evaluation of early stage and external research
and is brought on by our new collaborations like these. Our
goal has been to open the door to everybody and anybody who
wants to collaborate with us."
COMPANIES AND INSTITUTIONS MENTIONED
Dendright Pty. Ltd., Brisbane, Australia
Evotec AG (Xetra:EVT), Hamburg, Germany
Helmholtz Association, Berlin, Germany
Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J.
Karolinska Institute, Stockholm, Sweden
Karolinska Institutet Holding AB, Solna, Sweden
Lead Discovery Center GmbH, Dortmund, Germany
MaRS Innovation, Toronto, Ontario
Max Planck Institute for Infection Biology, Berlin, Germany
Ontario Centres of Excellence (OCE), Toronto, Ontario
UniQuest Pty. Ltd., Brisbane, Australia
University of Queensland, Brisbane, Australia
University of Toronto, Toronto, Ontario
TARGETS AND COMPOUNDS
TNFα - Tumor necrosis factor α
REFERENCES
Edelson, S. "Mixing it up at Karolinska." BioCentury Innovations (2014)

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STRATEGY
STRATEGY
GSK AIMS HIGHER IN GENETICS
By Stephen Parmley, Senior Writer
GlaxoSmithKline plc’s launch of the independent Altius
Institute for Biomedical Sciences last month showed the pharma
is making the use of cutting-edge research and technologies
for gene regulation a top priority in guiding its drug discovery
and development. Altius’ primary mission is to help GSK
improve the success rate of its discovery pipeline by developing
innovative methods for analyzing gene regulatory networks and
applying those tools to target selection for new compounds.
“Now is the time to invest in improving target selection because
it is the first major decision in the drug discovery pipeline and
we think it is probably the place where you can ideally spend
the least to have the biggest impact,” said Lon Cardon, SVP of
alternative discovery and development at GSK.
During the first five years of the 10-year collaboration between
GSK and Altius, the pharma will provide the institute with
more than $95 million to fund basic research; develop the
instrumentation, automation and computational tools for
studying gene regulation; and apply those technologies and
discoveries to GSK’s drug discovery and development projects.
Although the pharma isn’t disclosing specific projects the
institute will work on, Cardon said the idea arose when GSK
realized its drug discovery process might benefit from recent
technological and computational breakthroughs in analyzing
how the human genome is regulated in normal and diseased
states.
Last week in Nature Genetics, a GSK team showed that
compounds that were approved or reached Phase III had
stronger genetic evidence for their mechanisms of action than
compounds that only reached earlier stages of development.
The findings suggested that molecules based on a mechanism
of action that involved a genetic link to the disease were
more likely to succeed, and the team estimated that selecting
genetically supported targets could double the success rate of
compounds making it from Phase I to approval. (See “Doubling
down”, page 7)
Cardon said the work of John Stamatoyannopoulous’ team on
the Encyclopedia of DNA Elements (ENCODE) project also
caught GSK’s attention as a way of selecting targets based on
genetic evidence. ENCODE is a National Human Genome
Research Institute (NHGRI) project that indexes functional
elements in DNA and maps gene regulatory networks.
GSK has tapped Stamatoyannopolous, who is an associate
professor of genome sciences and medicine professor at the
University of Washington, to lead research at Altius.
In the last three years, Stamatoyannopolous’ team has published
multiple ENCODE studies demonstrating gene expression in
disease is influenced by complex regulatory networks involving
transcription factors that bind regulatory DNA elements in
non-coding regions at large distances from genes.
His team identified transcription factor binding sites in
chromosomal DNA based on their sensitivity to nuclease
cleavage, then overlaid that information with SNPs and other
data from genomewide association studies. That allowed
the researchers to identify regulatory sequences that could
play a role in various cancers and autoimmune, metabolic
and neurodegenerative diseases, but that would have been
overlooked in studies focused on only the proximal regions of
genes.
For example, in a 2012 Science study, Stamatoyannopolous and
colleagues showed that SNPs associated with a wide variety
of autoimmune disorders fall within nuclease sensitive sites
in immune cells. Moreover, the team found that 24.4% of the
disease-associated SNPs fell within the recognition sequences of
"Now is the time to invest in
improving target selection because it
is the first major decision in the drug
discovery pipeline and we think it is
probably the place where you can
ideally spend the least to have the
biggest impact."
Lon Cardon, GlaxoSmithKline plc

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one or more of 15 transcription factors that interact with IRF9, a
transcription factor associated with type I interferon induction
and a critical component of the JAK/STAT signaling pathway.
That suggested dysregulated JAK/STAT-mediated type I
interferon responses may play important roles in diverse
inflammatory disorders and members of the network might be
viable therapeutic targets.
However, Stamatoyannopolous told BioCentury that ENCODE
initially focused on developing methodologies and automation
technologies, and on defining the basic math needed to analyze
the human genome. “The projects did not apply the technologies
to answer specific questions that would be relevant for
discovering medicines and understanding disease mechanisms,”
he said.
Stamatoyannopoulous’ and GSK’s mutual interest in using gene
regulatory networks to aid drug discovery brought the two
parties together for several pilot projects to determine whether
there were ways of applying information about gene regulation
and function, and the technologies needed to discover them, to
improve early stage drug discovery.
“We got very excited about the initial results of the pilot
studies and as a result we put our heads together to try to build
something more formal and broader that could reach all the way
across our pipeline,” which led to the idea to launch Altius, said
Cardon.
According to Stamatoyannopolous, the Altius building will be
located at the Seattle Waterfront and should be active by the end
of 2015.
STRATEGY
DOUBLING DOWN
A team at GlaxoSmithKline plc analyzing genetic data on compounds at all
stages of development has shown that compounds whose mechanism of
action had a genetic link to the disease were more likely to progress through
clinical development than those without such a link. The team estimated
that selecting genetically supported targets could double the success rate of
approval for compounds in late-stage clinical development.
Matthew Nelson, first author on the study and head of genetics at GSK, said,
“The farther you go into the drug development pipeline, the more likely the
drug target and disease indication have genetic evidence underlying them.”
Nelson said there were several successful examples at GSK where a drug
discovery effort started by selecting a target with a well-known genetic
association, but the strategy was not widespread. He noted that several years
ago GSK executives considered prioritizing drugs that had genetic evidence
supporting the mechanism to increase drug approval rates, but the pharma
had not done a systematic analysis of drug pipelines to determine whether
the data supported the strategy.
To address the question of how much weight should be given to genetic
evidence in guiding target selection, Nelson’s team analyzed historical data
on drugs in clinical development going back 40-50 years.
The group used a commercial compound database to categorize compounds
by their targets, and used the last stage of development reached for each
compound as a measure of success.
The team integrated information on 22,270 compounds known to modulate
1,824 human drug targets in 705 disease indications and eliminated
redundant compounds in the same drug class.
The team then analyzed common variant genetic association data from two
databases, the Online Mendelian Inheritance in Man (OMIM) database of
rare diseases and the GWASdb database, and created target-indication pairs
that matched potential causal genes with the associated disease indications.
The researchers then integrated both data sets to assess the link between
compounds and genetic support.
The team integrated information on approved drugs with information on
22,012 genes encoding human proteins and found that the gene targets
of successful drugs correlated with the presence of mutations or other
variations in genes associated with disease. For example, 206 of 389 target
genes (53%) for approved drugs were also associated with rare disease
genes identified from OMIM.
“That suggests to us that genes that are involved in rare human conditions are
far more likely to be associated with a drug target that is approved,” Nelson
said.
He added that the pattern wasn’t limited to rare diseases because gene
targets of approved drugs also had a correlation with genes identified in
GWASdb that were linked to common diseases.
In addition, the percent of target-indication pairs supported by genetic
evidence correlated with progression through drug development. That
provided statistical backing for using genetic association to increase the odds
of success in the clinic.
For example, the genetic support increased from 2.0% for target-indication
pairs that had only progressed as far as Phase I to 8.2% for drugs that were
approved.
Results were published in Nature Genetics.
Based on the analysis the group estimates that having genetic evidence
connecting a compound’s mechanism with the disease will double its chance
of successfully going from Phase I to approval.
“It doesn’t mean that by selecting targets with genetic support we are going
to automatically double success of the pipeline because many things going
into the pipeline already have some amount of genetic support,” Nelson said.
But he added that “even shifting the overall success rate for late-stage clinical
trials from 5% to 7% would have a very measurable impact.”
— Stephen Parmley

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Cardon told BioCentury that GSK decided to build an
independent institute rather than try to build a similar analytical
capability in-house. “We did not want to embed this in GSK
because we thought it would be too expensive to do so and by
the time we fully implemented it in an industrial environment it
would lose the edge completely,” he said.
BUILDING TECHNOLOGIES
One of GSK’s primary goals for Stamatoyannopoulos’ team at
Altius is to deliver new technologies in computational chemistry,
molecular biology, direct imaging and other systems needed to
analyze and apply gene regulation data to drug discovery.
“We are seeing a fundamental shift in the speed at which
the technologies are interrogating the dynamic genome,”
Stamatoyannopolous said. “In order to stay ahead and be at the
leading edge one has to continuously innovate in this area.”
“The kinds of technologies that we have on the books really
don’t exist yet in any kind of production form,” he said. “We
are not going to be taking an off-the-shelf instrument and
putting it into play. In some cases we are going to be using new
instrumentation that is in the development stages, in the areas of
advanced imaging and ultra-high throughput, high resolution
imaging.”
He said the enabling technologies will be organized in a
configuration that would be difficult to achieve in an academic
lab or traditional biotech setting. “What we are aiming
for is cleverly applying and developing automation and
miniaturization so that we can achieve high operational leverage
with a limited number of people.”
Stamatoyannopoulos added: “We are definitely going to be
pushing the translational aspect of this and we will be doing so
in collaboration with Seattle area institutions and others around
the country.”
Cardon said GSK has first rights to option any IP developed at
the institute.
GSK also retains rights to invest in the commercialization of
Altius’ IP and in any companies the institute spins out.
Altius Institute for Biomedical Sciences, Seattle, Wash.
GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.
National Human Genome Research Institute (NHGRI), Bethesda, Md.
University of Washington, Seattle, Wash.
IRF9 - Interferon regulatory factor 9
JAK - JAK kinase
REFERENCES
Maurano, M., et al. “Systematic localization of common disease-associated variation in regulato-
ry DNA.” Science (2012)
Nelson, M., et al. “The support of human genetic evidence for approved drug indications.” Nature
Genetics (2015)
Osherovich, L. “Cracking ENCODE.” SciBX: Science-Business eXchange (2012)
"These technologies can be applied
to derive fundamental insights about
how drugs are working and what are
the right pathways to go after."
John Stamatoyannopolous, University of Washington

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PRODUCT R&D
PRODUCT R&D
DOWNSTREAM WITHOUT A NET
By Stephen Parmley, Senior Writer
ModiQuest Research B.V. has discovered that its therapeutic
mAb against citrullinated histones has the potential to treat
autoimmune diseases by inhibiting the formation of neutrophil
extracellular traps that play a role in the pathogenesis of
autoimmunity. Because it acts on pathways downstream of PAD,
the mAb may have fewer side effects than PAD inhibitors already
in development.
Last month, ModiQuest spun out Citryll B.V. as a single-asset
companytodeveloptheleadtherapeuticanti-citrullinatedprotein
antibody (tACPA) for inflammatory diseases such as rheumatoid
arthritis (RA).
“Our therapeutic tACPA antibodies have an advantage over
small molecule PAD inhibitors because they don’t have a wide
tissue distribution like small molecules and they don’t inhibit
the normal function of PAD enzymes, and so have a decreased
likehood for adverse effects,” Citryll CEO Helmuth van Es said.
The five members of the PAD family of proteins sit atop a
pathological cascade that drives RA and other autoimmune
diseases. Various PADs, including PAD4, modify histones and
other proteins by replacing positively charged arginine residues
with neutral citrulline residues, which alters the tertiary structure
of the protein and exposes inflammatory neo-epitopes that can
make the proteins autoantigenic.
In neutrophils, activation of PAD4 can lead to hypercitrullination
of nuclear chromatin, which results in the formation of neutrophil
extracellular traps (NETs) that under normal circumstances
eliminate infectious pathogens from circulation. But dysregulated
formation and release of NETs also results in citrullinated proteins
entering the circulation, where they can be seen as autoantibodies
and trigger an inflammatory response. NET dysregulation has
been linked to several human autoimmune diseases, including
RA and systemic lupus erythematosus (SLE).
“Citrullinated proteins are released into circulation and at
some point tolerance against these autoantigens is broken and
rheumatoid arthritis develops,” said van Es. “Normally PADs are
not extracellular, but when you have tissue damage they can leak
out of the cell and then you get a whole cascade that slowly builds
up over the years in RA patients.”
In the environment of inflamed joints, extracellular PADs become
highly active and citrullinate proteins such as fibrinogen, which
contributes to an enhanced local inflammatory response.
However, citrullination of proteins by PADs is also important to
normal cellular functions such as skin keratinization, insulation
of neurons, and gene regulation. On that basis, researchers at
ModiQuest reasoned that targeting the citrullinated autoantigens
could be a safer alternative than pan-inhibition of PADs.
At least two companies, Padlock Therapeutics Inc. and its partner
Evotec AG, are developing PAD inhibitors that could treat
autoimmune diseases by blocking NET formation. Padlock is
currently focused on PAD2 and PAD4 because of their disease
associations but has not ruled out developing pan-PAD inhibitors.
The company declined a request to comment.
MODIQUEST’S QUEST
ModiQuest did not set out to develop therapeutic mAbs against
citrullinated proteins for autoimmune disease. Instead, the
company began by studying the functions of mAbs that are
naturally found in RA patients.
van Es said the mAbs arise prior to disease onset in RA, making
them useful diagnostic markers, and ModiQuest wanted to
determine whether the mAbs contributed to disease pathology or
were a by-product of it.
In 2013, a ModiQuest team identified and cloned multiple
antibodies against citrullinated proteins from RA patients and
tested them in mouse models of acute RA. Surprisingly, the team
"We have in our hands an antibody
that can inhibit NETosis, that binds
citrullinated epitopes on histones,
and could likely interfere with the
toxicity of histones."
Helmuth van Es, Citryll B.V.

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10 july 9, 2015 TOC
PRODUCT R&D
found that several of the mAbs did not exacerbate disease in the
models, but instead treated it.
The team also showed that combining one of these therapeutic
mAbs — now dubbed tACPAs — with dexamethasone reduced
inflammation and flares in a mouse model of chronic RA.
The researchers also mapped the epitope recognized by the lead
tACPA to a peptide sequence in the N-terminus of histone 2A, a
site that PAD4 citrullinates. The mAb did not stain tissue arrays
from healthy volunteers but did stain healthy granulocytes and
macrophages, indicating the compound might have minimal
off-target effects. However, ModiQuest did not determine the
antibodies’ full mechanism of action in that study.
The company reported the data in the Journal of Clinical &
Cellular Immunology.
In May, ModiQuest researchers reported that the lead tACPA
inhibited NET formation. In a human neutrophil-based assay
of calcium ionophore-induced NET formation, the lead tACPA
decreased NET formation compared with a control antibody. The
company presented the data at the 2015 Protein and Antibody
Engineering Summit (PEGS).
van Es told BioCentury that the tACPA inhibits formation of
NET lattices, which prevents the release of new autoantigens
and proinflammatory factors. In addition, he said, tACPAs could
work in concert with macrophages to enhance clearance of NETs,
NET remnants, and the toxic citrullinated histones from tissues
and circulation.
Those additional effects would give a tACPA more than just a
safety advantage over PAD inhibitors, said van Es. “We have
in our hands an antibody that can inhibit NETosis, that binds
citrullinated epitopes on histones, and could likely interfere with
the toxicity of histones, since circulating histones contribute to a
number of different disease phenotypes as well.”
Although Citryll has not selected the lead indication for the
tACPA, the company will continue testing the mAb in RA models
and will compare it to JAK and PAD inhibitors, van Es said.
“There is a whole bunch of diseases where we think inhibition of
NETs could be therapeutic,” such as idiopathic pulmonary fibrosis
(IPF), where NETs play a role in fibrosis formation, he said. “We
have preliminary in vivo data for IPF as well as colitis. We are
also developing biomarker assays based on the literature and our
own findings that should allow us to measure NET components
in the sera of RA patients and select the right patient population
for tACPA treatment.”
According to van Es, about 15% of RA patients have antibodies
that activate PAD4, resulting in severe disease. These antibodies
would be markers for patients most likely to benefit from tACPA.
In addition to raising seed funding, van Es said Citryll is actively
seeking a partner.
“Since we are a small company, we need to be very focused on
one disease,” he said. “We are looking for a development partner
because they might have more insights into progressing the
molecule in other diseases.”
ModiQuest has multiple pending and issued patents covering
the tACPA antibodies and their therapeutic uses in RA and
pulmonary fibrosis. Citryll has an exclusive option to license the
IP portfolio.
Citryll B.V., Oss, the Netherlands
Evotec AG (Xetra:EVT), Hamburg, Germany
ModiQuest Research B.V., Oss, the Netherlands
Padlock Therapeutics Inc., Cambridge, Mass.
JAK - JAK kinase
PAD (PADI) - peptidyl arginine deiminase
PAD2 (PADI2) - peptidyl arginine deiminase type II
PAD4 (PADI4) - peptidyl arginine deiminase type IV
REFERENCES
Chirivi, R., et al. “Anti-citrullinated protein antibodies as novel therapeutic drugs in rheumatoid
arthritis.” Journal of Clinical & Cellular Immunology (2013)
Martz, L. “Padlock’s keys to academia.” BioCentury Innovations (2015)
Rhodes, J. “Unlocking PADs.” BioCentury (2015)
"Our therapeutic tACPA antibodies
have an advantage over small
molecule PAD inhibitors because
they don't have a wide tissue
distribution like small molecules and
they don't inhibit the normal function
of PAD enzymes."
Helmuth van Es, Citryll B.V.

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11 july 9, 2015 TOC
SORTING OUT α-SYNUCLEIN
By Selina Koch, Staff Writer
Studies by two independent groups propose a new hypothesis
about how α-synuclein contributes to Parkinson’s disease,
suggesting that normal tetramers of the protein with α-helical
structure break up into unfolded monomers, then regroup into
toxic ribbon and fibril structures that spread from neuron to
neuron to propagate the pathology throughout the brain. The
findings point to tetramer stabilization as a possible therapeutic
strategy, and emphasize the importance of determining which
misfolded forms are most prevalent in patients.
Until now, α-synuclein has been linked to PD, but it hasn’t been
clear how mutations in the protein cause the disease or whether
different misfolded forms of α-synuclein give rise to distinct
pathologies.
The new evidence, which comes from groups at Harvard Medical
School and Catholic University Leuven, connects disease-linked
mutations with a build-up of unfolded α-synuclein monomers
that are more prone to forming toxic aggregates than tetramers.
In addition, it provides insights into the pathologies of the
different kinds of α-synuclein assemblies, by showing fibrils
are more toxic and have a greater capacity to propagate than
ribbons, whereas ribbons are more likely to form Lewy body-
like aggregates.
Kuldip Dave, director of research programs at the Michael
J. Fox Foundation for Parkinson’s Research (MJFF) told
BioCentury, “The results tell us more about why the pathology
and the progression of Parkinson’s disease are so heterogeneous.
Synuclein may misfold into different forms, and the ratios of
those forms in different cell types could be what drives disease
pathology one way or the other.”
The Harvard study, led by Dennis Selkoe, showed that rather
than existing exclusively as unfolded monomers, α-synuclein
primarily exists under healthy conditions as tetramers that are
in an equilibrium with monomers, and that the balance between
those forms contributes directly to disease pathology. Selkoe is a
professor of neurologic diseases at Harvard Medical School and
Brigham and Women’s Hospital.
“Our results showed that all of the missense mutations that
cause familial forms of Parkinson’s disease decrease α-synuclein
tetramers and increase monomers,” he told BioCentury.
The study from the Catholic University was led by Veerle
Baekelandt, and approached the question of how different forms
of α-synuclein contribute to PD from the opposite direction.
Her group looked at whether groups of α-synuclein proteins that
were already misfolded in different structures could reproduce
in rats the variety of pathologies seen in patients with PD or
other synucleinopathies, including dementia with Lewy bodies
and multiple system atrophy.
Baekelandt, a professor in the Laboratory for Neurobiology
and Gene Therapy in the Department of Neurosciences, told
BioCentury that her group’s results provide “the first clue why
aggregates of the same protein affect people differently.”
GOING NATIVE
Selkoe’s goal was to settle a controversy about which form of
α-synuclein predominates in healthy cells.
While most papers on α-synuclein describe it as an unfolded
monomer, Selkoe thinks the experimental conditions typically
used to study the protein, which involve lysing cells, disrupt its
natural multimeric, helical structure.
“The widespread idea that α-synuclein was a natively unfolded
protein seemed strange to us,” he said. “Not many proteins are
natively unstructured, since folding confers function.”
To capture the native form of α-synuclein found inside cells,
Selkoe’s group developed a method in which it kept cells intact
and used a cell permeable crosslinking agent to fuse adjacent
“Synuclein may misfold into different
forms, and the ratios of those forms
in different cell types could be what
drives disease pathology one way or
the other.”
Kuldip Dave, MJFF

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12 july 9, 2015 TOC
proteins within cells. Proteins remained unlinked if they were
not in direct contact or very close proximity to each other.
The team applied the method to human brain tissue biopsied
from a patient undergoing elective surgery for epilepsy. Selkoe
said the patient did not have PD, and noted that because there
is no evidence of altered α-synuclein in epilepsy, the sample
represents a non-PD brain.
The results showed α-synuclein primarily existed as a tetramer
and did not form dimers and trimers. The normal ratio of
tetramers to monomers was about 2:1; it was 3:1 when larger
multimers of up to about 7 units were included.
Selkoe’s team also showed that the method faithfully reproduced
the known patterns of tetramers, dimers and monomers for
other proteins.
“Our work indicates that tetramers of α-synuclein are the
normal functional form in neurons” and not an experimental
artifact, said Selkoe. He added that the tetramer to monomer
ratios his team reported might even underestimate the true
ratio in cells since the researchers’ crosslinking method doesn’t
capture every protein complex.
Nevertheless, he said, there are some α-synuclein monomers in
cells, and they seem to be in an equilibrium with tetramers and
larger multimers.
Next,thegrouplookedathowmutationsthatcausefamilialforms
of PD affect the tetramer-monomer equilibrium and found that
all five familial missense mutations shift the equilibrium away
from tetramers toward an excess of monomers. For example,
in neurons derived from a patient with the α-synuclein A53T
mutation, the tetramer to monomer ratio was about 25% lower
than in neurons in which the mutation had been corrected via
zinc-finger nuclease-based gene editing.
Selkoe noted that the mutation that causes the most aggressive
form of the disease in patients also produced the largest shift
in the tetramer to monomer ratio, while the mildest mutation
shifted the equilibrium the least.
In addition, because the familial E46K mutation exists in a
repeated motif within α-synuclein, the group inserted additional
copies of that mutation into other motifs and produced a dose-
dependent decrease in tetramers and increase in cell death.
The version with the most mutations formed cytoplasmic
aggregates resembling Lewy bodies, a hallmark of PD and other
synucleinopathies.
Data were reported in Nature Communications.
Selkoe said his team is now using its in vitro assays to screen
Harvard’s library of 200,000 compounds to find molecules that
can stabilize α-synuclein tetramers and decrease the number of
monomers available to form toxic assemblies.
He noted a precedent already exists for treating a neurological
disease with a small molecule stabilizer of a tetrameric protein
in Pfizer Inc.’s Vyndaqel tafamidis meglumine, which stabilizes
TTR and prevents its misfolding. The drug is approved in the
EU to treat TTR familial amyloid polyneuropathy.
“We’d love to collaborate with a company to take this into a
much more sophisticated and high throughput screen,” Selkoe
told BioCentury.
TOXIC TANGLES
While in vitro and animal studies suggest that α-synuclein can
take on a variety of misfolded forms, Baekelandt said her team’s
study was spurred by the lack of available data comparing how
the different α-synuclein assemblies contribute to PD and other
synucleinopathies.
"The widespread idea that α-synuclein was a natively
unfolded protein seemed strange to us. Not many
proteins are natively unstructured, since folding
confers function."
Dennis Selkoe, Harvard Medical School

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13 july 9, 2015 TOC
Her team built on a recent finding that groups of recombinant
α-synuclein proteins can be purified in vitro in two major forms,
fibrils and ribbons. In addition, she noted that α-synuclein forms
oligomers that are precursors to fibrils, which represent a third
structuralform.Whilelargeraggregates,includingLewybodiesand
Lewy neurites, have been found in vivo in all synucleinopathies, the
prevalence and toxicity of smaller, soluble α-synuclein assemblies
are only beginning to be explored, she said.
Baekelandt’steaminjectedthethreetypesofassemblies—fibrils,
ribbons and oligomers — into the substantia nigra of healthy
rats. While all three assemblies were taken up by dopaminergic
neurons at the injection site and spread via synapses to other
brain regions, fibrils persisted in the brain longer than ribbons
or oligomers, and caused greater impairments in neuronal
spiking and motor control, and increased cell death.
By four months post-injection, mice that had initially received
ribbons had many more large aggregates in the brain than mice
that had received fibrils or oligomers, although very few ribbons
remained in dopaminergic neurons. That suggested the ribbons
had been converted into Lewy-like aggregates or cleared. Only
fibrils were still detected in dopaminergic neurons at four
months.
In addition, by four months, the human α-synuclein fibrils had
been replaced by fibrils made of rat α-synuclein, which indicated
fibrils can induce endogenous α-synuclein to seed more fibrils.
Next, the team addressed the question of which was more
toxic — persistent fibrils or transient ribbons that give rise to
Lewy-like aggregates — by measuring the loss of dopaminergic
neurons and axons in each case.
While neither caused cell loss on its own, the team saw
differential effects on cell loss when the assemblies were
injected into animals overexpressing α-synuclein, which speeds
degeneration. Although both ribbons and fibrils exacerbated
cell loss caused by α-synuclein overexpression, fibrils produced
the larger effect.
Fibrils also impaired motor function and synaptic physiology to
a greater extent than ribbons. Only fibrils reduced spontaneous
forepaw movements in animals with normal levels of
α-synuclein, whereas both fibrils and ribbons worsened motor
behavior in α-synuclein overexpressors.
The team reported its results in Nature.
Baekelandt said her group’s findings suggest that fibrils are both
more persistent and toxic than ribbons or smaller oligomers,
and support the idea that Lewy-like aggregates might be the
cell’s way of sequestering assemblies to help protect neurons, at
least initially.
“Thefactthatallsynucleinspeciescancausesynapticimpairment
suggests that the strain with the highest propensity to resist
degradation and to propagate will have the largest capacity to
induce neurodegeneration in the long term,” she said.
Baekelandt also thinks that different types of α-synuclein
assemblies may give rise to different types of synucleinopathies.
She noted that , in the context of α-synuclein overexpression,
onlyribbonsproducedLewy-likeaggregatesinoligodendrocytes
— the primary site of α-synuclein pathology in multiple system
atrophy. “Our data suggest that strain conformation might be
a factor that influences a shift towards a more multiple system
atrophy-like phenotype,” she said.
However, she said we should “remain cautious” in
interpreting that result because neuronal inclusions were still
the dominant phenotype in the ribbon-injected α-synuclein
overexpressors.
MJFF’s Dave noted that although Baekelandt’s results add useful
information to the field, they were obtained with recombinant
proteins and might not reflect the types of α-synuclein
assemblies that exist in the brains of patients.
Baekelandt told BioCentury her team is planning studies to
validate the results in patient samples.
MJFF has its own initiative underway to determine which
forms of α-synuclein are most prevalent in patients. Dave said
that through the Species LEAPS (Linked Efforts to Accelerate
Parkinson’s Solutions) initiative, the foundation is funding and
coordinating the efforts of several labs to identify disease-linked
α-synuclein assemblies and validate them across multiple labs.
Selkoe’s lab is one of the groups being funded under Species
LEAPS.
"All of the missense mutations that
cause familial forms of Parkinson's
disease decrease α-synuclein
tetramers and increase monomers."
Dennis Selkoe, Harvard Medical School

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14 july 9, 2015 TOC
Selkoe said that in his upcoming studies funded by LEAPS, the
group is “especially going after aggregates that are still soluble
and not yet tied up in highly insoluble end-stage assemblies like
Lewy bodies.”
Dave noted that companies are pursuing strategies to prevent
and destroy aggregates. “Stabilizing tetramers will give drug
developers a new approach to preventing aggregate formation,”
he said.
Brigham and Women’s Hospital, Boston, Mass.
Catholic University Leuven, Leuven, Belgium
Harvard Medical School, Boston, Mass.
The Michael J. Fox Foundation For Parkinson’s Research, New York, N.Y.
Pfizer Inc. (NYSE:PFE), New York, N.Y.
SNCA - α-synuclein
TTR - Transthyretin
REFERENCES
Dettmer, U., et al. “Parkinson-causing α-synuclein missense mutations shift native tetramers to
monomers as a mechanism for disease initiation.” Nature Communications (2015)
Peelaerts, W., et al. “α-synuclein strains cause distinct synucleinopathies after local and system-
ic administration.” Nature (2015)
Zipkin, M. “Untangling α-synuclein.” BioCentury Innovations (2015)

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TOP TRANSLATIONAL TARGETS, 2013-14
The most frequently cited targets from selected disease areas, as published
in the Distillery from 2013-14, are shown in the charts below. The top 10 in
each disease area were chosen, except where multiple targets had the same
number of mentions. The Distillery covers articles that describe discoveries
or inventions with commercial potential. Items in blue represent targets
for which there are clinical stage compounds; orange represents targets
of preclinical compounds. The top cancer targets all have compounds in
clinical development, and although there are already eight marketed or
approved cancer therapeutics targeting epidermal growth factor receptor
2 (HER2; EGFR2; ErbB2; neu), it remained the most commonly studied
target in any disease area. By comparison, in neurology, chromosome 9
open reading frame 72 (C9orf72), NMDA receptor NR2A subtype (GRIN2A;
NR2A) and huntingtin (HTT) were frequently cited but have no disclosed
compounds in the clinic. Likewise, in autoimmune and infectious diseases,
serum/glucocorticoid regulated kinase 1 (SGK1) and interleukin-27 (IL-27)
were among the top 10 most studied targets but also have no disclosed
compounds in the clinic. Sources: BCIQ: BioCentury Online Intelligence,
BioCentury Innovations, SciBX: Science-Business eXchange
0 5 10 15 20
B cell lymphoma 2 (BCL-2; BCL2)
p53
Tubulin
Epidermal growth factor receptor 3 (EGFR3; HER3; ErbB3)
Smoothened (SMO)
Phosphoinositide 3-kinase (PI3K)
K-Ras (KRAS)
Signal transducer and activator of transcription 3 (STAT3)
MEK
Epidermal growth factor receptor (EGFR)
BRAF
HER2 (EGFR2; ErbB2; neu)
Cancer
0 5 10 15 20
NMDA receptor NR2A subtype (GRIN2A; NR2A)
β-site APP-cleaving enzyme 1 (BACE1)
Dopamine D3 receptor
Huntingtin (HTT)
Neurotrophic tyrosine kinase receptor 2 (NTRK2; TrkB)
α-synuclein (SNCA)
NMDA receptor
Microtubule-associated protein-τ (tau; MAPT; FTDP-17)
Chromosome 9 open reading frame 72 (C9orf72)
β-amyloid (Aβ)
Neurology
0 5 10 15 20
Serum/glucocorticoid regulated kinase 1 (SGK1)
RSV F protein
DNA gyrase
Type I interferon receptor
Interleukin-27 (IL-27)
Interleukin-1 (IL-1) β
HIV gp41
Ebola glycoprotein GP2
Ebola glycoprotein GP1
Influenza A virus hemagglutinin
CD4
HIV env
HIV gp120
Autoimmune & Infectious diseases

STRATEGY
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16 july 9, 2015 TOC
DISTILLERY
INDICATION: Autoimmune disease
In vitro and mouse studies suggest inhibiting DBC1 could help treat autoimmune
diseases. In vitro studies identified DBC1 as a binding partner of FOXP3, a Treg
cell marker. In normal mice, knockout of DBC1 increased levels of FOXP3-positive
Treg cells and increased their suppressive functions compared with normal DBC1
expression. In the mouse experimental autoimmune encephalomyelitis (EAE) model
of multiple sclerosis (MS), DBC1 knockout delayed disease onset and decreased
disease severity compared with normal DBC1 expression. Next steps could include
identifying roles for DBC1 in other models of autoimmune disease.
TARGET/MARKER/PATHWAY: Deleted in breast cancer 1
(DBC1; CCAR2); forkhead box P3 (FOXP3)
LICENSING STATUS: Patent and licensing status
unavailable
PUBLICATION DETAILS: Gao, Y. et al. Proc. Natl. Acad. Sci.
USA; published online Jun. 8, 2015
doi: 10.1073/pnas.1421463112
CONTACT: Bin Li, Shanghai Institutes for Biological
Sciences, Chinese Academy of Sciences, Shanghai, China
e-mail: binli@sibs.ac.cn
CONTACT: Song Guo Zheng, Third Affiliated Hospital at
Sun Yat-Sen University, Guangzhou, China
e-mail: szheng1@hmc.psu.edu
AUTOIMMUNE DISEASE
DISTILLERY
THE DISTILLERY brings you this week’s most essential scientific findings in therapeutics, distilled by BioCentury Innovations editors from a
weekly review of more than 400 papers in 41 of the highest-impact journals in the fields of biotechnology, the life sciences and chemistry. The
Distillery goes beyond the abstracts to explain the commercial relevance of featured research, including licensing status and companies working
in the field, where applicable. This week in therapeutics includes important research findings on targets and compounds, grouped first by disease
class and then alphabetically by indication.
THERAPEUTICS
INDICATION: Acute lymphoblastic leukemia (ALL)
In vitro and mouse studies suggest antagonizing CXCL12-CXCR4 signaling could
help treat T cell-ALL (T-ALL). Levels of the CXCL12 receptor CXCR4 were higher on
T-ALL cells from patients than on T cells from healthy controls. In a mouse model of
T-ALL, deletion of CXCL12 decreased T-ALL expansion and tumor burden compared
with normal CXCL12 expression, and shRNA targeting CXCR4 decreased motility,
homing and propagation potential of T-ALL cells compared with control shRNA.
In xenograft and other mouse models of T-ALL, bone marrow-specific CXCR4
knockout, shRNA targeting CXCR4 or a CXCR4 antagonist decreased leukemia
burden and increased survival compared with normal CXCR4 expression, a control
shRNA or vehicle, respectively. Next steps include testing CXCR4 and CXCL12
antagonists in combination with approved T-ALL therapies in vivo.
TARGET/MARKER/PATHWAY: CXC chemokine receptor
4 (CXCR4; NPY3R); chemokine CXC motif ligand 12
(CXCL12; SDF-1)
unavailable
PUBLICATION DETAILS: Pitt, L. et al. Cancer Cell;
published online Jun. 8, 2015
doi:10.1016/j.ccell.2015.05.002
CONTACT: Iannis Aifantis, New York University School of
Medicine, New York, N.Y.
e-mail: iannis.aifantis@nyumc.org
CONTACT: Susan R. Schwab, same affiliation as above
e-mail: susan.schwab@med.nyu.edu
LICENSING STATUS: Unpatented; unavailable for licensing
PUBLICATION DETAILS: Passaro, D. et al. Cancer Cell;
doi: 10.1016/j.ccell.2015.05.003
CONTACT: Diana Passaro, The Francis Crick Institute,
London, U.K.
e-mail: diana.passaro@crick.ac.uk
CONTACT: Jacques Ghysdael, Institut Curie, Orsay, France
e-mail: jacques.ghysdael@curie.fr
CANCER

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17 july 9, 2015 TOC
DISTILLERY
THERAPEUTICS
INDICATION: Acute myelogenous leukemia (AML)
In vitro and mouse studies suggest inhibiting clpP could help treat a subset of AML.
Levels of the mitochondrial proteome protein clpP were higher in 45% of 511 AML
samples from patients than in normal hematopoietic progenitor cells. In human
AML cell lines and AML patient samples expressing high levels of clpP, shRNA
targeting clpP or a small molecule clpP inhibitor decreased growth and survival
compared with control shRNA or vehicle. In mice with human AML xenografts, a
clpP inhibitor decreased tumor growth compared with vehicle. Next steps could
include testing the clpP inhibitor in additional models of AML.
TARGET/MARKER/PATHWAY: clpP
unavailable
PUBLICATION DETAILS: Cole, A. et al. Cancer Cell;
doi:10.1016/j.ccell.2015.05.004
CONTACT: Aaron D. Schimmer, University of Toronto,
Toronto, Ontario
e-mail: aaron.schimmer@utoronto.ca
CANCER
INDICATION: Cancer
Mouse studies suggest combining DPP-4 inhibitors with immune checkpoint
inhibitors could help treat cancer. In a mouse model of melanoma, homozygous
knockout of DPP-4 decreased tumor growth compared with heterozygous DPP-4
knockout. In a mouse model of colon cancer, the DPP-4 inhibitor Januvia sitagliptin
increased numbers of tumor-infiltrating CD3-positive T cells and NK cells and
decreased tumor growth compared with vehicle. In the melanoma model, Januvia
plus mAbs against PD-1 and CTLA-4 decreased tumor growth compared with the
two mAbs or any agent alone. Next steps include testing DPP-4 inhibitors in clinical
trials on hepatocellular carcinoma (HCC).
Merck & Co. Inc. and Ono Pharmaceutical Co. Ltd. market Januvia to treat Type II
diabetes.
TARGET/MARKER/PATHWAY: Dipeptidyl peptidase-4
(DPP-4; CD26); programmed cell death 1 (PD-1; PDCD1;
CD279); CTLA4 (CD152)
LICENSING STATUS: Patented; available for licensing
PUBLICATION DETAILS: da Silva, R. et al. Nat. Immunol.;
doi:10.1038/ni.3201
CONTACT: Matthew L. Albert, Pasteur Institute, Paris,
France
e-mail: albertm@pasteur.fr
INDICATION: Cancer
In vitro studies suggest combining a leinamycin analog with inducers of reactive
oxygen species (ROS) could help treat cancer. In normal cells, leinamycin undergoes
reductive activation to an episulfonium ion that alkylates DNA and inhibits growth
at IC50
values of about 2 nM, but has little inhibitory activity in cancer cells that
are under oxidative stress. Biosynthesis in engineered bacteria and in vitro testing
of leinamycin analogs identified a compound that was oxidatively activated by
ROS to generate the episulfonium ion. In two human prostate cancer cell lines, the
compound plus an ROS-inducing agent inhibited proliferation at IC50
values of 1-2
μM, whereas the compound alone exhibited no growth inhibition in the cancer cell
lines or a human prostate epithelial cell line. Ongoing studies include testing the
compound in mouse models of cancer.
TARGET/MARKER/PATHWAY: DNA
PUBLICATION DETAILS: Huang, S.-X. et al. Proc. Natl.
Acad. Sci. USA; published online Jun. 8, 2015
doi:10.1073/pnas.1506761112
CONTACT: Ben Shen, The Scripps Research Institute,
Jupiter, Fla.
e-mail: shenb@scripps.edu

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18 july 9, 2015 TOC
DISTILLERY
THERAPEUTICS
INDICATION: Melanoma
Mouse studies suggest TNFα inhibitors could help treat HLA-A-positive
melanomas. In mice with melanoma tumors expressing high levels of MHC, the
mouse homolog of HLA-A, TNFα knockout increased the number of CD8+
tumor-
infiltrating lymphocytes and decreased tumor growth compared with normal TNFα
expression. Also in the model, Enbril etanercept decreased tumor growth compared
with vehicle. Next steps include determining the frequency of HLA-A expression in
melanoma biopsies.
Amgen Inc. markets the TNFα inhibitor Enbrel to treat multiple autoimmune
diseases.
TARGET/MARKER/PATHWAY: Major histocompatibility
complex class I A (HLA-A); major histocompatibility
complex class I (MHC); tumor necrosis factor (TNF) α
LICENSING STATUS: Patented; licensing status
undisclosed
PUBLICATION DETAILS: Bertrand, F. et al. Cancer Res.;
published online May 14, 2015
doi:10.1158/0008-5472.CAN-14-2524
CONTACT: Bruno Segui, INSERM UMR 1037, Toulouse,
France
e-mail: bruno.segui@inserm.fr
CANCER
INDICATION: Heart failure
In vitro and mouse studies suggest a small molecule enhancer of SERCA2A
SUMOylation could help treat heart failure. Levels of SUMOylated SERCA2A
were lower in cardiac cells from a mouse model of heart failure than in cells from
normal mice. Screening of a small molecule library in a human cell-based assay of
SERCA2A SUMOylation, followed by testing of hits in rat cardiomyocytes, identified
a compound that SUMOylated SERCA2A to increase cellular contractility and
calcium transients compared with vehicle. In the mouse model of heart failure, the
compound increased SUMOylation of SERCA2A in heart cells, heart contractility
and heart relaxation compared with vehicle. Next steps include generating analogs
of the compound with improved PK/PD properties.
Celladon Corp. and AmpliPhi Biosciences Corp. have AAV1/SERCA2a (Mydicar), a
recombinant adeno-associated viral (AAV) vector bearing the gene for SERCA2A,
in Phase II to treat heart failure.
TARGET/MARKER/PATHWAY: ATPase Ca++ transporting
cardiac muscle slow twitch 2 (ATP2A2; SERCA2A); small
ubiquitin-like modifier (SUMO)
LICENSING STATUS: Patent pending; unlicensed
PUBLICATION DETAILS: Kho, C. et al. Nat. Commun.;
doi:10.1038/ncomms8229
CONTACT: Roger J. Hajjar, Icahn School of Medicine at
Mount Sinai, New York, N.Y.
e-mail: roger.hajjar@mssm.edu
CARDIOVASCULAR
INDICATION: Hypertension
Cell culture and mouse studies suggest BMP9 could help treat pulmonary arterial
hypertension (PAH). Mutations in BMPRII have been associated with PAH
pathogenesis. In assays in endothelial cells from PAH patients harboring BMPRII
mutations, pretreatment with BMP9 decreased cytokine-induced apoptosis and
lipopolysaccharide (LPS)- or cytokine-induced monolayer permeability — two
markers of PAH pathology — compared with no pretreatment. In three mouse
models of PAH, including transgenic mice expressing mutant human BMPRII, BMP9
decreased right ventricular systolic pressure and pulmonary arterial muscularization
compared with vehicle. Next steps include optimization of BMP9 for clinical use.
TARGET/MARKER/PATHWAY: Bone morphogenetic
protein 9 (BMP9; GDF2); bone morphogenetic protein
receptor type II (BMPRII)
LICENSING STATUS: Patent application filed; licensing
status undisclosed
PUBLICATION DETAILS: Long, L. et al. Nat. Med.;
doi:10.1038/nm.3877
CONTACT: Nicholas Morrell, Addenbrooke’s Hospital,
Cambridge, U.K.
e-mail: nwm23@cam.ac.uk

STRATEGY
PRODUCT R&D
19 july 9, 2015 TOC
DISTILLERY
THERAPEUTICS
INDICATION: Hypertension; Pulmonary
Rat studies suggest cationic lipopolyamine-based nanoparticles loaded with small
RNA-based therapeutics could help treat pulmonary arterial hypertension (PAH)
and other lung diseases. In a rat model of PAH, nanoparticles loaded with an anti-
miR-145 antisense oligonucleotide accumulated in the lung and several other
tissues, and decreased miR-145 levels in the lung compared with the liver, spleen and
kidneys. Also in the model, the nanoparticles decreased pulmonary arteriopathy,
pulmonary hypertension and cardiac dysfunction compared with nanoparticles
loaded with a control oligo. Next steps by Celsion Corp. include additional studies
to determine the nanoparticles’ mechanism of lung-specific activity.
Celsion has EGEN-002, an RNA-based therapeutic formulated with the
nanoparticles, in preclinical testing to treat PAH.
TARGET/MARKER/PATHWAY: microRNA-145 (miR-145)
LICENSING STATUS: Cationic lipopolyamine-based
nanoparticles patented by Celsion Corp.; unavailable for
licensing; available for partnering
PUBLICATION DETAILS: McLendon, J. et al. J. Control.
Release; published online May 13, 2015
doi:10.1016/j.conrel.2015.05.261
CONTACT: Jared McLendon, University of South Alabama
College of Medicine, Mobile, Ala.
e-mail: jmclendon@jagmail.southalabama.edu
CARDIOVASCULAR; PULMONARY
INDICATION: HIV / AIDS
Cell culture studies suggest P2RX7 inhibitors or imipramine could help treat HIV
infection. In an assay of ATP-stimulated virion release in HIV-infected human
macrophage cell lines, a research-grade inhibitor of P2RX7 or imipramine — an
inhibitor of microvesicle shedding — decreased virion release compared with no
treatment. Next steps include identifying other host molecules that interact with
P2RX7 during HIV virion release.
Mallinckrodt plc markets the tricyclic antidepressant (TCA) Tofranil imipramine
hydrochloride to treat depression and incontinence.
Evotec AG and Zhejiang Conba Pharmaceutical Co. Ltd. have EVT 401, an oral small
molecule P2RX7 antagonist, in Phase II testing to treat inflammation and Phase I
testing to treat rheumatoid arthritis (RA).
Lead Discovery Center GmbH has two P2RX7 antagonists in preclinical testing: AFC-
5128 to treat pain and multiple sclerosis (MS), and AFC-5278 to treat osteoporosis.
Lead Discovery Center and Merck KGaA have other P2RX7 antagonists in preclinical
testing to treat neurological disease.
TARGET/MARKER/PATHWAY: Purinergic receptor P2X
ligand-gated ion channel 7 (P2RX7; P2X7)
LICENSING STATUS: Unpatented; available for partnering
PUBLICATION DETAILS: Graziano F. et al. Proc. Natl. Acad.
Sci. USA; published online Jun. 8, 2015
doi:10.1073/pnas.1500656112
CONTACT: Guido Poli, San Raffaele Scientific Institute,
Milan, Italy
e-mail: poli.guido@hsr.it
INFECTIOUS DISEASE

STRATEGY
PRODUCT R&D
20 july 9, 2015 TOC
DISTILLERY
THERAPEUTICS
INDICATION: Influenza virus
In vitro and mouse studies suggest a peptide derived from the TIR domain of TLR2
could help treat influenza infection. In human cell-based assays, screening of
a peptide library derived from the TLR2 TIR domain identified a compound that
bound the TIR domain of TIRAP with a Kd
of 40 nM and decreased agonist-induced
signaling of multiple TLRs in human macrophages compared with a control peptide.
In a mouse model of lethal influenza infection, the compound decreased TLR-
induced secretion of inflammatory cytokines compared with control peptide and
increased survival to 78% compared with 12.5% and 10% for control peptide and
vehicle, respectively. Next steps include testing the compound in mouse models of
other lethal viral infections.
TARGET/MARKER/PATHWAY: Toll-interleukin 1 receptor
(TIR) domain containing adaptor protein (TIRAP); toll-like
receptor 2 (TLR2)
PUBLICATION DETAILS: Piao, W. et al. Cell Rep.; published
online Jun. 18, 2015
doi:10.1016/j.celrep.2015.05.035
CONTACT: Vladimir Y. Toshchakov, University of
Maryland School of Medicine, Baltimore, Md.
e-mail: evtoshchakov@som.umaryland.edu
INFECTIOUS DISEASE
INDICATION: Tuberculosis
In vitro and mouse studies suggest the griselimycin analog cyclohexylgriselimycin
(CGM) could help treat tuberculosis. Chemical synthesis and in vitro testing of
analogs of Streptomyces-derived griselimycin identified CGM as a DnaN inhibitor
that bound M. tuberculosis DnaN with a Kd
of 0.2 nM, and exhibited greater
antibacterial potency against M. tuberculosis culture and an M. tuberculosis-infected
macrophage cell line than the parent compound. In a mouse model of tuberculosis,
CGM decreased bacterial burden compared with the parent compound, and
CGM plus the generic tuberculosis drugs rifampin and pyrazinamide accelerated
clearance of lung infection compared with rifampin and pyrazinamide alone. Next
steps include further preclinical testing of CGM and identifying compounds that
target DnaN in other pathogenic bacteria.
TARGET/MARKER/PATHWAY: DNA polymerase III β
subunit (DnaN)
LICENSING STATUS: Patented by Sanofi; licensing status
unavailable
PUBLICATION DETAILS: Kling, A. et al. Science; published
online Jun. 4, 2015
doi: 10.1126/science.aaa4690
CONTACT: Rolf Müller, Saarland University, Saarbrücken,
Germany
e-mail: rolf.mueller@helmholtz-hzi.de

STRATEGY
PRODUCT R&D
21 july 9, 2015 TOC
DISTILLERY
THERAPEUTICS
INDICATION: Osteoporosis
Cell culture and rodent studies suggest indazole-based inhibitors of RANKL
signaling could help treat osteoporosis. Chemical synthesis and in vitro testing
of indazole carboxylic acid analogs identified a compound that inhibited RANKL-
induced NF-κB signaling in mouse macrophages and decreased RANKL- and CSF1-
induced osteoclastogenesis in rat osteoclast progenitors by 90% compared with
vehicle. In a mouse model of osteoporosis, the compound increased trabecular bone
volume, bone thickness and trabecular bone number — a measure of bone density
and structure — compared with vehicle. Next steps could include optimizing the
compound and confirming its molecular target.
Amgen Inc., Daiichi Sankyo Co. Ltd. and GlaxoSmithKline plc market the anti-
RANKL mAb Prolia denosumab to treat osteoporosis. Amgen and Daiichi Sankyo
also market the mAb for bone repair and bone cancer and have it approved for
musculoskeletal indications.
Ablynx N.V. and Eddingpharm Inc. have ALX-0141, a nanobody against RANKL, in
Phase I testing to treat osteoporosis and bone cancer.
Apexigen Inc. has APX008, an antibody against RANKL, in preclinical testing to
treat osteoporosis and bone cancer.
TARGET/MARKER/PATHWAY: Receptor activator of
NF-κB ligand (RANKL; TNFSF11); macrophage colony-
stimulating factor 1 (CSF1; M-CSF)
unavailable
PUBLICATION DETAILS: Kuo, T. et al. J. Med. Chem.;
doi:10.1021/jm502014h
CONTACT: Hsin-Yi Hung, China Medical University
Hospital, Taichung, Taiwan
e-mail: z10308005@email.ncku.edu.tw
CONTACT: Wen-Mei Fu, National Taiwan University,
Taipei, Taiwan
e-mail: wenmei@ntu.edu.tw
MUSCULOSKELETAL
INDICATION: Huntington’s disease (HD)
Mouse studies suggest inhibiting RHES in the brain could help treat HD. In a
transgenic mouse model of HD expressing mutant huntingtin (HTT), systemic
homozygous and heterozygous knockout of RHES decreased motor deficits, anxiety-
driven behaviors, ventricle expansion and brain weight loss compared with normal
RHES expression. In two mouse models of HD with homozygous RHES knockout,
viral vector-mediated expression of RHES in the striatum promoted earlier onset
of motor deficits than control vectors, and vector-mediated expression of RHES in
the cerebellum increased motor deficits and loss of cerebellar neurons compared
with control vector. Next steps include developing in vitro cell-based assays of RHES
activity to screen for inhibitors.
TARGET/MARKER/PATHWAY: Ras homolog enriched in
striatum (RHES; RASD2; TEM2)
PUBLICATION DETAILS: Swarnkar, S. et al. Neurobiol. Dis.;
doi:10.1016/j.nbd.2015.05.011
CONTACT: Srinivasa Subramaniam, The Scripps Research
Institute, Jupiter, Fla.
e-mail: essubrama@scripps.edu
NEUROLOGY

STRATEGY
PRODUCT R&D
22 july 9, 2015 TOC
DISTILLERY
THERAPEUTICS
INDICATION: Tissue replacement
Mouse studies suggest inhibiting HPGD could help regenerate tissues after
transplantation or injury. In vitro high throughput screening of small molecule library
identified a compound that inhibited HPGD with a Ki
of 0.1 nM. In a mouse model
of bone marrow transplantation, the compound increased neutrophil, platelet and
red blood cell recovery and bone marrow engraftment compared with vehicle. In
mouse models of colitis and liver injury, the compound increased proliferation of
colonocytes and hepatocytes, respectively, and promoted tissue regeneration. Next
steps include toxicology studies of an analog of the compound and testing HPGD
inhibition in other tissue regeneration models.
TARGET/MARKER/PATHWAY: Hydroxyprostaglandin
dehydrogenase 15 NAD (HPGD; 15-PGDH)
LICENSING STATUS: Patent application filed; available for
licensing or partnering
PUBLICATION DETAILS: Zhang, Y. et al. Science; published
online Jun. 11, 2015
doi:10.1126/science.aaa2340
CONTACT: Sanford Markowitz, Case Western Reserve
University, Cleveland, Ohio
e-mail: sxm10@cwru.edu
CONTACT: Stanton Gerson, same affiliation as above
e-mail: slg5@cwru.edu
CONTACT: James Willson, University of Texas
Southwestern Medical Center, Dallas, Texas
e-mail: james.willson@utsouthwestern.edu
CONTACT: Joseph Ready, same affiliation as above
e-mail: joseph.ready@utsouthwestern.edu
CONTACT: Bruce Posner, same affiliation as above
e-mail: bruce.posner@utsouthwestern.edu
TRANSPLANT

STRATEGY
PRODUCT R&D
23 july 9, 2015 TOC
DISTILLERY
TECHNIQUES
TECHNOLOGY: Binding assays
A high throughput method could determine binding affinities between globular
protein domains and linear peptide ligands. The method co-incubated globular
domains from proteins and resin saturated with peptide ligands in a 384-well filter
plate. During plate filtration, microfluidic capillary electrophoresis measured the
quantity of unbound domain flowing out of the plate, and the proportion of bound
to unbound domain was used to calculate a binding intensity, from which Kd
could
be estimated. In a proof-of-concept experiment, the method obtained Kd
values for
the binding of 209 human PDZ domain-containing proteins to two viral peptides
with PDZ binding motifs that were in good agreement with previously determined
values (R2
= 0.76). Next steps could include adapting the method to other globular
domains and linear peptides.
DESCRIPTION: High throughput chromatographic assay
for measuring protein binding intensity
unavailable
PUBLICATION DETAILS: Vincentelli, R. et al. Nat. Methods;
published online June 8, 2015
doi:10.1038/nmeth.3438
CONTACT: Gilles Travé, Centre Nationale de le Recherche
Scientifique (CNRS), Illkirch, France
e-mail: trave@unistra.fr
ASSAYS AND SCREENS
TECHNOLOGY: Animal models
A mouse model of delayed remyelination could be used to screen for therapies to
treat MS. The model was generated by treating mice with the demyelinating toxin
cuprizone, then adoptively transferring myelin-reactive T helper type 17 (Th17) CD4+
T cells from normal mice to delay remyelination. The mouse model exhibited lower
myelin levels than cuprizone-treated mice that did not receive Th17 CD4+
T cells,
and less axonal loss than the experimental autoimmune encephalomyelitis (EAE)
mouse model of MS. The models also had higher levels of CD4+
T cell infiltration
into the brain and more demyelinated axons than cuprizone-treated mice or normal
mice. Next steps could include examining remyelination therapies in this model.
DESCRIPTION: Delayed remyelination mouse model of
multiple sclerosis (MS)
unavailable
PUBLICATION DETAILS: Baxi, E. et al. J. Neurosci.;
published online June 3, 2015
doi:10.1523/JNEUROSCI.3817-14.2015
CONTACT: Anne R. Gocke, The Johns Hopkins University,
Baltimore, Md.
e-mail: agocke4@jhu.edu
Contact: Peter A. Calabresi, same affiliation as above
e-mail: pcalabr1@jhmi.edu
DISEASE MODELS

STRATEGY
PRODUCT R&D
24 july 9, 2015 TOC
DISTILLERY
TECHNIQUES
TECHNOLOGY: Nanoparticles
Nanoparticles cross-linked to T cells could help deliver cytotoxic payloads to
tumors in lymph nodes. Lymphocyte accumulation in lymph nodes depends on the
homing receptor L selection (CD62L; SELL). Polyethylene glycol (PEG)-conjugated
nanoparticles loaded with the active metabolite of irinotecan were cross-linked to
free thiols on the surface of mouse T cells primed to express CD62L with a mixture
of cytokines and mitogens. In a mouse lymphoma cell line, the nanoparticle-T cell
conjugates decreased viability compared with unconjugated T cells or nanoparticles.
In a mouse model of Burkitt’s lymphoma, the nanoparticle-T cell conjugates
increased T cell homing to lymph nodes, decreased tumor growth and increased
survival. Next steps could include testing other cytotoxic agents and T cells primed
to express other homing receptors.
The generic topoisomerase I (TOP1) inhibitor irinotecan is marketed to treat
multiple cancers.
DESCRIPTION: Nanoparticles with cytotoxic payloads
cross-linked to T cells
unavailable.
PUBLICATION DETAILS: Huang, B. et al. Sci. Transl. Med.;
doi:10.1126/scitranslmed.aaa5447
CONTACT: Darrell J. Irvine, Massachusetts Institute of
Technology (MIT), Cambridge, Mass.
e-mail: djirvine@mit.edu
DRUG DELIVERY
TECHNOLOGY: Gene therapy
InvitrostudiessuggestpaCas9couldallowspatialandtemporalcontrolovergenome
editing. The paCas9 construct uses a pair of split Cas9 fragments, each fused to a
photoswitchable protein that dimerizes upon exposure to blue light and joins the
Cas9 fragments. In HEK or HeLa cell lines, paCas9 plus sgRNA specifically induced
DNA breaks at the sgRNA target sites only when exposed to light. In cells treated
with paCas9 and sgRNA to insert the enhanced green fluorescent protein (EGFP)
gene, exposure to slit-patterned blue light induced a corresponding slit pattern of
EGFP-associated fluorescence. In HEK cells treated with two other paCas9-sgRNA
systems, incubation in light followed by incubation in the dark showed that paCas9
activity was reversible. Next steps include testing the tool in other cell types.
DESCRIPTION: Photoactivatable CRISPR-associated
protein 9 (Cas9) (paCas9) for spatial and temporal
genome editing control
LICENSING STATUS: Patent application filed; available for
licensing
PUBLICATION DETAILS: Nihongaki, Y. et al. Nat.
Biotechnol.; published online Jun. 15, 2015
doi:10.1038/nbt.3245
CONTACT: Moritoshi Sato, University of Tokyo, Tokyo,
Japan
e-mail: cmsato@mail.ecc.u-tokyo.ac.jp
DRUG PLATFORMS

STRATEGY
PRODUCT R&D
25 july 9, 2015 TOC
DISTILLERY
TECHNIQUES
TECHNOLOGY: MRI
A gadolinium nanoparticle-based MRI agent could help detect GBM, a tumor type
that highly expresses interleukin-13 (IL-13) receptor α2 (IL-13RA2; IL-13R; CD213A2).
The agent consisted of gadolinium-containing metalfullerene nanoparticles coated
with positively charged amine functional groups and conjugated to an IL-13-derived
peptide. In a human GBM cell line, the agent was internalized and localized in the
nucleus more efficiently than the same nanoparticles conjugated to a scrambled
control peptide. In mice with orthotopic xenograft GBM tumors, MRI with the
agent produced higher-contrast images of tumors at lower concentrations than
MRI with Magnevist gadopentetate dimeglumine. Next steps by Luna Innovations
Inc. include developing the gadolinium-based, IL-13-conjugated nanoparticles for
diagnostic and therapeutic applications.
Bayer AG markets Magnevist gadopentetate dimeglumine, a gadolinium-based
injectable contrast medium, as an MRI agent to visualize lesions with abnormal
vascularity in the brain, spine and associated tissues.
DESCRIPTION: Gadolinium-based metalfullerene
nanoparticle as imaging agent for glioblastoma multiforme
(GBM) tumors
LICENSING STATUS: Patented; licensed to Luna
Innovations Inc.
PUBLICATION DETAILS: Li, T. et al. J. Am. Chem. Soc.;
doi:10.1021/jacs.5b03991
CONTACT: Harry Dorm, Virginia Tech Carilion Research
Institute at Virginia Polytechnic Institute and State
University, Roanoke, Va.
e-mail: hdorn@vt.edu
CONTACT: Zhi Sheng, same affiliation as above
e-mail: zhisheng@vtc.vt.edu
IMAGING

DISTILLERY
STRATEGY
PRODUCT R&D
26 july 9, 2015 TOC
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