The document discusses research from the Rappaport Institute focusing on developing new therapeutic approaches for various diseases. It describes projects involving generating soluble chemokine receptors to suppress cancers and inflammatory diseases, identifying molecules that can inhibit tumor growth and angiogenesis, developing inhibitors of the heparanase enzyme to prevent cancer metastasis, using autoantibodies as biomarkers for prostate cancer, and applying optogenetics approaches for cardiac arrhythmias treatment.

1. T H E R A P P A P O R T I N S T I T U T E
CHEMOKINES, INFLAMMATORY AUTOIMMUNE
DISEASES, AND CANCER THERAPY
Chemokines are key mediators of the inflammatory process and therefore represent
potential therapeutic targets for inflammatory autoimmune diseases. In cancerous
diseases, chemokines direct the migration of metastatic cells and function as
survival, growth and angiogenic factors. Cancerous cells also produce chemokines
and express their receptors. Therefore, neutralization of chemokines could inhibit
the development and progression of these diseases.
Prof Nathan Karin and his research team have developed a unique approach
to generating stable soluble chemokine receptors and fusion chemokine proteins.
These highly neutralizing molecules have been found to be effective in suppressing
cancers and inflammatory autoimmune diseases in experimental animal models.
Projects available for licensing include – antiSRB-1 mAb, CCR-2-Ig, CXCL-11-Ig
and CCR-5-Ig.
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Opportunities
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2. ANGIOGENESIS AND CANCER
Angiogenesis, the growth of blood vessels, is an important process in embryonic
development and during healing of injured tissues. Malignant tumors can be
regarded as new developing organs and as such, require blood-borne nutrients
for growth. Thus, tumors have to induce angiogenesis. Antiangiogenic therapy is
a new form of cancer therapy, the goal of which is to inhibit tumor angiogenesis
and thereby starve the tumor by disrupting its blood supply. Unlike conventional
chemotherapy, angiogenic therapy attacks only the cells of newly-grown blood
vessels.Therefore,antiangiogenic drugs are tolerated better than chemotherapeutic
drugs and have fewer and less severe side effects.
Prof Gera Neufeld of the Rappaport Institute and his group has identified a
new class of naturally-occurring molecules, semaphorines, which can inhibit tumor
progression and angiogenesis. These inhibitors were found to effectively inhibit
the growth of cancer tumors and metastasis in various animal models. Projects
available for licensing include UNCL-Sema3E and UNCL-Sema3c.
PREVENTING CANCER METASTASIS VIA INHIBITION OF
THE HEPARANASE ENZYME
In order to metastasize, malignant cells must acquire two abilities:
1) the ability to invade tissues – metastasis; and
2) the ability to attract blood vessels – angiogenesis.
Prof IsraelVlodavsky of the Rappaport Institute has shown that the heparanase
enzyme can provide malignant cells with both abilities. His research has yielded a
technology for developing unique inhibitors of the heparanase enzyme and found
that these monoclonal antibodies are effective in preventing tumor growth and
metastasis in several models in vivo.
A NOVEL BIOMARKER FOR PROSTATE CANCER
Prostate cancer is one of the most common types of cancer found in men over the
age of 50. Its development is preceded by benign hypertrophy (BPH).
Prostate-specific antigen (PSA) is the diagnostic biomarker commonly utilized to
diagnose prostate hypertrophy.However,it cannot distinguish between hypertrophy
and malignancy or predict the critical shift from the former to the latter. Prof
Nathan Karin has discovered that patients who suffer from prostate cancer
develop an autoantibody response against a particular chemokine in an attempt
to restrain the disease. Importantly, these autoantibodies are produced only during
the malignant stage of the disease and may constitute a marker to distinguish
between benign hypertrophy and the malignant stages.Therefore, these antibodies
have the potential to be more useful diagnostic biomarkers for prostate cancer
than PSA.
T H E R A P P A P O R T I N S T I T U T E

3. INDUCED PLURIPOTENT STEM CELLS (iPSCs)
iPSCs are a type of pluripotent stem cell artificially derived from a non-
pluripotent cell - typically an adult somatic cell - by inducing a “forced”
expression of specific genes. iPSCs provide unprecedented opportunities for
developing new medical therapies for debilitating diseases.
Prof Lior Gepstein and Prof Ofer Binah are investigating the potential
of iPSC-based therapies. Prof Gepstein has recently established a novel iPSC
experimental platform, in which therapies can be investigated optimally in
a human-like environment. This new platform enables development of new
molecules to different cardiovascular diseases and syndromes, definition
of new indications for generic molecules and evaluation of cardiovascular
related adverse events induced by new molecules.
HAPTOGLOBIN PHENOTYPING
In addition to genetic factors, it has become clear that illness duration and
control of the patient’s blood sugar determine the risk level for developing
diabetic eye, kidney, or heart disease in diabetic patients.
Prof Andrew Levy has developed a novel test method for identifying
high-risk diabetic patients, which is based on the hemoglobin-binding
protein, haptoglobin. The test has been validated in over 10,000 diabetic
patients worldwide, and the results of this testing have been published in
prestigious peer-reviewed medical journals. The value of the test is its ability
to identify the subset of diabetic patients who should be treated aggressively
with regard to management of their blood sugar and lipid (cholesterol) levels,
and high blood pressure.
BioRap is looking for a partner to market this diagnostic assay for managing
patients with diabetes-related complications as well as to license the
technology, to serve as an improved diagnostic tool in diabetes related
clinical studies for assaying inclusion/exclusion criteria outside the US.
ONE MOLECULE WITH SEVERAL THEREAPEUTIC
MODALITIES AGAINST CANCER
One of the obstacles in clinical oncology is that tumors sometimes acquire
resistance to therapy and spread. Throughout the years, various therapeutic
agents have been developed aiming to directly target tumor cells or
inhibit tumor-supporting cells in its microenvironment. The development of
immunomodulatory agents and antiagiogenic drugs has made a significant
impact on the oncology field in recent years. Yet, it is currently clear that
a combinatorial treatment modality against cancer is required in order to
enhance therapy outcome and delay resistance and metastasis. Prof. Yuval
Shaked and Prof.AmiAronheim have worked together to develop a drug
which acts against tumor cells and host cells at the tumor microenvironment.
They have generated a stable recombinant protein which modulate the
immune system against tumor cells, inhibits tumor cell proliferation and
metastasis and block angiogenesis.This molecule has shown significant anti-
tumor and anti-metastatic activities with no toxicity in several aggressive
tumor models in mice.
T H E R A P P A P O R T I N S T I T U T E
NOD-SCID mice were implanted with HCT116
cells.When tumors reached a size of 50mm3, mice
were either implanted with pumps (150µg hIL31-
IgG) or injected biweekly (50µg hIL-31-IgG). ***
p<0.001.

4. T H E R A P P A P O R T I N S T I T U T E
OPTOGENETICS FOR THE TREATMENT OF
CARDIAC ARRHYTHMIAS
Optogenetics approaches, utilizing light-sensitive proteins, have emerged as
unique experimental paradigms to modulate neuronal excitability and have
consequentially revolutionized neuroscience. The group of Dr. Lior Gepstein
is developing similar strategies to also control cardiac-tissue excitation by light
and consequentially to design new therapeutic measures for different cardiac
disorders. Specifically this group has demonstrated in vitro and in vivo the ability
to pace cardiac tissue following activation of the light-sensitive depolarizing
channel Channelorhodopsin-2 and to suppress cardiac tissue electrical activity
following activation of hyperpolarizing light-sensitive proteins. This technology
is now being explored to target specific cardiac disorders such as different
cardiac bradyarrhythmias, tachyarrhythmias, and heart failure with mechanical
dyssynchrony.
NEW STRATEGIES FOR TREATMENT AND PREVENTION
OF CANCER
The Extracellular Matrix MetalloProteinase INducer (EMMPRIN, also known as
CD147) was found to be over-expressed in 77% of human tumors, and this
overexpression is correlated with increased angiogenesis, progression, and
metastasis, as EMMPRIN can induce the expression of both VEGF and MMPs.
Previous attempts to inhibit MMPs largely failed to inhibit tumor progression in
clinical trials, and the use of anti-VEGF antibodies provided only temporary relief.
However, because EMMPRIN can simultaneously induce many types of MMPs as
well as VEGF, it represents an alternative, more attractive therapeutic target.
Assist. Prof. Miki Rahat and her group identified a new and specific epitope
in the EMMPRIN protein, which is responsible for the induction of both MMPs
and VEGF.This epitope is now targeted by two new immunotherapy approaches:
one that is based on the use of epitope-specific monoclonal antibodies, and
the other is based on active vaccination against the epitope modified as a
multiple antigenic peptide (MAP). These two types of molecules can be used as
immunotherapy strategies in the treatment of cance.
Effects of the epitope-specific MAP on
lung metastases in comparison to the
scrambled control.
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