99mTc-EC-Metronidazole)
99mTc-EC-metronidazole
("99mTc-EC-MN") is being
studied as a cellular hypoxia targeting agent for oncology and
as a functional imaging agent to assess neurological disease.
Plans are to submit an IND application to the FDA in the 2nd
quarter of 2008 to start a Phase I clinical trial for
neurological applications. The following is an example of how
99mTc-EC-MN can be used is
in neurology. A collaborative study conducted in South Korea on
patients who had suffered ischemic stroke to the brain evaluated
the relationship between neurological outcome and uptake of
99mTc-EC-MN in peri-infarcted
regions of the brain. 99mTc-EC-MN
was used to identify hypoxic (absence of oxygen) tissue. When
used in conjunction with 99mTc-ECD,
a blood flow perfusion agent, 99mTc-EC-MN
was found to be useful in predicting neurological outcome in
patients within the first 48 hours following ischemic stroke,
thus giving the neurologist important information on whether the
patient may have salvageable tissue and thus benefit from tissue
rescue therapy. The results of the 99mTc-EC-MN
study were published in the cardiology journal Stroke.
34(4):982-986,2003.

The above images are of two patients who
have suffered infarct damage to the right side of the brain.
Slide #1 for each patient is an MRI image which shows the area
effected. Slide #2 shows the infarct area using
99m Tc labeled ECD, a perfusion
agent. Slide #3 shows the area of the brain (outlined in yellow)
that indicates hypoxic tissue within the impacted region. The
potentially viable tissue is illuminated using
99mTc labeled metronidazole.
This information is useful to the neurologist in deference to
making a decision regarding further surgical intervention for
the patient.
The company also believes that
99mTc-EC-MN will be effective in
measuring tumor hypoxia and thus will provide the medical
oncologist with useful and important information on selection of
therapy. Whether a tumor is hypoxic is important in the decision
to give the patient external radiation treatment. This potential
application will be pursued following the neurological study
187Re-EC-G
The company is developing a cold metallic
chemotherapeutic agent, 187Re-EC-G,
which has been evaluated in pre-clinical studies as a
stand-alone therapeutic agent for the treatment of non-Hodgkin’s
lymphoma. A successful SCID mice study recently completed
demonstrated good tolerance and therapeutic effectiveness. One
of the advantages of this agent will be that it is a target
specific therapeutic that uses EC-G to deliver the cold metallic
Re into the DNA of metabolically active cancer cells.. Another
advantage is that EC-G does not normally localize in the brain
or heart. This should reduce the potential adverse effects to
either organ including cardiotoxicity.
187Re-EC-G
should provide an alternative chemotherapy option for medical
oncologists in the treatment of various cancer types to include
NHL. Assuming that clinical endpoints are achieved in the
clinical study expected to start in the 4th quarter 2008,
187Re-EC-G should provide
clinical equivalent efficacy commonly associated with other
chemotherapy alternatives (such as Rituxan). The Company is
completing the cGMP 187Re-EC-G
kits with J-Star Research (New Jersey) and is preparing to start
the final phase of the preclinical study in early 2008. This
will be followed by the filing of an IND with the FDA to start
clinical trials. The current plan is for the clinical trial
protocol to compare 187Re-EC-G
with Rituxan in the treatment of lymphoma. Clinical studies of
other indications will follow
In-Situ
Hydrogel
In-Situ Hydrogel is a high yield
radio/chemotherapy delivery system that enables the physician to
treat inoperable or surgically nonresectable tumors. The
following are several advantages of In-Situ Hydrogel:
-
The hydrogel will contain both a
therapeutic radionuclide (i.e. ,188Re)
and a chemotherapeutic drug. Upon direct injection into the
tumor mass, the proprietary hydrogel compound encapsulates
the radionuclide and chemotherapeutic drug. The radioactive
decay of the radionuclide remains trapped within the
hydrogel while the chemotherapeutic drug is slowly released.
This results in minimal impact to healthy surrounding tissue
thus significantly reducing adverse toxicity normally
associated with systemic chemotherapy agents or external
beam radiation.
-
Could be considered as an alternative
to brachytherapy with the advantage of providing uniform
therapy to the entire tumor mass such as in prostate cancer.
The choice of 188Re
as the therapeutic radionuclide has the advantage of a
comparatively short half-life (17 hours) which would permit
repeat doses of therapy without the complications associated
with seed implants ( brachytherapy). The company is planning to
complete preclinical studies in 2008 and start clinical trial
studies by the 3rd quarter 2009.
188Re-EC-G
The second radiotherapeutic agent being
developed from EC Technology is 188Re-EC-G.
One of the key attributes of 188Re-EC-G
is that (like 187Re-EC-G)
it also functions intracellular where the compound is taken up
into the cell nuclei and translocated into the DNA. This should
make the radiotherapy especially efficacious. Diagnostic imaging
with 99mTc-EC-G in
combination with using 188Re-EC-G
for therapy is a good illustration of how Molecular Imaging
(99mTc-EC-G) can be used to assess the efficacy of “target
specific therapy”.( 188Re-EC-G)
The advantage of target specific therapy is that it targets all
metabolically active cancer sites (both primary and metastatic)
independent of the location in the body. This differs from
“image-guided therapy” which only targets cancers which are
visualized by either radiological or nuclear techniques
188Re-EC-G
is a very different form of radiation therapy than traditional
external beam radiation which has been a staple cancer therapy
for decades. Historically, with external beam radiation therapy,
it was difficult to avoid impacting healthy tissue surrounding
the tumor, thus causing unwanted adverse effects from the
treatment. In addition, it has been difficult to provide a high
enough dose of radiation for especially large cancers, such a
mesothelioma, due to toxicity. More recently, Intensity
Modulated Radiation Therapy (IMRT) has been developed to reduce
the impact to surrounding healthy tissue as well as provide for
more intense doses of radiation to the targeted area. Another
form of radiotherapy, brachytherapy (radioactive seed implant
therapy), has gained widespread acceptance but is used mainly as
a treatment option for prostate cancer but it’s application is
limited to large tumors which are visualized radiographically.
Alternatively, 188Re-EC-G
is administered systemically and localizes in all metabolically
active cancer sites. Since it’s localization is
intracellular,the beta particle decay of the 188Re kills cancer cells from
inside the tumor and creates minimal adverse damage to
surrounding healthy tissue. The agent therefore accomplishes
it’s intended objective which is to efficiently and effectively
kill the malignant cells with minimal damage to surrounding
healthy tissue.
Several years ago, the FDA approved the
first two radioimmunotherapeutic agents - Zevalin (developed by
Biogen IDEC) and Bexxar (developed by Corixa that is now part of
GlaxoSmithkline). Zevalin is comprised of a CD-20 monoclonal
antibody (ibritumomab) that is first radiolabeled with
111In for dosimetry imaging and
then labeled with 90Y for
radiotherapy. The CD-20 monoclonal antibody attaches to the
outer surface of the tumor membrane. It is unable to penetrate
inside the tumor due to its molecular weight, thus the position
of the therapeutic radioisotope results in a killing radius that
impacts both healthy as well as malignant cells. Bexxar is also
a CD-20 monoclonal antibody; however, the antibody is labeled
with 131I for therapy.
Bexxar occupies the same space in the market as Zevalin for the
treatment of non-Hodgkin’s lymphoma. With both Zevalin and
Bexxar, the radioisotopes have a long half-life (eight days for
131I and 2.7 days for 90Y).
By contrast, 188Re has a half-life of 17 hours and a penetration
of almost a centimeter that will allow the radiopharmaceutical
to effectively treat even large tumors. Localization of the .
188Re directly in the
cell’s nucleus should significantly increase the killing power
of the agent compared to the extra cellular localization of both
Zevalin and Bexxar and should also provide minimal damage to
surrounding healthy tissue. To determine the proper dose of
188Re to administer, the patient
will first receive 99mTc-EC-G
and dosimetry estimates obtained using a SPECT or SPECT/CT
camera. The advantage of using 99mTc
to perform the dosimetry is that 99mTc
and 188Re are part of the
same family of isotopes and should yield more accurate dose
information. Further, 188Re-EC-G
will not suffer the limited application (NHL) that confront both
Zevalin and Bexxar since the proposed agent will be efficacious
for treatment of all metabolically active cancer types and will
be more economical per dose.
N4Technology
99mTc-N4-Tyrosine
is a diagnostic imaging agent being developed for the diagnosis
and assessment of Parkinson’s and Huntington’s disease. Also,
99mTc-N4-Tyrosine
will be studied as a diagnostic imaging agent to assess EGFR
tyrosine kinase activity in tumor cells. The goal is to
determine whether a patient will benefit from tyrosine kinase
therapy.
The Company is presently developing a pre-clinical study
collaboration agreement with a major pharmaceutical company. The
collaboration agreement will, among other things, focus on
potential clinical imaging applications in neurological
diseases. Cell>Point will supply all GMP material. The
pharmaceutical company will contribute the animal models and
will fund the pre-clinical research. In addition, the
pharmaceutical company will retain the right to publish the
results of its pre-clinical research work. Cell>Point will have
unfettered rights to the imaging applications that are
identified by the research work.
99mTc-EC-Guanosin
99mTc-EC-guanosin
is a new DNA marker that is incorporated into DNA/RNA syntheses.
The radiopharmaceutical compound will initially be evaluated as
a target specific agent for brain and prostate cancer. The
company plans to submit an IND application to the FDA in the 2nd
quarter 2009 for authorization to commence a Phase I clinical
trial study.
188Re-EC-Guanosin
The Company has made a decision to move
forward with the radiothrapeutic form of EC-guanosin. Potential
clinical applications include brain and prostate cancers.
A unique feature of EC conjugated to
guanosin is that the compound does not cross the blood-brain
barrier unless there is a breakdown in the barrier such as that
caused by a brain lesion. The first clinical trial will evaluate
whether 188Re-EC-guanosin can be an effective targeted radiotherapeutic for the treatment of certain brain tumors. The
specific targeted application will be for adult brain tumors
which are not considered candidates for surgical excision or
external beam radiotherapy.
The second clinical trial will focus on the
treatment of prostate cancer. Currently, there are two different
approaches to radiation treatment, one being external beam
radiation and the other is brachytherapy. About 30% of those
patients electing to receive treatment for their prostate cancer
receive one or both of these forms of radiation treatment.
188Re-EC-Guanosin represents an alternative form of radiation
treatment for this disease. It has the advantage of being target
specific (localizes in the prostate cancer cells) and therefore
treats the cancer directly. This differs from extertnal beam
radiation which can cause significant residual damage to tissue
surrounding the prostate gland including the bladder and bowel.
Brachytherapy has disadvantages to include
the fact it typically can only be administered to the patient
once and the radioactive seeds can migrate out of the intended
target area causing damage to normal tissue and consequently
decreasing treatment to the tumor mass.
Beta Cell
Technology
99mTc-DTPH-Glipizide
is being evaluated as a beta cell specific diagnostic agent for
the early detection and assessment of pancreatic cancer. In
addition, the Company will determine whether this technology has
potential applications for early diagnosis of diabetes or
pancreatitis.
The Company and a major pharmaceutical
company are exploring a collaboration involving beta cell
technology. The collaboration agreement will, among other
things, focus on potential clinical imaging applications.
Cell>Point will supply all GMP material. The pharmaceutical
company will contribute the animal models and will fund the
pre-clinical research. In addition, the pharmaceutical company
will retain the right to publish the results of its pre-clinical
research work. Cell>Point will have unfettered rights to the
imaging applications that are identified by the research work.