U.S. patent application number 17/574963 was filed with the patent office on 2022-05-05 for one step 64cu-babasar-rgd2 production method.
The applicant listed for this patent is University of Southern California. Invention is credited to Peter Conti, Shuanglong Liu.
Application Number | 20220133919 17/574963 |
Document ID | / |
Family ID | |
Filed Date | 2022-05-05 |
United States Patent
Application |
20220133919 |
Kind Code |
A1 |
Liu; Shuanglong ; et
al. |
May 5, 2022 |
ONE STEP 64Cu-BaBaSar-RGD2 PRODUCTION METHOD
Abstract
A method of preparing a .sup.64Cu-BaBaSar-RGD.sub.2 solution is
provided. The method includes lyophilizing a solution of
BaBaSar-RGD.sub.2 and adding a .sup.64Cu solution to the
lyophilized BaBaSar-RGD.sub.2.
Inventors: |
Liu; Shuanglong; (Monterey,
CA) ; Conti; Peter; (Pasadena, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
University of Southern California |
Los Angeles |
CA |
US |
|
|
Appl. No.: |
17/574963 |
Filed: |
January 13, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16205985 |
Nov 30, 2018 |
11253617 |
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17574963 |
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62593723 |
Dec 1, 2017 |
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International
Class: |
A61K 51/08 20060101
A61K051/08; A61K 51/12 20060101 A61K051/12; A61K 51/04 20060101
A61K051/04 |
Claims
1. A kit for comprising: a lyophilized powder of BaBaSar-RGD.sub.2,
a buffer salt and instructions for reconstituting the lyophilized
powder with a .sup.64Cu solution comprising .sup.64CuCl.sub.2.
2. The kit according to claim 1, wherein the buffer salt is sodium
acetate buffer.
3. The kit according to claim 1, wherein the instructions comprise
adding the .sup.64Cu solution to the lyophilized powder.
4. The kit according to claim 1, comprising about 50 .mu.g
BaBaSar-RGD.sub.2.
5. The kit according to claim 1, wherein the kit has a shelf life
of over three months at room temperature.
6. The kit according to claim 1, wherein the kit has a shelf life
of over a year when stored at a temperature of 2-8.degree. C.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 16/205,985 filed Nov. 30, 2018, now pending;
which claims the benefit under 35 USC .sctn. 119(e) to U.S.
Application Ser. No. 62/593,723 filed Dec. 1, 2017, now expired.
The disclosure of each of the prior applications is considered part
of and is incorporated by reference in the disclosure of this
application.
FIELD OF THE INVENTION
[0002] The present invention relates in general to the preparation
of imaging probes.
BACKGROUND OF THE INVENTION
[0003] Tumor-induced angiogenesis plays a critical role in tumor
progression and metastasis. Without new vasculature and blood
circulation, tumor stops growing at the size of 1-2 mm3 and may
become necrotic or even apoptotic since diffusion is already
insufficient to supply the tissue with oxygen and nutrients (1, 2).
Substantial efforts have been made to develop therapeutic
strategies that interrupt the angiogenic process to stop the tumor
growth (3). Integrin .alpha.v.beta.3 is a vital component for the
angiogenic process by mediating endothelial cell (EC) migration and
survival during angiogenesis (4). For neovasculature formation, ECs
need to migrate into an avascular region and to extensively remodel
the extracellular matrix (ECM). In this process, integrins
.alpha.v.beta.3, an immunoglobulin superfamily molecule has proved
to be one of the most important cell adhesion receptors for various
ECM proteins. While in normal tissues, expression of integrin
.alpha.v.beta.3 is much lower, making integrin .alpha.v.beta.3 an
ideal target for diagnosis and therapy in cancer study. A protocol
to non-invasively quantify its expression levels will provide a
method to document integrin levels, which can support the
anti-integrin .alpha.v.beta.3 treatment for the patients, and
effectively monitor treatment progress for the integrin
.alpha.v.beta.3-positive patients. Non-invasive detection and
quantification of integrin .alpha.v.beta.3 is also leading to the
diagnosis of many types of cancer at their earliest stages (5).
[0004] Peptides containing Arg-Glu-Asp (RGD) amino acid sequence
have a high binding affinity and selectivity for integrin
.alpha.v.beta.3 (6). In the last two decades, a number of peptides
containing RGD sequences have been developed to target tumors
overexpressing .alpha..sub.v.beta..sub.3 receptors (7). RGD
peptides have been modified and radiolabeled for positron emission
tomography (PET) probe development. .sup.18F-galacto-RGD is the
first RGD probe tested in human subjects for detecting
.alpha..sub.v.beta..sub.3 expression. With conjugation of a sugar
moiety for reducing the liver uptake, .sup.18F-galacto-RGD is still
specifically binding to integrin .alpha..sub.v.beta..sub.3, shows a
more desirable biodistribution in humans, and provides a better
visualization of .alpha..sub.v.beta..sub.3 expression in tumors
with high contrast (8). However, a major disadvantage for
.sup.18F-galacto-RGD is the long and sophisticated preparation,
including multiple synthetic steps that complicate routine
production (9). Due to the importance of RGD peptides, continued
efforts have been made to achieve desirable PET probes for easy
production, optimal pharmacokinetics, and higher tumor uptake, such
as .sup.18F-AH111585 (10-12), .sup.18F-alfatide (13,14),
.sup.18F-RGD-K5 (15,16), .sup.18F-FPPRGD.sub.2 (17,18),
.sup.18F-fluciclatide (12,19), and .sup.68Ga-NOTA-PRGD.sub.2
(20).
[0005] .sup.64Cu (T.sub.1/2.sup.=12.7 h; .beta..sup.+ 0.653 MeV
[17.8%]) has been widely used for radiolabeling proteins,
antibodies and peptides for PET probe development. The low
.beta..sup.+ energy of .sup.64Cu gives a resolution down to 1 mm in
PET images and is important to achieve lower radiation doses for
the patients (21). Cage-like hexaazamacrobicyclic sarcophagine
chelator completely encapsulates the coordinated Cu.sup.2+ ions.
Their complexes exhibit enhanced thermodynamic and kinetic
stability to copper-binding proteins in vivo (22). Starting from
hexaazamacrobicyclic sarcophagine, a BaBaSar chelator for
conjugation with RGD peptide (BaBaSar-RGD.sub.2) was developed. The
.sup.64Cu labeling chemistry for BaBaSar-RGD.sub.2 was achieved at
room temperature to give a quantitative yield. The resulting
.sup.64Cu-BaBaSar-RGD.sub.2 probe shows great stability both in
vitro and in vivo, providing high tumor uptake and low normal organ
uptake in U87MG glioblastoma tumor bearing mice (23). Due to the
wide application of RGD peptide in diagnostic and therapeutic
applications, there is a need for PET radiotracer for integrin
imaging that can be made easily. Such a PET radiotracer would be of
great interest to both radiochemists and physicians.
SUMMARY OF THE INVENTION
[0006] One aspect of the present invention is directed to a method
of preparing a .sup.64Cu-BaBaSar-RGD.sub.2 solution. The method
includes lyophilizing a solution of BaBaSar-RGD.sub.2 and adding a
.sup.64Cu solution to the lyophilized BaBaSar-RGD.sub.2.
[0007] In one embodiment, the .sup.64Cu solution includes
.sup.64CuCl.sub.2.
[0008] In another embodiment, the .sup.64Cu solution includes
buffer salts.
[0009] In another embodiment, the solution of BaBaSar-RGD.sub.2
includes buffer salts.
[0010] In another embodiment, the buffer salts include sodium
acetate buffer.
[0011] Another aspect of the present invention is directed to a
method preparing a .sup.64Cu-BaBaSar-RGD.sub.2 solution. The method
includes lyophilizing a .sup.64Cu-BaBaSar-RGD.sub.2 solution and
reconstituting the .sup.64Cu-BaBaSar-RGD.sub.2 solution with an
aqueous solution.
[0012] In one embodiment, the .sup.64Cu-BaBaSar-RGD.sub.2 solution
includes buffer salts.
[0013] In another embodiment, the buffer salts include sodium
acetate buffer.
[0014] Another aspect of the present invention is to provide a kit
for preparing a positron emission tomography (PET) probe. The kit
includes a lyophilized powder of BaBaSar-RGD.sub.2 and instructions
on how to reconstitute the lyophilized powder with a .sup.64Cu
solution.
[0015] In some embodiments, the .sup.64Cu solution comprises a
.sup.64Cu.sup.2+ salt dissolved or dispersed in a suitable liquid
medium. The .sup.64Cu solution comprises a .sup.64Cu halide salt,
wherein the halide is selected from a group that includes fluorine,
chlorine, bromine and iodine.
[0016] In some embodiments, the .sup.64Cu solution can include one
or more buffer salts.
[0017] In some embodiments, the solution of BaBaSar-RGD.sub.2 can
include one or more buffer salts.
[0018] Other aspects and advantages of the invention will be
apparent from the following description and the appended
claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1: Kit production process of
.sup.64Cu-BaBaSar-RGD.sub.2.
[0020] FIG. 2: Structure of RGD peptide and the synthesis route for
.sup.64Cu-BaBaSar-RGD.sub.2.
[0021] FIG. 3: Analytical radio trace HPLC chromatogram for the
purity of the .sup.64Cu-BaBaSar-RGD.sub.2.
[0022] FIG. 4: Decay-corrected anterior maximum-intensity
projections of PET/CT at 1, 5, 10, 20, 40, 60, 120, and 180 min
after injection of .sup.64Cu-BaBaSar-RGD.sub.2 in macaque
monkey.
[0023] FIG. 5: Structures of AnAnSar, BaAnSar, BaMalSar, and
MalMalSar.
[0024] FIGS. 6-7: Additional peptides to be used in present
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0025] Unless otherwise indicated herein, all terms used herein
have the meanings that the terms would have to those skilled in the
art of the present invention. Practitioners are particularly
directed to current textbooks for definitions and terms of the art.
It is to be understood, however, that this invention is not limited
to the particular methodology, protocols, and reagents described,
as these may vary.
[0026] To promote the clinical application of
.sup.64Cu-BaBaSar-RGD.sub.2 in humans, the present invention
provides a straightforward, one-step synthesis of
.sup.64Cu-BaBaSar-RGD.sub.2 radiopharmaceutical using a preloaded
cold kit.
[0027] The present invention provides a one-step production of
radiopharmaceutical .sup.64Cu-BaBaSar-RGD.sub.2 with a kit
preloaded with all the precursors. FIG. 1 discloses the process of
production. Furthermore, this method is not limited to the
production of .sup.64Cu-BaBaSar-RGD.sub.2. When biological ligands
other than RGD peptides are conjugated with the BaBaSar chelator,
the same kit method associated with BaBaSar chelator could be used
too. For example, other peptides can be used in place of RGD. In
addition, other chelators, preferably sarcophagine based chelators,
such as AnAnSar, BaAnSar, BaMalSar, and MalMalSar can be used in
place of BaBaSar. Therefore, this kit method provides a universal
method for .sup.64Cu radiopharmaceutical production.
General Method
[0028] BaBaSar-RGD.sub.2 was synthesized as previously reported
(23). All commercial chemicals were of analytic grade and used
without further purification. .sup.64Cu in hydrochloric acid was
obtained from Washington University (St. Louis, Mo.) or produced in
the Molecular Imaging Center Cyclotron Facility. Analytic
reversed-phase high-performance liquid chromatography (RP-HPLC)
using a Phenomenex Luna column (5.mu., C.sub.18, 250.times.4.6 mm)
were performed on a Dionex U3000 chromatography system with a diode
arrays detector and radioactivity flow-count (Eckert & Ziegler,
Valencia, Calif.). The recorded data were processed using
Chromeleon version 7.20 software. The flow rate of analytical HPLC
was 1.0 mL/min. The mobile phase starts from 95% solvent A (0.1%
trifluoroacetic acid [TFA] in water) and 5% solvent B (0.1% TFA in
acetonitrile [MeCN]). From 2 to 32 min, the mobile phase ramped to
35% solvent A and 65% solvent B. The ultraviolet (UV) detector of
HPLC was set at 254 nm. The endotoxin analysis was performed on a
portable Endosafe.RTM.-PTS.TM. system consisting of LAL reagent and
endotoxin controls applied to a single use, polystyrene
cartridge.
Radiopharmaceutical Preparation
[0029] Preparation of .sup.64Cu-BaBaSar-RGD.sub.2 Production
Kit
[0030] The 18.2 M.OMEGA.cm water from in-house GenPure.TM. station
was treated with chelex 100 resin 48 hours before use. All the
solution hereafter was prepared with this treated water. The
lyophilized BaBaSar-RGD.sub.2 (1.0 mg) was dissolved in 1.0 mL
sodium acetate buffer (NaOAc, 0.1 M, pH 5.5). The pH of
BaBaSar-RGD.sub.2 solution was adjusted to pH 5.5 using 0.1 M
sodium hydroxide (NaOH). Then, the BaBaSar-RGD.sub.2 solution was
equally aliquoted to 20 Eppendorf vials (1.5 mL). The filled vials
were frozen using dry ice and then transferred to the bottles of
the Labconco Freeze Dry System (pressure<100 mTorr). After the
solvent was removed, the vials containing BaBaSar-RGD.sub.2 powder
were then sealed and stored at -18.degree. C. for .sup.64Cu
labeling.
.sup.64Cu-Labeling Chemistry
[0031] 64CuCl2 (5-30 mCi) purchased from Washington University at
St. Louis was reconstituted using 200-300 .mu.L NaOAc buffer (0.1
M, pH 5.5) and added to a vial prepared in above section. The vial
was gently shaking at room temperature for 5 min. After the
reaction was quenched with 5.0 mL saline, the activity passed
through a 0.22 .mu.m sterile filter (Pall Corp.) into a 10 mL
Allergy vial for quality control test and animal/human
injection.
Kit Preparation
[0032] A cold kit can contain 50 .mu.g BaBaSar-RGD.sub.2 ligand to
which .sup.64CuCl.sub.2 is to be complexed, and buffer salts to
adjust the pH suitable for the labelling conditions. The kits are
prepared in a lyophilized form and have a long shelf life of over 3
months at room temperature. When the cold kits are stored in a
refrigerator at 2-8.degree. C., the shelf life is over a year.
Radiochemistry
[0033] The labeling chemistry for .sup.64Cu-BaBaSar-RGD.sub.2 is
disclosed in FIG. 2. The .sup.64Cu-labeling yield for
.sup.64Cu-BaBaSar-RGD.sub.2 was >99% based on HPLC analysis
(FIG. 3). However, after passing through 0.22 .mu.m Pall filter to
remove pyrogen, approximately 15-20% .sup.64Cu-BaBaSar-RGD.sub.2
was trapped onto the filter and the overall recovered yield for
.sup.64Cu-BaBaSar-RGD.sub.2 is about 80% calculated from the loaded
.sup.64Cu. The radiochemical purity of .sup.64Cu-BaBaSar-RGD.sub.2
was >99% based on radiotrace analytical HPLC (FIG. 3). The
retention times for free .sup.64CuCl.sub.2 and
.sup.64Cu-BaBaSar-RGD.sub.2 on HPLC were 2.5 and 13.9 min,
respectively. The reaction crude without purifications did not show
free .sup.64Cu in HPLC chromatograms. Therefore, no further
purification is needed for the final product.
Quality Control
[0034] All the quality control results met the pre-specified limits
for 3 validation runs. These included half-life, appearance, pH
value, identity, endotoxin amount, etc. (Table 1). The specific
activity determined by HPLC analysis was between 389.2 and 605.4
mCi/.mu.mol (average.+-.SD, 473.0.+-.116.2 mCi/.mu.mol). Therefore,
a human dose (<25 mCi) of .sup.64Cu-BaBaSar-RGD.sub.2 contained
less than 125 .mu.g of RGD peptide.
TABLE-US-00001 TABLE 1 Quality Control Data from 3 Synthesis Runs
QC Test Release Criteria Run 1 Run 2 Run 3 Product (mCi) none 5.5
6.2 4.5 Visual Inspection Clear, colorless Yes Yes Yes
Radiochemical Identity RRT = 0.9-1.1 1.0 1.0 1.0 Radiochemical
Purity >90% 99% 100% 99% Specific Activity >100 15.7 14.4
22.4 (mCi/.mu.mol) Dose pH 4.5-7.5 5.5 6.0 6.0 Sterile Filter
>45 64 64 62 Integrity Test (psi) Radionuclidic Identity
12.6-12.8 h 12.7 12.7 12.7 (t.sub.1/2) Endotoxin Analysis
.ltoreq.17.5 <5 <5 <5 (EU/mL)
Absorbed Dose Estimates from Macaque Imaging
[0035] The injection of 13.1-19.7 MBq/kg of
.sup.64Cu-BaBaSar-RGD.sub.2 in macaque monkey produced no
observable effects on vital signs (blood pressure, pulse, and
electrocardiogram) during and 24-h after PET scan. The PET images
at 1, 5, 10, 20, 40, 60, 120, and 180 min after injection are
disclosed in FIG. 4. At 1 min, rapid uptake of
.sup.64Cu-BaBaSar-RGD.sub.2 was observed in the heart, and liver.
The bladder content was visualized at 10 min after injection and
more and more activity was accumulated in urine bladder content.
The bladder did not void because the macaque monkey was under
anesthesia. Gallbladder uptake was not observed during the whole
scan. Rapid clearance of activity in the liver was observed in the
images at time points after 1 min. The urinary bladder had the
highest uptake, with 51.37%.+-.8.73% of injected activity at 1 h
post injection. The maximum uptake for the liver, and kidneys were
37.40.+-.6.63% ID (9 min) and 26.79.+-.4.35% ID (0.5 min)
respectively. At 3 h of post injection, 8.62%.+-.1.41% of injected
activity was found in the gallbladder, small intestine, and upper
and lower portions of the large intestine.
[0036] The mean organ doses for the male human phantom were
calculated with Olinda/EXM using .sup.64Cu-BaBaSar-RGD.sub.2
biodistribution in monkey (Table 2). The kidneys had the highest
radiation-absorbed doses (108.43 .mu.Gy/MBq), followed by the
bladder wall (87.07 .mu.Gy/MBq). The mean effective dose of
.sup.64Cu-BaBaSar-RGD.sub.2 was 15.30.+-.2.21 .mu.Sv/MBq. When
925-MBq of .sup.64Cu-BaBaSar-RGD.sub.2 is administrated into human
subject, the effective dose for the non-voiding model is estimated
to be 14.2 mSv, which is comparable to the estimated 6.23 mSv dose
in a whole-body PET scan with 2-deoxy-2-[.sup.18F]fluoro-D-glucose
(.sup.18F-FDG) (24). The estimated doses for the female human were
higher by 18% because body and organ sizes of women are smaller
than those men (data not shown).
[0037] Venous blood samples were withdrawn from monkey during the
PET scan. Based on the decay corrected activity per unit of blood
sample, it was found that .sup.64Cu-BaBaSar-RGD.sub.2 was cleared
rapidly from the blood. By 3 h after injection, 2.88.+-.0.88% ID
remained (range, 2.07-3.82% ID). At 22 h after injection, the
activity in the blood decreased to 0.79.+-.0.52% ID. Based on the
percentage of injected dose in blood sample, the half life of
.sup.64Cu-BaBaSar-RGD.sub.2 in blood pool was calculated as
12.1.+-.4.0 min (n=3).
TABLE-US-00002 TABLE 2 Estimated Human Absorbed Doses of
.sup.64Cu--BaBaSar-RGD2 to Normal Organs Using Biodistribution Data
from Macaque Monkey Organs Mean .+-. SD (.mu.Gy/MBq) Adrenals 3.34
.+-. 0.52 Brain 1.27 .+-. 0.22 Breasts 1.34 .+-. 0.23 Gall bladder
Wall 3.07 .+-. 0.49 LLI Wall 2.86 .+-. 0.44 Small Intestine 4.53
.+-. 0.68 Stomach Wall 2.11 .+-. 0.34 ULI Wall 2.47 .+-. 0.39 Heart
Wall 4.39 .+-. 0.62 Kidneys 108.43 .+-. 16.41 Liver 7.54 .+-. 1.15
Lungs 1.67 .+-. 0.28 Muscle 1.88 .+-. 0.31 Ovaries 2.88 .+-. 0.44
Pancreas 2.86 .+-. 0.45 Red Marrow 9.29 .+-. 1.02 Osteogenic Cells
7.01 .+-. 0.91 Skin 1.38 .+-. 0.24 Spleen 6.78 .+-. 0.88 Testes
2.03 .+-. 0.33 Thymus 1.56 .+-. 0.26 Thyroid 1.39 .+-. 0.24 Urinary
Bladder Wall 87.07 .+-. 12.38 Uterus 4.16 .+-. 0.63 Total Body 2.76
.+-. 0.42 Effective Dose* 15.30 .+-. 2.21 *In unit of
.mu.Sv/MBq
[0038] Integrin .alpha.v.beta.3-targeted radiopharmaceutical
.sup.64Cu-BaBaSar-RGD.sub.2 has been successfully synthesized with
the one-step kit method. The straightforward method greatly
simplifies the production process and benefits the clinical
application of .sup.64Cu-BaBaSar-RGD.sub.2. Human radiation
dosimetry of .sup.64Cu-BaBaSar-RGD.sub.2 was estimated after
intravenous administration in macaque monkey, by PET imaging and
OLINDA/EXM calculations. The critical organs were kidneys and
urinary bladder wall. The mean effective dose, determined with the
male adult model, was 15.30.+-.2.21 .mu.Sv/MBq. This PET probe
demonstrates an acceptable radiation dose comparable to other
reported RGD-derived radiopharmaceuticals. These demonstrate great
promise of .sup.64Cu-BaBaSar-RGD.sub.2 as an integrin marker, with
a desirable biodistribution and safety characteristics in monkey.
Therefore, .sup.64Cu-BaBaSar-RGD.sub.2 can safely be used in human
scan for further evaluation of its performance as an
integrin-targeting probe.
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