Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1999-04-14
2001-01-09
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001730, C534S010000, C534S014000, C530S350000, C536S001110, C536S115000, C536S055200
Reexamination Certificate
active
06171577
ABSTRACT:
TECHNICAL FIELD
The present invention is directed to radiolabeled annexins, including annexin-hexose conjugates such as hexose moiety conjugates, and components thereof. The present invention is also generally directed to modifications of the annexin components for the use in the preparation of radiolabeled annexins. Also contemplated by the present invention are imaging protocols which involve the administration of, for example, a radiolabeled annexin-hexose moietyconjugate. The annexin component of the conjugate serves to deliver the radiolabeled active component of the conjugate to vascular thrombi target sites. The hexose component of the conjugate facilitates rapid elimination of the radiolabeled annexin-hexose moiety conjugates from the circulation of a recipient.
BACKGROUND OF THE INVENTION
When patients present with chest pain, palpitations or any other symptoms of coronary trauma or disease, the presence of vascular thrombi in the heart is a potential significant complicating factor for treatment. If a medical practitioner could non-invasively determine whether one or more vascular thrombi were present and, if present, the location of those vascular thrombi, better evaluation of treatment options would be possible. Furthermore, if a medical practitioner could determine that no vascular thrombi were present, thereby eliminating a potential complication in treatment, cardiac conditions could be treated more safely and effectively.
Most present techniques for determining the presence of vascular thrombi are invasive and/or cumbersome, and/or fail to detect such thrombi with good sensitivity and specificity. Thus, an imaging agent usefor for non-invasive vascular thrombi imaging is desirable.
Annexins are a class of proteins that are characterized by calcium-mediated binding to anionic phospholipids. Anionic phospholipids are about 20-fold more highly associated with activated platelets than quiescent platelets, and activated platelets are associated with vascular thrombi.
Radioiodinated annexin V has been shown to localize to vascular thrombi in vivo, but has suboptimal imaging characteristics, possibly due to the pronounced beta phase of blood clearance owing to possible transiodination and/or metabolic degradation with reincorporation into serum macromolecules or non-target tissues. Free radioactive iodine or iodine-containing metabolic degradation products exposed non-target tissues, especially the thyroid gland, to radioactivity. Iodine radioisotopes I-123, I-124 and I-131 with imagable photons suffer from various drawbacks. Iodine-131 has particulate emission and its gamma emission is too high in energy for optimal imaging. Iodine-124 emits positrons and high energy gamma photons. Finally, I-iodine-123 radiolabel with superior imaging properties is expensive and difficult to obtain and is not therefore practical for wide spread use. Consequently, improved radiolabeled annexin compounds are desirable.
In addition, conventional imaging and therapy are often plagued by the problem that the generally attainable targeting ratio (ratio of administered dose localizing to target versus administered dose circulating in blood, or ratio of administered dose localizing to target versus administered dose migrating to bone marrow) is low. Improvement in targeting ratio is also sought.
Thus, for the foregoing reasons there is still a need for a thrombus imaging product with increased sensitivity to image small thrombi, such as carotid thrombi or intracardiac thrombi and those present in coronary arteries after angioplasty or during myocardial infarctions or in cerebral arteries during stroke. Development of a radiolabeled thrombus imaging agent capable of detecting intracoronary thrombi would represent a breakthrough product of great clinical and commercial significance. The present invention fulfills this need and provides further related advantages.
SUMMARY OF THE INVENTION
The present invention provides radiolabeled annexin-hexose moiety conjugates and methods of making and using the same. The present invention further provides an annexin component that is altered in such a way as to provide an accessible sulfhydryl group and/or other amino acid groups for derivatization so as to serve to improve the imaging properties of annexin. Annexin-ccntaining conjugates of the present invention are suitable for radiolabeling with a diagnostic imaging agent. Preferred conjugates of the present invention include:
an annexin;
a hexose moiety; and
an N
2
S
2
chelating compound associated with the annexin.
Also provided by the present invention are radiolabeled annexin-hexose moiety-conjugates which include:
an annexin;
a hexose moiety;
an N
2
S
2
chelating compound associated with the annexin; and
a diagnostic radionuclide complexed by the chelating compound.
Another preferred conjugate of the present invention includes:
a modified annexin, wherein the modification provides an accessible sulfhydryl group; and
a hexose moiety recognized by a mammalian liver receptor, wherein the hexose moiety is conjugated to the annexin.
Another preferred conjugate of the present invention includes:
a modified annexin, wherein the modification provides an accessible sulfhydryl group;
a hexose moiety recognized by a mammalian liver receptor; and
a N
x
S
y
chelating compound, wherein the hexose moiety is conjugated to the modified annexin directly or via the chelating compound and the chelating compound is conjugated to the modified annexin directly or via the hexose moiety.
Another preferred conjugate of the present invention includes:
an annexin multimer;
a hexose moiety recognized by a mammalian liver receptor; and
a N
x
S
y
chelating compound, wherein the hexose moiety is conjugated to the multimer directly or via the chelating compound and the chelating compound conjugated to the multimer directly or via the hexose moiety.
Another preferred conjugate of the present invention includes:
an annexin; and
an esterase-sensitive N
x
S
y
chelating compound conjugated to the annexin.
Another preferred conjugate of the present invention includes:
a modified annexin, wherein the modification provides acessible sulfhydryl group; and
a N
x
S
y
chelating compound conjugated to the annexin.
Another preferred conjugate of the present invention includes:
a modified annexin, wherein the modification provides an accessible sulfhydrl group; and
an esterase-sensitive N
x
S
y
chelating compound conjugated to the annexin.
Another preferred conjugate of the present invention includes:
an annexin multimer; and
a N
x
S
y
chelating compound conjugated to the annexin.
Another preferred conjugate of the present invention includes:
an annexin multimer; and
an esterase-sensitive N
x
S
y
chelating compound conjugated to the annexin.
It will be understood by one of ordinary skill in the art that where a chelating compound is a component of the conjugate, any one of the above preferred conjugates further includes a radionuclide complexed by :he chelating compound.
A preferred annexin for use in the present invention is annexin V. A modified annexin is extended on the C-terminus or N-terminus by a number of a amino acids. A preferred modified annexin for use in the present invention is extended on the N-terminus. This addition of the extension results in a modification to the annexin whereby an accessible sulfhydryl group is provided for. Thus, the modified annexin can be conjugated to a hexose moiety, such as a hexose cluster, (e.g., N-acetylgalactosamine cluster; or provide for an endogenous radiolabel chelation site, thus eliminating the need for intermediate production of an amine-directed active ester containing the radiolabel; or provide for multimer production.
The modified annexin component of the conjugate allows for rapid binding of the radiolabel to the annexin, thus providing for a simplified labeling procedure for clinical use. In some embodiments of the present invention, the modification to the annexin provides for acceleration of blood clearance thereby reducing the background radioactivity of the blood pool.
Also
Fritzberg Alan R.
Kasina Sudhakar
Reno John M.
Tait Jonathan
Dees Jose′ G.
Hartley Michael G.
NeoRx Corporation
Seed Intellectual Property Law Group PLLC
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