Induced nuclear reactions: processes – systems – and elements – Nuclear transmutation
Reexamination Certificate
2000-11-29
2004-01-20
Jordan, Charles T. (Department: 3641)
Induced nuclear reactions: processes, systems, and elements
Nuclear transmutation
C376S105000, C376S109000, C376S115000, C376S152000, C376S162000, C376S195000, C376S137000, C376S157000, C376S159000, C376S194000, C376S200000, C376S202000, C376S190000
Reexamination Certificate
active
06680993
ABSTRACT:
I. BACKGROUND OF THE INVENTION
A. Field of the Invention
The present invention generally relates to processes and methods for producing, isolating, and using radiochemicals. More specifically, the methods and processes of this invention are directed to the preparation of Actinium-225 and daughters having high radiochemical and radionuclidic purity, which may be used for the preparation of alpha-emitting radiopharmaceuticals, in particular, for linkage to therapeutics such as those containing monoclonal antibodies, proteins, peptides, antisense, statin, natural products and hormones. The alpha-emitting radionuclide Actinium-225 and daughters can be used for both therapeutic and diagnostic purposes.
B. Description of Related Art
After cardiovascular disease, cancer is the second leading cause of death in the United States, accounting for one-fifth of the total mortality. Lung, prostate, and colorectal cancer are the leading cancers in men, and women are most frequently plagued by breast, lung and colorectal cancer.
Surgical removal is a frequently used therapeutic approach to treatment, but it is, obviously, invasive. Chemotherapy and radiotherapy have the advantage of being non-invasive, but have the potential disadvantage of being too non-specific. That is, killing of cancer cells is obtained with good success, yet the collateral damage can be serious. In fact, collateral damage is the major side effect of these approaches, and is often the reason patients choose to forego chemotherapy and radiotherapy in favor of surgery.
Generally, these systemic methods rely on differences between the cancer cells and the normal cells for targeting. For example, cancer cells proliferate at a faster rate than normal cells, and this difference has been exploited. The greater rate of proliferation results in a greater rate of uptake of toxic substances, as compared to the rate of uptake for normal cells. Thus, where cell toxins are introduced systemically, cancer cells take up the toxins more rapidly than normal cells, and are thereby killed to a greater extent. Obviously, this is not ideal, as any normal cell death is highly undesirable. However, the killing of normal cells by cancer therapeutic agents is a very real side effect, and as mentioned above, is a major reason patients forgo such therapy.
A number of methods have been used with success to increase the specificity of cancer targeting. These methods frequently take advantage of a some other difference between the cancer cells and the normal cells. Differences that have been exploited with good success are the structural differences between cancer cells and normal cells. These structural differences include cell surface antigens, receptors, or other surface proteins or molecules that are differentially expressed between the types of cells. Any such difference may be exploited.
For example, many tumor cells have an increased number of certain cell surface antigens as compared to normal cells. Targeting agents such as monoclonal antibodies may be used to specifically target and bind to the cell surface antigens on the tumor cells, resulting in the localization and internalization of the therapeutic agents. Specifically, for example, monoclonal antibodies such as the anti-gp160 antibody for human lung cancer (see Sugiyama et al., “Selective Growth Inhibition of Human Lung Cancer Cell Lines Bearing a Surface Glycoprotein gp160 by
125
I-Labeled Anti-gp160 Monoclonal Antibody,” Cancer Res. 48:2768-2773 (1988), a “FNT-1” monoclonal antibody for human cervical carcinoma (see Chen et al., “Tumor Necrosis Treatment of ME-180 Human Cervical Carcinoma Model with
131
I-Labeled TNT-1 Monoclonal Antibody,”
Cancer Res
. (1989) August 15;49(16):4578-85), and antibodies against the epidermal growth factor receptor for KB carcinoma (see Aboud-Pirak et al., “Efficacy of Antibodies to Epidermal Growth Factor Receptor Against KB Carcinoma In Vitro and in Nude Mice,” J. National Cancer Institute 80(20):1605-1611 (1988) have been used to specifically localize tumor cells.
Various radiotherapeutic agents have also been utilized to kill tumor cells including, for example, the beta-emitters Iodine-131, Copper-67, Rhenium-186, and Yttrium-90. Beta-emitters, however, are disadvantageous because of their low specific activity, low linear energy transfer, low dose rates (allowing for cell repair of radiation damage), damage to surrounding normal tissues, and in some cases the lack of an associated imageable photon (e.g., Yttrium-90).
Alpha-emitting radionuclides are much more appropriate toxins and have the potential to more effectively treat disease. Unlike conventional systemic radiation therapy utilizing a gamma-emitter, in cell-directed radiation therapy, targeting agents seek out and attach a radioisotope to targeted cancer cells. The selective cytotoxicity offered by alpha-particle-emitting radionuclide constructs is a result of the high linear energy transfer, at least 100 times more powerful than that delivered by beta-emitting radionuclides, short particle path length (50-80 micrometers), and limited ability of cells to repair damage to DNA.
Because the radiation of alpha-emitting radionuclides only penetrates a few cell lengths in depth, there is much less of the collateral damage to healthy tissues and cells common to chemotherapy and beta- and gamma-emitting radionuclides used for radionuclide therapy. The short penetration distance allows for precise targeting of the cancer cells. Alpha-emitting radionuclides are among the most potent cytotoxic agents known and appear safe in human use.
For example, beta-emitting Iodine-131 (8.02-day half-life) is used for the treatment of non-Hodgkin's Lymphoma, thyroid carcinoma, and other cancers. While the iodine preferentially localizes in the thyroid tissue, this treatment is still problematic because the radionuclide penetrates the tissue to a depth of 10 mm and can cause collateral damage to healthy tissues and cells. When given in sufficient doses to kill 1:91 cancer cells (up to 600 millicuries), Iodine-131 can impair or destroy bone marrow in patients, necessitating a marrow transplant. This is a very dangerous and painful process. Another beta-particle-emitting radioisotope utilized for radionuclide constructs is Yttrium-90, which because of its high energy levels, also deeply penetrates human tissue and can cause collateral damage to healthy cells or organs.
Actinium-225, Bismuth-212, Lead-212, Fermium-255, Terbium-149, Radium-223, Bismuth-213 and Astatine-211 are all alpha-emitting radionuclides that have been proposed for radionuclide therapy. Of these radionuclides, Actinium-225 (5.8 MeV alpha-emitter with a 10-day half-life) and its daughter, Bismuth-213 (46-minute half-life) may be the most efficacious. Alpha-emitting Astatine-211 also has been proposed as an appropriate alpha-emitting medical radionuclide, but would be less useful due to its short half-life (7.21 hours), which could create distribution problems.
Bismuth-213 has a shorter half-life than Actinium-225, but its physical and biochemical characteristics, its production, and its radiopharmacological characteristics, make it a good candidate for use in humans. Dr. Otto Gansow pioneered the development of alpha radioimmunotherapy, developing the linkers used to bind the monoclonal antibody to radiobismuth. (See U.S. Pat. Nos. 4,923,985, 5,286,850, 5,124,471, 5,428,154 and 5,434,287 to Gansow et al.) The alpha-emitting radioisotope Bismuth-213, in conjunction with targeting molecules, is showing promise in clinical trials using Bismuth-213 in alpha-radioimmunotherapy.
Bismuth-213 is currently being evaluated in a clinical trial for treatment of Acute Myeloblastic Leukemia (AML) and could have the potential for treatment of a range of diseases including T-Cell leukemia, non-Hodgkins lymphoma, the micrometastases associated with a range of diseases including prostate cancer, and other diseases. It has been found that Bismuth-213 could be used to halt the arteriole growth that feeds solid tumors and lung cancers. This therapy, currently
Satz Stanley
Schenter Scott
Ivey Floyd E.
Jordan Charles T.
Liebler Ivey & Connor
Richardson John
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