Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1998-11-05
2002-07-09
Nolan, Patrick J. (Department: 1644)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S009100, C424S001110, C424S001650
Reexamination Certificate
active
06416734
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to cancer therapeutics and diagnostic methods.
Cancer is one of the most common of all human diseases, resulting in over 500,000 deaths annually in the United States alone. Cancer typically is detected by the physician as an abnormal growth, or tumor, which causes illness by production of biochemically active molecules, by local expansion, or by invasion into neighboring or outlying tissue sites. The symptoms of the illness depend upon the specific molecular product(s) of the cancer. Thus, each type of cancer has a characteristic developmental history that describes the likely clinical course of the particular neoplastic process. For example, it is known that breast cancer spreads most frequently to the lungs, liver, bone, and brain.
Early detection and diagnosis of cancer is often necessary for devising an optimal treatment plan for a patient. By determining the presence of early metastatic disease, treatment can often be designed which increases the chance for cure, or delay the development of symptoms if a cure is not achievable. Radiographic imaging is one such procedure widely used for the detection and diagnosis of various disease states, including cancer. For example, radiactive tracers or imaging agents are used for imaging studies to detect sites of human disease. Such tracer molecules are designed to concentrate at a target and define the extent of a tumor or other disease state. Isotopes coupled to monoclonal antibodies, for example, are of clinical interest as applied to cancer screening. Imaging agents are most effective if they show a high specific localization at the target site, i.e., a high target-to-background contrast. The contrast produced by an imaging agent, e.g., a labelled monoclonal antibody, is largely determined by its biodistribution in vivo. Accordingly, to improve the ability to detect abnormalities such as cancer, the development of imaging agents specifically targeted to cancerous cells is considered essential.
As for cancer treatment, although current therapies such as surgery, biologic therapies, radiotherapies, and chemotherapies have saved and improved countless lives, they remain imperfect solutions. Indeed, a major clinical problem is that many cancers remain unresponsive to these therapies. For example, the capacity to cure disseminated cancer is dependent on combination chemotherapy, alone or together with biologic therapy, surgery, and/or radiotherapy. Moreover, many cancer cells have been found to develop resistance to many anti-cancer drugs attenuating their therapeutic effectiveness. Accordingly, the search has begun for new anti-cancer compounds which can interact with oncogene products, gene regulators, and growth factors and their receptors. Research employing the tools of molecular biology promises to provide a new array of anti-cancer agents.
SUMMARY OF THE INVENTION
In general, the invention features compositions and methods for the protection, treatment, and diagnosis of neoplasia, in particular, cancer. The invention is based on my discovery that unglycosylated recombinant human alpha-fetoprotein made in a prokaryote (e.g.,
E. coli
) is useful for treating and diagnosing mammals with neoplasms, especially malignant tumors, such as breast or prostate carcinomas, and other carcinomas caused by a proliferation of malignant cells which express receptors which are recognized by recombinant human alpha-fetoprotein.
In one aspect, the invention features a method of inhibiting a neoplasm in a mammal (e.g., a human patient), involving administering to the mammal a therapeutically effective amount of recombinant human alpha-fetoprotein or an anti-neoplasm fragment or analog thereof. Preferably, the neoplasm is a malignant tumor (e.g., a breast tumor or a prostate tumor); and the recombinant human alpha-fetoprotein is produced in a prokaryotic cell (e.g.,
E. coli
) and is unglycosylated. In preferred embodiments, the cells of the neoplasm express a receptor which is recognized by the recombinant human alpha-fetoprotein. Such a neoplasm is generally a carcinoma such as an adenocarcinoma or a sarcoma. In preferred embodiments, the neoplasm proliferates in response to a hormone, e.g, estrogen or androgen. Preferably, administration of recombinant human alpha-fetoprotein inhibits the proliferation of cells of the neoplasm or, alternatively, kills cells of the neoplasm in the mammal. The method further includes administering to the mammal a chemotherapeutic agent.
In another aspect, the invention features a method of protecting a mammal from developing a neoplasm, involving administering to the mammal a therapeutically effective amount of recombinant human alpha-fetoprotein. Preferably, the recombinant human alpha-fetoprotein is produced in a prokaryotic cell (e.g.,
E. coli
) and is unglycosylated.
In another aspect, the invention features a hybrid cytotoxin including a recombinant human alpha-fetoprotein (or a fragment or analog thereof) linked to a cytotoxic agent. Examples of such cytotoxic agents include, without limitation, diptheria toxin, Pseudomonas exotoxin A; ricin and other plant toxins such as abrin, modecein, volkensin, viscumin; chlorea toxin (produced by
Vibrio cholerae
bacteria); the so-called “Shiga-like” toxins (produced by
E. coli
and other enteric bacteria); Salmonella heat-labile enterotoxin; and
E. coli
heat-labile enterotoxin. In other preferred embodiments, the cytotoxic agents is non-proteinaceous. Examples of such non-proteinaceous cytotoxic agents include, without limitation, anti-cancer agents such as doxorubicin, as well as &agr;-emitting radionuclides such as astatine and &bgr;-emitting nuclides such as yttrium. Preferably, the cytotoxic agent of the hybrid cytotoxin is linked by a peptide bond to the recombinant human alpha-fetoprotein, and the hybrid toxin is produced by expression of a genetically engineered hybrid DNA molecule. In other preferred embodiments, the cytotoxic agent of the hybrid cytotoxin is a protein; such a cytotoxic agent is chemically conjugated to the recombinant human alpha-fetoprotein.
In other aspects, the invention features a detectably-labelled recombinant human alpha-fetoprotein or a detectably-labelled fragment or analog thereof capable of binding to a human neoplastic cell. Preferably such a molecule is labelled with a radionuclide, e.g., technetium-99m, iodine-125, iodine-131, or indium. Other detectable labels include, without limitation, enzymes, fluorophores, or other moieties or compounds which emit a detectable signal (e.g., radioactivity, fluorescence, color) or emit a detectable signal after exposure of the label to its substrate or, alternatively, the detectable signal can be an epitope recognized by an antibody (e.g., an epitope of alpha-fetoprotein or an epitope which is specifically engineered into the recombinant alpha-fetoprotein such as the HA or myc epitopes). Preferably, the molecule targets a malignant tumor (e.g. a breast tumor, a prostate tumor, or a carcinoma) which express a receptor which is recognized by the recombinant alpha-fetoprotein (or fragment or analog thereof). Typically, such recombinant alpha-fetoprotein is produced in a prokaryotic cell (e.g.,
E. coli
) and is unglycosylated.
Detectably-labelled recombinant human alpha-fetoprotein is useful for methods of imaging a neoplastic cell-containing region in a human patient in vivo. In general, the method involves: (a) providing a detectably-labelled molecule of recombinant human alpha-fetoprotein (or a fragment or analog thereof); (b) administering the molecule to the patient; (c) allowing the labelled molecule to bind and allowing unbound molecule to be cleared from the region; and (d) obtaining an image of the neoplastic cell-containing region. Preferably, the region is the breast or is the prostate. In other preferred embodiments, the region, without limitation, is liver tissue, is lung tissue, is spleen tissue, is pancreatic tissue, is brain tissue, is lymph tissue, or is bone marrow. Preferably, the image is obtained using dynamic gamma
Clark & Elbing LLP
Martinex R&D Inc.
Nolan Patrick J.
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