Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1993-10-07
1996-05-07
Fleisher, Mindy
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
4241551, 4241561, 436501, G01N 33574, A61K 39395
Patent
active
055145540
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates generally to methods for selecting putative anti-cancer agents and for determining the efficacy of such agents useful in the treatment of a cancer characterized by expression of a surface oncogene product. This invention further relates generally to compositions selected by such methods.
BACKGROUND OF THE INVENTION
The transformation of a normal cell into a malignant cell characteristically results, among other things, in the uncontrolled proliferation of the progeny cells, which exhibit immature, undifferentiated morphology, and expression or overexpression of oncogenes not normally expressed by normal, mature cells. It is the goal of cancer therapy to selectively kill or inhibit the uncontrolled growth of such malignant cells, while not adversely effecting normal cells.
Traditional chemotherapeutic agents are highly cytotoxic agents which preferably have greater affinity for malignant cells than normal cells or at least preferentially effect malignant cells based on their high rate of metabolic activity. Where an oncogene product unique to a malignant cell is expressed or overexpressed on its surface membrane, it may be used to target such malignant cells for destruction using chemotherapeutic agents designed to specifically interact with the oncogene product. Extremely precise methods of targeting malignant cells for destruction have become available with the advent of cytotoxic conjugates, consisting of a potent cytotoxin chemically linked to an affinity molecule, such as a monoclonal antibody, having specificity for a unique protein produced by a malignant cell, such as a cell surface antigen. Using immunocytochemical and molecular analyses, it is possible to precisely identify the composition and structure of an oncogenic protein and produce a monoclonal antibody which has the capacity to specifically bind the oncogenic protein, and thus, increase the accuracy of delivering the cytotoxin to the intended target cell.
Besides cytotoxic conjugates, it has been proposed to use monoclonal antibodies which specifically bind to the surface of a cancer cell. Anti-tumor effects of monoclonal antibodies may be achieved through the effector function of the antibody molecule through natural immunological response to the antigen-antibody complex. In this respect, certain monoclonal antibodies have been shown to result in a reduction of tumor size. Undesirably, however, other monoclonal antibodies which specifically bind to such antigens on the surface of the malignant cell have no effect or, worse, actually accelerate the growth of the malignancy, even though such antibodies are specific for the same malignant cell type and the same oncogene product as the antibodies that reduce tumor size. In view of the unpredictability of the effect, if any, of an antibody on malignant cells, it has not been possible to determine, prior to starting therapy, whether one or more selected antibodies would react as anti-tumor agents or provide an accurate prognosis. Heretofore, it has not been possible to determine which antibody preparations, of a selection of monoclonal antibodies (each of which is capable of specifically binding an oncogenic protein) are tumor antagonists, and which are tumor agonists that may undesirably accelerate proliferation of the malignancy. It would be desirable to be able to determine in an in vitro assay method which antibody preparation (or combination of antibodies) having specific affinity for an oncogene product, and how much thereof, would be predicted to inhibit the proliferation of malignant cells and provide a good prognosis for the patient. It would be desirable to provide an in vitro method for prognosticating the efficacy of a proposed therapeutic agent (or combination of agents) and dosage thereof, which method is time-and cost-effective, as well as minimally traumatic to a cancer patient, so that the method may be practically employed in the great variety of cancer cases to be found among different patients.
SUMMARY OF THE INVENTION
We have di
REFERENCES:
patent: 5288477 (1994-02-01), Bacus
Becton Dickinson and Company
Carter Philip W.
Fleisher Mindy
Highet David W.
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