Drug – bio-affecting and body treating compositions – Conjugate or complex of monoclonal or polyclonal antibody,...
Reexamination Certificate
1996-08-02
2002-04-30
Ungar, Susan (Department: 1642)
Drug, bio-affecting and body treating compositions
Conjugate or complex of monoclonal or polyclonal antibody,...
C424S179100, C424S181100, C424S183100
Reexamination Certificate
active
06379669
ABSTRACT:
BACKGROUND OF THE INVENTION
Cancer, the second highest cause of death in the U.S.A., is one of the most dreaded diseases. Unfortunately, the incidence of many types of cancer (such as prostate, breast, ovary, colon, pancreas, lung) has been increasing during the last 25 years. In addition, numerous infectious diseases, many of which are drug resistant, are becoming prevalent in the industrialized world or are moving into the industrialized world from the non-industrialized world. All solid organ tumors (some are identified above) possess many clones or subpopulations of cancer cells, which make them heterogeneous tumors that are very difficult to treat. A common problem in developing therapies for each of these categories of diseases is targeting the therapeutic molecule(s) to many clones of tumor cells that may be found in several loci in patients.
Among cancers, adenocarcinoma of the prostate (CAP) is the most prevalent neoplasm and is the leading cause of cancer death in males in the U.S.A. In nearly 50% of patients, neoplastic prostate cells have spread at the time of diagnosis. Benign prostatic hypertrophy (BPH) results in over 400,000 surgical procedures in the U.S.A., which usually are done to correct urinary obstruction. This makes benign prostatic hypertrophy the second most common reason for surgery in males in the U.S. Human prostate cancer, benign prostatic hypertrophy, and prostatitis require about 5 million physician visits, 900,000 hospitalizations with 40,000 deaths, and costs over $3 billion/year in the U.S.A. Similar estimates can be made for the industrialized countries of Europe. In addition, the World Health Organization has determined that BPH and prostatitis are world-wide health problems. Clearly, the current and potential need for a treatment for these conditions is very large.
The current chemotherapeutic and endocrine treatments for prostate cancer as well as benign prostatic hyperplasia suffer from at least two major limitations, lack of drug/treatment specificity and drug resistance. Lack of specificity has led to utilization of higher doses of chemotherapeutic and endocrine drugs, which adversely affect many organs without tumors and have numerous unpleasant side effects in patients. Furthermore, drug resistance (chemoresistance), usually due to development of multidrug resistance proteins (Mdr) such as P-glycoproteins (Pgp), often negates the treatment effects in a relatively short time. Drug resistance varies from tumor to tumor and in different types of tumors. Most patients who develop chemoresistant tumors usually do not respond to other chemotherapeutic drugs or their combinations. This results in treatment failure and death of the patient, usually within a year. Because of the potential for drug resistance, the specific drug must act on many clones (or subpopulations) of tumor cells directly and quickly to be effective, before they develop drug resistant proteins.
To overcome the limitations imposed by drug resistant proteins, the chemotherapeutic drugs must be highly specific to the target cells such as neoplastic cells of prostate, breast, ovary, colon, or other solid organ tumors. Furthermore, the drug should have minimum to no effects on the unrelated organs or tissues as well as minimal side effects in patients.
The existing treatments for prostate cancer include surgery, radiation, endocrine therapy, and chemotherapy. These often have limited value, especially in patients with metastatic disease because these treatments are unable to specifically target metastatic cancer cells. Therefore, new approaches are required to improve treatment effects on prostate cancer as well as other solid organ neoplasms, such as those in the breast, ovary, cervix, colon and lung. There is a need to target bioactive compounds in other diseases and disorders as well.
Therefore, there is a need for highly specific drugs that could overcome the above limitations and at the same time target many subpopulations of neoplastic cells or dysfunctional tissues or organs. For cancers, it is important to target the tumors before they develop drug resistance for improvements in the treatments of prostate and other cancers.
SUMMARY OF THE INVENTION
The concept of targeting a specific organ requires consideration of biological characteristics of the normal organ as well as its tumors and disease states. For example, in human prostate, prostatic specific antigen (PSA) and prostatic acid phosphatase (PACP) are organ-specific enzymes and are usually secreted by prostatic epithelial cells in sufficient amounts. Therefore, the biological properties of these enzymes can be used to develop highly specific drug conjugates that would then specifically target prostatic epithelial cells, but not other types of cells in other organs which usually do not secrete these enzymes.
The present invention provides compositions and methods for delivering bioactive compounds to target organ tissues. One embodiment Of the method includes an immunoconjugate that recognizes a substance in a solid tissue. The immunoconjugate includes a polyclonal or monoclonal antibody, preferably a polyclonal antibody, as a binding or recognition moiety and a bioactive agent. The solid tissue can be a normal or benign tissue, preferably a tumor. In a specific embodiment, the tumor is a prostate tumor.
A polyclonal antibody has greater potential of recognizing many more epitopes of the substance associated with the solid tissue, e.g. PSA or (PACP) in the case of the prostate, than a monoclonal antibody. Therefore, a polyclonal antibody would recognize more of the clones or tumor cells than a monoclonal antibody. Thus, an immunoconjugate prepared utilizing polyclonal antibody IgG or its fragments will bind to most of the target cells that are producing an organ-specific enzyme, moiety, or substance.
The binding moiety is a molecule that recognizes and can bind to a molecule, substance and the like which is unique to the solid tissue. The binding moiety can be a polyclonal antibody or derivative or fragment thereof. Preferably, the binding moiety is an IgG. A conjugate in which the binding moiety is an antibody or antibody fragment that is conjugated to a bioactive substance, e.g. chemotherapeutic, hormonal or cytotoxic drugs, produces an immunoconjugate.
The bioactive agent is a molecule that modifies a biological or biochemical response or action, that modifies the activity of a cell or biomolecule, or that affects an organism or part thereof. A preferred bioactive agent is a chemotherapeutic agent.
One embodiment of the invention is a method for delivering a bioactive substance to a target solid tissue in an animal which includes administering to the animal an immunoconjugate that includes a binding moiety and a bioactive agent. In the method, the amount of immunoconjugate administered is effective to result in delivery of sufficient bioactive substance to the solid tissue to have the desired effect. The method can be used in intact humans or animals, or in experimental systems such as organ culture.
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