Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-06-08
2002-07-16
Bansal, Geetha P. (Department: 1642)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007100, C435S007200, C435S007210, C435S007900, C424S174100, C424S143100, C424S179100, C424S183100, C424S152100, C424S155100, C514S025000, C436S501000, C436S538000
Reexamination Certificate
active
06420126
ABSTRACT:
Throughout this application various publications are referenced within parentheses. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
The present invention relates generally to lysosomal and vesicular secretory pathways and, more particularly, to tumor antigen discovery and to methods of intracellularly targeting therapeutic agents.
Neoplastic cell transformations, or cancer, is a disease which results in more than 2.3 million deaths annually, or greater than 20% of all deaths reported to the World Health Organization in the industrialized countries. Neoplastic cell transformations manifests as a group of cells that proliferate outside the normal growth control mechanisms and can be considered a collection of many different diseases which differ in their genetic basis, progression and clinical outcome.
The standard methods of treatment for cancer currently include surgery, radiation therapy, and chemotherapy using cytotoxic drugs. Such methods can be effective if treatment is initiated early enough. However, each therapeutic approach comes with inherent problems. Perhaps the most significant of these problems include unacceptable toxic side effects and the lack of complete surgical removal of the entire neoplastic growth. An additional problem in treating cancer results from metastasis of the primary tumor to secondary sites if treatment is not complete or initiated early before substantial progression of the disease.
Immunotherapy is one approach to overcome the lack of specificity inherent in today's current treatments. In general, immunotherapy offers several advantages which include not only the ability to generate antibodies to essentially any desired antigen but also the ability to produce antibodies that exhibit high specificity and binding affinity to the particular antigen of interest. This high specificity and binding affinity allows specific targeting of therapeutic agents to essentially all diseased cells in which there is an identified and specific antigen marker. However, any cross reactivity of the antibody to other antigens or the presence of significant quantities of the marker antigen on the surface of non-diseased cells will lead to binding and the unfortunate targeting of toxic agents to normal cell types. Thus, the specificity and efficiency of targeting is the combined function of both the specificity of the antibody and the reliability of the antigen marker.
The discovery of such putative antigen markers generally occurs through a fortuitous observation, or can result from a labor intensive effort to specifically screen and identify putative tumor specific antigens. The latter of such efforts generally involves either the generation of a panel of antibodies against tumor cell surface antigens and then screening of the panel against tumor and control cells to determine which antibodies may be significantly reactive and specific for a particular tumor cell type. The percentage of those antibodies screened that are ultimately identified as being reactive with tumor cell specific markers is usually a very low percentage.
There are now a number of antibodies which recognize cell surface antigens reported to be preferentially expressed on neoplastic cells. These antibodies are increasingly being applied in the clinic as diagnostic tools and as potential therapeutic treatments. However, even with highly specific antibodies or antigen markers there still remains at least one major problem which leads to several side effects and a lower quality of life. This problem results from the toxicity of the therapeutic agents that are conjugated to the tumor specific antibodies. Such agents generally include radioisotopes which are highly toxic to all cells which come in contact with the antibody conjugate and especially to the neighboring cells around the targeted tumor cell mass. One possibility to overcome such side effects would be to selectively introduce the toxic agent intracellularly. Such an intracellular targeting scheme would require not only the identification of a tumor cell specific marker and generation of a highly specific antibody, but also that the marker antigen undergo internalization to avoid toxic side effects to surrounding normal cells.
Lymphocyte marker antigens have been identified which undergo internalization from the cell surface. Many of these lymphocyte antigens, if not all of them, are cell surface proteins which include cytokine receptors, T cell receptors, major histocompatibility and the like. In regard to cells outside of the lymphocyte lineage, there are relatively very few internalizing antigens that are known to exist for solid tumors. One example is the transferrin receptor which naturally functions as a carrier of iron between the extracellular and intracellular environment. Another example is the mannose-6-phosphate receptor which directs soluble lysosomal enzymes to prelysosomal compartments. Antigens of this category which are known to normally cyclize between different cellular locations also generally exhibit poor tumor cell specificity.
Of those few antigens that are currently being evaluated as internalizing antigens for solid tumors, most if not all were unfortunately discovered by serendipity. For example, the Le
y
antigen was initially characterized as being an altered glycosylation product found on the cell surface of tumorigenic cells. Other antigens include lysosomal membrane proteins such as those belonging to the lamp-1 or lamp-3 families. The Le
y
antigen is now thought to be an altered glycosylation product which is primarily associated with lamp-1. However, because these antigens were discovered independently of one another and their full potential could not be appreciated for the therapeutic benefit of essentially many different types of cancers.
Thus, there exists a need for the therapeutic treatment of tumors to enable the consistent and efficient identification of novel internalizing antigen markers. Such novel internalizing antigens can be used to enhance the specificity of immunotherapeutic approaches. The present invention satisfies this need and provides related advantages as well.
SUMMARY OF THE INVENTION
The invention provides a method of reducing the proliferation of a neoplastic cell. The method consists of contacting the neoplastic cell with a cytotoxic or cytostatic binding agent specifically reactive with an aberrantly expressed vesicular membrane associated neoplastic cell specific internalizing antigen. The neoplastic cell specific internalizing anitgen can be selected from the group consisting of lamp-2 and limp II families of lysosomal integral membrane proteins. Also provided is a method of intracellular targeting of a cytotoxic or cytostatic agent to a neoplastic cell population. The method consists of administering to an individual containing a neoplastic cell population a cytotoxic or cytostatic binding agent specifically reactive with an aberrantly expressed vesicular membrane associated neoplastic cell specific internalizing antigen that is expressed by the neoplastic cell population, wherein the cytotoxic or cytostatic binding agent is bound by the neoplastic cell specific internalizing antigen and is internalized into the intracellular compartment. A method of reducing tumor growth through the intracellular targeting of a cytotoxic agent is also provided.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to novel methods for targeting immunoconjugates to neoplastic cell populations. The methods rely on the identification and utilization of neoplastic cell specific internalizing antigens to achieve high specificity for the target cell population. One advantage of the methods is that they employ cell surface antigens which undergo internalization of the bound immunoconjugate into the cytoplasm. This internalization provides greater specificity and therapeutic efficacy since toxic side effec
Huse William D.
Watkins Jeffry D.
Bansal Geetha P.
Campbell & Flores LLP
Ixsys Inc.
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