Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Cancer cell or component thereof
Reexamination Certificate
2000-02-07
2002-10-22
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Cancer cell or component thereof
C424S130100, C424S133100, C424S135100, C424S138100, C424S141100, C530S387100, C530S387300, C530S387700
Reexamination Certificate
active
06468547
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of immunology and protein chemistry. More specifically, the present invention relates to a enhancement of tumor cell chemosensitivity and radiosensitivity using single chain secretory antibodies.
2. Description of the Related Art
Ovarian carcinoma is the leading cause of death from gynecologic cancer in the United States. Approximately 26,600 new cases were estimated to occur in 1995, resulting in 14,500 deaths from this disease. This figure exceeds the number of deaths from all other gynecologic malignancies combined. Over 70% of the patients present with late stage disease, the majority of which cannot be completely resected at the time of initial surgery. Chemotherapy has become the primary adjunct to surgery in obtaining a clinical remission or enhanced disease free survival in ovarian cancer patients. Although response to initial chemotherapy in ovarian cancer patients approaches 70%, most are transient and approximately 80% of patients (particularly those with advanced stage disease) will recur and eventually die of disease. Although a variety of salvage agents and strategies have been investigated, few have demonstrated long term effectiveness. In this regard, the five-year survival of patients with stage III disease remains, 15% to 30%.
Various approaches have been developed to accomplish gene therapy for cancer. There is increasing recognition that cancer results from a series of accumulated, acquired genetic lesions. To an ever larger extent, the genetic lesions associated with malignant transformation and progression are being identified. The recognition and definition of, the molecular basis of carcinogenesis makes it rational to consider genetic approaches to therapy. In this regard, a number of strategies have been developed to accomplish cancer gene therapy. These approaches include: 1) mutation compensation; 2) molecular chemotherapy; and 3) genetic immunopotentiation. For mutation compensation, gene therapy techniques are designed to rectify the molecular lesions in the cell having undergone malignant transformation. For molecular chemotherapy, methods have been developed to achieve selective delivery or expression of a toxin gene in cancer cells to achieve their eradication. Genetic immunopotentiation strategies attempt to achieve active immunization against tumor-associated antigens by gene transfer methodologies. Whereas the biology of each malignant disease target will likely dictate the approach taken, the majority of clinical gene therapy trials involve the genetic immunopotentiation approach. For most tumor types, however, the absence of clinical evidence of an anti-tumor effect has suggested the need for alternative approaches.
In addition to the gene therapy strategies discussed above, several reports have suggested that gene transfer approaches may be adjunctive to conventional chemotherapeutic modalities. In this regard, methods to enhance tumor cell conversion of cytotoxic prodrugs to their active forms have been developed. These include methods to enhance tumor cell metabolism of standard anti-tumor agents, such as oxazaphosphorines, by tumor cell transduction with cytochrome P-450. In another approach, transfer of viral or prokaryotic genes, such as the herpes simplex virus thymidine kinase (HSVTK), and
E. coli
cytosine deaminase are employed to sensitize tumor cells to the prodrugs ganciclovir or 5-fluorucytosine (5-FC), respectively, by conversion to toxic metabolites. In addition to these strategies, methods have been proposed based upon specifically reverting the molecular basis of the drug-resistant phenotype. This approach is based upon the concept that tumor cell drug resistance may be the result of diverse genetic alterations. These include mutational changes that lead to modifications in the structure of level of topoisomerase, to increased detoxification reactions, or to interference with the delivery of cytotoxic drug to intracellular targets. In addition, alterations affecting the regulation of the cell cycle and apoptosis are highly associated with drug resistance. These include inactivation of tumor suppressor genes, in particular p53 and Rb, and overexpression of proto-oncogenes such as those belonging to the myc family. Thus, based upon an understanding of the molecular basis of drug resistance, gene therapy strategies have been proposed to correct the genetic lesions etiologic of the drug resistant phenotype. To this end, augmentation of deficient tumor suppressor gene functions can restore tumor cell chemosensitivity. Roth et al. have shown that p53 gene replacement can enhance lung cancer chemosensitivity to cisplatin (CDDP). These studies establish the concept that gene transfer methods may be used in conjunction with conventional chemotherapeutic agents to achieve a synergistic antitumor effect. It is further suggested that specific rectification of the tumor cells genetic lesions can restore chemosensitivity.
Gene transfer approaches may be adjunctive to conventional radiation therapy. In this regard, methods to enhance tumor cell conversion of non-cytotoxic prodrugs to their active forms have been developed. The active forms of these drugs are potential or known radiosensitizers. One approach, transfer of viral or prokaryotic genes, such as herpes simplex thymidine kinase (HSVTK), and
E. coli
cytosine deaminase are employed to sensitize tumor cells to the prodrugs ganciclovir or 5-fluorocytosine (5-FC), respectively, by conversion to toxic metabolites. Both of these systems have also been employed to demonstrate enhanced radiation sensitivity. An alternative employed to enhance radiosensitivity in tumors involves the use of radiation inducible promoters to control gene expression. The tumor necrosis factor-&agr; (TNF&agr;) gene under the control of the early growth response-1 (egr-1) promoter, was used to show radiosensitization in vitro and in vivo. In addition, to these strategies, methods have been proposed based upon specifically reverting the molecular basis of the radiation resistant phenotype. Alterations affecting the regulation of the cell cycle and apoptosis are highly associated with radiation resistance or sensitization. These alterations include inactivation of tumor suppressor genes, in particular p53 and Rb, and overexpression of proto-oncogenes such as those belonging to the ras and myc families, although this is not universal. Inactivating DNA DSB repair genes could be an effective method to dramatically increase the radiosensitivity of human tumor cell lines. Thus, based upon an understanding of the molecular basis of radiation sensitivity/resistance, gene therapy strategies may provide novel mechanisms to enhance radiation efficacy.
The erbB-2 oncogene is important to the malignant transformation of selected neoplasms including ovarian carcinomas. ErbB-2 is a 185 kDa transmembrane protein kinase receptor with homology to the family of epithelial growth factor receptors. Aberrant expression of the erbB-2 gene may play a role in neoplastic transformation and progression. Specifically, ectopic expression of erbB-2 is capable of transforming rodent fibroblasts in vitro. In addition, transgenic mice carrying either normal or mutant erbB-2 develop a variety of tumors, including neoplasms of mammary origin. Importantly, it has been shown that amplification and/or overexpression of the erbB-2 gene occurs in a variety of human epithelial carcinomas, including malignancies of the ovary, breast, gastrointestinal tract, salivary gland, and lung. In the context of ovarian carcinoma, a direct correlation has been noted between overexpression of erbB-2 and aggressive tumor growth with reduced overall patient survival. As erbB-2 overexpression may be a key event in malignant transformation and progression, strategies to ablate its expression would be therapeutic.
Overexpression of erbB-2 is associated with tumor cell chemoresistance. In addition to its direct role in neoplastic conversion, erbB-2 overexpressio
Buchsbaum Donald J.
Curiel David T.
Stackhouse Murray
Adler Benjamin Aaron
Huff Sheela
UAB Research Foundation
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