Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1994-07-29
2002-10-22
Ketter, James (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S012200, C514S169000, C424S009100, C530S333000, C530S333000, C552S502000, C552S509000, C552S526000, C552S557000, C552S610000, C552S638000, C552S641000
Reexamination Certificate
active
06468981
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the field of chemical compounds comprising steroid and poly-L-lysine moieties. Such compounds may also be complexed with nucleic acids and are useful for targeting biologically active materials to prostate cell nuclei for example for gene therapy, or cancer therapy or diagnosis.
BACKGROUND OF THE INVENTION
Prostate cancer is the most commonly diagnosed cancer in American males, with an expected incidence of 200,000 in 1994. The projected deaths from prostate cancer are 38,000 in the same year. No curative therapy exists for advanced or metastatic prostate cancer. Chemotherapy is ineffective. Androgen ablation is palliative and non-curative. The molecular characterization of the disease has progressed very rapidly in the past few years, and it now appears that gene therapy will be the treatment of choice for advanced and metastatic disease within ten years. Several potential genetic targets of therapy exist including replacement of tumor suppressor genes, or metastasis suppressor genes, shutdown of oncogenes, and genetic induction of programmed cell death (apoptosis).
Prostate cancer is a genetically diverse disease. Some prostate cancers over-express the Ras oncoprotein, but not all. Approximately half of the prostate cancers fail to express retinoblastoma (RB) mRNA (Petros, J. A. et al. [1991], “Investigation of retinoblastoma transcripts in primary prostatic adenocarcinoma,” J. Urology 145:293A; Bookstein, R., et al. [1990], “Introduction of a normal retinoblastoma gene [RB] into retinoblastoma,” Science, 247:712-715). Absent or abnormal RB transcripts will result in lack of protein expression and lack of normal regulation of cell cycle.
Some prostate cancers show the common p53 promoter mutation (Bookstein, R. et al. [1993], “p53 is mutated in a subset of advanced-stage prostate cancers,” Cancer Res. 53:3369-3373), but most do not. This genetic diversity is consistent with the well-accepted “multi-hit” theory of solid tumor oncogenesis, and is responsible for the varied clinical manifestations of the disease. This genetic diversity is also responsible for the hormonal responsiveness of some tumors and the hormonal resistance of others.
Correction of mutant RB or p53 stops tumor growth. The RB gene was shown to be mutant in a prostate cancer cell line, and the transfection of wild-type RB shown to abrogate tumorigenicity in nude mice (Bookstein, R., et al. [1990], “Suppression of Tumorigenicity of Human Prostate Carcinoma Cells by Rephasing a Mutated RB Gene” Science, 247:712-715) and in human tumor cells. (Chen, P-L, et al. [1990], “Genetic Mechanisms of Tumor Suppression by the Human p53 Gene,” Science 250:1576-1580). Subsequent reports which indicated that this was an uncommon event in primary human tumors (Isaacs, W. B., et al. [1991], “Wild-type p53 suppresses growth of human prostate cancer cells containing mutant p53 alleles,” Cancer Res. 51:4716-4720) were flawed in assaying for only one mutation. Studies in our laboratories have demonstrated that in fact up to fifty percent of tumors fail to make normal RB transcripts (Petros, J. A. et al. [1991], “Investigation of retinoblastoma transcripts in primary prostatic adenocarcinoma,” J. Urology 145:293A), and it is likely that an even greater percentage will be shown to be abnormal when large numbers of tumors have been assayed for protein expression. Similarly, p53 has been shown to be mutated in twenty to twenty-five percent of advanced-stage prostate cancers (Bookstein, R. et al. (1993), “p53 is mutated in a subset of advanced-stage prostate cancers,” Cancer Res. 53:3369-3373), but relatively few early stage prostate cancers. The reintroduction of p53 into cell lines with mutant p53 abolished their ability to grow and divide (Isaacs, W. B., et al. [1991], “Wild-type p53 suppresses growth of human prostate cancer cells containing mutant p53 alleles,” Cancer Res. 51:4716-4720).
A further tumor suppressor gene is p16 (also known as Multiple Tumor Suppressor 1 (MTS1), which encodes the p16 inhibitor of cyclin-dependent kinase 4 (Kamb, A., et al. [1994], “A cell cycle regulator potentially involved in genesis of many tumor types,” Science 264 436-440; Nobori, T., et al. [1994], “Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers,” Nature 368:753-756). DNA encoding genes for suppression of metastasis of prostate cancer is also known to the art, and has been used via microcell-mediated chromosome transfer to suppress metastatic ability of microcell hybrids (Ichikawa, T., et al., “Suppression of metastasis of rat prostatic cancer by introducing human chromosome 8,” Cancer Res. 54:2299-2302).
Polylysine DNA complexes have been used to transfer genes into cells in vitro (Curiel, D. T., et al. (1991), “Adenovirus enhancement of transferrin-polylysine-mediated gene delivery,” Proc. Natl. Acad. Sci. USA 88:8850-8854; PCT application PCT/EP92/02234 for “Composition for Introducing Nucleic Acid Complexes Into Higher Eukaryotic Cells,” claiming priority to U.S. application Ser. No. 07/937,788 to Curiel, et al. filed Sep. 2, 1992, which is fully incorporated herein by reference) and in vivo (Gao, L., et al. [1993], “Direct In Vivo Gene Transfer to Airway Epithelium Employing Adenovirus-polylysine-DNA complexes,” Human Gene Therapy 4:17-24).
The surface receptor for asialoorosomucoid has been found to mediate DNA uptake in hepaitocytes. A soluble DNA carrier system consisting of an asialoglycoprotein linked to poly-L-lysine has been used to bind DNA and hepatitis B virus DNA constructs to liver cells. Liver cells express specific surface receptors for asialoorosomucoid. Covalent linkage of asialoorosomucoid with poly-L-lysine followed by ionic bonding with DNA creates a soluble delivery system (Wu, G. Y. and Wu, C. H. [1987], “Receptor-mediated in vitro gene transformation by a soluble DNA carrier,” J. Biol. Chem. 262:4429-4432). The same asialoorosomucoid-poly-L-lysine-DNA construct has been used to selectively transform the liver in vivo in a rat model. (Wu, G. Y. and Wu, C. W. [1988], “Receptor-mediated Gene Delivery and Expression in Vivo,” J. Biol. Chem. 368:14621-14624). Transformation of asialoglycoprotein receptor-positive human hepatoma cells with this system has also has also been shown. (Liang T. J., et al. [1993], “Targeted transfection and expression of hepatitis B viral DNA in human hepatoma cells,” J. Clin. Invest. 91:1241-1246). Using this receptor-mediated delivery and targeting system it has been possible to induce production of proteins encoded for by the DNA so introduced. This has been shown to be receptor mediated since competitive binding with non-linked asialoorosomucoid abrogated the expression. In addition, receptor-negative cells do not take up the DNA or express the proteins. After intravenous injection, DNA complexed with asialoglycoprotein-polylysine conjugates is expressed transiently. Cytoplasmic vesicles are the main site of persistence of endocytosed DNA (Chowdhury, N. R., et al. [1993], “Fate of DNA Targeted to the Liver by Asialoglycoprotein Receptor-mediated Endocytosis in Vivo,” J. Biol. Chem. 268:11265-11271).
Transferrin-polycation complexes (transferrin-polylysine and transferrin-protamine) have been used to transfer reporter genes into hematopoietic cells (Zenke, M., et al. [1990], “Receptor-mediated endocytosis of transferrin-polycation conjugates: an efficient way to introduce DNA into hematopoietic cells,” Proc. Natl. Acad. Sci. U S A, 87:3655-3659; Wagner, et al. [1990], “Transferrin-polycation conjugates as carriers for DNA uptake into cells,” Proc. Natl. Acad. Sci. U S A 87:3410-3414). (A transferrin-poly-L-lysine is commercially available as hT fpL/AdpL of Serva Biochemical and was used in combination with antibody-bound adenovirus to improve efficiency of endocytosis in HeLa cells in culture (Michael, S. L. et al., [1993] “
Liotta Dennis C.
Petros John Anthony
Emory University
Greenlee Winner and Sullivan P.C.
Ketter James
Schnizer Richard
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