Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
2001-03-21
2004-02-17
Guzo, David (Department: 1636)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C435S091400, C435S091410, C435S091420, C435S320100, C435S235100, C435S369000, C435S457000, C435S375000, C435S069100, C514S04400A
Reexamination Certificate
active
06692736
ABSTRACT:
TECHNICAL FIELD
This invention relates to new replication competent adenovirus vectors comprising an internal ribosome entry site which replicate preferentially in target cells. The present invention also relates to cell transduction using adenovirus vectors comprising an internal ribosome entry site.
BACKGROUND
Diseases involving altered cell proliferation, particularly hyperproliferation, constitute an important health problem. For example, despite numerous advances in medical research, cancer remains the second leading cause of death in the United States. In the industrialized nations, roughly one in five persons will die of cancer. Traditional modes of clinical care, such as surgical resection, radiotherapy and chemotherapy, have a significant failure rate, especially for solid tumors. Neoplasia resulting in benign tumors can usually be completely cured by surgical removal of the tumor mass. If a tumor becomes malignant, as manifested by invasion of surrounding tissue, it becomes much more difficult to eradicate. Once a malignant tumor metastasizes, it is much less likely to be eradicated.
Excluding basal cell carcinoma, there are over one million new cases of cancer per year in the United States alone, and cancer accounts for over one half million deaths per year in this country. In the world as a whole, the five most common cancers are those of lung, stomach, breast, colon/rectum, and uterine cervix, and the total number of new cases per year is over 6 million.
In the United States, transitional cell carcinoma (TCC) accounts for 90 to 95 percent of all tumors of the bladder. Squamous cell carcinoma (SCC) represents 5 to 10 percent, and adenocarcinoma approximately 1 to 2 percent. Squamous cell and adenomatous elements are often found in association with transitional cell tumors, especially with high grade tumors. Bladder cancer is generally divided into superficial and invasive disease. A critical factor is the distinction between those tumors that are confined to the mucosa and those that have penetrated the basement membrane and extended into the lamina propria. The term “superficial bladder tumor” is generally used to represent a tumor that has not invaded the muscularis. Invasive tumors are described as those that have invaded the muscularis propria, the perivesical fibroadipose tissue, or adjacent structures. Carcinoma in situ (CIS) is a high grade and aggressive manifestation of TCC of the bladder that has a highly variable course.
A number of urothelial cell-specific proteins have been described, among which are the uroplakins. Uroplakins (UP), including UPIa and UPIb (27 and 28 kDa, respectively), UPII (15 kDa), and UPIII (47 kDa), are members of a group of integral membrane proteins that are major proteins of urothelial plaques. These plaques cover a large portion of the apical surface of mammalian urothelium and may play a role as a permeability barrier and/or as a physical stabilizer of the urothelial apical surface. Wu et al. (1994)
J. Biol. Chem.
269:13716-13724. UPs are bladder-specific proteins, and are expressed on a significant proportion of urothelial-derived tumors, including about 88% of transitional cell carcinomas. Moll et al. (1995)
Am. J. Pathol.
147:1383-1397; and Wu et al. (1998)
Cancer Res.
58:1291-1297. The control of the expression of the human UPII has been studied, and a 3.6-kb region upstream of the mouse UPII gene has been identified which can confer urothelial-specific transcription on heterologous genes (Lin et al. (1995)
Proc. Natl. Acad. Sci. USA
92:679-683). See also, U.S. Pat. Nos. 5,824,543 and 6,001,646.
Melanoma, a malignant neoplasm derived from melanocytes of the skin and other sites, has been increasing in incidence worldwide. The American Joint Committee on Cancer recognizes five different forms of extraocular melanoma occurring in humans: lentigo maligna melanoma; radial spreading; nodular; acral lentiginous; and unclassified. Known melanoma-associated antigens can be classified into three main groups: tumor-associated testis-specific antigens MAGE, BAGE, GAGE, and PRAME; melanocyte differentiation antigens tyrosinase, Melan-A/MART-1 (for Melanoma Antigen Recognized by T cells), gp100, tyrosinase related protein-1(TRP-1), tyrosinase related protein-2 (TRP-2); and mutated or aberrantly expressed antigens MUM-1, cyclin-dependent kinase 4 (CDK4), beta-catenin, gp100-in4, p15, and N-acetylglucosaminyltransferase V. See, for example, Kirkin et al. (1998)
Exp. Clin. Immunogenet.
15:19-32. Tyrosinase, TRP-1, and TRP-2 are enzymes involved in melanin biosynthesis and are specifically expressed in melanocytes. Antigenic epitopes of MART-1 have been studied extensively, with the aim of developing a melanoma vaccine. An immunodominant epitope, MART-1(27-35) has been reported to be recognized by a majority of CD8+cytotoxic T cell clones generated to MART-1. These MART-1(27-35)-specific CTLs specifically lyse autologous tumor cell lines expressing the epitope. Faure and Kourilsky (1998)
Crit. Rev. Immunol.
18:77-86. However, others have reported that presence of such CTLs is not accompanied by a significant clinical response. Rivoltini et al. (1998)
Crit. Rev. Immunol.
18:55-63.
A major, indeed the overwhelming, obstacle to cancer therapy is the problem of selectivity; that is, the ability to inhibit the multiplication of tumor cells without affecting the functions of normal cells. For example, in traditional chemotherapy of prostate cancer, the therapeutic ratio, (i.e., the ratio of tumor cell killing to normal cell killing) is only 1.5:1. Thus, more effective treatment methods and pharmaceutical compositions for therapy and prophylaxis of neoplasia are needed.
Accordingly, the development of more specific, targeted forms of cancer therapy, especially for cancers that are difficult to treat successfully, is of particular interest. In contrast to conventional cancer therapies, which result in relatively non-specific and often serious toxicity, more specific treatment modalities, which inhibit or kill malignant cells selectively while leaving healthy cells intact, are required.
Gene therapy, whereby a gene of interest is introduced into a malignant cell, has been attempted as an approach to treatment of many cancers. See, for example, Boulikas (1997)
Anticancer Res.
17:1471-1505, for a description of gene therapy for prostate cancer. A gene of interest can encode a protein which is converted into a toxic substance upon treatment with another compound, or it can encode an enzyme that converts a prodrug to a drug. For example, introduction of the herpes simplex virus gene encoding thymidine kinase (HSV-tk) renders cells conditionally sensitive to ganciclovir. Zjilstra et al. (1989)
Nature
342: 435; Mansour et al. (1988)
Nature
336: 348; Johnson et al. (1989)
Science
245: 1234; Adair et al. (1989)
Proc. Natl. Acad. Sci. USA
86: 4574; Capecchi (1989)
Science
244: 1288. Alternatively, a gene of interest can encode a compound that is directly toxic, such as, for example, diphtheria toxin. To render these treatments specific to cancer cells, the gene of interest is placed under control of a transcriptional regulatory element (TRE) that is specifically (i.e., preferentially) active in the cancer cells. Cell- or tissue-specific expression can be achieved by using a TRE with cell-specific enhancers and/or promoters. See generally Huber et al. (1995)
Adv. Drug Delivery Reviews
17:279-292.
A number of viral vectors and non-viral delivery systems (e.g., liposomes), have been developed for gene transfer. Of the viruses proposed for gene transfer, adenoviruses are among the most easily produced and purified. Adenovirus also has the advantage of a high efficiency of transduction (i.e., introduction of the gene of interest into the target cell) and does not require cell proliferation for efficient transduction. In addition, adenovirus can infect a wide variety of cells in vitro and in vivo. For general background references regarding adenovirus and development of adenoviral vector systems, see Graham et al. (1973)
Virolo
Henderson Daniel R.
Li Yuanhao
Little Andrew S.
Yu De-Chao
Bozicevic Field & Francis LLP
Cell Genesys Inc.
Guzo David
Judge Linda R.
Marvich Maria
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