Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-08-23
2001-12-18
Hauda, Karen M. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C435S455000
Reexamination Certificate
active
06331525
ABSTRACT:
BACKGROUND OF THE INVENTION
Production of interferons (IFNs) is one of the immune system's non-specific defenses against viruses, microbes, tumors and other antigens. Rather than protecting cells directly, IFNs activate surrounding cells by binding to IFN-specific receptors on these cells, thereby activating the production of intracellular effector proteins (Baron et al. (1994)
Antiviral Res
. 24: 97-110). These effector proteins then mediate various immune responses (e.g., antitumor, antiviral, and immunomodulatory).
Interferons consist of three families of protein molecules, &agr;, &bgr;, and &ggr;, which differ in the agents which induce them and in the cell types which produce them. While there is only one human IFN-&bgr; gene and one human IFN-&ggr; gene, there are at least 17 different human IFN-&agr; genes, each of which likely plays a separate role in modulating specific immune functions. Within these 17 genes, there are also subgroups (variants) of genes. For example, for human IFN-&agr;2, there are three subgenes, IFN-&agr;2a, IFN-&agr;2b and IFN-&agr;2c. Human IFN-&agr; is induced by foreign cells, virus-infected cells, tumor cells, bacterial cells and viral envelopes in several types of leukocytes (e.g., B lymphocytes and macrophages). The second type of IFN, IFN-&bgr;, is induced by viral and other foreign nucleic acids in many body cells, including fibroblasts, epithelial cells and macrophages. The third type of IFN, IFN-&ggr;, is induced in T lymphocytes by foreign antigens for which the T cells have specific receptors. The sequences for most of the aforementioned IFN genes as they occur in nature are published and many have been deposited with the American Type Culture Collection (ATCC) (Rockville, Md.). Specifically, the sequences for human IFN-&agr;1 and IFN-&agr;2 are published in Weber et al. (1987) EMBO J. 6:591-598. The sequence for human IFN-&agr;2b is published in Streuli et al. (1980)
Science
209:1343-1347.
IFNs have a broad variety of therapeutic applications (Baron et al. (1991)
JAMA
266:1375-1383). Recent advances have led the Food and Drug Administration (FDA) to approve the use of IFNs in the clinical treatment of hairy cell leukemia, condyloma, acuminatum, Kaposi's sarcoma in AIDS patients, and type C hepatitis infection. In addition to these FDA-approved clinical applications, IFN-&agr; has been clinically approved in other countries for approximately 10 other conditions including basal cell carcinoma, non-Hodgkin's lymphoma, multiple myeloma, malignant myeloma, laryngeal papillomatosis, myelogenous leukemia, chronic delta hepatitis infection, and chronic hepatitis B infection (Baron et al. (1991), supra. at 1379).
One area in which the use of IFN therapy holds particular promise is in the treatment of chronic viral infections, such as HIV and hepatitis virus infections. It has been shown that clinically persistent hepatitis B (HBV) and hepatitis C (HBC) infections can be inhibited by administration of exogenous IFN (Hoofnagle (1992),
Interferon: Principles and Medical Applications
(Baron et al. (Eds)), pp. 433-462. For example, recent clinical studies performed on patients infected with chronic HBV demonstrated that administration of 5×10
6
U of IFN-&agr; daily for sixteen weeks resulted in disappearance of HBV viral DNA and hepatitis Be antigens (Baron et al. (1991), supra. at 1379). While the natural role of IFNs during chronic viral infections has not been determined fully, many variables govern its production and action in vivo, such as the site of production, distribution relative to the site of infection, concentration at the site of infection, and susceptibility of the virus to IFN.
IFN therapy currently involves administration of exogenous IFN to patients, generally by IV injection, on a frequent (e.g., daily) basis. High dosages are often required to achieve a sufficient concentration of IFN in target tissues (e.g., tissues surrounding infected cells). In addition, patients often experience a variety of adverse side effects and/or peripheral toxicities associated with systemic delivery of IFN.
Improved forms of IFN replacement therapy would be of great therapeutic value.
SUMMARY OF THE INVENTION
The present invention provides a molecular complex for targeted delivery of genes encoding interferon (IFN) to selected cells. The complex comprises a gene encoding an IFN protein, preferably human IFN-&agr;, IFN-&bgr; or IFN-&ggr;, releasably linked to a carrier molecule made up of a nucleic acid binding agent (e.g., a polycation) and a ligand which binds to a component on the surface of a target cell and is consequently internalized by the cell. In a preferred embodiment, the gene encodes human IFN-&agr;2b having the amino acid sequence shown in
FIG. 11
(SEQ ID NO:1).
The molecular complex can be targeted to a variety of cells via the carrier portion of the molecular complex. In one embodiment, the ligand of the carrier binds to the asialoglycoprotein receptor on liver cells. In another embodiment, the ligand is an antibody directed against the CD3 or CD5 receptor on T and B cells.
The molecular complex can be delivered to selected cells in vivo to treat a wide variety of diseases which are responsive to IFN therapy. Alternatively, the molecular complex can be delivered to selected cells in vitro (in culture) to produce recombinant IFN which can be administered as exogenous protein to patients in conventional IFN protein therapy.
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Baron et al. The interferons: Mechanisms of action and clinical applications. JAMA 266: 1375-1383, Sep. 11, 1991.*
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Carlo Dennis J.
Chiou Henry C.
Baker Anne-Marie
Hauda Karen M.
Lahive & Cockfield, LLP.
Nand, Esq. Richa K.
Remillard, Esq. Jane E.
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