Drug – bio-affecting and body treating compositions – Lymphokine – Interferon
Reexamination Certificate
1999-04-30
2001-10-02
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
Interferon
C424S085100, C514S002600, C514S008100
Reexamination Certificate
active
06296844
ABSTRACT:
BACKGROUND OF THE INVENTION
Hepatitis B virus (HBV) infection is a worldwide health problem. It causes a wide spectrum of pathologies ranging from inapparent infection to fatal hepatocellular diseases (Tiollais et al.,
Nature
317:489, 1985). The HBV virion is composed of an envelope, which carries the hepatitis B surface antigen (HBsAg), and a nucleocapsid. The nucleocapsid encloses a circular, partially double-stranded 3.2 kb DNA, which replicates via a RNA intermediate. The nucleocapsid is formed by the hepatitis B core antigen. When virions are present in the blood, an additional soluble antigen related to the nucleocapsid, the hepatitis B e antigen (HBeAg), is generally detected in the serum. Several studies have suggested that HBV is not directly hepatocytopathic and that host immune response to viral antigens presented on the surface of infected liver cells may play an important role in pathogenesis (Mondelli et al.,
J. Immunol.
129:2773, 1982; Mondelli et al.,
Arch. Pathol. Lab. Med.
112:489, 1988; Chisari et al.,
Microb. Pathog.
6:311, 1989).
The lack of suitable animal models for hepatitis B has hindered understanding of the molecular mechanisms responsible for hepatocyte death and viral clearance (Ochiya et al.,
Proc. Natl. Acad. Sci. USA
86:1875, 1989; Gripon et al.,
J. Virol.
62:4136, 1988). Germ-line transgenic mouse models have been produced to investigate the pathogenesis of HBV infection, but these animals are immunologically tolerant to HBV antigens and do not spontaneously develop hepatitis (Moriyama et al.,
Science
248:361, 1990). Hepatitis must be induced in these animals by a complicated, multi-step process involving, e.g., priming lymphocytes with HBV proteins in syngeneic animals and adoptive transfer of the primed cells in vivo (Moriyama et al., supra; Ando et al.,
J. EXP. Med.
178:1541, 1993).
SUMMARY OF THE INVENTION
The invention is based, in part, on the discovery that asialo-interferon&bgr; (asialo-IFN-&bgr;) effectively inhibits hepatitis B virus (HBV) replication in hepatocytes. Surprisingly, this level of inhibition achieved was higher than that achieved with native interferon-&bgr;, a result contrary to the previous understanding that asialo-interferon-&bgr; is less effective than native interferon-&bgr; in inhibiting virus replication in hepatocytes.
Accordingly, the invention features a method of treating viral hepatitis in a mammal (e.g., a human) by administering to the mammal a composition which includes a therapeutic amount of an asialo-interferon (e.g., asialo-IFN-alpha, asialo-IFN-&bgr;, or asialo-IFN-gamma). The method optionally includes a step of confirming that the mammal has viral hepatitis, e.g., hepatitis caused by hepatitis B virus infection or hepatitis C virus infection.
The optional confirming step can include measuring the level of hepatitis virus replication in the mammal. The level of virus replication can be measured by any means well known in the art, including hepatitis virus-specific polymerase chain reaction or by detecting hepatitis viral antigen (hepatitis B virus e antigen) in a bodily fluid (e.g., blood) of the mammal.
The composition can be administered via any suitable route, including subcutaneously, intramuscularly, intraarterially, or intravenously. In addition, the therapeutic amount can be about, e.g., 0.02 to 200 &mgr;g/kg body weight/day, 30 to 75 &mgr;g/kg body weight/day, or alternatively, 10,000 to 200,000 IU/kg body weight/day.
The composition can further include a pharmaceutically acceptable excipient, such as dextrose, an albumin, sodium chloride, a sodium phosphate, or water.
In another aspect, the invention features a method of targeting a glycoprotein to a hepatocyte by providing an asialoglycoprotein produced by removing sialic acid residues from a glycoprotein; and contacting the asialoglycoprotein with the hepatocyte. Among the glycoproteins that can be targeted to hepatocytes in this manner are IL-1, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-14, IL-15, erythropoietin, fibroblast growth factor, granulocyte-macrophage colony stimulating factor (GM-CSF), gamma interferon, tumor necrosis factor-&bgr;, leukemia inhibitory factor, macrophage colony stimulating factor (M-CSF), macrophage migration inhibitory factor, nerve growth factor, osteostatin M, platelet-derived growth factor, stem cell factor, thrombopoietin, vascular endothelia growth factor, or hepatocyte growth factor. The hepatocyte to be targeted can be within a liver, and the liver can be within a mammal (e.g., a human). The asialoglycoprotein can be contacted with the hepatocyte by intravenous, intraarterial, subcutaneous, or intramuscular injection of the asialoglycoprotein into the mammal.
The invention also features a composition including asialoglycoprotein produced by removing sialic acid residues from a glycoprotein, where the glycoprotein is interleukin-1 (IL-1), IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-14, IL-15, erythropoietin, fibroblast growth factor, granulocyte-macrophage colony stimulating factor (GM-CSF), gamma interferon, tumor necrosis factor-&bgr;, leukemia inhibitory factor (LIF), macrophage colony stimulating factor (G-CSF), macrophage migration inhibitory factor, nerve growth factor, osteostatin M, platelet-derived growth factor, stem cell factor, thrombopoietin, vascular endothelia growth factor, or hepatocyte growth factor. The invention also features a method for preparing a medicament, e.g., a medicament for treatment of a liver disorder (e.g., hepatitis) by admixing an asialoglycoprotein with a pharmaceutically acceptable carrier. The composition can further include a pharmaceutically acceptable excipient.
The methods and compositions of the invention can be used to deliver a glycoprotein to hepatocytes, including the delivery of IFN, in its asialo form, to treat viral hepatitis. These asialo glycoproteins are expected to have a higher specific activity in the liver than the native glycoproteins when administered to a patient. The use of other glycoprotein cytokines for treatment of specific diseases are also well known. For example, asialo-IL-1 can be used to treat anemia, as can asialo-IL-3, asialo-IL-6, and asialo-erythropoietin. Asialo-IL-7 and asialo-IL-10 can be used to stimulate the growth and differentiation of T cells. Asialo-IL-12 can be used to activate natural killer cells. Asialo-GM-CSF and asialo-G-CSF can be used to activate and proliferate macrophages.
In addition, asialo-IL-1 can be used to treat fulminant or subacute hepatitis. Asialo-IL-3 can be used to treat pancytopenia. Asialo-IL-6 can be used to treat fulminant hepatitis or acute exacerbation of chronic active hepatitis, or can be used to produce acute phase reactants for host defense. Asialo-IL-10 can be used to treat autoimmune hepatitis or primary biliary cirrhosis. Asialo-IL-12 can be used to treat hepatocellular carcinoma, hepatic metastatic tumors, HBV infection, hepatitis C virus infection, AIDS, or parasitic infections. Asialo-GM-CSF can be used to treat malignant tumors or leukemia. Hepatocyte growth factor can be used to treat hepatic cirrhosis, liver fibrosis, or chronic hepatitis.
Thus, the invention also includes a method of treating anemia in a mammal by providing a composition having a therapeutic amount of an asialoglycoprotein, the asialoglycoprotein being produced by removing sialic acid residues from a glycoprotein (e.g., IL-1, IL-2, or erythropoietin; and by administering to the mammal the composition.
Also included in the invention is a method of stimulating growth or differentiation of a T cell by providing an asialoglycoprotein produced by removing sialic acid residues from a glycoprotein (e.g., IL-7 or IL-10); and contacting the T cell with the asialoglycoprotein. The T cell can be within a mammal, and the contacting step can include administering to the mammal a composition comprising the asialoglycoprotein.
The invention also includes a method of stimulating growth or differentiation of a macrophage by providing an asialoglycoprotein produced by removing sial
Fish & Richardson P.C.
Mertz Prema
Murphy Joseph F.
The General Hospital Corporation
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