Compositions and methods for treating hepatitis-C

Details Compositions and methods for treating hepatitis-C Compositions and methods for treating hepatitis-C

1999-05-13

2001-08-28

Travers, Russell (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C424S114000

Reexamination Certificate

active

06281191

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to new compositions and methods for treating patients suffering from hepatitis-C and more particular compositions and methods for treating Fas antigen mediated apoptosis while simultaneously stimulating TNF-&agr; production and concurrently modulating TNF-&agr; receptor p55 (TNFR1) mediated apoptosis, providing treatment of apoptotic symptoms for patients suffering from diseases such as active viral hepatitis-C, and AIDS.
BACKGROUND OF THE INVENTION AND PRIOR ART
Homeostasis of multicellular organisms is controlled not only by proliferation and differentiation of cells but also by cell death. Physiological cell death mostly proceeds by apoptosis, a process which includes blebbing of the plasm membrane, condensation and segmentation of the nuclei and cytoplasm, extensive fragmentation of chromosomal DNA into nucleosome units, and cellular fragmentation into membrane apoptotic bodies which minimize the leakage of cellular constituents from the dying cell. Although apoptosis is necessary for normal development, pathological cell death occurs when the apoptotic process is either impaired or overactive contributing to a number of disease conditions, such as hepatitis-C, autoimmune disorders, diabetes, acute pancreatitis and numerous other disorders. Normalizing or modulating the apoptotic process; ie allowing apoptosis to carry out its important biological processes such as morphogenesis, tissue homeostasis, elimination of damaged or virally infected cells and the elimination of self-reactive clones from the immune system, would lead to therapeutic treatment for many of these degenerative diseases and disorders.
Apoptosis proceeds by two known triggering mechanisms; the Fas-antigen/ligand, and Tumor necrosis factor alpha(TNF-&agr;)-Tumor necrosis factor receptor-1 (TNFR1) killing pathways. Molecular and cellular characterization of Fas antigen (CD95), a cell-surface protein recognized by cytotoxic monoclonal antibodies, has led to its identity as a receptor for Fas ligand (FasL). FasL binds to Fas, which results in triggering target cell apoptosis. Exaggeration of this system leads to pathological cell death and tissue destruction. Upregulating this antigen relates to many pathological situations in non-lymphoid organs, the Fas signaling pathways remain elusive. It has been shown that Fas-induced apoptosis of primary cultured hepatocytes requires an inhibitor of translation or protein kinase inhibitors, suggesting that two distinct pathways of Fas signaling exist in hepatocytes.(Rouquet N., et al., Biochem. Biophys. Res. Com. 229:27-35 (1996)).
In the liver, apoptosis is a physiological process involved in the clearance of injured cells and hemostatic control. However, in patients with viral fulminant hepatitis, or with nonacute liver disease, dramatic liver failure or secondary cirrhosis results from the death of hepatocytes, which is caused by the activation of both 55-kD tumor necrosis factor receptor (TNFR1) or CD95 (Fas/Apo-1). These receptors are independent and differentially regulated triggers of murine apoptotic liver failure (Leist M.,et al., Mol. Med. 2:109-124(1996)).
In chronic and filminant hepatitis-C, Fas expression is upregulated in the hepatocytes, especially near liver infiltrating lymphocytes. (Okazaki M., et al. Dig. Dis. Sci. 41:2453-2458 (1996)). The same correlation has been established with hepatitis-B virus infection. (Mochizuki K, et al. Hepatol. 24:1-7(1996)). (Ando K., et al., J. Immunol. 158:5283-529(1997)) studied the killing mechanism of bystander cells, zo which have upregulated Fas antigen. They found that killing of the antigen presenting sensitive cells is mediated by Fas ligand. Okazaki et al., suggests that hepatitis Fas expression is associated with persistent infection of hepatitis-C virus. Fas expression is upregulated in and the same correlation has been established by Mochizuki et al., for hepatitis-B virus infection.
It has also been shown that effective bystander killing requires intracellular contact between CTLs and target cells. TNF-&agr; released from the CTLs mediates lysis of the bystander cells without a dose cell-cell contact. (Ando K., et al) Hepatic Fas expression was reduced significantly after treatment compared with the pretreatment values. Thus, a potential pathogenic treatment would require an antiapoptotic effect.
To date treatment of fulminant hepatitis relies mainly on orthotopic liver transplantation, which is limited by immunological complications and graft availability. Moreover, Fas mediated apoptosis occurs in hepatic allografts and is correlated with acute rejection. (Rouquet N., et al., Curr. Bio., 6:1192-1195(1996)). Thus, the task of a pathogenic treatment which unravels the Fas antigen blocking mechanism would allow for the design of an efficient treatment for apoptosis associated with viral hepatitis-C, acute liver failure and allograft rejection.
The development of biological response modifiers to increase macrophages mediated cytotoxicity by means of inducing TNF-&agr; production and nitric oxide (NO) expression has become an area of great interest. In this respect, muramyl peptides are regarded as a most promising stimulaters. D-peptidoglycans namely N-acetyl-D-glucosaminyl-(&bgr;1-4)-N-acetylmuramyl-L-alanyl-D-isoglutamine (GMDP) have been proposed as the cytotoxic agents capable of eliminating cancer cells and/or virus infected cells. (Ovchinnikov, et al. U.S. Pat. No. 4,395,399).
Later, a considerable amount of research was done in order to increase the immunostimulatory efficacy of muramyl peptides (GMDP) by creating new compositions. The new compositions included the addition of lipopolysaccharide (LPS), polysaccharide such as polylactide, in combination with GMDP and MDP to increase macrophage mediated cytotoxidty (Seyler et al., lnt. J. Immunopharmac., Vol.18, N6.pp385-392, (1996)). Zink-proline salt was proposed to improve homogenecity of the artificial lipid impurities in GMDP. (Grubhofer, U.S. Pat. No. 5,773,011). Additional, peptide has been affixed to muramyl peptide in order to increase their immunogenicity (Le Frander et al., U.S. Pat. No. 4,401,659). Neoglucoproteins having affinity to macrophages or monocytes has also been proposed as an immunogenic component bound to muramyl peptides. (Monsigny et al., U.S. Pat. No. 4,801,578). Contrary to prior art, the present invention strives to decrease or eliminate LPS and polysacchrides. The inventors have found that decreasing levels of these components increases the newly discovered apoptosis regulating properties of GMDP. Thus the inventors have demonstrated that the purity level of the GMDP effects its ability to protect cells and modulate apoptosis. Regulating negative apoptosis, which occurs in many chronic viral infections and neurodegenerative conditions, requires an absolutely opposite task that the prior art has considered for GMDP, that is the inhibition of the cellular immunotoxicity (FAS antigen mediated by CD8 lymphocytes and macrophages) and humoral cytotoxicity (TNF-&agr; mediated). For example, negative apoptosis is a main pathogenic pathway leading to liver necrosis and cirrhosis. Under such conditions, additional immunostimulation exerts detrimental effects with dangerous exaggeration of liver necrosis. Activated macrophages have been shown to be cytotoxic not only for isolated liver cells, but also in eight patients with hepatitis (Mizugoshi et al., Hepatogastroenterology, 1981;28:250-253). Moreover, the only treatment for hepatitis-C (based on the conventional strategy of macrophages stimulation by Interferons) failed to provide satisfactory results in these patients. Moreover, a high percentage of these patients experienced detrimental effects of this immunostimulation with prominent toxicity. Clinical symptoms of increased fatigue, viral load, and acceleration of liver necrosis is noticed as a consequence of the powerful immunostimulator, interferons. In direct opposition to conventional hepatitis-C treatments and prior use of GMDP, the present invention is not an immune stimulato

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