Chemistry: molecular biology and microbiology – Vector – per se
Reexamination Certificate
1995-06-07
2001-10-02
Schwartzman, Robert A. (Department: 1636)
Chemistry: molecular biology and microbiology
Vector, per se
C435S069300
Reexamination Certificate
active
06297048
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to methods for treating hepatitis infections, as well as hepatitis-associated carcinomas.
BACKGROUND OF THE INVENTION
Hepatitis is a systemic disease which predominantly affects the liver. The disease is typified by the initial onset of symptoms such as anorexia, nausea, vomiting, fatigue, malaise, arthralgias, myalgias, and headaches, followed by the onset of jaundice. The disease may also be characterized by increased serum levels of the aminotransferases AST and ALT. Quantification of these enzymes in serum indicates the extent of liver damage.
There are five general categories of viral agents which have been associated with hepatitis: the hepatitis A virus (HAV); the hepatitis B virus (HBV); two types of non-A, non-B (NANB) agents, one blood-borne (hepatitis C) and the other enterically transmitted (hepatitis E); and the HBV-associated delta agent (hepatitis D).
There are two general clinical categories of hepatitis, acute hepatitis and chronic hepatitis. Symptoms for acute hepatitis range from asymptomatic and non-apparent to fatal infections. The disease may be subclinical and persistent, or rapidly progress to chronic liver disease with cirrhosis, and in some cases, to hepatocellular carcinoma. Acute hepatitis B infection in adult Caucasians in the United States progresses to chronic hepatitis B in about 5% to 10% of the cases. In the remainder of the cases, approximately 65% are asymptomatic. In the Far East, infection is usually perinatal, and 50% to 90% progress to the chronic state. It is likely that the different rates of progression are linked to the age at infection rather than genetic differences in the hosts. In the United States, about 0.2% of the population is chronically infected, with higher percentages in high-risk groups such as physicians, drug addicts and renal dialysis patients. In countries such as Taiwan, Hong Kong and Singapore, the level in the population with hepatitis infection may be as high as 10%.
In the United States, about 20% of patients with chronic hepatitis die of liver failure, and a further 5% develop hepatitis B-associated carcinoma. In the Far East, a large percentage of the population is infected with HBV, and after a long chronic infection (20 to 40 years), approximately 25% of these will develop hepatocellular carcinoma.
After the development of serologic tests for both hepatitis A and B, investigators identified other patients with hepatitis-like symptoms, and with incubation periods and modes of transmission consistent with an infectious disease, but without serologic evidence of hepatitis A or B infection. After almost 15 years, the causative agent was identified as an RNA virus. This virus (designated “hepatitis C”) has no homology with HBV, retroviruses, or other hepatitis viruses.
Hepatitis C (HCV) appears to be the major cause of post-transfusion and sporadic non-A, non-B (NANB) hepatitis worldwide, and plays a major role in the development of chronic liver disease, including hepatocellular carcinoma (Kuo et al.,
Science
244:362-364, 1989; Choo et al.,
British Medical Bulletin
46(2):423-441, 1990). Of the approximately 3 million persons who receive transfusions each year, approximately 150,000 will develop acute hepatitis C (Davis et al.,
New Eng.J. Med
. 321(22):1501-1506, 1989). In addition, of those that develop acute hepatitis C, at least one-half will develop chronic hepatitis C.
Until recently, no therapy has proven effective for treatment of acute or chronic hepatitis B or C infections, and patients infected with hepatitis must generally allow the disease to run its course. Most anti-viral drugs, such as acyclovir, as well as attempts to bolster the immune system through the use of corticosteroids have proven ineffective (Alter, “Viral hepatitis and liver disease,” Zuckerman (ed.), New York: Alan R. Liss, pp. 537-42, 1988). Some anti-viral activity has been observed with adenosine arabinoside (Jacyna et al.,
British Med. Bull
. 46:368-382, 1990), although toxic side effects which are associated with this drug render such treatment unacceptable.
One treatment that has provided some benefit for chronic hepatitis B and C infections is the use of recombinant alpha interferon (Davis et al.,
New Eng. J. Med
. 321(22):1501-1506, 1989; Perrillo etal.,
New Eng. J. Med
. 323:295-301, 1990). However, for patients with hepatitis B infections only about 35% of infectees responded to such treatment, and in perinatal infectees only about 10% responded to treatment. For hepatitis C infections, despite apparent short-term success utilizing such therapy, six months after termination of treatment half of the patients who responded to therapy had relapsed. In addition, a further difficulty with alpha interferon therapy is that the composition frequently has toxic side effects such as nausea, and flu-like symptoms, which require reduced dosages for sensitive patients.
A disease which is related to hepatitis B and hepatitis C infections, is hepatocellular carcinoma. Briefly, hepatocellular carcinoma is the most common cancer worldwide. It is responsible for approximately 1,000,000 deaths annually, most of them in China and in sub-Saharan Africa. There is strong evidence of an etiologic role for hepatitis B infection in hepatocellular carcinoma. Carriers of the HBV are at greater than 90 times higher risk for the development of hepatocellular carcinoma than noncarriers. In many cases, hepatitis B virus DNA is integrated within the cellular genome of the tumor. Similarly, hepatitis C virus has also recently been found to be associated with hepatocellular carcinoma, based upon the observation that circulating HCV antibodies can be found in some patients with hepatocellular carcinoma. At present, surgical resection offers the only treatment for hepatocellular carcinoma, as chemotherapy, radiotherapy, and immunotherapy have not shown much promise (Colombo et al.,
Lancet
1006-1008, 1989; Bisceglie et al.,
Ann. of Internal Med
. 108:390-401, 1988; Watanabe et al.,
Int. J. Cancer
48:340-343, 1991; Bisceglie et al.,
Amer. J. Gastro
. 86:335-338, 1991).
Therefore, therapeutics that could serve to augment natural host defenses against hepatitis, or against tumor induction and progression, with reduced cytotoxicity, or that allows treatment of interferon non-responsive individuals would be very beneficial. The present invention provides such therapeutic agents, and further provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention is directed toward methods of treating hepatitis B and hepatitis C infections, as well as hepatocellular carcinomas (HCC). Within one aspect of the present invention, method are provided for treating hepatitis B infections in warm-blooded animals comprising the step of administering to a warm-blooded animal a vector construct which directs the expression of at least one immunogenic portion of a hepatitis B antigen, such that an immune response is generated. Within another aspect of the invention, an immunomodulatory cofactor may also be administered, or co-expressed along with an immunogenic portion of a hepatitis B antigen. Within another aspect, an immunogenic portion of a hepatitis B antigen is fused with a marker (e.g., an antibiotic resistance gene such as the neomycin gene), and administered such that an immune response is generated. Within various embodiments, the vector construct directs the expression of HBeAg, HBcAg, HBsAgs, ORF 5, ORF 6, the HBV pol antigen, or any combination of these antigens (e.g., HBeAg and HBcAg). Within one embodiment, the HBsAgs are selected from the group consisting of S, pre-S1, and pre-S2.
Within a related aspect of the present invention, vector constructs are provided which direct the co-expression of at least one immunogenic portion of a hepatitis B antigen and an immunomodulatory cofactor. Also provided are pharmaceutical compositions comprising the recombinant viruses in combination with a pharmaceutically acceptable carrier or diluent.
Within another aspect of the present i
Chang Stephen M. W.
Jolly Douglas J.
Lee William T. L.
O'Dea Joanne
Townsend Kay
Blackburn Robert P.
Chiron Corporation
Dollard Anne S.
McMasters David
Schwartzman Robert A.
LandOfFree
Hepatitis therapeutics does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Hepatitis therapeutics, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hepatitis therapeutics will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2583575