Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1999-10-29
2002-06-18
Wortman, Donna C. (Department: 1648)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S143100, C514S043000
Reexamination Certificate
active
06406695
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a new use for existing monoclonal antibodies known to prevent or treat immunological rejection of transplanted organ and tissues. Specifically, the invention provides for the first time a method of using an anti-IL-2 receptor monoclonal antibody for reversing severe viral hepatitis C.
2. Description of Related Art
Recent advances in the field of organ transplantation have lead to the development of new therapy regimens effective in preventing acute rejection episodes in transplant recipients. Several preparations of antibodies are known for use as immunosuppressive agents in treating acute graft rejection. Some of these antibodies interact with certain lymphoid cells, thereby impairing cell function. For example, lymphocyte immune globulin (antithymocyte globulin) can sharply reduce the number of thymus-derived lymphocytes (T-cells) in treated patients and inhibit normal responses of such T-cells. Patients receiving a short course (induction) antithymocyte globulin are typically on other maintenance immunosuppressive regimens (6). The U.S. Food and Drug administration approved in 1998 a commercial form of an anti-interleukin-2 (IL-2) receptor monoclonal antibody for use in kidney transplantation protocols. This anti-IL-2 receptor monoclonal antibody binds to IL-2 receptors to prevent stimulation of T-lymphocyte production in response to a foreign organ graft. T -lymphocytes are major immunological players in the biological mechanisms responsible for organ transplant rejection. Anti-IL-2 receptor monoclonal antibodies, such as basiliximab (Simulect®, Novartis), may be added to current immunosuppressive regimens containing cyclosporine and prednisone for reducing acute rejection episodes in renal transplant recipients. Such regimens appear effective in reducing irreparable damage to allografts subjected to acute rejection, improving post-transplant kidney function.
The addition of basiliximab to current immunosuppressive regimens permits organ recipients to be treated with a two-dose, four-day regimen in lieu of prior five-dose antibody regimens lasting 10 weeks. Basiliximab, cyclosporine and prednisone combination therapies reduce the incidence and severity of acute rejection episodes without increasing rates of infection and other associated consequences of nonspecific immunosuppression.
Similarly, clinical trials of a combination regimen containing daclizumab (Zenapax®, Hoffman-la Roche), mycophenolate mofetil, cyclosporine and corticosteroids have shown such a regimen to be efficacious in reducing acute rejection episodes within six months of kidney transplants. SMART™ Anti-Tac, the humanized monoclonal antibody (daclizumab) active ingredient of Zenapax®, binds to the alpha subunit of high affinity interleukin-2 receptors expressed on activated T-lymphocytes. Daclizumab antagonizes binding of IL-2 to high affinity IL-2 receptors, thereby suppressing T-lymphocyte activity against allografts.
Daclizumab-based therapy regimens improve organ transplant survival without unduly increasing therapy toxicity. Such humanized monoclonal antibodies have a longer half-life and are less likely to be targeting by a patient's immune system than non-humanized antibodies, such as previously tested mouse monoclonal antibodies. Humanized immunoglobulins are disclosed in, for example, U.S. Pat. Nos. 5,530,101 and 5,585,089.
Recurrence of hepatitis C following liver transplantation remains a feared complication in recipients of liver allografts. Frequent recurrence of hepatitis C infection following orthotopic liver transplantation (OLT) is common, affecting up to 75% of transplant recipients (1). Hepatitis C viral RNA is detected in 95% to 100% of liver transplant patients suffering from recurrent hepatitis C. Traditionally, severe hepatitis C recurrence following liver transplantation is treated by reduction or discontinuation of immunosuppressive therapy and a combination of antiviral drugs such as alpha interferon and ribavirin, a regimen which has proven to be ineffective. Severe hepatitis C or cirrhosis secondary to hepatitis C continue to be complicating factors in liver transplantation.
As noted herein, antiviral therapy for recurrent hepatitis C viral infection post-orthotopic liver transplantation has failed miserably to date. Cholestatic hepatitis has an incidence of 8% to 13% with a high morbidity level. Characteristics indicative of cholestatic hepatitis include early hepatitis C virus recurrence, moderate to high bilirubin levels, renal insufficiency, ascites, and elevated serum hepatitis C viral RNA concentrations (3).
Recent experimental evidence suggests that viral specific cytotoxic T-lymphocyte activation could be an important pathogenic mechanism of hepatocellular damage during chronic hepatitis C (2). Other studies indicate that only cells infected with non-cytopathic replicating viruses are destroyed by activated cytotoxic T-lymphocytes, due to viral induced expression of endogenous major histocompatibility complex (MHC) class I molecules (4). Cross-presentations of antigens expressed in virally infected peripheral organs could explain activation of cytotoxic T-lymphocytes (5).
Therefore, a need exists for improved therapy for patients with hepatitis C and against hepatitis C virus recurrence in patients undergoing liver transplantations.
SUMMARY OF THE INVENTION
Treatment of patients with severe hepatitis C by an anti-IL-2 receptor antibody according to the invention may result in selective blockade of the effector cytopathic mechanism of hepatocellular damage, while concurrent anti-viral therapy eventually decreases the viral load in such patients.
An embodiment of the invention is a method of treating viral hepatitis C in a patient comprising combining an effective amount anti-IL-2 receptor monoclonal antibody with an effective amount of at least one antiviral compound for administration to a patient;
administering to a patient a dosage of the combination of anti-IL-2 receptor monoclonal antibody and at least one antiviral compound; and
repeating administration of said dosage until liver function tests yield values in a clinically acceptable range,
wherein said dosage comprises administering either simultaneously or sequentially the anti-IL-2 receptor monoclonal antibody and the at least one antiviral compound.
Optionally, the method of treating viral hepatitis C in a patient may further comprise pretreating patients with an antihistamine or acetaminophen.
Another embodiment of the invention is a method of treating viral hepatitis C in a patient, wherein the patient is a liver transplant recipient suffering from recurrent cholestatic hepatitis C.
Yet another embodiment of the invention is a method of treating viral hepatitis C in a patient, wherein the effective amount of anti-IL-2 receptor monoclonal antibody comprises a dose of 2 mg/Kg of body weight.
Still another embodiment of the invention is a method of treating viral hepatitis C in a patient, wherein the dosage comprises a combination of an intravenously administered anti-IL-2 receptor antibody and at least one antiviral compound.
A further embodiment of the invention is a method of treating viral hepatitis C in a patient, wherein the dosage is repeated once weekly for up to six weeks.
A further embodiment of the invention is a method of treating viral hepatitis C in a patient, wherein a dosage comprises intravenously administering anti-IL-2 receptor monoclonal antibodies once every other week, and thereafter dosing is repeated monthly for at least one year.
DETAILED DESCRIPTION OF THE INVENTION
Recurrent cholestatic hepatitis C may be treated by reducing or suspending maintenance immunosuppression of patients, and administering anti-IL-2 receptor monoclonal antibody (Daclizumab) as a combination therapy with &agr;-interferon and ribavirin. Doses of &agr;-interferon typically are in the range of several million units. Ribavirin is administered at a level titrated to minimize side effects. Specifically, ribavirin may be administered
Pinna Antonio
Ricordi Camillo
Tzakis Andreas G.
Pillsbury & Winthrop LLP
University of Miami
Wortman Donna C.
LandOfFree
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