Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
1997-09-12
2003-06-10
Housel, James (Department: 1648)
Drug, bio-affecting and body treating compositions
Lymphokine
C424S085200, C435S385000, C930S140000, C930S145000
Reexamination Certificate
active
06576231
ABSTRACT:
FIELD OF THE INVENTION
The subject invention relates to methods for increasing the number of circulating CD4
+
T-lymphocytes in HIV-infected patients by the administration of granulocyte-macrophage colony stimulating factor (GM-CSF).
BACKGROUND OF THE INVENTION
Patients infected with Human Immunodeficiency Virus (HIV) experience a variable but progressive decline in immune function resulting in clinically apparent opportunistic infections and other diseases. (Crowe et al.,
J. Acquir. Immune Defic. Syndr.
4:770-76, 1991; Moss et al.,
AIDS
3:55-61, 1989). The onset of severe immunodeficiency in HIV-infected individuals is generally accompanied by a marked increase in viral load and a dramatic decline in circulating CD4
+
T-lymphocytes. Indeed, one of the clinical criteria for the diagnosis and reporting of AIDS (as established by the Centers for Disease Control and Prevention) is a decrease in the number of CD4
+
T-lymphocytes to <200 cells/mL. (Normal CD4
+
T-lymphocyte cell counts in healthy HIV
−
individuals range between 800 and 1600 cells/mL.) CD4
+
T-lymphocytes perform multiple immune-modulating functions. The decline in CD4
+
T-lymphocytes, and decline in cell-mediated immunity, is the primary factor responsible for the susceptibility of HIV-infected patients to many opportunistic infections characteristic of the adult immunodeficiency syndrome, or AIDS. Accordingly, an increase in CD4
+
T-lymphocytes is generally regarded as an indicator of efficacy for anti-HIV drugs.
Inhibition of HIV replication can increase CD4
+
T-lymphocyte counts. Such antiretroviral therapy typically involves combinations of drugs such as protease inhibitors, nucleoside analogs, and non-nucleoside reverse transcriptase inhibitors. Other agents, including biologics, have also demonstrated some antiviral effects. The decrease in viral load is generally, but not always, associated with an increase in the number of circulating CD4
+
T-cells. (Yarchoan et al.,
Ann Intern. Med.
115:184-89, 1991; Hirsch and D'Aquila,
N. Engl. J. Med.
328:1686-95, 1993; Volberding, P. A., In: Crowe et al., eds.,
Management of the HIV
-
Infected Patient,
pp. 53-63). Unfortunately, antiretroviral drugs do not result in complete reconstitution of the immune function. Moreover, inhibition of viral replication by these agents is temporary, due to the evolution of resistant strains of virus that can grow in the presence of the antiretroviral agents. (Cameroni et al., Third Human Retroviral Conference, January 1996, Abstract #LB6a).
Growth factor cytokines such as granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), and erythropoietin (EPO) have also been administered to patients with HIV. (Scadden et al., 1991, Levine et al.,
Blood
73:3148-54, 1991; Kaplan et al.,
J. Clin. Oncol.
9:929-40, 1991; Stricken and Goldberg,
Clin. Immunol. Immunopathol.
79:194-96, 1996; Miles et al.,
Blood
77:2109-17, 1991; Pluda et al.,
Hematol. Oncol. Clin. North Am.
5:229-48, 1991). Recently, GM-CSF has been the subject of several studies to evaluate its ability to prevent opportunistic infections in individuals with HIV.
LEUKINE®, a yeast-derived form of GM-CSF, is currently available for use in promoting myeloid cell recovery following bone marrow transplant post-myeloablative therapy for the treatment of malignancies. An
E. coli
-derived form of GM-CSF is also available for use in promoting the recovery of neutrophils in HIV-infected patients with granulocytopenia. (Scadden et al.,
J. Clin. Oncol.
9:802-08, 1991; Levine et al., Blood 78:3148-54, 1991; Kaplan et al.,
J. Clin. Oncol.
9:929-40, 1991; Hardy et al.,
Eur. J. Clin. Microbiol. Infect. Dis.
13:S34-S40, 1994). However, the widespread use of GM-CSF for treatment of HIV infection has been hindered by data from in vitro studies whose results suggest that this cytokine might actually enhance HIV replication (Bender et al.,
J. Immunol.
151:5416, 1993; Foli et al.,
Blood
8:2114, 1995; Pluda et al.,
Hematol. Oncol. Clin. North Am.
5:229-48, 1991). More recent studies have reported results which are inconsistent with earlier studies with regard to the effect of GM-CSF on HIV viral replication (Perno et al., Third Human Retroviral Conf., January 1996, Abstract #463; Pluda et al., Blood 76:463-72, 1990; Fletcher and Gasson,
Blood
71:652-58, 1988; Mitsuyasu, R. T. In: Volberding and Jacobson, eds.
AIDS Clinical Review,
N.Y., N.Y. 1993-94, pp. 189-212). It is now believed that in the presence of antiretroviral therapy, GM-CSF does not upregulate HIV viral replication. (Scadden et al., 1995; Davison et al.,
J. Clin. Pathol.
47:855-57, 1994, Scadden et al.,
AIDS Res. and Human Retroviruses
12:1151-59, 1996). Indeed, in vitro data have demonstrated the enhancement of AZT activity by GM-CSF due to increased intracellular concentration of the active triphosphorylated form of AZT. (Hammer and Gillis,
Antimicrob. Agents Chemother.
31:1046-50, 1987).
Developing effective therapies for HIV disease has presented a formidable challenge for medical researchers. Although significant advancements have been made in the treatment of HIV-infected patients, many patients remain untreatable due to ineffectiveness of the therapeutic drugs used or inability of the patients to tolerate the side effects of the therapies. Clearly, existing therapies do not yet offer a cure to HIV disease. Immune-modulating agents, such as GM-CSF, may therefore offer an additional alternative treatment.
SUMMARY OF THE INVENTION
The present invention provides methods for increasing CD4
+
lymphocyte counts in HIV-infected patients by the therapeutic administration of GM-CSF. This method of treatment has been demonstrated to induce an increase in the absolute number of circulating CD4
+
T-lymphocyte cells in patients concurrently receiving antiretroviral drugs, with no significant increase in viral load.
This invention is based on the results of a double-blinded, placebo-controlled study that enrolled HIV-infected patients at two study sites. In this study, patients receiving anti-retroviral agents for a minimum of eight weeks prior to study received therapeutically effective amounts of recombinant human GM-CSF or placebo. Viral load and CD4
+
T-lymphocyte counts were determined twice prior to the start of the study (baseline), then two weeks, four weeks, and eight weeks after the start of the study, and twice approximately four weeks after the treatment phase was completed. Results indicated that within the placebo arm of the study, there was no significant change in the median values for CD4
+
T-cell counts relative to the baseline. Within the GM-CSF arm of the study, a trend towards an increase in the median value for CD4
+
T-lymphocyte counts was observed between the baseline and all evaluations during the course of the study.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention provides methods for inducing an increase in the number of CD4
+
T lymphocytes in an HIV-infected patient by administering therapeutically effective amounts of granulocyte-macrophage stimulating factor (GM-CSF).
In accordance with the present invention, GM-CSF is administered to HIV-infected patients in amounts and for a time sufficient to induce a clinically significant increase in the patient's CD4
+
T-lymphocyte count. A “CD4
+
T-lymphocyte count” means the number of circulating CD4
+
T-lymphocytes in the patient's blood, expressed as CD4
+
T-lymphocyte cells per unit volume. Generally, CD4
+
lymphocyte counts are expressed as cells/mm
3
of whole blood. An increase in the CD4
+
T-lymphocyte count is defined as a rise relative to the baseline (i.e., before administration of GM-CSF) value. For the purposes of the present invention, a “clinically significant” increase in CD4
+
T-lymphocyte cells is an increase of greater than or equal to about 30% of the baseline value.
GM-CSF used in the
Housel James
Schering AG
SEED Intellectual Property Law Group PLLC
Winkler Ulrike
LandOfFree
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