Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
2000-06-26
2003-04-08
Kunz, Gary (Department: 1647)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C514S256000, C514S186000
Reexamination Certificate
active
06544504
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a method for controlling autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and psoriasis. In particular, the invention relates to the combined use of interleukin-10 and methotrexate for immuno-modulatory therapy.
BACKGROUND OF THE INVENTION
Interleukin 10 (IL-10), a cytokine produced by
T lymphocytes
, was first identified by its ability to inhibit interferon gamma (IFN-&ggr;) and IL-2 synthesis by mouse and human
T lymphocytes
[Fiorentino et al., 1989
, J. Exp. Med
. 170:2081-2089; Moore et al., 1990
, Science
248:1230-1252; Vieira et al., 1991
, Proc. Natl. Acad. Sci. USA
88:1172-1177]. IL-10 was subsequently shown to be produced by B cells [O'Garra et al., 1990
, Internat. Immunol
. 2:821-828] and macrophages [Fiorentino et al., 1991
, J. Immunol
. 147:3815-3822].
IL-10 exerts a wide range of effects on a variety of cell types. IL-10 inhibits the synthesis of a wide spectrum of cytokines produced by T cells and monocytes. In addition to inhibiting the synthesis of IFN-&ggr; and IL-2, IL-10 has also been shown to inhibit production of the monokines IL-1&agr;, IL-1&bgr;, IL-6 and TNF&agr; [de Waal et al., 1991
, J. Exp. Med
. 174:1209-1217]. IL-10 has growth promoting effects on murine thymocytes and T cells [MacNeil et al., 1990
, Immunol
. 145:4167] and mast cells [Thompson-Snipes et al., 1991
, J. Exp. Med
. 173:507-512], and it stimulates cytotoxic T-cell development [Chen and Zlotnik, 1991
, J. Immunol
. 147:528-533].
Mouse and human IL-10 have high sequence similarity with a protein encoded by an open reading frame in the Epstein-Barr Virus. The expression product of this open reading frame, named viral IL-10, also has the capacity to inhibit cytokine synthesis [Moore et al., 1990
, Science
248:1230-1252; Vieira etal., 1991
, Proc. Natl. Acad. Sci. USA
88:1172-1177].
Several cytokines, including IL-2, IFN-&ggr; and TNF-&agr;, have been shown to regulate the mixed lymphocyte reaction (MLR) [Shevach, 1985
, Annu. Rev. Immunol
. 3:397; Fidelus et al., 1982
, Transplantation
34:308; Tadmori et al., 1985
, J. Immunol
. 134:4542-4550; Tadmori et al, 1986
, J. Immunol
. 136:1155-1162; Novelli et al., 1991, 147:1445-1450; Landolfo et al., 1985
, Science
229:176-180; Shalaby et al., 988
, J. Immunol
. 141:499-505]. It has been reported that IFN-&ggr; may play an important role in MLR graft rejection [Novelli et al., 1991
, J. Immunol
. 147:1445-1450; Landolfo et al., 1985
, Science
229:176-180]. Antibodies to IFN-&ggr; or to TNF [Shalaby et al., 1988
, J. Immunol
. 141:499-505] have been shown to block MLR-induced proliferation. In these studies it was found that antibodies to IFN-&ggr; suppressed the MLR in human systems as well as allograft reactivity in vitro and in vivo in the mouse.
Methotrexate is known as N-[4-[[(2,4-diamino-6-pteridinyl)methyl] methylamino]benzoyl]-L-glutamic acid. The following references describe the preparation of methotrexate [see Seeger et al.,
J.Am.Chem.Soc
., 1949, 71:1753]; the metabolism of methotrexate [see Freeman,
J.Pharmacol.Exp.Ther
. 1958, 122:154; and Henderson et al.,
Cancer Res
. 1965, 25:1008, 1018]; the toxicity of methotrexate [Condit et al.,
Cancer
1960, 13:222-249]; the pharmacokinetic models of methotrexate [Bischoff, et al.,
J.Pharm.Sci
1970, 59:149]; the metabolism and pharmacokinetics of methotrexate [Evans,
Appl.Pharmacokinet
. 1980, 518-548]; the clinical pharmacology of methotrexate [Bertino,
Cancer Chemother
, 1981, 3: 359-375; Jolivet et al.,
N.Engl.J.Med
., 1983, 309: 1094-1104] and the clinical experience of methotrexate in rheumatoid arthritis [
J.Rheumatol
., 1985, 12, Suppl, 12, 1-44].
Methotrexate inhibits dihydrofolic acid reductase. Folic acid must be reduced to tetrahydrofolic acid by this enzyme in the process of DNA synthesis, repair and cellular replication. Therefore, methotrexate interferes with cellular reproduction.
SUMMARY OF THE INVENTION
The present invention provides a method for treating autoimmune disease comprising administering an effective amount of interleukin-10 (IL-10) and methotrexate (MTX) to a patient afflicted with an autoimmune disease.
This invention also provides a method for treating rheumatoid arthritis comprising administering an effective amount of interleukin-10 and methotrexate to a patient experiencing arthritis. Other conditions treatable by the method of the present invention include but are not limited to psoriasis, inflammatory bowel disease and multiple sclerosis.
Pharmaceutical compositions comprising a combination of IL-10 and MTX are also provided by this invention.
DETAILED DESCRIPTION OF THE INVENTION
In order that the invention described herein may be more fully understood, the following detailed description is set forth. All references cited herein are hereby incorporated in their entirety by reference.
It has unexpectedly been discovered that the combined/concurrent administration of IL-10 and MTX, or IL-10 and a MTX analogue, causes an unexpectedly strong suppression of T cell proliferation. While the invention is discussed herein in terms of the combined use of IL-10 and MTX, it is to be understood that an analogue of MTX may also be combined with IL-10 to cause synergistic suppression of T cell proliferation, and that such combinations are contemplated for use in the practice of this invention.
The combination of IL-10 and MTX can be advantageously used in the suppression of pathology associated with T cell responses. For example, considering the diverse biological activities of IL-10, the concurrent use of IL-10 and MTX provides long term treatment of inflammatory bowel disease and such autoimmune diseases as rheumatoid arthritis. The invention may also be used to treat autoimmune diseases such as diabetes mellitus, multiple sclerosis and myasthenia gravis; and to treat other diseases where MTX has been used, such as psoriasis.
Due to the activity of IL-10, MTX can be used in lower amounts, thereby avoiding or reducing the serious side effects normally associated with the use of this drug. The MTX/IL-10 combination therapy of the present invention is useful in treating patients who are non-responsive to MTX treatment alone. MTX/IL-10 therapy is also useful in patients who have developed a resistance to MTX due to its long-term use.
The methods of the invention can be used prophylactically or for treatment of established autoimmune disease. Individuals suitable for treatment by the methods of the invention include any individual at risk (predisposed) for developing rheumatoid arthritis, or an individual exhibiting clinical symptoms. Prophylactic use encompasses administration prior to onset of clinical symptoms of arthritis, to prevent or postpone onset of disease.
In the practice of the invention, IL-10 and-MTX are to be “concurrently” administered to a patient. Concurrently administering means the IL-10 and MTX are administered to the subject either (a) simultaneously in time (optionally by formulating the two together in a common carrier), or (b) at different times during the course of a common treatment schedule. In the latter case, the two compounds are administered sufficiently close in time to achieve the intended effect. The active agents may be administered together in a single pharmaceutical composition or separately. Both active agents (i.e., IL-10 and MTX) should be present in the patient at sufficient combined levels to be therapeutically effective. The routes of administration of the IL-10 and MTX may be the same or different. For any route of administration, single or divided doses may be used.
Generally, IL-10 and MTX are administered as a pharmaceutical composition comprising an effective amount of IL-10 and MTX in a pharmaceutical carrier. A pharmaceutical carrier can be any compatible, non-toxic substance suitable for del
Grint Paul C.
Narula Satwant
Hamud Fozia
Kunz Gary
Schering Corporation
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