Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1998-05-06
2001-03-27
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S141100, C514S002600, C514S008100, C514S012200, C514S885000
Reexamination Certificate
active
06207155
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to methods of depleting eosinophil levels and compositions used for such, and more particularly, to methods of treating diseases or conditions associated with elevated populations of eosinophils.
BACKGROUND
Eosinophils are white blood cells of the granulocytic lineage. Their normal functions include combating parasitic infections, particularly helminthic infections. See, e.g., Janeway, et al. (eds. 1996)
Immunobiology: The Immune System in Health and Disease
2nd Ed., Garland Publishing, New York, N.Y.; and Rich (ed. 1996)
Clinical Immunology: Principles and Practice
Mosby, St. Louis, Mo. However, their accumulation in tissues, a condition referred to as eosinophilia, is also associated with several abnormal or disease states, including hypereosinophilia, chronic pneumonia, allergic bronchopulmonary aspergillosis, Churg-Strauss Syndrome, atopic dermatitis, and most notably asthma. See, e.g., Frigas, et al. (1986)
J. Allergy Clin. Immunol.
77:527-537; Weller (1984)
J. Allergy Clin. Immunol.
73:1-10; and Frank, et al. (eds. 1995)
Samter's Immunological Diseases
5th Ed., vol. I-II, Little, Brown, and Co., Boston, Mass.
Currently glucocorticoid steroids are the preferred therapeutic drugs for treating the acute effects of allergic diseases, such as asthma. However, prolonged steroid treatment is associated with many deleterious side effects. See, e.g., Goodman and Gilman (eds.)
The Pharmacological Basis of Therapeutics
MacMillan Publishing Company, New York, N.Y. Moreover, the steroids apparently do not affect the production or accumulation of granulocytic cells, such as eosinophils, in the afflicted tissues. Such leads to treatment of symptoms rather than the underlying cause.
More recently, it has been shown that eosinophilia associated with certain immune disorders could be treated by the administration of an antagonist to interleukin-5 (IL-5). See, e.g., Coffman, et al. (1989)
Science
245:308-310; and Coffman, et al. U.S. Pat. No. 5,096,704. IL-5 is a potent eosinophil differentiation factor, but also exerts effects on other immune cells, e.g., B cells. However, this antagonist can affect other cell types besides eosinophils.
The availability of alternative or complementary approaches to the treatment of disorders associated with eosinophilia would have important clinical utility. Preventing the production or accumulation of eosinophils in the relevant tissues may block the underlying cause of these disorders or diseases.
SUMMARY OF THE INVENTION
The invention provides a method of depleting eosinophils by administering an effective amount of an antagonist against the receptor for an eosinophil chemokine, eotaxin. Applicants have observed that this leads to a decrease in the number of eosinophils. The receptor, designated CCR3 is expressed predominantly on eosinophils. Preferably, the antagonists to CCR3 are monoclonal antibodies, or binding compositions derived therefrom by standard techniques.
The present invention provides an antibody or binding composition which specifically binds a CCR3 receptor, reduces the level of eosinophilia in a sample, and does not block ligand binding. In preferred embodiments the antibody is a monoclonal antibody. Also provided is a sterile composition comprising the antibody or binding composition and a pharmaceutically acceptable carrier.
The invention encompasses a method of ameliorating an eosinophil related disease or disorder in an individual by administering an effective amount of the antibody or binding composition, either alone or in combination with an antagonist to interleukin-5 (IL-5) or a steroid. In preferred embodiments the antibody is a monoclonal antibody. An effective amount of the antibody or binding composition is, e.g., preferably at least 500 &mgr;g/kg body weight; usually at least 1000 &mgr;g/kg body weight; typically at least 5 mg/kg body weight; or ordinarily at least 10 mg/kg body weight; and ordinarily less than 100 mg/kg body weight; typically less than 50 mg/kg body weight; or usually less than 25 mg/kg body weight per week. Amelioration is a reduction in the level of eosinophils, e.g., 10%, 20%, 30%, or 50% or more. The eosinophil related disease may be a pulmonary inflammation; a dermatitis; or a hypereosinophilia. The antagonist to IL-5 can be an intact monoclonal antibody, a binding fragment thereof, a soluble receptor for IL-5, or an IL-5 mutein.
An effective amount of an IL-5 monoclonal antibody, binding fragment thereof, or soluble receptor is preferably at least 1 &mgr;g/kg body weight; usually at least 5 &mgr;g/kg body weight; or typically at least 10 &mgr;g/kg body weight; and generally less than 1000 &mgr;g/kg body weight; usually less than 500 &mgr;g/kg body weight; or preferably less than 100 &mgr;g/kg body weight per week. An effective amount of the mutein is preferably at least 100 &mgr;g/hour; usually at least 500 &mgr;g/hour; typically at least 1 mg/hour; and ordinarily at least 3 mg/hour; and preferably less than 100 mg/hour; usually less than 30 mg/hour; typically less than 10 mg/hour; or ordinarily less than 6 mg/hour. An effective amount or the steroid is preferably at least 1 mg/day; usually at least 2 mg/day; or typically at least 5 mg/day; and is ordinarily less than 100 mg/day; typically less than 50 mg/day; usually less than 20 mg/day; or preferably less than 10 mg/day.
The present invention further provides a method for detecting for the presence of eosinophils in a sample comprising the steps of contacting the sample with the antibody or binding composition and detecting the binding of the antibody or binding composition to a CCR3 receptor on the eosinophils. In preferred embodiments, the antibody is a monoclonal antibody and the antibody is detectably labeled.
Also encompassed is a method of isolating a population of cells expressing the CCR3 receptor from a mixture of cells by contacting the mixture with the antibody or binding composition and isolating the population of cells. In preferred embodiments the antibody is a monoclonal antibody. The antibody or binding composition is detectably labeled with a fluorescent moiety, a radioactive moiety, or is coupled to a magnetic bead. The cells are isolated by Fluorescent Activated Cell Sorting (FACS), or by magnetic cell sorting.
DETAILED DESCRIPTION OF THE INVENTION
Outline
I. General
II. Making antibodies
A. Making antigen
B. Making antibodies; binding compositions
C. Selecting mAb isotypes; binding composition conjugates
III. Immunoassays
IV. Uses
I. General
The invention is based, in part, on the discovery that a receptor for an eosinophil specific chemokine, eotaxin, is expressed predominantly on eosinophils. From an entire panel of about 30 monoclonal antibodies (mAb) surprisingly two mAbs were able to significantly reduce the level of eosinophils in mice parasitized with a helminth but without blocking ligand binding to the receptor. The reduced levels may be attributable to any of several mechanisms, e.g., complement fixation/depletion or opsonization by macrophages. See, e.g., Janeway, et al. (eds. 1996)
Immunobiology
Garland Publishing Inc., New York, N.Y.
The chemokines are a sub-family of chemoattractant cytokines that classically mediate leukocyte trafficking by binding to specific G-protein linked seven transmembrane spanning receptors. Chemokines are divided into four groups based on the primary sequence of the first two cysteines: the CXC, CC, C, and the newly discovered, CX3C families. The CXC and C chemokine families are effective predominantly on neutrophils and lymphocytes, respectively. The CC chemokines are preferentially effective on macrophages, lymphocytes, and eosinophils. Eosinophil specific chemokines include, e.g., RANTES, MCP-2, MCP-3, MCP-4, MIP-1&agr;, and recently described, eotaxin. See, e.g., Alam, et al. (1993)
J. Immunol.
150:3442-3448; Weber, et al. (1995)
J. Immunol.
154:4166-4172; Dahinden, et al. (1994)
J. Exp. Med.
179:751-756; Uguccioni, et al. (1996)
J. Exp. Med.
183:2379-2384; Rot, et al. (1992)
J. Exp. Med.
176:148
Coffman Robert L.
Grimaldi J. Christopher
Howard Maureen C.
Ching Edwin P.
Mertz Prema
Mohan-Peterson Sheela
Schering Corporation
Wang Hugh
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