Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds antigen or epitope whose amino acid sequence is...
Reexamination Certificate
2000-02-02
2003-11-11
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds antigen or epitope whose amino acid sequence is...
C424S130100, C424S158100
Reexamination Certificate
active
06645491
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to methods of using various chemokine related compositions, more particularly, to methods of treating skin diseases or conditions associated with misregulation of the chemokine MIP-3&agr;, a ligand for the CCR6 chemokine receptor.
BACKGROUND
The immune system consists of a wide range of distinct cell types, each with important roles to play. See Paul (ed. 1997)
Fundamental Immunology
4th ed., Raven Press, New York. The lymphocytes occupy central stage because they are the cells that determine the specificity of immunity, and it is their response that orchestrates the effector limbs of the immune system. Two broad classes of lymphocytes are recognized: the B lymphocytes, which are precursors of antibody secreting cells, and the T (thymus-dependent) lymphocytes. T lymphocytes express important regulatory functions, such as the ability to help or inhibit the development of specific types of immune response, including antibody production and increased microbicidal activity of macrophages. Other T lymphocytes are involved in direct effector functions, such as the lysis of virus infected-cells or certain neoplastic cells.
The chemokines are a large and diverse superfamily of proteins. The superfamily is subdivided into two classical branches, based upon whether the first two cysteines in the chemokine motif are adjacent (termed the “C-C” branch), or spaced by an intervening residue (“C-X-C”). A more recently identified branch of chemokines lacks two cysteines in the corresponding motif, and is represented by the chemokines known as lymphotactins. Another recently identified branch has three intervening residues between the two cysteines, e.g., CX3C chemokines. See, e.g., Schall and Bacon (1994)
Current Opinion in Immunology
6:865-873; and Bacon and Schall (1996)
Int. Arch. Allergy & Immunol.
109:97-109.
Many factors have been identified which influence the differentiation process of precursor cells, or regulate the physiology or migration properties of specific cell types. These observations indicate that other factors exist whose functions in immune function were heretofore unrecognized. These factors provide for biological activities whose spectra of effects may be distinct from known differentiation or activation factors. The absence of knowledge about the structural, biological, and physiological properties of the regulatory factors which regulate cell physiology in vivo prevents the modulation of the effects of such factors. Thus, medical conditions where regulation of the development or physiology of relevant cells is required remain unmanageable.
SUMMARY OF THE INVENTION
The present invention is based, in part, upon the surprising discovery that the MIP-3&agr; chemokine is expressed in inflamed skin cells. The chemokine is the ligand for the CCR6 receptor. See Greaves, et al. (1997)
J. Expt'l Med.
186:837-844. Both the ligand and receptor are expressed at essentially undetectable levels in normal skin, while both are highly upregulated in inflamed skin.
The present invention provides methods of modulating migration of a cell within or to the skin of a mammal comprising administering to the mammal an effective amount of: an antagonist of MIP-3&agr;; an agonist of MIP-3&agr;, and antagonist of CCR6; or an agonist of CCR6. Typically, the migration is within the skin; or may be chemotactic or chemokinetic. In preferred embodiments, the administering is systemic, local, topical, subcutaneous, intracutaneous, or transdermal. Often, the cell is a T cell, B cell, dendritic cell, or dendritic cell precursor. In other embodiments, the cell is a T cell, or moves into the dermal and/or epidermal layers of the skin.
In other embodiments, the administering is of an antagonist of MIP-3&agr;. Generally, the antagonist is selected from: a mutein of natural MIP-3&agr;; an antibody which neutralizes MIP-3&agr;; or an antibody which binds to CCR6. In various embodiments, the mammal is subject to a skin disease or condition, including one selected from cancer, cancer metastasis, skin transplant, or skin graft. Often, the antagonist is administered in combination with an antibiotic, antifungal, antiviral, or analgesic; or may be with an immune suppressive therapeutic, anti-inflammatory drug, growth factor, or immune adjuvant.
In another embodiment, the administering is with a primate MIP-3&agr;. Often, the modulating is attracting the cell, e.g., to a site of cutaneous lesion. The primate MIP-30&agr; may be administered in combination with an antibiotic, antifungal, antiviral, or analgesic; or with a vasodilator, growth factor, cytokine, anti-inflammatory drug, or immune adjuvant.
Alternatively, the invention provides a method of purifying a population of cells, the method comprising contacting the cells with MIP-3&agr;, thereby resulting in the identification of cells expressing a receptor for MIP-3&agr;. In certain embodiments, the receptor is CCR6, or the contacting results in specific migration of the cells to a site for purification, e.g., through pores of a membrane.
DETAILED DESCRIPTION OF THE INVENTION
Outline
I. General
II. Chemokine Agonists and Antagonists
A. MIP-3&agr; and Variants
B. Antibodies
C. Other Molecules
III. Immunoassays
IV. Uses
I. General
The invention is based, in part, on the surprising discovery that the chemokine MIP-3&agr; has been implicated in roles in skin immunity. In particular, MIP-3&agr; has been identified as a ligand for the chemokine receptor designated CCR6. Both MIP-3&agr; and CCR6 expression are undetectable in normal skin, while both are highly upregulated in inflamed skin samples.
The skin consists of a surface layer of epithelium called the epidermis and an underlying layer of connective tissue called the dermis. Under the dermis is a layer which contains large amounts of adipose tissue, the hypodermis. The skin serves a variety of functions, and variations in the character of the dermis and epidermis occur according to functional demands. The appendages of the skin, hair, nails, and sweat and sebaceous glands, are such local specializations of the epidermis. Together, the skin and its appendages form the integument. See, e.g., Fitzpatrick, et al. (eds. 1993)
Dermattology in General Medicine
4th ed., McGraw-Hill, NY; Bos (ed. 1989)
Skin Immune System
CRC Press, Boca Raton, Fla.; Callen (1996)
General Practice Dermatology
Appleton and Lange; Rook, et al. (eds. 1998)
Textbook of Dermatology
Blackwell; Habifor and Habie (1995)
Clinical Dermatology: A Color Guide to Diagnosis and Therapy
Mosby; and Grob (ed. 1997)
Epidemiology, Causes and Prevention of Skin Diseases
Blackwell.
The epidermis consists of many different cell types in various proportions. The most prevalent cell type is keratinocytes, which make up some 95% of the cells. Cells in the 1-2% range include melanocytes and Langerhans cells. The Langerhans cells are particularly important because they trap antigens that have penetrated the skin, and transport antigens to regional lymph nodes. A small population of &ggr;&dgr; T cells can also reside in the epidermis.
The dermis varies in thickness in different regions of the body. It is tough, flexible, and highly elastic, and consists of a feltwork of collagen fibers with abundant elastic fibers. The connective tissue is arranged into deep reticular and superficial papillary layers.
The chemokines are a sub-family of chemoattractant cytokines that were classically characterized by their ability to mediate leukocyte trafficking or migration by binding to specific G-protein-linked seven transmembrane spanning receptors, or GPCRs. Chemokines are divided into four groups based on the primary sequence of the first two cysteines: the CXC, CC, C, and CX3C families. The CXC and C families are effective predominantly on neutrophils and lymphocytes, respectively. The CC chemokines are preferentially effective on macrophages, lymphocytes, and eosinophils.
The chemokine MIP-3&agr;, from human, mouse, and rat, has been described earlier. See, e.g., human, GenBank HSU77035; mouse, Ge
Caux Christophe
Dieu-Nosjean Marie Caroline
Homey Bernhard
Oldham Elizabeth R.
Zlotnik Albert
Ching Edwin P.
Mertz Prema
Schering Corporation
Zaradic Sandy
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