Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
2000-12-05
2004-07-20
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S130100, C424S133100, C424S134100, C424S135100, C424S141100, C424S143100, C424S144100, C424S153100, C424S172100, C424S173100, C424S152100, C424S185100, C424S192100, C514S002600, C514S008100, C514S015800, C514S863000, C514S885000, C530S350000, C530S387100, C530S387300, C530S388100, C530S388200, C530S388220, C530S388700, C530S388730, C530S388750
Reexamination Certificate
active
06764681
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to methods of using inhibitors of the CD2/LFA-3 interaction in treating skin conditions characterized by increased T cell activation and abnormal antigen presentation in the dermis and epidermis in mammals, including humans. Such conditions include psoriasis, UV damage, e.g., photoaging, atopic dermatitis, cutaneous T cell lymphoma such as mycosis fungoides, allergic and irritant contact dermatitis, lichen planus, alopecia areata, pyoderma gangrenosum, vitiligo, ocular cicatricial pemphigoid, and urticaria.
BACKGROUND OF THE INVENTION
There are numerous skin conditions characterized by increased T cell activation and abnormal antigen presentation in the dermis and epidermis. The pathophysiologic mechanisms involved in the evolution of such inflammatory processes are poorly understood. However, it has become apparent that skin cells are important in the generation of a cutaneous inflammatory response (Kupper, “Immune and Inflammatory Processes in Cutaneous Tissues”,
J. Clin. Invest
., 86, pp. 1783-89 (1990)).
The normal adult epidermal population contains 1-2% Langerhans' cells and about 98% keratinocytes. Keratinocytes and other nonhematopoietically-derived cells resident in skin contribute to immune homeostasis and can produce various cytokines which influence migration of T cells and expression of adhesion molecules.
As antigen presenting cells, Langerhans' cells express a high density of Class II major histocompatibility complex (MHC) antigen on the cell surface. MHC Class II molecules bind peptides derived from endocytosed antigen and are recognized primarily by helper T lymphocytes. The T cell receptor on T cells recognizes antigen as a peptide fragment bound to the cell-surface molecules encoded by the MHC (Springer, “Adhesion Receptors of the Immune System”,
Nature
, 346, pp. 425-27 (1990)).
There are many interactions between molecules expressed on the surface of Langerhans' cells and the surface of T cells, in addition to the T cell receptor/MHC interaction. These surface molecules, often referred to as adhesion molecules, participate in a number of functions including cellular adhesion, antigen recognition, co-stimulatory signalling in T cell activation and stimulation of effectors of T cell cytotoxicity (“Adhesion Molecules in Diagnosis and Treatment of Inflammatory Diseases”,
The Lancet,
336, pp. 1351-52 (1990)). Such cell adhesion appears to be involved in activation of T cell proliferation in the generation of an immune response (Hughes et al., “The Endothelial Cell as a Regulator of T-cell Function”,
Immunol. Rev
., 117, pp. 85-102 (1990)).
Various skin conditions are characterized by increased T cell activation and abnormal antigen presentation in the dermis and epidermis (Cooper, “Immunoregulation in the Skin”, in
Cutaneous Lymphoma, Curr. Probl. Dermatol
., eds. van Vloten et al., 19, pp. 69-80 at pp. 73, 74, 76 (1990)). For example, in contact allergic dermatitis, activation of intracutaneous T cells is observed. It is known that skin from patients exhibiting atopic dermatitis contains an increased number of Langerhans' cells (Cooper, “Immunoregulation in the Skin”, in
Cutaneous Lymphoma, Curr. Probl. Dermatol
., eds. van Vloten et al., 19, at p. 74 (1990)). In psoriatic skin, there is an increased number of antigen presenting cells, composed of both Langerhans' cells and non-Langerhans' cell Class II MHC-bearing antigen presenting cells (Cooper, “Immunoregulation in the Skin”, in
Cutaneous Lymphoma, Curr. Probl. Dermatol
., eds. van Vloten et al., 19, at p. 75 (1990)).
UV exposed skin is characterized by an overall depletion of Langerhans' cells and migration of a non-Langerhans' cell antigen-presenting cell population into the epidermis, which activates autologous T cells to proliferate (Cooper, “Immunoregulation in the Skin” in
Cutaneous Lymphoma, Curr. Probl. Dermatol
., eds. van Vloten et al., 19, at pp. 75-76 (1990)). In human skin after 4 minimal erythemal doses of UV B, Langerhans' cells (the constitutive antigen presenting cell population) are inactivated for approximately 3 days (Cooper et al., “Effects Of Ultraviolet Radiation On Human Epidermal Cell Alloantigen Presentation: Initial Depression Of Langerhans Cell-Dependent Function Is Followed By Appearance Of T6-DR
+
Cells That Enhance Epidermal Alloantigen Presentation”,
J. Immunol
., 134, pp. 129-37 (1985)). In this type of UV damaged skin, the CD1a
−
DR
+
macrophage population (a population of antigen presenting cells) increases from 0% (normal skin) to approximately 2-10% of the entire epidermal cell population and is the cell population entirely responsible for the induction of T cell proliferation to alloantigen. (Cooper et al.,
J. Immunol
., supra (1985); Baadsgaard et al., “In Vivo Ultraviolet-Exposed Human Epidermal Cells Activate T Suppressor Cell Pathways That Involve CD4
+
CD45RA
+
Suppressor-Inducer T Cells”,
J. Immunol
., 145, pp. 2854-61 (1990)).
Cutaneous T cell lymphoma is characterized by the expansion of a malignant clonal population of T cells in the dermis and epidermis. Lesional epidermal cells contain increased numbers of CD1
+
DR
+
antigen presenting cells (Cooper, “Immunoregulation in the Skin” in
Cutaneous Lymphoma, Curr. Probl. Dermatol
., eds. van Vloten et al., 19, at pp. 76-77 (1990)).
Presently known therapies for the above mentioned skin diseases are inadequate. Steroids or cyclosporin A are commonly used in the treatment of psoriasis, lichen planus, urticaria, atopic dermatitis, UV damage, pyoderma gangrenosum, vitiligo, ocular cicatricial pemphigoid, alopecia areata, allergic and irritant contact dermatitis and cutaneous T cell lymphoma. In addition, for some of these skin conditions, various therapies include retinoids, PUVA, nitrogen mustard, interferon, chemotherapy, methotrexate, UV light, antibiotics and antihistamines. See generally Fitzpatrick,
Dermatology in General Medicine,
3rd ed., McGraw Hill (1987).
Side effects to these therapies are known. Most commonly encountered drawbacks for cyclosporin A include toxicity due to immunosuppression and renal and neural toxicity. Steroids have well known side effects including induction of Cushing Syndrome. Side effects of certain of the other aforementioned therapies include skin cancer, bone marrow and constitutional toxicities, ligament calcification, liver fibrosis and other disorders.
T cells play a major role in the immune response by interacting with target and antigen presenting cells. For example, T cell-mediated killing of target cells is a multi-step process involving, initially, adhesion of cytolytic T cells (the effector cells) to target cells. Also, helper T cells help initiate the immune response by adhesion to antigen presenting cells.
These interactions of T cells with target and antigen presenting cells are highly specific and depend on the recognition of an antigen on the surface of a target or antigen presenting cell by one of the many specific antigen receptors on the surface of T cells.
The receptor-antigen interaction of T cells and other cells is also facilitated by various T cell surface proteins, e.g., the antigen-receptor complex CD3 and accessory adhesion molecules such as CD4, LFA-1, CD8, and CD2. It is also facilitated by accessory adhesion molecules, such as LFA-3, ICAM-1 and MHC, that are expressed on the surface of the target or antigen presenting cells. For example, LFA-1 and its counter receptor ICAM-1 or ICAM-2, as well as CD2 and its counter receptor LFA-3 have been implicated in cellular adhesion and T cell activation. It is known that the LFA-1/ICAM and CD2/LFA-3 interactions are independent.
A number of other molecules present on resting T cells have also been implicated in T cell adhesion, including E2 (MIC2), VLA-4 (CD49d), CD44 (Hermes, Pgp-1, ECMRIII), and H19 (N4) (see Makgoba et al., “The CD2-LFA-3 and LFA-1-ICAM Pathways: Relevance to T-cell Recognition”,
Immunol. Today
, 10, pp. 417-22 (1989)).
One way in which
Cooper Kevin D.
Wallner Barbara P.
Biogen Inc.
Fish & Richardson P.C.
Gambel Phillip
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