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A method for treating allergies

An allergic, atopic technique for use in the field of cathepsin S inhibitors

Inactive Publication Date: 2005-07-20
ORTHO MCNEIL PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Activated T cells in turn activate several other components of the immune system, such as B cells and macrophages, which are critical to the body's response to pathogens, but which also contribute to allergic symptoms

Method used

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  • A method for treating allergies
  • A method for treating allergies
  • A method for treating allergies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Cathepsin S inhibition test.

[0160] Recombinant human cathepsin S (CatS) was expressed in a baculovirus system and purified in one step using a propylthio-dextran column. 10 L yielded about 700 mg of CatS, and the N-terminal sequence was characterized. The assay was performed in 100 mM sodium acetate pH 5.0 containing 1 mM DTT and 100 mM NaCl. The substrate of the test is

[0161] (Aedens) EKARVLAEAA (Dabcyl) K-amide

[0162] The substrate Km is about 5 uM, but the presence of substrate inhibition makes kinetic analysis difficult. For 20 uM substrate, the assay speed was linear for the range of 1-8 ng of CatS in a 100 μl reaction and gave an approximately 7-fold signal after 20 minutes consuming only 20% of the substrate. The main assay was started after stopping the reaction with 0.1% SDS and fluorescence was subsequently measured. For other tests, check every 20 minutes. The rate was calculated from the increase in slope and from this the percent inhibition wa...

Embodiment 2

[0164] Ex Vivo Inhibition of Allergic Responses by Cathepsin S Inhibitors

[0165] The following experiments demonstrate that cathepsin S inhibitors block human T cell responses to crude allergen extracts.

[0166] Materials and methods

[0167] Reagents: Glycerated crude allergen extracts of D. farinae (Dermataphagoides pteronyssinus, Dermataphagoides farinae) and ragweed [Ambrosia trifida (large), Ambrosia artemisiifolia (small)] were purchased from Hollister-Stier Laboratories (Minneapolis, MN). Concanavalin A (ConA) was purchased from Calbiochem (La Jolla, CA).

[0168] Donors: All allergic donors were screened for specific allergens using the RAST test. The HLA II haplotypes of these donors were determined by PCR.

[0169] Cell Culture: Human peripheral blood mononuclear cells (PBMC) were purified from Ficoll-Hypaque gradients of blood from allergic donors, followed by washing with phosphate-buffered saline (PBS). PBMC at 0.5-1.0×10 6 Concentrations of cells / well wer...

Embodiment 3

[0179] Monitoring Cathepsin S Inhibition in Human Blood

[0180] The effect of in vivo administration of the cathepsin S inhibitor in the clinical test kit can be monitored by detecting the accumulation of the rapid degradation product of the invariant chain (li), that is, the p10li fragment, in the blood of the subject. After administration of a cathepsin inhibitor for a period of time, e.g., 0.01 to 50 mg / kg / day, resulting in a plasma concentration of preferably 1 nM to 10 μM at 16 to 30 hours, blood is drawn and leukocytes are separated, e.g., by lysing red blood cells or by Ficoll-Hypaque Gradient centrifugation. Whole cell lysates of WBC were then prepared and analyzed by Western blot assay or ELISA assay. For Western blot experiments, cell lysates were first resuspended on SDS-PAGE gels. After transfer to nitrocellulose membranes, li and intermediate degradation products, including p10li, can be detected with a mouse mAb against li, such as Pin1.1, or with a rabbit pol...

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PUM

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Abstract

Use of cathepsin S inhibitors for the treatment of an allergic condition, in particular an atopic allergic condition, more specifically for the treatment of hay fever, asthma, atopic dermatitis or a food allergy.

Description

technical field [0001] The present invention relates to the use of cathepsin S inhibitors for the treatment of allergic disorders, especially atopic allergic disorders. Background technique [0002] Atopic allergy afflicts at least 20% of the population in developed countries and includes a wide range of IgE-mediated diseases hay fever, asthma, atopic dermatitis, and food allergy. Exposure of allergic patients to corresponding allergens causes allergen-specific IgE to bind mast cells, triggering degranulation and release of pro-inflammatory mediators such as histamine and eicosanoids, which cause streaking and flushing in skin tests reaction. It is characteristic that this early response is followed by a prolonged late response in which inflammatory cells, particularly eosinophils and activated TH-2 CD4 T cells, are recruited to the site of allergen exposure. Inflammatory cytokines produced by TH-2 cells, such as IL-4 and IL-5, play an important role in the production of I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/30A61K31/00A61K31/13A61K31/275A61K31/36A61K31/38A61K31/415A61K31/4155A61K31/4439A61K31/445A61K31/454A61K31/4745A61K31/495A61K31/496A61K31/519A61K31/53A61K31/5375A61K31/5377A61K31/541A61K31/55A61K45/00A61P1/00A61P11/02A61P11/06A61P17/04A61P27/14A61P37/00A61P37/08A61P43/00
CPCA61K31/519A61K31/454A61K31/496A61K31/275A61K31/5377A61K31/541A61K31/4745A61K31/00A61K31/4155A61K31/4439A61K31/495A61K31/53A61K31/13A61K31/55A61P1/00A61P11/02A61P11/06A61P17/04A61P27/14A61P37/00A61P37/08A61P43/00
Inventor 谷音L·卡尔森孙思泉R·L·图尔蒙德
Owner ORTHO MCNEIL PHARM INC
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