ANTI ONCOSTATIN M RECEPTOR BETA ANTIBODY
|発明の名称 （英語）||ANTI ONCOSTATIN M RECEPTOR BETA ANTIBODY|
|発明の概要（英語）||A monoclonal antibody against oncostatin M specific receptor beta subunit, a hybridoma capable of producing the same and a medicament for treating atopic dermatitis comprising the same.|
The immune system protects human body from bacterial, parasitic, fungal, viral infections and from the growth of tumor cells. However, the immune response can sometimes be unwanted and cause immune-mediated disorder. The disorder includes autoimmune disease, graft rejection, hypersensitivity, diseases associated with the over-stimulation of host's immune system by microbes. The autoimmune diseases result from immune responses against endogenous and/or exogenous antigens. Foreign substances, derived from bacteria, parasites, fungi or viruses, may mimic self-proteins and cause the immune system to erroneously launch an immune attack on self-cells and tissues, resulting in onset of the autoimmune diseases. The graft rejection is caused by the immune response in the transplant recipient (host) against the transplanted organ/tissue. When a subject is transplanted with grafts including kidney, pancreas, heart, lung, bone marrow, cornea and skin, the subject can launch an immune response (rejection) against the grafts. Hypersensitivity is an inappropriate immune response that has deleterious effects, resulting in significant tissue damage or even death. The response is characterized by the overproduction of cytokines. The exaggerated production of cytokines is known to contribute to sepsis characterized by cytokine-mediated lethal shock (Espat NJ, et al. J Surg Res. 1995 Jul; 59 (1): 153-8). Multiple organ dysfunction syndromes (MODS) are a major cause of morbidity and mortality in severe sepsis and shock. Cytokine-mediated lethal shock resulted from over-production of host cytokines is considered a main mechanism leading to MODS (Wang H, et al. Am J Emerg Med. 2008 Jul; 26 (6):711-5).
Atopic dermatitis is a pruritic inflammatory skin disease. The conventional medicinal agent for treating the atopic dermatitis is mainly a topical cream comprising as an active ingredient steroid compounds. However, such available medical agents are not always effective in the most critical symptoms such like pruritus in addition of exhibiting serious side effects caused by steroid compounds per se. Thus, the alternative agent possessing potent effect against pruritus and no serious side effect is expected to be provided.
The demonstrated in vivo activities of the cytokine family illustrate the enormous clinical potential of, and need for, other cytokines, cytokine agonists, and cytokine antagonists. Recently, several investigators have reported that interleukin (IL)-31 is involved in the pathogenesis of atopic dermatitis. Functional IL-31 receptor consists of IL-31 specific receptor A (IL-3 IRa) and OSMRp.
Oncostatin M (OSM) is a member of the IL-6 family of cytokines and its receptor consists of the OSM specific receptor beta subunit (OSMRP) and gpl30, the common receptor subunit of this cytokine family. OSM is produced by a variety of cells such as hematopoietic cells and fibroblasts and is suggested to play a role in immune reactions and hematopoiesis, while both OSM-deficient mice and OSMRP-deficient mice developed normally and were fertile (Tanaka et al, 2003).
Interleukin-31 is produced by activated CD4+ T cells. Overexpression of IL-31 in transgenic mice results in a pruritic skin condition that is similar to human atopic dermatitis (Dillon et al., 2004). Analysis of IL-31 levels in human dermatitis samples has shown increased expression of IL-31 in atopic dermatitis compared with healthy control populations, implicating
involvement of IL-31 in the pathogenesis of allergic skin diseases (Bilsborough et al., 2006; Sonkoly et al., 2006). IL-31 receptor alpha (IL-3 IRa) pairs with OSMRp to form the functional heterodimer receptor for IL-31 (Dillon et al., 2004). In addition, the present inventors have demonstrated complete co-localization of IL-3 IRa and OSMRP in both a subset of small-sized dorsal root ganglion (DRG) neurons and afferent fibers in the spinal cord and the dermis of the skin (Bando et al, 2006). Thus, IL-31 might be related to the pathogenesis of the dermatitis. However, treatment ofNC/Nga mice with severe atopic dermatitis with anti-IL-31 antibody failed to ameliorate skin lesions in spite of the reduction of scratching behavior (Grimstad et al., 2008), suggesting that blocking of IL-31 is not enough to prevent atopic dermatitis development.
Nucleic acid and amino acid sequences of OSMRP are known and sequenced (SEQ. ID Nos.1 and 2, respectively), and OSMRP is suggested to be associated with the biological activities mediated by OSM (WO95/33059).
It is known that an antagonist of OSM such as an antibody thereto or a small molecule can be used for the treatment or prophylaxis of an inflammatory arthropathy or inflammatory disorder, and for screening for such antagonists (W099/48523).
One of the present inventors studied actions of OSM on a pain-responsive neuron and provided a pharmaceutical composition for treating pains, especially treatment-resistant pain such as cancerous pain, neurogenic pain and inflammatory pains, which contains an OSM antagonist or the OSM or contains a transgenic vector containing a nucleic acid in which a cytotoxic gene is linked to a promoter of an OSM receptor beta-chain gene (JP 2005-247836 A).
In the previous report, the present inventors have demonstrated that OSMRp and IL-3 IRa were co-expressed in the same subset of small-sized nociceptive neurons of adult dorsal root ganglia (DRGs).
National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
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