JP7382625B2 - 掻痒治療剤 - Google Patents
掻痒治療剤 Download PDFInfo
- Publication number
- JP7382625B2 JP7382625B2 JP2019157118A JP2019157118A JP7382625B2 JP 7382625 B2 JP7382625 B2 JP 7382625B2 JP 2019157118 A JP2019157118 A JP 2019157118A JP 2019157118 A JP2019157118 A JP 2019157118A JP 7382625 B2 JP7382625 B2 JP 7382625B2
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- Prior art keywords
- pruritus
- protein
- amino acid
- histamine
- treating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
(1)インターロイキン27(IL-27)、及び/又はIL-27受容体アゴニストを有効成分として含む、掻痒治療剤。
(2)前記IL-27が、
a) 配列番号1で示すアミノ酸配列を有するヒト野生型p28タンパク質、
b) 配列番号1で示すアミノ酸配列に対して90%以上の同一性を有する変異型p28タンパク質、又は
c) 配列番号1で示すアミノ酸配列に対して1又は複数個のアミノ酸が付加、欠失、若しくは置換された変異型p28タンパク質
及び、
d) 配列番号2で示すアミノ酸配列を有するヒト野生型EBI3タンパク質、
e) 配列番号2で示すアミノ酸配列に対して90%以上の同一性を有する変異型EBI3タンパク質、又は
f) 配列番号2で示すアミノ酸配列に対して1又は複数個のアミノ酸が付加、欠失、若しくは置換された変異型EBI3タンパク質
からなり、ヒト野生型IL-27の活性を有する、(1)に記載の掻痒治療剤。
(3)前記掻痒がヒスタミン依存性掻痒である、(1)又は(2)に記載の掻痒治療剤。
(4)前記ヒスタミン依存性掻痒が蕁麻疹、虫刺症、又は薬疹による掻痒である、(3)に記載の掻痒治療剤。
(5)前記掻痒がヒスタミン非依存性掻痒である、(1)又は(2)に記載の掻痒治療剤。
(6)前記ヒスタミン非依存性掻痒が、アトピー性皮膚炎若しくは乾癬による掻痒、慢性突発性掻痒、又は老人性皮膚掻痒である、(5)に記載の掻痒治療剤。
(7)(1)~(6)のいずれかに記載の掻痒治療剤、並びに抗ヒスタミン剤、ステロイド剤、シクロスポリン、タクロリムス、ヒト型抗ヒトIL-4/IL-13受容体モノクローナル抗体、抗IL-31受容体ヒト化モノクローナル抗体、及びヒト型抗ヒトIL-17受容体Aモノクローナル抗体からなる群から選択される1以上を含む、掻痒治療用組成物。
1-1.概要
本発明の第1の態様は、掻痒治療剤である。
本態様の掻痒治療剤は、IL-27、及び/又はIL-27受容体アゴニストを有効成分として含む。本態様の掻痒治療剤は、ヒスタミン依存性及び非依存性掻痒に対して掻痒抑制効果を有する。
本明細書で頻用する以下の用語について定義する。
「インターロイキン27(IL-27)」とは、前述のように、インターロイキン12(IL-12)サイトカインファミリーに属するサイトカインであり、p28タンパク質とEBI3(Epstein-Barr virus induced-3)タンパク質から形成されるヘテロ二量体のタンパク質である(図1)。p28タンパク質は、IL-12のp35サブユニットに関連するタンパク質であり、ヒトでは243アミノ酸残基からなるポリペプチドである。EBI3タンパク質は、IL-12のp40サブユニットに関連するヘマトポエチン受容体ファミリーのメンバーである。EBI3タンパク質は、糖タンパク質であり、ヒトでは229アミノ酸残基からなるポリペプチドである。
本発明の掻痒治療剤は、必須の構成成分としてIL-27、及び/又はIL-27受容体アゴニストを有効成分として包含する。
以下、各構成成分について具体的に説明をする。
(1)IL-27
本発明の掻痒治療剤が有効成分としてIL-27を含む場合、IL-27を構成するp28タンパク質及びEBI3タンパク質は、任意の生物種に由来する野生型又は変異型のp28タンパク質及びEBI3タンパク質である。本発明の掻痒治療剤に包含されるIL-27を構成するp28タンパク質及びEBI3タンパク質の由来生物種は、限定しないが、例えばヒト、家畜(ウシ、ウマ、ヒツジ、ヤギ、ブタ、ニワトリ、ダチョウなど)、競走馬、愛玩動物(イヌ、ネコ、ウサギなど)、実験動物(マウス、ラット、モルモット、サル、マーモセットなど)などが挙げられる。例えば、IL-27を構成するp28タンパク質は、配列番号1で示すアミノ酸配列を有するヒト由来のp28タンパク質に由来する野生型又は変異型のp28タンパク質、配列番号5で示すアミノ酸配列を有するマウス由来のp28タンパク質に由来する野生型又は変異型のp28タンパク質であってもよい。また、IL-27を構成するEBI3タンパク質は、配列番号2で示すアミノ酸配列を有するヒト由来のEBI3タンパク質に由来する野生型又は変異型のEBI3タンパク質、配列番号6で示すアミノ酸配列を有するマウス由来のEBI3タンパク質に由来する野生型又は変異型のEBI3タンパク質であってもよい。また、IL-27を構成するp28タンパク質及びEBI3タンパク質が由来する生物種は、同一の生物種であってもよいし、異なる生物種であってもよい。好ましくは、IL-27を構成するp28タンパク質及びEBI3タンパク質は、治療対象の被験体と同一の種に由来する。より好ましくは、IL-27を構成するp28タンパク質及びEBI3タンパク質が由来する生物種は、ヒトである。好ましくは、IL-27は野生型IL-27の活性を有する。「野生型IL-27の活性を有する」とは、野生型IL-27の活性と同等以上の活性を有することをいう。具体的には、掻痒症患者又は掻痒症モデル動物に投与した場合に野生型IL-27と同等以上の掻痒抑制効果を有することをいう。
a) 配列番号1で示すアミノ酸配列を有するヒト野生型p28タンパク質、
b) 配列番号1で示すアミノ酸配列に対して70%以上、75%以上、80%以上、85%以上、90%以上、95%以上、96%以上、97%以上、98%以上、若しくは99%以上の同一性を有する変異型p28タンパク質、又は
c) 配列番号1で示すアミノ酸配列に対して1又は複数個のアミノ酸が付加、欠失、若しくは置換された変異型p28タンパク質
から選択されるいずれかのポリペプチドであり、さらにIL-27を構成するEBI3タンパク質は、
d) 配列番号2で示すアミノ酸配列を有するヒト野生型EBI3タンパク質、
e) 配列番号2で示すアミノ酸配列に対して70%以上、75%以上、80%以上、85%以上、90%以上、95%以上、96%以上、97%以上、98%以上、若しくは99%以上の同一性を有する変異型EBI3タンパク質、又は
f) 配列番号2で示すアミノ酸配列に対して1又は複数個のアミノ酸が付加、欠失、若しくは置換された変異型EBI3タンパク質
から選択されるいずれかのポリペプチドである。好ましくは、IL-27はヒト野生型IL-27の活性を有する。「ヒト野生型IL-27の活性を有する」とは、ヒト野生型IL-27の活性と同等以上の活性を有することをいう。具体的には、掻痒症患者又は掻痒症モデル動物に投与した場合にヒト野生型IL-27と同等以上の掻痒抑制効果を有することをいう。
本発明の掻痒治療剤が有効成分としてIL-27受容体アゴニストを含む場合、IL-27受容体アゴニストは、IL-27受容体を活性化して完全又は部分的に受容体を介する応答を誘導し、掻痒抑制効果を有する物質であれば、特に限定しない。本発明の掻痒治療剤に包含されるIL-27受容体アゴニストは、内因性物質、外来(外因性)物質のいずれでもよいが、上記(1)のIL-27を含まないものとする。IL-27受容体アゴニストは、いかなる化合物であってもよく、限定しないが、例えば、核酸(核酸アプタマーを含む)、タンパク質(抗体及び抗原結合性断片を含む)、若しくは多糖などの高分子化合物、或いはヌクレオシド、ヌクレオチド、アミノ酸、ペプチド(ペプチドアプタマーを含む)、糖、脂質、ビタミン、若しくはホルモンなどの低分子化合物であってもよい。
本発明の掻痒治療剤の剤形は、有効成分であるIL-27及び/又はIL-27受容体アゴニストを不活化させないか、又はさせにくく、かつ投与後に生体内でその薬理効果を十分に発揮し得る剤形であれば特に限定しない。
本発明の掻痒治療剤を投与する方法は、掻痒症の治療のために、生体に有効量投与することができる方法であれば、当該分野で公知のあらゆる方法を適用することができる。
本発明の掻痒治療剤を掻痒症を有する被験体に投与することによって、ヒスタミン依存性掻痒及びヒスタミン非依存性掻痒のいずれに対しても掻痒抑制効果を奏する。特に、抗ヒスタミン剤はアトピー性皮膚炎などのヒスタミン非依存性掻痒に対して奏効しないのに対して、本発明の掻痒治療剤は、アトピー性皮膚炎などのヒスタミン非依存性掻痒に対しても掻痒抑制効果を奏する。
2-1.概要
本発明の第2の態様は、掻痒治療用組成物である。
本態様の掻痒治療用組成物は、第1態様に記載の掻痒治療剤、薬学的に許容可能な担体、さらに選択成分として他の有効成分を包含して成る。本態様の掻痒治療用組成物は、ヒスタミン依存性及び非依存性掻痒に対して掻痒抑制効果を有する。
本態様の掻痒治療用組成物は、第1態様に記載の掻痒治療剤及び薬学的に許容可能な担体、並びに選択成分として他の有効成分を包含して成る。
以下、第1態様に記載の掻痒治療剤以外の各構成成分について具体的に説明をする。
本発明の掻痒治療用組成物に含まれる「他の有効成分」は、掻痒抑制効果を有する成分であれば、限定しない。本発明の掻痒治療用組成物に含まれる「他の有効成分」は、特に、炎症抑制によらずに直接的に掻痒を抑制する成分、又は炎症抑制を通じて間接的に掻痒を抑制する成分のいずれであってもよい。
「薬学的に許容可能な担体」とは、製剤技術分野において通常使用し得る溶媒及び/又は添加剤であって、生体に対して有害性がほとんどないか又は全くないものをいう。
本態様の掻痒治療用組成物は、第1態様に記載の掻痒治療剤にさらなる掻痒抑制効果を有する成分を加えることによって、掻痒抑制効果が増強されている。
(目的)
ヒスタミン依存性掻痒の動物モデルを用いて、擦過行動を指標としてIL-27の鎮痒効果を評価する。
マウスの頬皮下に起痒物質であるヒスタミンを皮下接種することによって、マウスにおいて掻痒を惹起した。マウスはSPFで飼育された9週齢のICRを使用し、ヒスタミンを皮下接種する部位をバリカンと剃毛クリームを用いて事前に剃毛した。ヒスタミンは、PBSに溶解した50mMのヒスタミン二塩酸塩(Sigma-ALDRICH、H7250)を2μL使用した。
IL-27投与群及びコントロール群における、ヒスタミン接種前1時間に対する接種後1時間の擦過行動回数の変化率を図2に示す。コントロール群(n=7個体)では、ヒスタミン投与後に擦過行動回数が約300%に増加した(図2)。一方、IL-27投与群(n=7個体)では、ヒスタミン接種後で擦過行動回数は増加せず、ヒスタミン投与による擦過行動が有意に抑制された(図2)。この結果から、IL-27がヒスタミン依存性掻痒に対して掻痒抑制効果を有することが示された。
(目的)
ハプテン(感作性化合物)の皮膚反復塗布によって誘導されるマウスのアトピー性皮膚炎モデルにおいて、擦過行動を指標としてIL-27の鎮痒効果を評価する。
5匹の剃毛したマウスの腹部にハプテンとして3%オキサゾロンをピペットマンを使用して直接25μl塗布することで感作を行った。感作の一週間後から、剃毛したマウスの両頬に0.5%オキサゾロン(Sigma-ALDRICH、E0753)を3日毎に計8回反復塗布(20μL/片頬)することで、アトピー性皮膚炎様の炎症による慢性掻痒症を生じさせた。最後の塗布から24時間後にPBSに溶解した0.1 mg/mlのrIL-27をマウスの頬に20 μL皮下接種し、投与前後における擦過行動を記録した。
rIL-27投与前後の各1時間における、5匹の個体別の継時的擦過行動回数を図3に示す。rIL-27投与により、擦過行動回数が有意に減少することが明らかとなった(図3)。
Claims (7)
- インターロイキン27(IL-27)を有効成分として含む、掻痒治療剤(ただし、アレルギー疾患治療薬及び自己免疫疾患治療薬を除く)。
- 前記IL-27が、
a) 配列番号1で示すアミノ酸配列を有するヒト野生型p28タンパク質、
b) 配列番号1で示すアミノ酸配列に対して90%以上の同一性を有する変異型p28タンパク質、又は
c) 配列番号1で示すアミノ酸配列に対して1又は複数個のアミノ酸が付加、欠失、若しくは置換された変異型p28タンパク質
及び、
d) 配列番号2で示すアミノ酸配列を有するヒト野生型EBI3タンパク質、
e) 配列番号2で示すアミノ酸配列に対して90%以上の同一性を有する変異型EBI3タンパク質、又は
f) 配列番号2で示すアミノ酸配列に対して1又は複数個のアミノ酸が付加、欠失、若しくは置換された変異型EBI3タンパク質
からなり、ヒト野生型IL-27の活性を有する、請求項1に記載の掻痒治療剤。 - 前記掻痒がヒスタミン依存性である、請求項1又は2に記載の掻痒治療剤。
- 前記ヒスタミン依存性の掻痒が蕁麻疹、虫刺症、又は薬疹による掻痒である、請求項3に記載の掻痒治療剤。
- 前記掻痒が、慢性突発性掻痒又は老人性皮膚掻痒である、請求項1又は2に記載の掻痒治療剤。
- 請求項1~5のいずれか一項に記載の掻痒治療剤を含む、掻痒治療用組成物(ただし、アレルギー疾患治療薬及び自己免疫疾患治療薬を除く)。
- 抗ヒスタミン剤をさらに含む、請求項6に記載の掻痒治療用組成物。
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