JP6256490B2 - 癌治療剤 - Google Patents
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- JP6256490B2 JP6256490B2 JP2016007079A JP2016007079A JP6256490B2 JP 6256490 B2 JP6256490 B2 JP 6256490B2 JP 2016007079 A JP2016007079 A JP 2016007079A JP 2016007079 A JP2016007079 A JP 2016007079A JP 6256490 B2 JP6256490 B2 JP 6256490B2
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Description
本発明に係る蛋白質(以下、B cell immunoglobulin receptor 1(BIR1)と呼ぶことがある。)のアミノ酸配列およびそれをコードするDNAの塩基配列が国際公開第99/33873号パンフレットに報告されている。しかしながら、本発明に係る蛋白質の機能は十分解明されていないし、ましてやそのアンタゴニストおよびアゴニストの用途については全く知られていない。
(1) 配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアンタゴニストを含有してなる免疫賦活剤、
(2) アンタゴニストが、細胞内シグナル伝達に対する前記(1)記載の蛋白質による抑制を減弱ないし阻害する物質である前記(1)記載の免疫賦活剤、
(3) 前記(2)記載の物質が、前記(1)記載の蛋白質のリガンド結合を阻害する物質である前記(2)記載の免疫賦活剤、
(4) 前記(2)記載の物質が、前記(1)記載の蛋白質の細胞内領域へのホスファターゼの結合を阻害する物質である前記(2)記載の免疫賦活剤、
(5) 前記(2)記載の物質が、ホスファターゼ活性を阻害する物質である前記(2)記載の免疫賦活剤、
(6) リガンド結合を阻害する物質が、前記(1)記載の蛋白質の細胞外領域中の任意の領域を含む蛋白質もしくはポリペプチドまたはそれらに対する抗体である前記(3)記載の剤、
(7) 前記(6)記載の蛋白質またはポリペプチドが、配列番号1で表わされるアミノ酸配列のアミノ酸1〜227、配列番号2で表わされるアミノ酸配列のアミノ酸1〜227、配列番号3で表わされるアミノ酸配列のアミノ酸1〜132、配列番号4で表わされるアミノ酸配列のアミノ酸1〜137、配列番号5で表わされるアミノ酸配列のアミノ酸1〜42および配列番号6で表わされるアミノ酸配列のアミノ酸1〜132から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を含む蛋白質またはポリペプチドである前記(6)記載の免疫賦活剤、
(8) ホスファターゼが、SHP−1、SHP−2、SHIP−1および/またはSHIP−2である前記(4)または前記(5)記載の免疫賦活剤、
(9) 癌、免疫不全症および感染症から選択される疾患の予防および/または治療剤である前記(1)記載の免疫賦活剤、
(10) 配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアンタゴニストをスクリーニングする方法であって、
(i)被験化合物の存在下で、その細胞外領域を含む蛋白質またはポリペプチドとリガンドを接触させる工程、
(ii)その細胞外領域を含む蛋白質またはポリペプチドとリガンドの結合によって変動するシグナルを検出する工程、および
(iii)被験化合物の存在下と非存在下での工程(ii)のシグナル強度を比較することによって、その結合を阻害する化合物をスクリーニングする工程からなる方法、
(11) 配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアンタゴニストをスクリーニングする方法であって、
(i)被験化合物の存在下で、その細胞内領域を含む蛋白質またはポリペプチドとホスファターゼを接触させる工程、
(ii)その細胞内領域を含む蛋白質またはポリペプチドとホスファターゼの結合によって変動するシグナルを検出する工程、および
(iii)被験化合物の存在下と非存在下での工程(ii)のシグナル強度を比較することによって、その結合を阻害する化合物をスクリーニングする工程からなる方法、
(12) 配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアンタゴニストをスクリーニングする方法であって、
(i)被験化合物の存在下で、配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質を発現する細胞またはその細胞外領域を含む蛋白質もしくはポリペプチドとリガンドを発現する細胞もしくはリガンドを接触させる工程、
(ii)工程(ii)における接触によって変動するシグナルを検出する工程および
(iii)被験化合物の存在下と非存在下での工程(ii)のシグナル強度を比較する工程からなる方法、
(13) 配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアンタゴニストの有効量を哺乳動物に投与することを特徴とする免疫賦活方法、
(14) 免疫賦活剤を製造するための、配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアンタゴニストの使用、
(15) 配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアンタゴニストの有効量を哺乳動物に投与することを特徴とする癌、免疫不全症および感染症から選択される疾患の予防および/または治療方法、
(16) 癌、免疫不全症および感染症から選択される疾患の予防および/または治療剤を製造するための、配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアンタゴニストの使用、
(17) 配列番号3〜6で表わされるアミノ酸配列から選択される一つのアミノ酸配列と同一もしくは実質的に同一のアミノ酸配列を有する蛋白質またはその部分ペプチド、
(18) 配列番号3〜6で表わされるアミノ酸配列から選択される一つのアミノ酸配列と同一もしくは実質的に同一のアミノ酸配列を有する蛋白質またはその部分ペプチドをコードするポリヌクレオチド
(19) 配列番号3〜6で表わされるアミノ酸配列から選択される一つのアミノ酸配列と同一もしくは実質的に同一のアミノ酸配列を有する蛋白質またはその部分ペプチドに対する抗体、
(20) 配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアゴニストを含有してなる免疫抑制剤、
(21) アゴニストが、細胞内シグナル伝達に対する前記(20)記載の蛋白質による抑制を保持ないし増強する物質である前記(20)記載の剤、
(22) 前記(21)記載の物質が、前記(20)の蛋白質とその蛋白質が発現する細胞に発現する受容体を架橋する物質である前記(21)記載の剤、
(23) 前記(21)記載の物質が、前記(20)の蛋白質に対するアゴニスト抗体である前記(21)記載の剤、
(24) 自己免疫疾患、臓器移植後の拒絶反応、アレルギー性疾患および炎症性疾患から選択される疾患の予防および/または治療剤である前記(20)記載の剤、
(25) 自己免疫疾患が、ループス抗凝固因子が高値な疾患、全身性エリテマトーデス、関節リウマチ、多発性硬化症または高安動脈炎である前記(24)記載の剤、
(26) 配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアゴニストの有効量を哺乳動物に投与することを特徴とする免疫抑制方法、
(27) 免疫抑制剤を製造するための、配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアゴニストの使用、
(28) 配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアゴニストの有効量を哺乳動物に投与することを特徴とする自己免疫疾患、臓器移植後の拒絶反応、アレルギー性疾患および炎症性疾患から選択される疾患の予防および/または治療方法、および
(29) 自己免疫疾患、臓器移植後の拒絶反応、アレルギー性疾患および炎症性疾患から選択される疾患の予防および/または治療剤を製造するための、配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質のアゴニストの使用に関する。
(i)本発明に係る蛋白質へのリガンド結合を阻害し、本発明に係る蛋白質にアゴニスト活性を有しない物質、
(ii)本発明に係る蛋白質の細胞内領域へのホスファターゼの結合を阻害する物質、
(iii)当該ホスファターゼの活性を阻害する物質、および
(iv)本発明に係る蛋白質の細胞内領域に結合したホスファターゼの活性を阻害する物質などが挙げられる。
そのような物質として好ましくは、蛋白質、ポリペプチドまたは抗体であり、具体的には、本発明に係る蛋白質の細胞外領域中の任意の領域を含む蛋白質もしくはポリペプチドおよびそれらに対する抗体などが挙げられる。
「本発明に係る蛋白質の細胞外領域中の任意の領域を含む蛋白質またはポリペプチド」における「任意の領域」とは、本発明に係る蛋白質に対してアンタゴニスト活性を有するものであれば、本発明に係る蛋白質の細胞外領域中のいずれの領域ものであってもよい。
本発明に係る蛋白質の細胞外領域中の任意の領域を含む蛋白質またはポリペプチドは、公知のタンパク質発現法および精製法あるいは実施例に記載の方法によって調製することができる。
「本発明に係る蛋白質にアゴニスト活性を有しない」とは、本発明に係る蛋白質の機能を刺激する活性を持たないことを意味する。
(i)本発明に係る蛋白質とその蛋白質が発現する細胞に発現する受容体を架橋する物質、
(ii)本発明に係る蛋白質に対するアゴニスト抗体および
(iii)本発明に係る蛋白質に対するリガンドなどが挙げられる。
ここで、「細胞内シグナル」とは、例えば、B細胞受容体もしくはB細胞受容体複合体、活性化Fc受容体、CD14/TLR4複合体、FcεRIなどから生じる細胞内シグナルが挙げられる。また、「細胞内シグナル伝達に対する本発明に係る蛋白質による抑制を保持ないし増強する」こととしては、例えば、本発明に係る蛋白質の細胞内領域に結合したホスファターゼによる細胞内シグナル伝達を担う分子の脱リン酸化状態の持続あるいは頻度の増加などが挙げられる。
細胞内シグナル伝達に対する本発明に係る蛋白質による抑制を保持ないし増強する物質としての「本発明に係る蛋白質とその蛋白質が発現する細胞に発現する受容体を架橋する物質」としては、例えば、蛋白質、ポリペプチドおよび抗体などが挙げられる。そのような物質として好ましくは、本発明に係る蛋白質とその蛋白質が発現する細胞に発現する受容体をともに認識する抗体が挙げられる。
以上のように、細胞内シグナル伝達に対する本発明に係る蛋白質による抑制を保持ないし増強する物質は、自己免疫疾患、臓器移植後の拒絶反応、アレルギー性疾患または炎症性疾患の予防および/または治療薬として有用である。
本発明明細書において、本発明に係る蛋白質のアンタゴニストあるいはアゴニストをスクリーニングする方法(以下、本発明のスクリーニング方法と呼ぶこともある。)としては、例えば、蛍光偏光ホモジニアスアッセイ、時間分解蛍光アッセイ、蛍光共鳴エネルギー転移アッセイ、化学増幅型ルミネッセンス プロキシミティーホモジニアスアッセイ、RIアッセイ、バイオルミネッセンス共鳴エネルギー転移アッセイ、Two−ハイブリッドレポータージーンアッセイ、細胞内Ca2+濃度測定アッセイ、ELISAアッセイなどを用いて実施することができる。
これらポリペプチドには、任意に、酵素、蛍光物質、蛍光蛋白質、発光物質または放射性同位元素などの検出ラベルが付加されたものが使用できる。これら検出ラベルの付加は、本発明に係る蛋白質の細胞外領域を含む蛋白質またはポリペプチドとリガンドの結合の後あるいは前に、これらを認識する物質あるいは抗体を介して付加されてもよい。具体的には、本発明に係る蛋白質の細胞外領域を含む蛋白質またはポリペプチドあるいはリガンドをビオチン標識し、一方にアビジン標識された上記検出ラベルを添加することによって付加することができる。本発明に係る蛋白質の細胞内領域を含む蛋白質またはポリペプチドとホスファターゼの結合においても同様である。
「本発明に係る蛋白質の細胞外領域を含む蛋白質またはポリペプチドとリガンドの結合によって変動するシグナル」あるいは「本発明に係る蛋白質の細胞内領域を含む蛋白質またはポリペプチドとホスファターゼの結合によって変動するシグナル」とは、上記検出ラベルとしての蛍光物質または蛍光蛋白質より発せられる蛍光、あるいは放射性同位元素からの放射線などが挙げられる。また、上記検出ラベルとしての酵素と発色基質との反応による発色も挙げられる。上記酵素、蛍光物質、蛍光蛋白質、発光物質、放射性同位元素および発色基質は、市販のものを使用することができる。
「配列番号1〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一または実質的に同一のアミノ酸配列を有する蛋白質を発現する細胞とリガンドを発現する細胞もしくはリガンドの接触によって変動するシグナル」としては、例えば、それら細胞の細胞内cAMP濃度、細胞内Ca2+濃度、IP3濃度、細胞内シグナル伝達分子(例えば、Erk2など)のリン酸化あるいは脱リン酸化、本発明に係る蛋白質へのホスファターゼの結合、産生サイトカイン(例えば、インターロイキン2(IL−2)など)量などに対応するシグナル(例えば、発色、蛍光、発光、放射線など)などが挙げられる。
本発明明細書において、「配列番号3〜6で表わされるアミノ酸配列から選択される一つのアミノ酸配列と同一もしくは実質的に同一のアミノ酸配列を有する蛋白質もしくはその部分ペプチド」における「実質的に同一のアミノ酸配列を有する蛋白質」とは、配列番号3〜6で表わされるアミノ酸配列から選択される一つのアミノ酸配列を有する蛋白質の機能と同じ機能を有する蛋白質であって、その配列番号3〜6から選択されるアミノ酸配列中の一部のアミノ酸(好ましくは1〜5個、より好ましくは1〜2個)が欠失したもの、その一部のアミノ酸(好ましくは1〜5個、より好ましくは1〜2個)が他のアミノ酸と置換したもの、そのアミノ酸配列に数個のアミノ酸(好ましくは1〜5個、より好ましくは1〜2個)が付加または挿入されたもの、およびそれらを組み合わせたアミノ酸配列を有するものも含まれる。ここで、上記アミノ酸の欠失、置換または付加あるいは挿入の位置は特に限定されない。以下、「配列番号3〜6で表わされるアミノ酸配列から選択される一つのアミノ酸配列と同一もしくは実質的に同一のアミノ酸配列を有する蛋白質」を「本発明の蛋白質」と呼ぶこともある。
本発明の蛋白質には、C末端がカルボキシル基、カルボキシレート、アミドまたはエステル(−COOR)のいずれであってもよい。ここで、エステルにおけるRとしては、例えば、C1〜6アルキル基(例えば、メチル、エチル、n−プロピル、イソプロピル、n−ブチルなど)、C3〜8シクロアルキル基(例えば、シクロペンチル、シクロヘキシルなど)、C6〜12アリール基(例えば、フェニル、α−ナフチルなど)、フェニル−C1〜2アルキル基(例えば、ベンジル、フェネチルなど)、α−ナフチル−C1〜2アルキル基(例えば、α−ナフチルメチルなど)、C7〜14アラルキル基、ピバロイルオキシメチル基などが用いられる。
さらに、本発明の蛋白質には、N末端のアミノ酸残基(例えば、メチオニン残基など)のアミノ基が保護基(例えば、C1〜6アシル基(例えば、ホルミル基、アセチル基など)など)で保護されているもの、生体内で切断されて生成するN末端のグルタミン残基がピログルタミン酸化したもの、分子内のアミノ酸の側鎖上の置換基(例えば、−OH、−SH、アミノ基、イミダゾール基、インドール基、グアニジノ基など)が適当な保護基(例えば、C1〜6アシル基(例えば、ホルミル基、アセチル基など)など)で保護されているもの、あるいは糖鎖が結合した糖蛋白質などの複合蛋白質なども含まれる。
本発明の部分ペプチドは、C末端がカルボキシル基、カルボキシレート、アミドまたはエステル(−COOR)のいずれであってもよい。ここで、エステルにおけるRとしては、本発明の蛋白質について前記したと同様のものが挙げられる。本発明の部分ペプチドがC末端以外にカルボキシル基を有している場合、カルボキシル基がアミド化またはエステル化されているものも本発明の部分ペプチドに含まれる。この場合のエステルとしては、例えば、上記したC末端のエステルなどが用いられる。
本発明明細書において、「配列番号3〜6で表わされるアミノ酸配列から選択される一つのアミノ酸配列と同一もしくは実質的に同一のアミノ酸配列を有する蛋白質またはその部分ペプチドをコードするポリヌクレオチド」としては、本発明の蛋白質または部分ペプチドをコードする塩基配列を有するものであればいかなるものであってもよい。一つのアミノ酸をコードするコドンは1〜6種類知られており、例えば、PheにはTTTまたはTTC、LeuにはTTA、TTG、CTT、CTC、CTAまたはCTG、IleにはATT、ATCまたはATA、MetにはATG、ValにはGTT、GTC、GTAまたはGTG、SerにはTCT、TCC、TCAまたはTCG、ProにはCCT、CCC、CCAまたはCCG、ThrにはACT、ACC、ACAまたはACG、AlaにはGCT、GCC、GCAまたはGCG、TyrにはTATまたはTAC、HisにはCATまたはCAC、GlnにはCAAまたはCAG、AsnにはAATまたはAAC、LysにはAAAまたはAAG、AspにはGATまたはGAC、GluにはGAAまたはGAG、CysにはTGTまたはTGC、TrpにはTGG、ArgにはCGT、CGC、CGAまたはCGG、SerにはAGTまたはAGC、ArgにはAGAまたはAGG、およびGlyにはGGT、GGC、GGAまたはGGGがそれぞれ対応しているので、本発明の蛋白質またはその部分ペプチドをコードするポリヌクレオチドには、各アミノ酸に対応する各コドンが任意に組み合わされたポリヌクレオチドが含まれる。以下、配列番号3〜6で表わされるアミノ酸配列から選択される一つのアミノ酸配列と同一もしくは実質的に同一のアミノ酸配列を有する蛋白質またはその部分ペプチドをコードするポリヌクレオチドを「本発明のポリヌクレオチド」と呼ぶこともある。
本発明のポリヌクレオチドは、ゲノムDNA、cDNA、合成DNA、RNA、DNA−RNAハイブリッドのいずれでもよい。
本発明のポリヌクレオチドは、本発明のスクリーニングにも使用できる。
本発明のポリヌクレオチドは、公知の方法に従って、トランスジェニック動物、ノックアウト動物または本発明の蛋白質もしくは本発明に係る蛋白質の発現が低下した動物を作製するために使用することができる。
本発明のポリヌクレオチドに対するアンチセンスDNAは、本発明のポリヌクレオチドの一部(好ましくはDNA)を上記のようなベクターのアンチセンス領域に挿入することにより製造することができる。
本発明明細書において、配列番号3〜6で表わされるアミノ酸配列から選択されるアミノ酸配列と同一もしくは実質的に同一のアミノ酸配列を有する蛋白質またはその部分ペプチドに対する抗体(以下、本発明の抗体と呼ぶことがある。)とは、本発明の蛋白質またはその部分ペプチドを認識する抗体であれば、ヒト由来抗体、マウス由来抗体、ラット由来抗体、ニワトリ由来抗体、ウサギ由来抗体またはヤギ由来抗体のいずれの抗体でもよく、さらにそれらのポリクローナルもしくはモノクローナル抗体、完全型もしくは短縮型(例えば、F(ab')2、Fab'、FabおよびFv断片など)抗体、キメラ化抗体、ヒト化抗体または完全ヒト型抗体のいずれのものでもよい。そのような抗体は、本発明の蛋白質の細胞外領域の部分ペプチドを抗原として、公知の抗体または抗血清の製造法に従って製造することができる。細胞外領域の部分ペプチドは、公知のタンパク質発現ならびに精製法によって調製することができる。
本発明の蛋白質またはその部分ペプチドに対する抗体は、本発明の蛋白質を検出することができるので、免疫不全症、癌もしくは感染症あるいは自己免疫疾患、臓器移植後の拒絶反応、アレルギー性疾患もしくは炎症性疾患の診断用および/または検査用試薬として用いることができる。
本発明に係る蛋白質のアンタゴニストとして挙げられる当該蛋白質の細胞外領域中の任意の領域を含む蛋白質もしくはポリペプチド、本発明のスクリーニング方法において使用される本発明に係る蛋白質の細胞外領域を含む蛋白質またはポリペプチドもしくはその細胞内領域を含む蛋白質またはポリペプチドならびに本発明の蛋白質もしくはその部分ペプチドは、公知のタンパク質発現法および精製法あるいは実施例に記載の方法によって製造することができる。例えば、
(1)生体または培養細胞から精製単離する方法、
(2)ペプチドを合成する方法、および
(3)遺伝子組み換え技術を用いて生産する方法などが挙げられる。
例えば、大腸菌で発現させる場合には、成熟蛋白部分をコードするDNAの5’末端に開始コドン(ATG)を付加し、得られたcDNAを、適当なプロモーター(例えば、trpプロモーター、lacプロモーター、λPLプロモーター、T7プロモーターなど)の下流に接続し、大腸菌内で機能するベクター(例えば、pBR322、pUC18、pUC19など)に挿入して発現ベクターを作製する。次に、この発現ベクターで形質転換した大腸菌(例えば、E.Coli DH1、E.Coli JM109、E.Coli HB101株など)を適当な培地で培養して、その菌体より目的とする蛋白質またはペプチドを得ることができる。また、バクテリアのシグナルペプチド(例えば、pelBのシグナルペプチドなど)を利用すれば、ペリプラズム中に目的とする蛋白質またはペプチドを分泌することもできる。さらに、他のポリペプチドとの融合蛋白質を生産することもできる。
ペプチド合成法は、例えば、固相合成法、液相合成法のいずれであってもよい。本発明の蛋白質を構成し得る部分ペプチドもしくはアミノ酸と残余部分とを縮合し、生成物が保護基を有する場合は保護基を脱離することにより目的とする蛋白質を製造することができる。ここで、縮合や保護基の脱離は、公知の方法、例えば、
(i)M. Bodanszky, M.A. Ondetti, Peptide Synthesis, Interscience Publishers, New York (1966)、
(ii)Schroeder, Luebke, The Peptide, Academic Press, New York (1965)、
(iii)泉屋信夫他、ペプチド合成の基礎と実験、丸善(株)(1975)、
(iv)矢島治明 および榊原俊平、生化学実験講座 1、蛋白質の化学IV,205,(1977)、
(v)矢島治明監修、続医薬品の開発、第14巻,ペプチド合成,広川書店に記載された方法に従って行われる。
また、本発明の蛋白質または部分ペプチドを他の蛋白質あるいはタグ(抗体の定常領域、グルタチオンSトランスフェラーゼ、プロテインA、FLAGタグ、ヘキサヒスチジンタグなど)との融合蛋白質として発現させることも可能である。融合蛋白質は、アフィニティークロマトグラフィーによる精製および/あるいは適当なプロテアーゼ(例えば。エンテロカイネース、トロンビンなど)による切り出しが可能であり、効率よく精製できる利点がある。
本発明に係る蛋白質をコードするポリヌクレオチドおよび本発明の蛋白質または部分ペプチドをコードするポリヌクレオチドは、公知の取得ないし製造方法および精製法あるいは実施例に記載の方法によって取得ないし製造することができる。例えば、化学合成によって、または本発明の蛋白質または部分ペプチドの一部をコードする合成DNAプライマーを用いてPCR法により増幅することによって、あるいは本発明の蛋白質または部分ペプチドの一部をコードする合成DNAをプローブとしたハイブリダイゼーション法によって得ることができる。
本発明に係る蛋白質の細胞外領域中の任意の領域を含む蛋白質もしくはポリペプチドに対する抗体または本発明の蛋白質またはその部分ペプチドに対する抗体は、本発明に係る蛋白質の細胞外領域中の任意の領域を含む蛋白質もしくはポリペプチドまたは本発明の蛋白質もしくはその部分ペプチドのそれぞれを認識し得る抗体であれば、ポリクローナル抗体、モノクローナル抗体のいずれであってもよいが、特に哺乳動物由来のモノクローナル抗体が好ましい。哺乳動物由来のモノクローナル抗体としては、ハイブリドーマにより産生されるもの、および遺伝子工学的手法により抗体遺伝子を含む発現ベクターで形質転換した宿主により産生されるものがある。
本発明に係る蛋白質のアンタゴニストまたはそれを含んでなる医薬組成物は、免疫賦活活性を有することから、癌、免疫不全症もしくは感染症の予防および/または治療に用いることができる。
その他、例えば、病原性原生動物(例えば、トリパノソーマ、マラリアおよびトキソプラズマ)、細菌(例えば、マイコバクテリウム、サルモネラおよびリステリア)および真菌(例えば、カンジダ)による感染などに対しても有効であると考えられる。
本発明に係る蛋白質のアゴニストまたはそれを含んでなる医薬組成物の投与により、その予防および/または治療が期待できるアレルギー性疾患として、例えば、喘息、気管支喘息、アトピー性皮膚炎、蕁麻疹、アレルギー性鼻炎(例えば、花粉症など)、アレルギー性結膜炎(例えば、花粉症など)、アレルギー性胃腸炎、アナフィラキシーショック、食物アレルギーなどが挙げられる。
(1)本発明の予防剤または治療剤の予防および/または治療効果の補完および/または増強、
(2)本発明の予防剤または治療剤の動態、吸収改善、投与量の低減および/または
(3)本発明の予防剤または治療剤の副作用の軽減のために他の薬剤と組み合わせて、併用剤として投与してもよい。
抗ウイルス薬としては、例えば、抗HIV薬、抗インフルエンザウイルス薬、抗ヘルペスウイルス薬、インターフェロン−αもしくはβおよび各種免疫グロブリンが挙げられる。
免疫抑制薬としては、例えば、アザチオプリン、アスコマイシン、エベロリムス、オルソクローンOKT3、コルチコステロイド、サラゾスルファピリジン、シクロスポリン、シクロフォスファミド、シロリムス、タクロリムス水和物、デオキシスパーガリン、ブシラミン、プレドニゾロン、ミコフェノール酸モフェチル、ミゾリビン、メチルプレドニゾロン、メトトレキサート、レフルノミドおよび抗ヒトリンパ球グロブリンなどが挙げられる。
もちろん前記したように、投与量は種々の条件により変動するので、上記投与量より少ない量で充分な場合もあるし、また範囲を越えて投与の必要な場合もある。
経口投与のための内服用固形剤には、錠剤、丸剤、カプセル剤、散剤および顆粒剤などが含まれる。カプセル剤には、ハードカプセルおよびソフトカプセルが含まれる。また錠剤には舌下錠、口腔内貼付錠および口腔内速崩壊錠などが含まれる。
非経口投与のための注射剤としては、すべての注射剤を含み、点滴剤をも包含する。例えば、筋肉への注射剤、皮下への注射剤、皮内への注射剤、動脈内への注射剤、静脈内への注射剤、腹腔内への注射剤、脊髄腔への注射剤および静脈内への点滴剤などを含む。
非経口投与のための点眼剤には、点眼液、懸濁型点眼液、乳濁型点眼液、用時溶解型点眼液および眼軟膏が含まれる。
これらの吸入剤は公知の方法に準じて製造される。
例えば、吸入用液剤の場合には、防腐剤(例えば、塩化ベンザルコニウムまたはパラベンなど)、着色剤、緩衝化剤(例えば、リン酸ナトリウムまたは酢酸ナトリウムなど)、等張化剤(例えば、塩化ナトリウムまたは濃グリセリンなど)、増粘剤(例えば、カリボキシビニルポリマーなど)、吸収促進剤などを必要に応じて適宜選択して調製される。
吸入用液剤を投与する際には通常噴霧器(例えば、アトマイザーまたはネブライザー)が使用され、吸入用粉末剤を投与する際には通常粉末薬剤用吸入投与器が使用される。
非経口投与のためその他の組成物としては、ひとつまたはそれ以上の活性物質を含み、常法により処方される直腸内投与のための坐剤および腟内投与のためのペッサリーなどが含まれる。
ヒト正常組織、血液細胞および細胞株におけるBIR1のmRNA発現を調べるために、BIR1特異的プライマーを設計し、TaKaRa Ex Taq(TaKaRa社製)を用いてPCRを行った。この時使用したプライマーの配列を以下に示す。
5’−GAACAGGCTCCTCTTCTGGAG−3’(配列番号13)
5’−GGTTCACCTTTTCCATCCTGG−3’(配列番号14)
PCRは、最初96℃下で1分間保持し、続いて、98℃下で10秒間、56℃下で30秒間、72℃下で30秒間の温度操作を35回繰り返し、最後に72℃で10分間保持して行った。
ヒト正常組織および血液細胞の発現解析には、Human MTC Panel I、Human MTC Panel II、Human Immune System MTC Panel、Human Blood Fractions MTC Panel(BD Clontech社製)を用い、ヒト細胞株の発現解析には常法に従い全RNAから逆転写反応にて作製したcDNAを用いた。PCR産物をアガロースゲル電気泳動後、ゲルをエチジウムブロマイド(Ethidium bromide)染色し、BioDoc-It System(UVP社製)にて画像データを得た。その結果を図1に示す。
BIR1は脾臓、リンパ節などの免疫系組織およびCD14陽性細胞(単球)、CD19陽性細胞(B細胞)で高発現していた。また、ヒト細胞株では、BIR1は単球分化能を有するK562、HL−60、単球系細胞株であるU937、THP−1、B細胞株であるRaji、CCRF−SBおよびFLEB−14−14で発現が確認された。
ヒト単球系細胞株を用い、各種炎症刺激によるBIR1の発現を検討した。THP−1細胞およびU937細胞を1×106cells/2mLでリポポリサッカライド(LPS)(1μg/mL)、フォルボールミリステートアセテート(PMA)(100ng/mL)、IFN−γ(100ng/mL)、TNF−α(10ng/mL)あるいはLPS+IFN−γ(1μg/mL+100ng/mL)で1、3、8、24、48および120時間刺激し、全RNAを回収した。BIR1に特異的なプライマー;5’−CACAGCCATGGAAGTTGGAATC−3’(配列番号15)および5’−GAGTGTTTGGCCTCATCTTGG−3’(配列番号16)とQuantiTect SYBR Green RT-PCR Kit(QIAGEN社製)を用いて、ABI PRISM 7000 Sequence Detection System(Applied Biosystems社製)によりBIR1のRNAを定量した。PCRの反応は、最初50℃下で30分間保持し、続いて95℃下で15分間保持した。次に、94℃下で10秒間、56℃下で30秒間、72℃下で1分間の温度操作を45回繰り返して行った。その結果、図2に示すように、BIR1の遺伝子発現はTHP−1細胞ではTNF−α以外の刺激で8〜48時間以降に上昇し、U937細胞ではいずれの刺激でも24〜48時間以降で上昇した。
Autoimmune Disease Profiling Array(BD Clontech社製)を用いて、自己免疫疾患患者由来の各種血液細胞におけるBIR1の発現を調べた。ヒトBIR1部分長cDNA断片を鋳型として、Random Primer DNA Labeling Kit Ver.2(TaKaRa社製)を用いて[α−32P]dCTP(PerkinElmer社製)標識したBIR1特異的プローブを作製した。使用した部分長cDNA断片を配列番号17に示す。
プローブ作製以降のプレハイブリダイゼーション、ハイブリダイゼーションおよび洗浄の操作は添付文書に従った。BAS2000(FUJIFILM社製)を用いて画像データを取得し、BAStation Ver.2.21のImage Analyzer IIにて画像データから各ドットのPSL(Photo-Stimulated Luminescence;放射線量と比例)値を求め、各サンプルにおけるBIR1の発現量を数値化した。統計解析は健常人に対してWilcoxon(Mann-Whitney)testを実施した。その結果を図3に示す。
健常人と比較して、ループス抗凝固因子患者の単球、関節リウマチ、多発性硬化症および高安動脈炎患者のB細胞でBIR1の発現量は有意に増加していた。
ヒトCD14陽性細胞(単球)およびCD19陽性細胞(B細胞)由来cDNA(Human Blood Fractions MTC Panel)(BD Clontech社製)を鋳型として、TaKaRa LA Taq(TaKaRa社製)を用いてPCRを行った。設計したヒトBIR1に特異的なプライマーを以下に示す。
5’−ATGTGGAGCCATTTGAACAGGCTCCTC−3’(配列番号18)
5’−TCAGAAGTTGAGTTCAGAATAGAC−3’(配列番号19)
PCRは、最初96℃下で1分間保持し、続いて、98℃下で10秒間、56℃下で30秒間、72℃下で1分30秒間の温度操作を35回繰り返し、最後に72℃で10分間保持して行った。PCR産物をアガロースゲル電気泳動後に単離し、T/Aベクターにサブクローニングした。BigDye Terminator v3.1 Cycle Sequencing Kit(Applied Biosystems社製)の添付文書に従い、ABI PRISM 3100 Genetic Analyzer(Applied Biosystems社製)にて各cDNA断片の配列を決定した。
その結果、既知のアイソフォーム(免疫グロブリン(Ig)ドメインが2個存在;BIR1L)(配列番号1および2)以外に、新たにC末端側のIgドメインが欠失したアイソフォーム(BIR1S1)(配列番号3)、N末端側のIgドメインが欠失したアイソフォーム(BIR1S2)(配列番号4)、両方のIgドメインが欠失したアイソフォーム(BIR1ΔIg)(配列番号5)およびBIR1S1の細胞内領域の一部が欠失したアイソフォーム(BIR1ΔCyt)(配列番号6)が同定された。N末端側のIgドメインは配列番号1に記載のアミノ酸配列中アミノ酸番号41−122に、C末端側のIgドメインは配列番号1に記載のアミノ酸配列中アミノ酸番号138−203に相当する部分である。
BIR1が抑制性シグナルを伝達するか否かを検討した。Proc. Natl. Acad. Sci. U.S.A. 98: 13866-13871 (2001)やJ. Immunol. 162: 3168-3175 (1999)などで報告された方法に従い、以下の材料を作製した。マウスFcγRIIB(FcR)の細胞外領域、膜貫通領域および細胞内領域6アミノ酸(アミノ酸番号1〜252)のC末端側にBIR1の細胞内領域(配列番号1のアミノ酸番号251〜343)を連結したFcR−hBIR1(wt)キメラ蛋白(配列番号20)をコードするDNAを、β−アクチンプロモーターの下流に挿入し、FcRキメラ蛋白発現ベクターを構築した。また、QuikChange Multi Site-Directed Mutagenesis Kit(Stratagene社製)を用いて、BIR1の細胞内領域の6つのチロシン残基のすべてをフェニルアラニン残基に置換した変異体(FcR−hBIR1(YWF))(配列番号21)の発現ベクターを作製した。これらのFcRキメラ発現ベクターと、既知の抑制性レセプターであるヒトKIR2DL3のFcRキメラ(FcR−hKIR2DL3)(配列番号22)発現ベクターをGene Pulser Xcell Electroporation System(BIO-RAD社製)を用いて、マウスB細胞株A20IIA1.6(マウスFcγRIIB欠損細胞株)(J.Immunol. 136: 348-356 (1986))に導入した。各導入細胞をFITC標識ラット抗マウスCD16/CD32抗体(2.4G2)(BD Pharmingen社製)で染色後、FACSCalibur(BD Biosciences社製)にてFcRキメラ蛋白の発現量を確認した。
図4に示すように、それぞれ同程度のFcRキメラ蛋白を安定発現した細胞であった。
FcRキメラ安定発現細胞に2.5mmol/L probenecid存在下37℃で30分間Fura2−AM(終濃度:5μmol/L)(和光純薬工業(株)製)を取り込ませた。Fura2−AMを除去後、2.5mmol/L probenecid含有HEPES/Hanks’緩衝液中に37℃で30分間静置した。遠心して上清を除去した後、細胞を5×106cells/mLで2.5mmol/L probenecid含有HEPES/Hanks’緩衝液に懸濁し、Ca2+測定用96ウェルプレートに100μL/wellで播種した。細胞外Ca2+非存在下での実験では、Ca2+不含Hanks’溶液にて調製した1mmol/L EGTA/2.5mmol/L probenecid含有HEPES/Hanks’緩衝液を用い、同様の操作を行った。室温で30分間静置後、Spectrofluorometer FDSS-4000(浜松ホトニクス社製)を用いて340nm/380nmの蛍光強度比を測定し、細胞内Ca2+濃度の変動を検出した。測定開始30秒後に、ウサギ抗マウスIgG(H+L)抗体のF(ab’)2(33μg/mL)もしくはインタクト(intact)(49.5μg/mL)(Zymed社製)を10μL/wellで添加した。
図5に示すように、インタクトの抗体を添加してBIR1キメラ蛋白がBCRと架橋された場合に、BIR1キメラ蛋白はBCRを介した細胞内Ca2+濃度の上昇を抑制することが明らかとなった。一方、BIR1の細胞内チロシン残基をフェニルアラニン残基に置換した変異体では細胞内Ca2+濃度の上昇は抑制されなかった。また、BIR1の細胞内Ca2+濃度上昇の抑制パターンは陽性対照であるKIR2DL3と異なっていた。細胞外Ca2+非存在下でBIR1とKIR2DL3の細胞内Ca2+濃度上昇の抑制パターンを比較した結果、KIR2DL3は細胞外Ca2+非存在下でも細胞内Ca2+濃度上昇を完全に抑制したのに対して、BIR1は抑制することができなかった。BIR1は既知の抑制性レセプターであるFcγRIIBと同様の結果を示した(Cell 90: 293-301 (1997))。
以上の結果から、本発明に係る蛋白質であるBIR1は、免疫抑制受容体として機能することが示された。
BIR1が活性化されたときに細胞内チロシン残基がリン酸化され、ホスファターゼがリクルートされるかどうかを検討した。Ca2+含有HEPES/Hanks’緩衝液に懸濁した3×107個のFcRキメラ安定発現細胞をウサギ抗マウスIgG(H+L)抗体のF(ab’)230μg/mLあるいはインタクト45μg/mL(Zymed社製)で、37℃で3分間刺激した。その後、細胞をlysis buffer(1% NP−40,50mmol/L Tris−HCl,pH8.0,150mmol/L NaCl,50mmol/L NaF,10% glycerol,1mmol/L Na3VO4,1mol/L PMSF,protease inhibitor cocktail tablet(Roche Diagnostics社製))で溶解した。細胞溶解液をラット抗マウスCD16/CD32抗体(2.4G2)(BD Pharmingen社製)を結合させたProtein A/G PLUS-Agarose(Santacruz社製)と4℃で5時間以上反応させた。FcRキメラ蛋白およびそれらの結合分子を免疫沈降した後、定法に従って、ウェスタンブロッティングを行った。メンブレンをphosphotyrosine(4G10)(Upstate社製)、SHP−1、SHP−2、SHIP−1に対する一次抗体(Santacruz社製)で反応後、ホースラディッシュペルオキシダーゼ(HRP)標識した二次抗体(Santacruz社製)を反応させ、ECL検出システム(Amersham Biosciences社製)にてバンドを検出した。
その結果、図6に示すように、インタクト抗体を添加してBIR1キメラ蛋白がBCRと架橋された場合に、BIR1キメラ蛋白の細胞内チロシン残基がリン酸化された。またその時、BIR1キメラ蛋白の細胞内領域にSHP−1、SHP−2、SHIP−1がリクルートされた。一方、BIR1の細胞内チロシン残基をフェニルアラニン残基に置換した変異体ではホスファターゼはリクルートされなかった。
BIR1がBCRを介した下流のシグナル伝達分子のリン酸化を抑制するかどうかを検討した。Ca2+含有HEPES/Hanks’緩衝液に懸濁した6×106個のFcRキメラ安定発現細胞を、30μg/mL ウサギ抗マウスIgG(H+L)抗体のF(ab’)2あるいは45μg/mL インタクト(Zymed社製)で、37℃で3分間刺激した。Lysing solution(Cell Lysis Kit;BIO-RAD社製)で細胞溶解液(500ng/μL)を調製した。各シグナル伝達分子のリン酸化はBio-Plex Phospho 7-Plex Assay(BIO-RAD社製)を用いて定量した。
その結果、図7に示すように、KIR2DL3と同様に、インタクト抗体を添加してBIR1キメラ蛋白がBCRと架橋された場合に、BIR1キメラ蛋白はBCRを介したErk2のリン酸化を抑制した。一方、BIR1の細胞内チロシン残基をフェニルアラニン残基に置換した変異体はErk2のリン酸化を抑制しなかった。
BIR1がBCRを介したIL−2産生を抑制するかどうかを検討した。1×105個のFcRキメラ安定発現細胞を96ウェルプレートに播種し、10μg/mL ウサギ抗マウスIgG(H+L)抗体のF(ab’)2あるいは5μg/mL インタクト(Zymed社製)にて37℃で24時間刺激した。Quantikine Immunoassay Mouse IL-2 ELISA Kit(R & D Systems社製)を用いて、各培養上清中のIL−2量を測定した。
その結果、図8に示すように、インタクト抗体を添加してBIR1キメラ蛋白がBCRと架橋された場合に、BIR1キメラ蛋白はBCRを介したIL−2産生を抑制した。一方、BIR1の細胞内チロシン残基をフェニルアラニン残基に置換した変異体はIL−2産生を抑制しなかった。また、以前に報告された通り、KIR2DL3もIL−2産生を抑制した。
BIR1が抑制性シグナルを伝達するのに重要な配列ITIMドメインおよび結合するホスファターゼを同定した。BIR1(配列番号1)の細胞内チロシン残基を含むペプチド(Y3:Biotin−HSQELQ313YATPVF(配列番号23)、Y5:Biotin−DSYKSG336YVYSEL(配列番号24)、Y6:Biotin−YKSGYV338YSELNF(配列番号25))およびそれに対応するリン酸化ペプチド(pY3:Biotin−HSQELQ313(pY)ATPVF(配列番号26)、pY5:Biotin−DSYKSG336(pY)VYSEL(配列番号27)、pY6:Biotin−YKSGYV338(pY)SELNF(配列番号28))を合成した(Sigma Genosys社に委託)。また、マウスPIR−BのITIM配列を含むペプチドおよびリン酸化ペプチド(Y3:Biotin−ESQDVT794YAQLCS(配列番号29)およびpY3:Biotin−ESQDVT794(pY)AQLCS(配列番号30))を陽性対照として合成した。これらのペプチドを抗ビオチン抗体(Sigma社製)を介してProtein A/G PLUS-Agarose(Santacruz社製)に結合させた後、A20IIA1.6細胞の溶解液と4℃で2時間反応させた。免疫沈降後、定法に従ってウェスタンブロッティングを行った。メンブレンをSHP−1、SHP−2、SHIP−1(Santacruz社製)に対する一次抗体で反応後、HRP標識した二次抗体(Santacruz社製)を反応させ、ECL plus Western Blotting Detection System(Amersham Biosciences社製)を用いてバンドを検出した。
その結果、図9に示すように、BIR1のpY3がSHP−1、SHP−2と結合し、pY6はSHP−1、SHP−2、SHIP−1と結合した。一方、pY5はいずれのホスファターゼとも結合しなかった。BIR1の細胞内領域には従来のITIMのコンセンサス配列(I/V/L/SXYXXL/V)と一致する配列は存在しないが、ヒトBIR1の313番目と338番目のチロシン残基が新たなITIMとして機能することが明らかとなった。
(1)可溶化ヒトBIR1L/Fcキメラ蛋白を用いた抗原感作
可溶化ヒトBIR1L/Fcキメラ蛋白60μgをTiterMaxアジュバント(Sigma社製)と混合し、BALB/cマウスの腹腔内に投与した。初回投与2週間後に、抗原(60μg)をTiterMaxアジュバントと混合し、マウスの腹腔内に投与した。追加免疫約10日後に、抗原(40μg)をマウスの腹腔内に最終投与した。3日後に、マウスから脾臓を摘出した。
(2)抗ヒトBIR1モノクローナル抗体の作製
上記(1)で得た脾臓よりリンパ球を分離し、マウスミエローマP3U1と約4:1で混合し、ポリエチレングリコールを用いて細胞融合を行った。RPMI1640/15%FCS/HAT培地によりハイブリドーマを選択し、可溶化ヒトBIR1L/Fcキメラ蛋白を用いたELISAおよびヒトBIR1L安定発現CHO細胞を用いたフローサイトメトリーにより目的の抗体を産生しているハイブリドーマのスクリーニングを行った。陽性ハイブリドーマを限界希釈法によりクローニングし、抗ヒトBIR1モノクローナル抗体産生ハイブリドーマを取得した。このようにして得たハイブリドーマをBALB/cマウスの腹腔に接種後,2週間以降に腹水を採取した.腹水中に産生された抗体はProsep−Gカラム(ミリポア社製)などを用いて精製した。
図10に示すように、作製された抗ヒトBIR1モノクローナル抗体はヒトBIR1を認識した(図中、Clone#170、#68、#95、#31は抗ヒトBIR1モノクローナル抗体の各クローンを表わし、2ndAbは陰性対照を、Anti-FLAG M2は陽性対照を表わす。)。
(3)抗ヒトBIR1ポリクローナル抗体の作製
可溶化ヒトBIR1L/Fcキメラ蛋白(100μg/0.5mL)を等量のフロイント完全アジュバント(DIFCO社製)と混合し、ウサギの背部皮下に投与した。2週間後、抗原(100μg/0.5mL)を等量のフロイント不完全アジュバント(DIFCO社製)と混合し、ウサギの背部皮下に投与した。2週間後、尾静脈より試験採血し、抗体価の上昇をヒトBIR1L安定発現CHO細胞を用いてフローサイトメトリーにて確認した。抗体価が低い場合は、さらに1〜2回の追加免疫を行い、抗血清を作製した。
10μg/mL ウサギ抗マウスIgG(H+L)抗体(Zymed社製)および実施例3で作製した10μg/mL 抗ヒトBIR1モノクローナル抗体を、定法に従い、96ウェルプレートに固定する。被験化合物(低分子化合物、ペプチド、抗体など)を添加し、ヒトBIR1を安定発現させたA20IIA1.6細胞を1×105個/100μL/wellで播種する。37℃で24時間培養後、Quantikine Immunoassay Mouse IL-2 ELISA Kit(R & D Systems社製)を用いて、各培養上清中のIL−2量を測定する。被験化合物非添加の陰性対照と比較してIL−2量を減少させる化合物または増加させる化合物をヒトBIR1のシグナル伝達を変化させる化合物として選別する。
ヒトBIR1の2箇所のITIM領域由来のリン酸化ペプチド(Biotin−HSQELQ313(pY)ATPVF(配列番号26)またはBiotin−YKSGYV338(pY)SELNF(配列番号28))を抗ビオチン抗体(Sigma社製)を固定した96ウェルプレートに結合させる。被験化合物(低分子化合物、ペプチド、抗体など)を添加した後、A20IIA1.6細胞の溶解液を添加し、4℃で2時間保温する。PBSで5回洗浄後、SHP−1、SHP−2およびSHIP−1に対する一次抗体(Santacruz社製)を添加する。室温で2時間反応後、PBSで5回洗浄し、HRP標識した二次抗体(Santacruz社製)を添加する。室温でさらに2時間反応後、ペルオキシダーゼ用発色キット(住友ベークライト(株)製)を用いてリン酸化ペプチドに結合したホスファターゼ量を測定する。被験化合物非添加の陰性対照と比較してホスファターゼ量を減少させる化合物または増加させる化合物を選別する。
ヒト単球細胞株THP−1細胞(1×106cells/2mL)にLPS(1μg/mL)および/またはIFN−γ(100ng/mL)の存在下または非存在下で被験化合物(低分子化合物、ペプチド、抗体など)を添加し、37℃で24時間培養する。各細胞から全RNAを抽出し、ヒトBIR1に特異的なプライマー;5’−CACAGCCATGGAAGTTGGAATC−3’(配列番号15)および5’−GAGTGTTTGGCCTCATCTTGG−3’(配列番号16)とQuantiTect SYBR Green RT-PCR Kit(QIAGEN社製)を用いてABI PRISM 7000 Sequence Detection System(Applied Biosystems社製)によりBIR1のRNAを定量する。LPSおよび/またはIFN−γの存在下で被験化合物非添加の陰性対照と比較してRNA量を減少させる化合物または増加させる化合物を選別する。あるいはLPSおよびIFN−γの非存在下で被験化合物非添加の陰性対照と比較してRNA量を減少させる化合物または増加させる化合物を選別する。
本発明の蛋白質またはその部分ペプチドおよび本発明の蛋白質またはその部分ペプチドに対する抗体は、本発明に係る蛋白質のアンタゴニストとして、癌、免疫不全症もしくは感染症の予防および/または治療に有用である。さらに、本発明の蛋白質またはその部分ペプチドは、本発明の蛋白質またはその部分ペプチドに対する抗体の製造において、抗原として使用できる。本発明のポリヌクレオチドは、本発明の蛋白質またはその部分ペプチドの製造に使用できる。
Claims (3)
- 配列番号3〜6で表わされるアミノ酸配列から選択される一つのアミノ酸配列を有する蛋白質をコードするポリヌクレオチドと相補的な塩基配列またはその一部を有するポリヌクレオチドを有効成分とし、当該ポリヌクレオチドが、アンチセンスDNA、siRNAまたはリボザイムである免疫賦活剤。
- 配列番号3〜6で表わされるアミノ酸配列から選択される一つのアミノ酸配列を有する蛋白質をコードするポリヌクレオチドが、配列番号9〜12から選択される何れかで表わされる塩基配列を有するポリヌクレオチドである、請求項1記載の免疫賦活剤。
- 請求項1記載のポリヌクレオチドが、単独で、あるいはレトロウイルスベクターまたはアデノウイルスベクターに挿入されて投与されることを特徴とする、請求項1または2記載の免疫賦活剤。
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US20030232411A1 (en) * | 1997-12-26 | 2003-12-18 | Ono Pharmaceutical Co., Ltd. | Novel polypeptide, cDNA encoding the same, and use thereof |
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WO2007122815A1 (ja) * | 2006-04-14 | 2007-11-01 | Ono Pharmaceutical Co., Ltd. | Bir1に対する二価抗体 |
JP2008128819A (ja) * | 2006-11-21 | 2008-06-05 | Genome Soyaku Kenkyusho:Kk | 花粉症に対する予防又は治療作用を有する物質の評価方法及びスクリーニング方法、並びに、花粉症の予防又は治療のための薬剤及びその製造方法 |
EP2103628A4 (en) * | 2006-12-14 | 2012-02-22 | Forerunner Pharma Res Co Ltd | MONOCLONAL ANTIBODY ANTI-CLAUDIN 3, AND TREATMENT AND DIAGNOSIS OF CANCER USING SUCH ANTIBODY |
CA2863658C (en) * | 2012-02-03 | 2023-03-14 | Emory University | Immunostimulatory compositions, particles, and uses related thereto |
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US20180080696A1 (en) * | 2016-09-22 | 2018-03-22 | Bruce Luchner | Variable Refrigerant Flow System with Decoupled Refrigerant and Air Distribution Subsystems |
BR112019014761A2 (pt) * | 2017-01-18 | 2020-03-03 | Tairx, Inc. | Composições para uso no tratamento de doenças inflamatórias do intestino e da colite intestinal |
BR112020018049A2 (pt) * | 2018-03-07 | 2020-12-29 | Poseida Therapeutics, Inc. | Composições de cartirina e métodos para uso |
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JPH11187882A (ja) * | 1997-12-26 | 1999-07-13 | Ono Pharmaceut Co Ltd | 新規なポリペプチド、その製造方法、そのポリペプチドをコードするcDNA、そのcDNAからなるベクター、そのベクターで形質転換された宿主細胞、そのポリペプチドの抗体、およびそのペプチドまたは抗体を含有する薬学的組成物 |
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JP2015044853A (ja) | 2015-03-12 |
JP5811123B2 (ja) | 2015-11-11 |
US20150093383A1 (en) | 2015-04-02 |
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JP5272310B2 (ja) | 2013-08-28 |
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JPWO2006043615A1 (ja) | 2008-05-22 |
US20130064818A1 (en) | 2013-03-14 |
US8333969B2 (en) | 2012-12-18 |
EP1806147B1 (en) | 2014-04-30 |
WO2006043615A1 (ja) | 2006-04-27 |
US20110070236A1 (en) | 2011-03-24 |
ES2481641T3 (es) | 2014-07-31 |
EP1806147A4 (en) | 2009-07-01 |
US9856299B2 (en) | 2018-01-02 |
EP1806147A1 (en) | 2007-07-11 |
US8945557B2 (en) | 2015-02-03 |
EP2465538A2 (en) | 2012-06-20 |
US20180118797A1 (en) | 2018-05-03 |
EP3115057B1 (en) | 2019-09-04 |
US20090155277A1 (en) | 2009-06-18 |
JP2016145196A (ja) | 2016-08-12 |
ES2750600T3 (es) | 2020-03-26 |
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