JP2020203922A - 線維症を治療するための組成物及び方法 - Google Patents
線維症を治療するための組成物及び方法 Download PDFInfo
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Abstract
Description
本発明は、米国国立衛生研究所助成金番号CA163200及びAA11999に基づく助成を受け、政府の支援によりなされたものである。政府は、本発明に対し、一定の権利を有する。
必要とする対象において、線維症、膵炎及び/または膵臓がんを治療し、阻害し、その重症度を低減させ、及び/またはその予防を促進するための組成物及び方法が本明細書にて提供される。組成物は、IL−4/IL−13受容体機能の阻害物質を含む。
本明細書にて引用される全ての公開物は、それぞれの個々の公開物または特許出願が参考として本明細書に援用されることが具体的かつ個別に示された場合と同様に、その全体を参考として本明細書に援用する。以下の説明には、本発明を理解する際に有用となり得る情報が含まれる。本明細書に記載される情報のいずれかが先行技術であること、もしくはここに特許請求する発明に関連していること、または具体的もしくは暗示的に参照されるあらゆる公開物が先行技術であることを自認するものではない。
[本発明1001]
必要とする対象において、疾患状態を治療し、阻害し、その重症度を低減させ、及び/またはその予防を促進するための方法であって、
(i)IL−4/IL−13受容体の阻害物質を含む組成物を提供する段階と、
(ii)前記対象の前記疾患状態を治療するために、治療上有効な量の前記組成物を前記対象に投与する段階と
を含む、前記方法。
[本発明1002]
前記疾患状態が線維症及び/またはがんである、本発明1001の方法。
[本発明1003]
前記疾患状態が膵線維症、膵炎及び/または膵臓がんである、本発明1001の方法。
[本発明1004]
前記疾患状態が肺線維症または肺がんである、本発明1001の方法。
[本発明1005]
前記がんが慢性膵炎と関係する、本発明1002の方法。
[本発明1006]
前記がんが器官の線維化と関係する、本発明1002の方法。
[本発明1007]
線維症が、縦隔線維症、骨髄線維症、後腹膜線維症、進行性塊状線維症、腎性全身性線維症、クローン病、ケロイド、強皮症/全身性硬化症、関節線維症、ペロニー病、デュピュイトラン拘縮、癒着性関節包炎、肝臓線維症、肺線維症、膵線維症、腸線維症、心臓線維症またはこれらの組み合わせのうちのいずれか1つ以上である、本発明1002の方法。
[本発明1008]
前記がんが、リンパ腫、肉腫、脳がん、乳がん、大腸がん、肺がん、肝細胞がん、胃がん、膵臓がん、子宮頸がん、卵巣がん、肝臓がん、膀胱がん、尿路がん、甲状腺がん、腎臓がん、癌腫、黒色腫、頭頸部がん、脳がん及び前立腺がんのうちのいずれか1つ以上である、本発明1002の方法。
[本発明1009]
本発明1001の方法によって、がん転移を低減または阻害するための方法。
[本発明1010]
前記IL−4/IL−13受容体の阻害物質が、小分子、ペプチド、タンパク質、アプタマー、抗体またはその断片、核酸分子、IL−4及びIL−4/IL−13受容体に特異的な結合部位を含む二重特異性ポリペプチド剤、ならびにIL−13及びIL−4/IL−13受容体に対する結合部位を含む二重特異性ポリペプチド剤からなる群から選択される、本発明1001の方法。
[本発明1011]
前記二重特異性ポリペプチドが、IL−4に特異的に結合する抗体またはその抗原結合部分と、IL−4/IL−13受容体に結合する抗体またはその抗原結合部分とを含む、本発明1010の方法。
[本発明1012]
前記二重特異性ポリペプチドが、IL−13に特異的に結合する抗体またはその抗原結合部分と、IL−4/IL−13受容体に結合する抗体またはその抗原結合部分とを含む、本発明1010の方法。
[本発明1013]
前記核酸分子がIL−4/IL−13受容体のsiRNA分子である、本発明1010の方法。
[本発明1014]
前記抗体が、モノクローナル抗体またはその断片、ポリクローナル抗体またはその断片、キメラ抗体、ヒト化抗体、ヒト抗体、アンタゴニスト抗体、二重特異性抗体及び一本鎖抗体からなる群から選択される、本発明1010の方法。
[本発明1015]
前記IL−4/IL−13受容体阻害物質が、CSRM53567、CSRM535671、CSRM535672及び/もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上である、本発明1010の方法。
[本発明1016]
前記阻害物質が、配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYRまたはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になるCSRM53567である、本発明1015の方法。
[本発明1017]
前記阻害物質が、配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYR−ASPまたはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になるCSRM535671である、本発明1015の方法。
[本発明1018]
前記阻害物質が、配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP CYS−TYR−GLUまたはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になるCSRM535672である、本発明1015の方法。
[本発明1019]
前記組成物が、静脈内、筋肉内、腹腔内、経口または吸入により投与される、本発明1001のいずれかの方法。
[本発明1020]
前記IL−4/IL−13受容体阻害物質の前記有効な量が、約0.1〜0.5mg/kg/日、0.5〜5mg/kg/日、5〜10mg/kg/日、10〜20mg/kg/日、20〜50mg/kg/日、50〜100mg/kg/日、100〜200mg/kg/日、200〜300mg/kg/日、300〜400mg/kg/日、400〜500mg/kg/日、500〜600mg/kg/日、600〜700mg/kg/日、700〜800mg/kg/日、800〜900mg/kg/日または900〜1000mg/kg/日である、本発明1001の方法。
[本発明1021]
前記対象がヒトである、本発明1001の方法。
[本発明1022]
前記対象が前記疾患状態を発症する前、その間、またはその後に、前記組成物が前記対象に投与される、本発明1001の方法。
[本発明1023]
前記組成物が、1日あたり1〜3回または1週あたり1〜7回、前記対象に投与される、本発明1001の方法。
[本発明1024]
前記組成物が、1〜5日間、1〜5週間、1〜5ヶ月間または1〜5年間、前記対象に投与される、本発明1001の方法。
[本発明1025]
前記対象を外科手術、放射線療法、化学療法またはこれらの組み合わせで治療する段階を更に含む、本発明1001の方法。
[本発明1026]
前記組成物が化学療法剤を更に含む、本発明1001の方法。
[本発明1027]
(i)IL−4/IL−13受容体阻害物質と、
(ii)薬学的に許容される担体と
を含む、医薬組成物。
[本発明1028]
前記IL−4/IL−13受容体阻害物質が、CSRM53567、CSRM535671、CSRM535672及び/もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上である、本発明1027の医薬組成物。
[本発明1029]
(i)ある量の、IL−4/IL−13受容体阻害物質を含む組成物と、
(ii)線維症及び/またはがんを治療し、阻害し、その重症度を低減させ、及び/またはその予防を促進することを必要とする哺乳動物対象に、前記組成物の治療上有効な量を投与するための説明書と
を含む、キット。
[本発明1030]
前記IL−4/IL−13受容体阻害物質が、CSRM53567、CSRM535671、CSRM535672及び/もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上である、本発明1029のキット。
[本発明1031]
CSRM53567、CSRM535671、CSRM535672及び/もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上の配列を有する、単離された及び精製されたIL−4/IL−13受容体阻害物質。
[本発明1032]
本発明1031のIL−4/IL−13受容体阻害物質をコードするポリヌクレオチド。
[本発明1033]
本発明1032のcDNA分子。
[本発明1034]
本発明1033のcDNA分子を含むベクター。
[本発明1035]
適合性のある宿主細胞にトランスフェクトされた本発明1034のベクターを含む、宿主ベクター系。
[本発明1036]
前記適合性のある宿主細胞が、原核細胞または真核細胞である、本発明1035の宿主ベクター系。
本明細書中に引用される全て参考文献は、完全に記載されているかのように、その全体が参考として援用される。別途の定義がない限り、本明細書で使用される技術用語及び科学用語は、本発明が属する技術分野の当業者によって一般的に理解されている意味と同一の意味を有する。Allen et al.,Remington:The Science and Practice of Pharmacy 22nd ed.,Pharmaceutical Press(September 15,2012)、Hornyak et al.,Introduction to Nanoscience and Nanotechnology,CRC Press(2008)、Singleton and Sainsbury,Dictionary of Microbiology and Molecular Biology 3rd ed.,revised ed.,J.Wiley&Sons(New York,NY 2006)、Smith,March’s Advanced Organic Chemistry Reactions,Mechanisms and Structure 7th ed.,J.Wiley&Sons(New York,NY 2013)、Singleton,Dictionary of DNA and Genome Technology 3rd ed.,Wiley−Blackwell(November 28,2012)、及びGreen and Sambrook,Molecular Cloning:A Laboratory Manual 4th ed.,Cold Spring Harbor Laboratory Press(Cold Spring Harbor,NY 2012)は、本出願に使用される多数の用語に関する一般的な指針を当業者に提供する。抗体の作製方法に関する参考文献については、Greenfield,Antibodies A Laboratory Manual 2nd ed.,Cold Spring Harbor Press(Cold Spring Harbor NY,2013)、Kohler and Milstein,Derivation of specific antibody−producing tissue culture and tumor lines by cell fusion,Eur.J.Immunol.1976 Jul,6(7):511−9、Queen and Selick,Humanized immunoglobulins(米国特許第5,585,089号、1996年12月)、及びRiechmann et al.,Reshaping human antibodies for therapy,Nature 1988 Mar 24,332(6162):323−7を参照されたい。
IL−4/IL−13受容体機能を標的にする阻害物質及び許容される担体/賦形剤を含むか、これらからなるか、またはこれらから本質的になる医薬組成物が本明細書にて提供される。種々の実施形態において、阻害物質は、小分子、ペプチド、タンパク質、アプタマー、抗体もしくはその断片、核酸分子、IL−4及びIL−4/IL−13受容体に特異的な結合部位を含む二重特異性ポリペプチド、IL−13及びIL−4/IL−13受容体に特異的な結合部位を含む二重特異性ポリペプチドまたはこれらの組み合わせのうちのいずれか1つ以上である。
ヌクレオプラスミン
K−K/R−X−K/R(配列番号6)コンセンサス
及びPY−NLSが挙げられる(例えば、Dingwall et al.J Cell Biol 188 107:841−9及びMakkerh et al.Curr Biol.1996 6:1025−7を参照されたい。両文献は、更なる考察のために、その全体を参考として本明細書に援用する)。哺乳動物細胞にて使用するための分泌シグナルペプチドの非限定的な例には、ヒトアルブミンシグナルペプチド
ヒトキモトリプシンシグナルペプチド
ヒトインターロイキン−2シグナルペプチド
ヒトトリプシノゲン−2シグナルペプチド
及びシグナルペプチダーゼ、フーリンまたは他のプロホルモン転換酵素による前駆体切断のためのシグナルに関するコード領域を含む配列(例えば、PC3)が挙げられる。例えば、フーリンによって切断されるシグナル(ペプチド)配列(PACEとしても知られる、米国特許第5,460,950号参照)、他のサブチリシン(PC2、PC1/PC3、PACE4、PC4、PC5/PC6、LPC/PC7IPC8/SPC7及びSKI−Iを含む;Nakayama,Biochem.J.,327:625−635(1997));エンテロキナーゼ(米国特許第5,270,181号参照)またはキモトリプシンを、本明細書にて定義されるシグナル(ペプチド)配列に導入することができる。更なるシグナルペプチドは、当該技術分野において知られており、シグナルペプチドの選択は、細胞種、成長条件及びペプチドの所望の行き先による影響を受け得る。
必要とする対象において、疾患状態を治療し、阻害し、その重症度を低減させ、及び/またはその予防を促進するための方法が本明細書にて提供される。方法は、IL−4/IL−13受容体の阻害物質を含む組成物を提供することと、疾患状態を治療し、阻害し、その重症度を低減させ、及び/またはその予防を促進するために、有効量の組成物を対象に投与することとを含む。種々の実施形態において、疾患状態は、線維症及び/またはがんである。いくつかの実施形態において、IL−4/IL−13受容体の阻害物質は、CSRM53567、CSRM535671、CSRM535672及び/もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上である。一実施形態において、対象は、ヒトである。種々の実施形態において、本明細書に記載の組成物は、対象が疾患状態を発症する前、その間、またはその後に、対象に投与される。いくつかの実施形態において、組成物は、1日あたり1〜3回または1週あたり1〜7回、対象に投与される。いくつかの実施形態において、組成物は、1〜5日間、1〜5週間、1〜5ヶ月間または1〜5年間、対象に投与される。
CSRM53567、CSRM535671、CSRM535672もしくはこれらの組み合わせ、またはこれらのバリアント、誘導体、薬学的同等物、ペプチド模倣物もしくは類似体のうちのいずれか1つ以上を作製するための方法が本明細書にて提供される。CSRM53567、CSRM535671、CSRM535672もしくはこれらの組み合わせ、またはこれらのバリアント、誘導体、薬学的同等物、ペプチド模倣物もしくは類似体は、組み換えであってもよいし、化学的に合成してもよい(Murali,R.and Green,M.Pharmaceuticals 2012 Vol 5 209−235)。これらは、限定するものではないが、His6、エピトープ(例えば、myc、V5、FLAGまたはソフトエピトープ)、ストレプトアビジン、ビオチン、アビジン、テトラシステイン、カルモジュリン結合タンパク質、エラスチン様ペプチド、融合タンパク質(例えば、グルタチオン−S−トランスフェラーゼ、マルトース結合タンパク質、セルロース結合ドメイン、チオレドキシン、NusAまたはミスチン)、キチン結合ドメイン、GFP、アルカリホスファターゼ、クチナーゼ、O6−アルキルグアニンアルキルトランスフェラーゼ(AGT)またはハロタグを含む、1つ以上の精製タグにより修飾され得る。一実施形態において、CSRM53567は、アミノ酸配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYR(配列番号1)またはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になる。別の実施形態において、CSRM535671は、アミノ酸配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYR−ASP(配列番号2)またはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になる。更なる実施形態において、阻害物質CSRM535672は、アミノ酸配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP CYS−TYR−GLU(配列番号3)またはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になる。
IL−4/IL−13受容体機能を標的にする阻害物質及び許容される担体/賦形剤を含むか、これらからなるか、またはこれらから本質的になる医薬組成物が本明細書にて提供される。種々の実施形態において、阻害物質は、CSRM53567、CSRM535671、CSRM535672もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上である。一実施形態において、阻害物質は、アミノ酸配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYR(配列番号1)またはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になるCSRM53567である。別の実施形態において、阻害物質は、配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYR−ASP(配列番号2)またはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になるCSRM535671である。別の実施形態において、阻害物質は、配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYR−GLU(配列番号3)またはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になるCSRM535672である。
本発明はまた、必要とする対象における、がん及び/もしくは線維化疾患の治療、がん及び/もしくは線維化疾患の阻害、がん及び/もしくは線維化疾患の低減またはがん及び/もしくは線維化疾患予防の促進ためのキットを提供する。キットは、必要とする対象において、がん及び/または線維化疾患を治療し、阻害し、及び/またはその重症度を低減させるためのIL−4/IL−13受容体阻害物質を含む組成物と、組成物の使用説明書とを含む。いくつかの実施形態において、IL−4/IL−13受容体阻害物質は、小分子、ペプチド、タンパク質、アプタマー、抗体もしくはその断片、核酸分子またはIL−4もしくはIL−13及びIL−4/IL−13受容体に特異的な結合部位を含む二重特異性ポリペプチド剤である。種々の実施形態において、阻害物質は、CSRM53567、CSRM535671、CSRM535672もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上である。
IL−4/IL−13受容体機能を阻害するように設計された阻害物質CSRM53567が本明細書にて提供される。慢性炎症及び組織線維症を特徴とする慢性膵炎モデルにおける、CSRM53567の利益の証拠を提供する。慢性炎症及び線維症の機序におけるIL−4/IL−13受容体の役割、ならびにがんにおけるそれらのプロセスの役割に関する現時点での知見では、IL−4/IL−13受容体を阻害する作用物質が幅広い慢性炎症/線維化疾患及びがんに有益であることが示唆されている。
CSRM53567: TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYR(配列番号1)(CYS2−CYS11ジスルフィド)
CSRM535671: TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYR−ASP(配列番号2)(CYS2−CYS11ジスルフィド)
CSRM535672: TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYR−GLU(配列番号3)(CYS2−CYS11ジスルフィド)
実験方法
マウス:BALB/c、C57BL/6、SJL、B6.SJL、IL−4Rα−/−、CCR2KOマウス系統をJackson Laboratoryから購入し、所内で飼育した。BALB/cバックグラウンドのLysMcreIL−4Rαflox/flox(参考文献24)及びIL−4/IL−13−/−マウスを記載のとおりに作製した(McKenzie,G.J.,et al. Simultaneous disruption of interleukin(IL)−4 and IL−13 defines individual roles in T helper cell type 2−mediated responses.J.Exp.Med.189,1565−1572(1999))。実験マウスは全て年齢(6〜8週齢)と性別を一致させ、動物実験についてはスタンフォード大学動物実験委員会の承認を受けた。
。サンプルは、GAPDHに対して正規化し、別途の記載がない限り、未処置対照群に対する誘導倍率で示した。
マクロファージは、マウスCP及びヒトCPで増加する。
ヒトCPにおける線維症の発病機序に関する研究は、外科手術から得られる組織の入手可能性に制限があることから、限定されている。したがって、CPの発生及び進行を調べるには、ヒト疾患の全ての側面を再現するには限界があるものの、動物モデルが有用である(Saluja,A.K.&Dudeja,V.Gastroenterology 144,1194−1198(2013);Lerch,M.M.&Gorelick,F.S.Gastroenterology 144,1180−1193(2013))。マウスでは、コレシストキニン類似体のセルレインで膵臓を過剰刺激すると、APに至り、膵臓に対する連続的な急性損傷により膵臓の慢性炎症が生じる(Witt,H.,et al. Gastroenterology 132,1557−1573(2007);Lerch,M.et al.Gastroenterology 144,1180−1193(2013))。実験的CPを引き起こすために、4週間(週3回)にわたり、反復的にAPを誘導した。セルレインによる反復処置を受けたマウスは、白血球浸潤、膵線維症及び体重と比較して膵臓の大きさが小さいことと一致する腺房細胞の減少を伴う、CPの形態学的徴候を見せた。
AAMは、マウスCP及びヒトCPで優位である。
CPにおけるマクロファージの分極状態を決定するために、対照マウス及びCPマウスの両方から遺伝子発現分析のためにSSC−AlowCD1lb+単球/マクロファージを選別した。遺伝子発現プロファイルにより、CPの膵臓単球/マクロファージにおいて、YM1、CD206、CD301、IL−10、TGFβ及びPDGFβなどのM2関連遺伝子が、対照と比較して増加していることが明らかになった(図3a)。更に、CPにおけるAAMの存在は、フローサイトメトリーを使用することで、M2関連マーカー(CD206、IL−10及びIL−4Rα)の増加及びM1関連マーカー(主要組織適合遺伝子複合体クラスII(MHCII))及び腫瘍−壊死因子アルファ(TNFα)発現の減少または不変が示されたとおり、更に確認された(図3b)。対照的に、AP誘導時における膵臓マクロファージの動的遺伝子発現を評価すると、TNFαの増加及びCD206、CD301の減少という古典的活性化プロファイルがAPマウスで認められた。TNFαとは異なり、IL−10の発現は、M1の後期反応と考えることができる(Murray,P.J.&Wynn,T.A.J.Leukoc.Biol 89,557−563(2011))。しかし、膵臓マクロファージでは、APにおけるIL−10は、CP(図3)と比較して極めて低い発現であり、同じ程度ではないが、CPでは、APと比較して、わずかに高いYM1発現量が認められる。Arg1は、古典的とAAMの両方で発現されることが最近示された(Murray,P.J.et al.Immunity 41,14−20(2014))。フローサイトメトリーのデータは、F4/80+マクロファージの大部分でCD206は陽性であるが、TNFαは陽性でないという免疫蛍光染色に基づき、CPマウス由来の膵臓の組織学的分析と一致した。類似の所見がヒトCP組織でも観察され、CD68+細胞は、CD206を発現したが、TNFαを発現しなかった(図3c、d)。
PSCはマクロファージの選択的活性化を促進する。
マクロファージは、局所微小環境シグナルに応じて、その活性化状態及び機能を迅速に変えることができる、極めて不均質な細胞である(Sica,A.&Mantovani,A.J.Clin.Invest.122,787−795(2012);Murray,P.J.&Wynn,T.A.Nat.Rev.Immunol.11,723−737(2011))。PSCがCPにおいて果たす重要な役割を考慮して、本発明者らは、PSCがマクロファージの分極化及び機能に関与するのかどうか問うた。CPマウスからPSCを単離し、そのサイトカイン産生をLuminexアッセイで評価した。全体的に、IFNγ、TNFα及びIL−1βなどの複数の炎症誘発性サイトカインの発現が非常に低かった。対照的に、PSCは、IL−4、IL−5、IL−13、IL−10及びTGFβを多く分泌した。これは、Th2と線維形成促進性サイトカインのバイアスを示している(図4a)。
IL−4Rαシグナル欠損は、AAMを制限し、CPを防ぐ。
CPにおけるマクロファージの選択的活性化の重要性を調査するために、IL−4及びIL−13を欠くマウスでCPを誘導した。IL−4/IL−13−/−マウスは、他の疾患モデルにおいて、AAMを欠くことがわかっている(Nguyen,K.D.et al.Nature 480,104−108(2011))。WT同等マウスとは異なり、IL−4/IL−13−/−マウスは、膵臓相対サイズがより大きく(WT:5.95±0.11〜1.71±0.05、IL−4/IL−13−/−:5.98±0.20〜2.89±0.07;図5a)、リアルタイムPCR及び免疫蛍光分析を使用して、αSMA(α−SMA)及びCol1α1(コラーゲン1A1)などの膵臓における線維症に関連する遺伝子発現がより低い(図5b、c)ことから示されるように、CPにかかりにくかった。更に、WTマウスと比較して、IL−4/IL−13−/−マウス膵臓から単離したマクロファージは、CD206の発現がより低いことから、膵臓マクロファージの選択的活性化の低減が示唆される(図5d)。
IL−4/IL−13遮断は、確立されたCPを改善する。
実験的CP関連線維形成におけるIL−4Rαシグナル伝達の上記所見及び重要性を鑑みて、本発明者らは、確立された疾患の治療法として、IL−4Rαシグナル伝達遮断を使用できるかどうか試験しようとした。IL−4/IL−13阻害ペプチド(CSRM53567)を使用した。まず、阻害物質をインビトロタイトレーションアッセイにて試験すると、阻害物質は、1μMで、マウスIL−4/IL−13誘導性M2分極化及びCD206発現を有意に減少させた。次いで、セルレイン反復注入を2週間受け、膵臓サイズが有意に減少し、α−SMA発現が存在したマウスにおいて、阻害物質の効果を試験した。対照処置群と比較して、阻害物質での処置により、膵臓線維症が抑えられた(図6a〜e)。更に、阻害物質による膵臓マクロファージの選択的活性化の阻害がフローサイトメトリーの使用により確認された(図6f)。これらの観察結果は、概念実証として、CPの治療可能性を実証するものである。次いで、hPSCによるヒトマクロファージのM2分極化を阻害することについて、阻害物質の能力を試験した。このペプチドは、実際に、ヒトマクロファージのhPSC媒介性M2分極化を阻害することができた(図6g)。
一般に、CPは、不可逆的な線維化疾患として認められており、現在の治療技術は、良くても支持的なものであり、痛みならびに外分泌及び内分泌の機能不全に関連する合併症を制御することに焦点が置かれている(Witt,H.,et al.Gastroenterology 132,1557−1573(2007))。膵線維症におけるPSCについての発見及び中心的役割に従って、CPの潜在的治療法については、PSCの阻害または非活性化が提案されている(Talukdar,R.&Tandon,R.K.J.Gastroenterol.Hepatol.23,34−41(2008))。しかしながら、CP進行中の免疫応答及び免疫細胞のPSC活性化に対する関与は、まだ十分理解されていない。本研究では、マクロファージの特徴及び役割を探るとともに、CPにおけるマクロファージとPSCとの相互作用の機序を特定することを目指している。本発明者らの結果は、AAMがCP線維形成において重要な役割を果たし、標的にすることが可能であり得る重要な経路を定めていることを示している。
Claims (36)
- 必要とする対象において、疾患状態を治療し、阻害し、その重症度を低減させ、及び/またはその予防を促進するための方法であって、
(i)IL−4/IL−13受容体の阻害物質を含む組成物を提供する段階と、
(ii)前記対象の前記疾患状態を治療するために、治療上有効な量の前記組成物を前記対象に投与する段階と
を含む、前記方法。 - 前記疾患状態が線維症及び/またはがんである、請求項1に記載の方法。
- 前記疾患状態が膵線維症、膵炎及び/または膵臓がんである、請求項1に記載の方法。
- 前記疾患状態が肺線維症または肺がんである、請求項1に記載の方法。
- 前記がんが慢性膵炎と関係する、請求項2に記載の方法。
- 前記がんが器官の線維化と関係する、請求項2に記載の方法。
- 線維症が、縦隔線維症、骨髄線維症、後腹膜線維症、進行性塊状線維症、腎性全身性線維症、クローン病、ケロイド、強皮症/全身性硬化症、関節線維症、ペロニー病、デュピュイトラン拘縮、癒着性関節包炎、肝臓線維症、肺線維症、膵線維症、腸線維症、心臓線維症またはこれらの組み合わせのうちのいずれか1つ以上である、請求項2に記載の方法。
- 前記がんが、リンパ腫、肉腫、脳がん、乳がん、大腸がん、肺がん、肝細胞がん、胃がん、膵臓がん、子宮頸がん、卵巣がん、肝臓がん、膀胱がん、尿路がん、甲状腺がん、腎臓がん、癌腫、黒色腫、頭頸部がん、脳がん及び前立腺がんのうちのいずれか1つ以上である、請求項2に記載の方法。
- 請求項1に記載の方法によって、がん転移を低減または阻害するための方法。
- 前記IL−4/IL−13受容体の阻害物質が、小分子、ペプチド、タンパク質、アプタマー、抗体またはその断片、核酸分子、IL−4及びIL−4/IL−13受容体に特異的な結合部位を含む二重特異性ポリペプチド剤、ならびにIL−13及びIL−4/IL−13受容体に対する結合部位を含む二重特異性ポリペプチド剤からなる群から選択される、請求項1に記載の方法。
- 前記二重特異性ポリペプチドが、IL−4に特異的に結合する抗体またはその抗原結合部分と、IL−4/IL−13受容体に結合する抗体またはその抗原結合部分とを含む、請求項10に記載の方法。
- 前記二重特異性ポリペプチドが、IL−13に特異的に結合する抗体またはその抗原結合部分と、IL−4/IL−13受容体に結合する抗体またはその抗原結合部分とを含む、請求項10に記載の方法。
- 前記核酸分子がIL−4/IL−13受容体のsiRNA分子である、請求項10に記載の方法。
- 前記抗体が、モノクローナル抗体またはその断片、ポリクローナル抗体またはその断片、キメラ抗体、ヒト化抗体、ヒト抗体、アンタゴニスト抗体、二重特異性抗体及び一本鎖抗体からなる群から選択される、請求項10に記載の方法。
- 前記IL−4/IL−13受容体阻害物質が、CSRM53567、CSRM535671、CSRM535672及び/もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上である、請求項10に記載の方法。
- 前記阻害物質が、配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYRまたはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になるCSRM53567である、請求項15に記載の方法。
- 前記阻害物質が、配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP−CYS−TYR−ASPまたはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になるCSRM535671である、請求項15に記載の方法。
- 前記阻害物質が、配列TYR−CYS−ASP−ASP−PHE−VAL−GLY−SER−PHE−ASP CYS−TYR−GLUまたはその類似体、薬学的同等物もしくはペプチド模倣物を含むか、これらからなるか、あるいはこれらから本質的になるCSRM535672である、請求項15に記載の方法。
- 前記組成物が、静脈内、筋肉内、腹腔内、経口または吸入により投与される、請求項1のいずれか一項に記載の方法。
- 前記IL−4/IL−13受容体阻害物質の前記有効な量が、約0.1〜0.5mg/kg/日、0.5〜5mg/kg/日、5〜10mg/kg/日、10〜20mg/kg/日、20〜50mg/kg/日、50〜100mg/kg/日、100〜200mg/kg/日、200〜300mg/kg/日、300〜400mg/kg/日、400〜500mg/kg/日、500〜600mg/kg/日、600〜700mg/kg/日、700〜800mg/kg/日、800〜900mg/kg/日または900〜1000mg/kg/日である、請求項1に記載の方法。
- 前記対象がヒトである、請求項1に記載の方法。
- 前記対象が前記疾患状態を発症する前、その間、またはその後に、前記組成物が前記対象に投与される、請求項1に記載の方法。
- 前記組成物が、1日あたり1〜3回または1週あたり1〜7回、前記対象に投与される、請求項1に記載の方法。
- 前記組成物が、1〜5日間、1〜5週間、1〜5ヶ月間または1〜5年間、前記対象に投与される、請求項1に記載の方法。
- 前記対象を外科手術、放射線療法、化学療法またはこれらの組み合わせで治療する段階を更に含む、請求項1に記載の方法。
- 前記組成物が化学療法剤を更に含む、請求項1に記載の方法。
- (i)IL−4/IL−13受容体阻害物質と、
(ii)薬学的に許容される担体と
を含む、医薬組成物。 - 前記IL−4/IL−13受容体阻害物質が、CSRM53567、CSRM535671、CSRM535672及び/もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上である、請求項27に記載の医薬組成物。
- (i)ある量の、IL−4/IL−13受容体阻害物質を含む組成物と、
(ii)線維症及び/またはがんを治療し、阻害し、その重症度を低減させ、及び/またはその予防を促進することを必要とする哺乳動物対象に、前記組成物の治療上有効な量を投与するための説明書と
を含む、キット。 - 前記IL−4/IL−13受容体阻害物質が、CSRM53567、CSRM535671、CSRM535672及び/もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上である、請求項29に記載のキット。
- CSRM53567、CSRM535671、CSRM535672及び/もしくはこれらの組み合わせ、またはこれらの類似体、薬学的同等物もしくはペプチド模倣物のうちのいずれか1つ以上の配列を有する、単離された及び精製されたIL−4/IL−13受容体阻害物質。
- 請求項31に記載のIL−4/IL−13受容体阻害物質をコードするポリヌクレオチド。
- 請求項32に記載のcDNA分子。
- 請求項33に記載のcDNA分子を含むベクター。
- 適合性のある宿主細胞にトランスフェクトされた請求項34に記載のベクターを含む、宿主ベクター系。
- 前記適合性のある宿主細胞が、原核細胞または真核細胞である、請求項35に記載の宿主ベクター系。
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