JP2008537727A - 線維性障害を治療するための組成物および方法 - Google Patents
線維性障害を治療するための組成物および方法 Download PDFInfo
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Abstract
Description
本発明は、線維性障害を治療するための組成物および方法に関する。
創傷治癒の一部としての組織修復のプロセスは、2つの期を伴う。第一期は再生期であり、損傷を受けた細胞が、同じ種類の細胞に置き換えられる。第二期は、線維増殖または線維化とも呼ばれる線維性組織の形成であり、結合組織が、正常な実質組織を置き換える。組織修復プロセスは、線維化期が抑制されずに続き、広範囲に及ぶ組織リモデリングおよび永続的な瘢痕組織の形成を導く場合、病原性になりうる(Wynn, Nature Rev. Immunol. 4, 583(2004))。
本発明は、組織において、サイトカイン、胸腺間質リンホポエチン(TSLP)の量または活性を調節することによって、組織における線維芽細胞集積およびコラーゲン沈着を調節するための方法を提供する。1つの側面において、本発明は、線維性障害を患う被験体において、線維化を減少させるかまたは防止する方法であって、療法的有効量の少なくとも1つのTSLPアンタゴニストを投与することを含む、前記方法を提供する。別の側面において、本発明は、こうした障害を患う被験体における線維性障害の防止または治療のための薬剤の調製における、少なくとも1つのTSLPアンタゴニストの使用を提供する。本発明は、線維性障害を患う被験体において、線維化を防止するかまたは減少させるための薬剤組成物であって、薬学的に許容しうるキャリアーと混合された、TSLPに対する少なくとも1つのアンタゴニストの療法的有効投薬量を含む、前記組成物をさらに提供する。線維性障害には、限定されるわけではないが、強皮症、間質性肺疾患(ILD)、特発性肺線維症(IPF)、慢性B型またはC型肝炎感染から生じる肝線維症、放射線誘導性線維症、および創傷治癒から生じる線維症が含まれる。
本発明は、組織において、サイトカイン、胸腺間質リンホポエチン(TSLP)の量または活性を調節することによって、組織における線維芽細胞集積およびコラーゲン沈着を調節する方法を提供する。TSLPは、動物における線維性障害に特徴的な、線維芽細胞集積およびコラーゲン沈着を誘導することが見出されている。1つの側面において、本発明は、TSLPまたはTSLPアゴニストを投与することによって、線維化増加が好適でありうる状況において、線維化を増加させる方法を提供する。別の側面において、本発明は、被験体を、TSLPに対する少なくとも1つのアンタゴニストの療法的有効量で治療することによって、線維性障害を患う被験体において、線維化を減少させるかまたは防止するための方法および組成物を提供する。別の側面において、本発明は、線維性障害を患う被験体における線維性障害の防止または治療のための薬剤の調製における、少なくとも1つのTSLPアンタゴニストの使用を提供する。別の側面において、本発明は、被験体において、線維化を防止するかまたは減少させるための薬剤組成物であって、薬学的に許容しうるキャリアーと混合された、TSLPに対する少なくとも1つのアンタゴニストの療法的有効投薬量を含む、前記組成物を提供する。
胸腺間質リンホポエチン(TSLP)は、4つのαらせん束のI型サイトカインを指し、該サイトカインは、IL−2ファミリーのメンバーであるが、IL−7に最も緊密に関連する。サイトカインは、特定の刺激に応答して分泌される低分子量制御タンパク質であり、標的細胞膜上の受容体に対して作用する。サイトカインは、多様な細胞応答を制御する。サイトカインは一般的に、Cytokines, A. Mire−SluisおよびR. Thorne監修, Academic Press, New York, (1998)などの参考文献に記載される。
PCT特許出願公報WO 03/032898に記載されるように、増殖のために活性TSLPを必要とする、ヒトTSLPRを発現するBAF細胞(BAF/HTR)を用いたアッセイにおいて、TSLP活性を測定可能である。BAF/HTRバイオアッセイは、ヒトTSLP受容体をトランスフェクションされているネズミ・プロBリンパ球細胞株(Steven F. Ziegler, Virginia Mason Research Center, ワシントン州シアトルから得た細胞株)を利用する。BAF/HTR細胞は、増殖のため、huTSLPに依存し、そして試験試料に添加された活性huTSLPに応答して増殖する。インキュベーション期間後、Alamar Blue色素I(Biosource Internationalカタログ番号DAL1100、10μl/ウェル)を添加することによって、細胞増殖を測定する。代謝的に活性であるBAF/HRT細胞は、Alamar Blueを取り込み、そして還元し、この色素の蛍光特性の変化を導く。huTSLP活性に関するさらなるアッセイには、例えば、米国特許第6,555,520号に記載されるような、TSLPによるヒト骨髄からのT細胞増殖の誘導を測定するアッセイが含まれる。別のTSLP活性は、Levinら, J. Immunol. 162:677−683(1999)およびPCT特許出願WO 03/032898を参照した際に記載されるような、STAT5を活性化する能力である。さらなるアッセイには、Soumelisら、上記を参照した際に記載されるような、TSLPが誘導する、初代ヒト単球および樹状細胞からのCCL17/TARC産生が含まれる。
本発明記載のTSLPアンタゴニストは、TSLPの少なくとも1つの活性を阻害するかまたは遮断し、あるいは該サイトカインまたはその受容体の発現を遮断する。サイトカイン活性の阻害または遮断は、例えば、該サイトカインのその受容体への結合に干渉し、そして/または該サイトカインのその受容体への結合から生じるシグナル伝達を遮断する、1以上の阻害剤を使用することによって達成可能である。
抗体
アンタゴニストには、サイトカインまたはその受容体のいずれかに結合し、そして該サイトカインの少なくとも1つの活性を減少させるかまたは遮断する抗体が含まれる。本明細書において、用語「抗体」は、ポリクローナル抗体(例えばAntibodies: A Laboratory Manual, HarlowおよびLane(監修), Cold Spring Harbor Press, (1988)を参照されたい)、およびモノクローナル抗体(例えば、米国特許第RE 32,011号、第4,902,614号、第4,543,439号、および第4,411,993号、ならびにMonoclonal Antibodies: A New Dimension in Biological Analysis, Plenum Press, Kennett, McKearnおよびBechtol(監修)(1980)を参照されたい)を含む、損なわれていない(intact)抗体を指す。本明細書において、用語「抗体」はまた、F(ab)、F(ab’)、F(ab’)2、Fv、相補性決定領域(CDR)断片、一本鎖抗体(scFv)、またはこれらの組み合わせなどの抗体断片も指し、これらは、DNA組換え技術によって、あるいは損なわれていない抗体の酵素的または化学的切断によって、産生可能である。抗体にはまた、少なくとも、ポリペプチドに対して特異的抗原結合を与えるのに十分な免疫グロブリン部分を含有する、融合タンパク質などのポリペプチドも含まれる。抗体にはまた、dAb(VHドメイン)、ディアボディ(各々がVHおよびVL鎖を有する、2つのポリペプチド鎖を含む、二価抗体)、ならびにトリアボディおよびテトラボディ(各々がVHおよびVL鎖を有する、それぞれ、3つおよび4つのポリペプチド鎖を持つ抗体)。抗体にはまた、組換えDNA技術によって、あるいは損なわれていない抗体の酵素的または化学的切断によって産生される、ミニボディ(WO 94/09817に記載されるようなもの)、およびマキシボディまたはscFv−Fc融合体(Powersら, J. Immunol Meth 251, 123−135(2001))も含まれる。
TSLPに対するアンタゴニストには、TSLP、TSLPR、またはIL−7Rα/TSLPRヘテロ二量体受容体に結合し、リガンド−受容体結合を阻害するかまたは遮断し、そして/またはサイトカイン活性を減少させるかまたは遮断することが可能な、ペプチドおよびポリペプチドが含まれる。他の線維化促進性因子に対するペプチドおよびポリペプチド・アンタゴニストには、適用可能な場合、リガンド、リガンド受容体、またはヘテロ二量体受容体に結合可能なペプチドまたはポリペプチドが含まれる。本明細書において、用語「ポリペプチド」は、長さまたは翻訳後修飾にかかわらず、ペプチド結合によって連結されるいかなるアミノ酸鎖も指す。「ペプチド」は、一般的に、およそ2アミノ酸からおよそ50アミノ酸の間の、アミノ酸のより短い鎖を指す。ポリペプチドおよびペプチドには、天然タンパク質、合成または組換えポリペプチドおよびペプチドが含まれる。本明細書において、用語「アミノ酸」は、20の標準的なα−アミノ酸ならびに天然存在および合成誘導体を指す。ポリペプチドは、LまたはDアミノ酸あるいはその組み合わせを含有してもよい。本明細書において、用語「ペプチド模倣体」は、1以上のアミノ酸に対して置換された非アミノ酸構造を有する、ペプチド様構造を指す。
可溶性リガンド
ペプチドおよびポリペプチド・アンタゴニストには、可溶性リガンド・アンタゴニストが含まれる。本明細書において、用語「可溶性リガンド・アンタゴニスト」は、TSLP受容体または他の線維化促進性因子受容体、あるいはヘテロ二量体受容体に結合して、そしてサイトカイン受容体結合および/またはシグナル伝達および活性を遮断することが可能な、可溶性ペプチド、ポリペプチドまたはペプチド模倣体を指す。可溶性リガンド・アンタゴニストには、リガンドに対して実質的な相同性を維持するが、その活性は維持しない、サイトカインの変異体が含まれ、NまたはC末端一部切除(truncation)などの一部切除、置換、欠失、およびアミノ酸残基に対する非アミノ酸ペプチド模倣体の置換などのアミノ酸配列中の他の改変が含まれる。例えば、可溶性リガンド・アンタゴニストは、サイトカイン受容体に結合可能であるが、シグナル伝達を可能にしない。本発明の目的のため、タンパク質は、アミノ酸配列が互いに少なくとも80%、好ましくは少なくとも約90%、より好ましくは少なくとも約95%同一である場合に、別のタンパク質に「実質的に類似」である。
可溶性受容体
ペプチドおよびポリペプチド・アンタゴニストには、TSLP(または他の線維化促進性因子)に結合し、そして/またはTSLP受容体結合を遮断するかまたは阻害し、そしてそれによって、サイトカイン活性を減少させるかまたは遮断することが可能な、修飾されたかまたはそうでない、サイトカイン受容体の一部切除型または断片がさらに含まれる。サイトカイン受容体のこれらの一部切除型には、例えば、天然存在可溶性ドメイン、ならびに、NまたはC末端のタンパク質分解による変異が含まれる。可溶性ドメインには、単独か、あるいはさらなるペプチドまたは修飾に付着した、受容体の細胞外ドメインのすべてまたは一部が含まれる。ヒトTSLPRの可溶性ドメインは、配列番号4のほぼアミノ酸25〜231である。IL−7Rαの可溶性ドメインは、米国特許第5,264,416号の図2のほぼアミノ酸1〜219である。受容体の可溶性ドメインを、Fc融合体などの融合タンパク質として提供することもまた可能である。
ペプチドおよびポリペプチド
化学合成、タンパク質の消化、または組換え技術、ファージ・ディスプレイ、RNA−ペプチド・スクリーニング、および他のアフィニティー・スクリーニング技術を含む、当該技術分野に知られる方法いずれによって、本発明のペプチドおよびポリペプチド・アンタゴニストを生成してもよい。例えば、慣用的技術にしたがって、溶液中または固体支持体上で、ポリペプチドおよびペプチドを合成してもよい。多様な自動化合成装置が商業的に入手可能であり、そして既知のプロトコルにしたがって、こうした装置を用いてもよい。例えば、各々、本明細書に援用される、StewartおよびYoung(上記); Tamら, J Am Chem Soc, 105:6442, (1983); Merrifield, Science 232:341−347(1986); BaranyおよびMerrifield, The Peptides, GrossおよびMeienhofer監修, Academic Press, New York, 1−284; Baranyら, Int J Pep Protein Res, 30:705−739(1987);ならびに米国特許第5,424,398号を参照されたい。固相ペプチド合成のための方法が、例えば、Coliganら, Curr Prot Immunol, Wiley Interscience, 1991, Unit 9に記載される。
本発明記載のTSLPおよび他の線維化促進性サイトカインに対するアンタゴニストには、該サイトカインまたはその受容体の発現を防止するかまたは減少させるアンタゴニストが含まれる。これらには、標的mRNA(センス)またはDNA(アンチセンス)配列に結合可能な一本鎖ポリヌクレオチド配列(RNAまたはDNAいずれか)を含むアンチセンスまたはセンス・オリゴヌクレオチドが含まれる。本発明にしたがったアンチセンスまたはセンス・オリゴヌクレオチドは、サイトカインまたはその受容体いずれかをコードする、標的とされるポリヌクレオチド配列の断片を含む。こうした断片は、一般的に、少なくとも約14ヌクレオチド、典型的には、約14〜約30ヌクレオチドを含む。所定のタンパク質をコードする核酸配列に基づいて、アンチセンスまたはセンス・オリゴヌクレオチドを得る能力は、例えば、SteinおよびCohen(Cancer Res. 48:2659, 1988)、ならびにvan der Krolら(BioTechniques 6:958, 1988)に記載される。アンチセンスまたはセンス・オリゴヌクレオチドが標的核酸配列に結合した結果、RNAse HによるmRNAの分解増進、スプライシングの阻害、転写または翻訳の未成熟な終結を含むいくつかの手段の1つによって、あるいは他の手段によって、タンパク質の発現を遮断するかまたは阻害する二重鎖が形成される。こうして、アンチセンス・オリゴヌクレオチドを用いて、タンパク質の発現を遮断することも可能である。アンチセンスまたはセンス・オリゴヌクレオチドは、修飾糖−ホスホジエステル主鎖(またはWO91/06629に記載されるものなどの他の糖連結)を有するオリゴヌクレオチドをさらに含み、そしてここで、こうした糖連結は内因性ヌクレアーゼに耐性である。耐性糖連結を持つ、こうしたオリゴヌクレオチドは、in vivoで安定である(すなわち酵素分解に抵抗可能である)が、標的ヌクレオチド配列に結合可能な配列特異性を保持する。
本発明記載の1以上のTSLPアンタゴニストを含有する薬剤組成物は、本発明の範囲内である。さらに、線維化促進性因子に対するアンタゴニストに加えて、1以上のTSLPアンタゴニストを含有する薬剤組成物を提供する。こうした組成物は、薬学的に許容しうる材料と混合された、療法的または予防的有効量の各アンタゴニストを含む。本明細書において、有効量は、線維性障害に関して、被験体を治療するのに十分な量である。典型的には、アンタゴニストは、動物への投与のため、十分に精製されるであろう。
以下のプロトコルにしたがって、ネズミTSLP(R&D Systems)を15匹の8週齢Balb/c雌マウス(Charles River)に投与した。ネズミを各5匹の3群に分けた。第1群には、週3回、1週間注射し(総数3回の注射);第2群には、週3回、2週間注射し(総数6回の注射)、そして第3群には、週3回、6週間注射した(総数18回の注射)。マウスには、100μlのPBS中、10μgのTSLPを左わき腹に、そして対照として100μlのPBSを右わき腹に、皮内注射した。最後の注射の72時間後、動物を麻酔し、末端採血を行い、そしてさらなる分析のため、血清を単離した。皮膚を採取し、ホルマリン中で固定し、そして病理学的評価のため、H&E(ヘマトキシリンおよびエオジン)染色用のスライドを作製した。
これらの結果は、マウスの皮膚に精製TSLPを注射すると、早ければ注射後2週間で、上皮下線維芽細胞集積およびコラーゲン沈着が導かれることを立証する。この反応は、6週間の時間経過に渡って増加し、そして観察される皮膚の肥厚、浮腫、ならびに表皮、真皮および皮下組織における有意な細胞集積を伴った。この応答は、線維性疾患の促進におけるTSLPの関与を立証する。
Claims (31)
- 線維性障害を患う被験体において、線維化を減少させるかまたは防止する方法であって、被験体に療法的有効量の胸腺間質リンホポエチン・アンタゴニストを投与することを含む、前記方法。
- アンタゴニストが胸腺間質リンホポエチン結合剤である、請求項1の方法。
- 剤が、アンタゴニスト性抗体、ペプチドまたはポリペプチド結合剤、可溶性胸腺間質リンホポエチン受容体、可溶性IL−7受容体α/胸腺間質リンホポエチン・ヘテロ二量体受容体、あるいは小分子アンタゴニストからなる群より選択され、胸腺間質リンホポエチンに結合する、請求項2の方法。
- アンタゴニスト抗体が、ヒト抗体、ヒト化抗体、一本鎖抗体、または抗体断片からなる群より選択される、請求項3の方法。
- ペプチドまたはポリペプチド結合剤、可溶性受容体または可溶性ヘテロ二量体受容体が、Fcドメインをさらに含む、請求項3の方法。
- アンタゴニストが胸腺間質リンホポエチン受容体アンタゴニストである、請求項1の方法。
- アンタゴニストが、アンタゴニスト性抗体、可溶性リガンド、および小分子からなる群より選択され、胸腺間質リンホポエチン受容体に結合する、請求項6の方法。
- 抗体が、ヒト抗体、ヒト化抗体、一本鎖抗体、または抗体断片からなる群より選択される、請求項7の方法。
- 可溶性リガンドがFcドメインをさらに含む、請求項7の方法。
- アンタゴニストが、アンタゴニスト性抗体、可溶性リガンド、および小分子からなる群より選択され、IL−7受容体α/胸腺間質リンホポエチン受容体ヘテロ二量体に結合する、請求項6の方法。
- 抗体が、ヒト抗体、ヒト化抗体、一本鎖抗体、または抗体断片からなる群より選択される、請求項10の方法。
- 可溶性リガンドがFcドメインをさらに含む、請求項10の方法。
- 線維性障害が、強皮症、間質性肺疾患、特発性肺線維症、慢性B型またはC型肝炎から生じる線維症、放射線誘導性線維症、および創傷治癒から生じる線維症からなる群より選択される、請求項1の方法。
- 線維化促進性(profibrotic)サイトカインに対する第二のアンタゴニストを投与することをさらに含み、該サイトカインが、トランスフォーミング増殖因子β(TGF−β)、インターロイキン−4(IL−4)、インターロイキン−5(IL−5)、インターロイキン−9(IL−9)、インターロイキン−13(IL−13)、顆粒球/マクロファージ−コロニー刺激因子(GM−CSF)、腫瘍壊死因子アルファ(TNF−α)、インターロイキン−1ベータ(IL−1β)、結合組織増殖因子(CTGF)、インターロイキン−6(IL−6)、オンコスタチンM(OSM)、血小板由来増殖因子(PDGF)、単球走化性タンパク質1(CCL2/MCP−1)、ならびに肺および活性化制御ケモカイン(CCL18/PARC)より選択される、請求項1の方法。
- 線維性障害を患う被験体において、線維化を減少させるかまたは防止するための薬剤組成物であって、薬学的に許容しうるキャリアーと混合された、療法的有効量の胸腺間質リンホポエチン・アンタゴニストを含む、前記組成物。
- アンタゴニストが胸腺間質リンホポエチン結合剤である、請求項15の組成物。
- 剤が、アンタゴニスト性抗体、ペプチドまたはポリペプチド結合剤、可溶性胸腺間質リンホポエチン受容体、可溶性IL−7受容体α/胸腺間質リンホポエチン・ヘテロ二量体受容体、および小分子アンタゴニストからなる群より選択され、胸腺間質リンホポエチンに結合する、請求項16の組成物。
- アンタゴニスト抗体が、ヒト抗体、ヒト化抗体、一本鎖抗体、または抗体断片からなる群より選択される、請求項17の組成物。
- 可溶性受容体がFcドメインをさらに含む、請求項17の組成物。
- アンタゴニストが胸腺間質リンホポエチン受容体アンタゴニストである、請求項15の組成物。
- アンタゴニストが、アンタゴニスト性抗体、可溶性リガンド、および小分子からなる群より選択され、胸腺間質リンホポエチン受容体に結合する、請求項20の組成物。
- アンタゴニスト性抗体が、ヒト抗体、ヒト化抗体、一本鎖抗体、または抗体断片からなる群より選択される、請求項21の組成物。
- 可溶性リガンドがFcドメインをさらに含む、請求項21の組成物。
- アンタゴニストが、アンタゴニスト性抗体、可溶性リガンド、および小分子からなる群より選択され、IL−7受容体α/胸腺間質リンホポエチン受容体ヘテロ二量体に結合する、請求項20の組成物。
- アンタゴニスト性抗体が、ヒト抗体、ヒト化抗体、一本鎖抗体、または抗体断片からなる群より選択される、請求項24の組成物。
- 可溶性リガンドがFcドメインをさらに含む、請求項24の組成物。
- 線維性障害が、強皮症、間質性肺疾患、特発性肺線維症、慢性B型またはC型肝炎感染から生じる肝線維症、放射線誘導性線維症、および創傷治癒から生じる線維症からなる群より選択される、請求項15の組成物。
- 線維化促進性サイトカインに対する第二のアンタゴニストをさらに含み、該サイトカインが、トランスフォーミング増殖因子β(TGF−β)、インターロイキン−4(IL−4)、インターロイキン−5(IL−5)、インターロイキン−9(IL−9)、インターロイキン−13(IL−13)、顆粒球/マクロファージ−コロニー刺激因子(GM−CSF)、腫瘍壊死因子アルファ(TNF−α)、インターロイキン−1ベータ(IL−1β)、結合組織増殖因子(CTGF)、インターロイキン−6(IL−6)、オンコスタチンM(OSM)、血小板由来増殖因子(PDGF)、単球走化性タンパク質1(CCL2/MCP−1)、ならびに肺および活性化制御ケモカイン(CCL18/PARC)より選択される、請求項15の組成物。
- 組織中の線維芽細胞集積およびコラーゲン沈着を調節する方法であって、組織中の胸腺間質リンホポエチンの量または活性を調節することを含む、前記方法。
- 胸腺間質リンホポエチンまたは胸腺間質リンホポエチン受容体の量が減少する、請求項29の方法。
- 胸腺間質リンホポエチンまたは胸腺間質リンホポエチン受容体の量が、アンチセンス・オリゴヌクレオチドまたは干渉RNAの使用を通じて減少する、請求項30の方法。
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BR112012010707B1 (pt) | 2009-11-04 | 2022-08-30 | Merck Sharp & Dohme Corp | Anticorpo ou fragmento de ligação ao antígeno do mesmo, composição, e, uso do anticorpo ou fragmento de ligação ao antígeno do mesmo |
US9775921B2 (en) | 2009-11-24 | 2017-10-03 | Alderbio Holdings Llc | Subcutaneously administrable composition containing anti-IL-6 antibody |
US9724410B2 (en) | 2009-11-24 | 2017-08-08 | Alderbio Holdings Llc | Anti-IL-6 antibodies or fragments thereof to treat or inhibit cachexia, associated with chemotherapy toxicity |
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PL1843789T3 (pl) | 2011-09-30 |
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