JP2016196457A - インテグリンαvβ8中和抗体 - Google Patents
インテグリンαvβ8中和抗体 Download PDFInfo
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- JP2016196457A JP2016196457A JP2016079967A JP2016079967A JP2016196457A JP 2016196457 A JP2016196457 A JP 2016196457A JP 2016079967 A JP2016079967 A JP 2016079967A JP 2016079967 A JP2016079967 A JP 2016079967A JP 2016196457 A JP2016196457 A JP 2016196457A
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- αvβ8
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- C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
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Abstract
【解決手段】αvβ8と特異的に結合する単離された抗体であって、特定の配列のCDR1配列、特定配列のCDR2配列及び特定配列のCDR3を含む重鎖可変領域と、特定配列のCDR1配列、特定配列のCDR2配列で、XaaがチロシンであるCDR2配列及び特定配列のCDR3配列とを有する単離された抗体、好ましくはモノクロナール抗体。アイソタイプがIgG1、IgG2、IgG3又はIgG4である抗体。好ましくはヒト抗体又はヒト化抗体。
【選択図】なし
Description
本出願は、2010年2月18日に提出された米国仮出願第61/305,749号、および2010年12月30日に提出された米国仮出願第61/428,814号の優先権を主張し、それらの開示内容はその全体が参照により本明細書に組み入れられる。
本発明は、米国国立衛生研究所(National Institutes of Health)によって授与された助成金HL63993号、NS-44155号、U01 AI075443号の下で、政府の支援を受けて行われた。政府は本発明に一定の権利を有する。
多機能性サイトカインであるトランスフォーミング増殖因子-β(TGF-β)は、無脊椎動物種および脊椎動物種において、発育期および成体期における免疫細胞、内皮細胞、上皮細胞および間葉細胞の生物現象に大きな役割を果たしている。哺乳動物では、これらの機能は3種のアイソフォーム、TGF-β1、2および3によって媒介され、これらはそれぞれ広範に発現される。3種のアイソフォームはすべて、同じ細胞表面受容体(TGFBR2およびALK5)と相互作用し、同じ細胞内シグナル伝達経路を通じてシグナルを伝達し、それらの経路には古典的(canonical)(すなわち、SMAD)または非古典的(すなわち、MAPK、JUN、PI3K、PP2A、Rho、PAR6)シグナル伝達エフェクターが関与する。TGF-βシグナル伝達が、TGF-β受容体装置から、細胞質SMAD-2/3のリン酸化、SMAD-4との複合体形成、SMAD-2/3/4複合体の核移行、および、線維形成反応に関与する多くの遺伝子のプロモーター領域に位置するSMAD応答エレメントとの結合を経由して伝わる古典的TGF-βシグナル伝達経路は、非常に詳細に研究されている。しかし、各アイソフォームは、類似のシグナル伝達パートナーを有するものの、おそらくはTGF-β受容体に対する結合親和性、活性化機序、シグナル伝達の強度もしくは持続時間、または空間的および/もしくは時間的分布の違いによって、個別の生物学的機能を果たす。
[本発明1001]
活性のある成熟TGFβペプチドの放出を阻害するが、αvβ8発現細胞上のαvβ8に対する潜在型TGFβの接着を大きくは阻害しない、αvβ8と特異的に結合する単離された抗体。
[本発明1002]
β8と特異的に結合する、本発明1001の単離された抗体。
[本発明1003]
SEQ ID NO:11のポリペプチド配列中にあるβ8上のエピトープと特異的に結合する、本発明1001の単離された抗体。
[本発明1004]
αvβ8に対する結合に関して、SEQ ID NO:5、SEQ ID NO:6およびSEQ ID NO:7の3種の軽鎖CDRを含む軽鎖可変領域ならびにSEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10の3種の重鎖CDRを含む重鎖可変領域を有する抗体と競合する、本発明1001の単離された抗体。
[本発明1005]
SEQ ID NO:5、SEQ ID NO:6およびSEQ ID NO:7の3種の軽鎖CDRを含む軽鎖可変領域ならびにSEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10の3種の重鎖CDRを含む重鎖可変領域を有する、本発明1001の単離された抗体。
[本発明1006]
SEQ ID NO:3または4の軽鎖可変領域およびSEQ ID NO:1または2の重鎖可変領域を有する、本発明1001の単離された抗体。
[本発明1007]
アイソタイプがIgG1、IgG2、IgG3またはIgG4である、本発明1001の単離された抗体。
[本発明1008]
モノクローナル抗体である、本発明1001の単離された抗体。
[本発明1009]
ヒト抗体、ヒト化抗体またはキメラ抗体である、本発明1001の単離された抗体。
[本発明1010]
本発明1001の抗体および薬学的に許容される添加剤を含む薬学的組成物。
[本発明1011]
本発明1001の抗体をコードする、単離された核酸。
[本発明1012]
本発明1011の核酸を含む、単離された発現ベクター。
[本発明1013]
本発明1012のベクターを含む、単離された宿主細胞。
[本発明1014]
個体におけるTGFβ活性化を低減させる方法であって、本発明1001〜1009のいずれかの抗体をそれを必要とする個体に投与して、それにより、その個体におけるTGFβ活性化を低減させる段階を含む方法。
[本発明1015]
個体がヒトである、本発明1014の方法。
[本発明1016]
個体が、慢性閉塞性肺疾患(COPD)、喘息、関節炎、線維性障害、炎症性脳自己免疫疾患、多発性硬化症、脱髄性疾患(例えば、横断性脊髄炎、デビック病、ギラン・バレー症候群)、神経炎症、腎疾患、腺癌、扁平上皮癌、神経膠腫、乳癌、ならびに癌の増殖および転移からなる群より選択される少なくとも1つの病状を有し、かつTGFβの低減が病状の改善をもたらす、本発明1014の方法。
[本発明1017]
線維性障害が、気道線維症、特発性肺線維症、非特異的間質性肺炎、感染後肺線維症、びまん性肺胞障害、膠原血管病関連肺線維症、薬剤誘発性肺線維症、珪肺症、アスベスト関連肺線維症、呼吸細気管支炎、呼吸細気管支炎間質性肺疾患、剥離性間質性線維症、特発性器質化肺炎、慢性過敏性肺炎、薬剤関連肺線維症、腎線維症および肝線維症からなる群より選択される、本発明1016の方法。
[本発明1018]
生物試料中のインテグリンβ8の存在を判定する方法であって、
生物試料を、標識化抗体を形成させるための検出可能な標識と結びつけられた本発明1001〜1009のいずれかの抗体と接触させる段階;および
標識化抗体の存在を検出して、それにより、インテグリンβ8の存在を判定する段階
を含む方法。
[本発明1019]
判定がインビトロにおいてである、本発明1018の方法。
[本発明1020]
判定がインビトロにおいてである、本発明1018の方法。
[本発明1021]
慢性閉塞性肺疾患(COPD)、喘息、関節炎、線維性障害、炎症性脳自己免疫疾患、多発性硬化症、脱髄性疾患(例えば、横断性脊髄炎、デビック病、ギラン・バレー症候群)、神経炎症、腎疾患、腺癌、扁平上皮癌、神経膠腫、乳癌、ならびに癌の増殖および転移からなる群より選択される病状を検出するために用いられる、本発明1018の方法。
[本発明1022]
個体におけるTGFβ活性化を低減させる方法であって、インテグリンαvβ8のアンタゴニストをそれを必要とする個体に投与して、それにより、その個体におけるTGFβ活性化を低減させる段階を含む方法。
[本発明1023]
アンタゴニストが、活性のある成熟TGFβペプチドの放出を阻害するが、αvβ8発現細胞上のαvβ8に対する潜在型TGFβの接着を大きくは阻害しない、本発明1022の方法。
[本発明1024]
個体がヒトである、本発明1022の方法。
[本発明1025]
アンタゴニストがαvβ8と特異的に結合する抗体である、本発明1022の方法。
[本発明1026]
個体が、慢性閉塞性肺疾患(COPD)、喘息、関節炎、線維性障害、炎症性脳自己免疫疾患、多発性硬化症、脱髄性疾患(例えば、横断性脊髄炎、デビック病、ギラン・バレー症候群)、神経炎症、腎疾患、腺癌、扁平上皮癌、神経膠腫、乳癌、ならびに癌の増殖および転移からなる群より選択される少なくとも1つの病状を有し、かつTGFβの低減が病状の改善をもたらす、本発明1022の方法。
[本発明1027]
線維性障害が、気道線維症、特発性肺線維症、非特異的間質性肺炎、感染後肺線維症、びまん性肺胞障害、膠原血管病関連肺線維症、薬剤誘発性肺線維症、珪肺症、アスベスト関連肺線維症、呼吸細気管支炎、呼吸細気管支炎間質性肺疾患、剥離性間質性線維症、特発性器質化肺炎、慢性過敏性肺炎、薬剤関連肺線維症、腎線維症および肝線維症からなる群より選択される、本発明1026の方法。
序論
本発明は一部、ある種の抗αvβ8アンタゴニスト、抗αvβ8抗体またはイムノコンジュゲートが、αvβ8媒介性のTGF-β活性化を選択的に擾乱させるが、固定化したTGF-βに対するαvβ8発現細胞の細胞接着は擾乱させないという発見に基づく。したがって、本発明は、個体におけるTGFβ活性化を低減させる方法であって、αvβ8のアンタゴニスト(例えば、低分子、抗αvβ8抗体またはイムノコンジュゲート)をそれを必要とする個体に投与して、それにより、その個体におけるTGFβ活性化を低減させることによる方法を対象とする。本発明はまた、SEQ ID NO:5、SEQ ID NO:6およびSEQ ID NO:7の3種の軽鎖CDRを含む軽鎖可変領域ならびにSEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10の3種の重鎖CDRを含む重鎖可変領域を有する抗体も提供する。
「インテグリンβ8」という用語は、itgb8、ITGB8、β8などの用語と互換的に用いられる。ITGB8は典型的には、ヒト配列のことを指して用いられ、一方、itgb8はマウス配列のことを指す。ヒトタンパク質配列はUniprotアクセッション番号P26012で見ることができ、一方、マウス配列はUniprotアクセッション番号Q0VBD0を有する。
トランスフォーミング増殖因子β(TGFβ)は当初、培養下にある非新生物性細胞における形質転換表現型を誘導することのできるタンパク質(腫瘍細胞株より分泌される)として特徴づけられた。この効果は、TGFβの除去後に細胞が正常表現型に復帰したことによって実証されたように、可逆的であった。現時点で、TGFβ1〜TGFβ5が同定されている。これらのタンパク質は類似したアミノ酸領域を有する。
TGFβ活性化を共培養アッセイで判定するためには、αvβ8を発現する被験細胞を、ルシフェラーゼ遺伝子を作動させるプラスミノーゲンアクチベーターインヒビター-1プロモーターのTGF-β応答性断片を安定的にトランスフェクトしたミンク肺上皮細胞であるTMLC細胞と共培養する(Abe et al. (1994) Annal Biochem 216:276)。TMLC細胞はTGFβに対する応答性が高く、それが生じるTGFβ活性化のバックグラウンド値は極めて低い。TMLC細胞はこのため、発光を読み取り値として用いて活性TGFβの存在に関して検査するために、他の細胞株との共培養下または無細胞画分中で用いることができる。アッセイは、記載された通り(Abe (1994);Munger (1999)に、抗TGFβ阻止抗体(10μg/ml、1D11;R&D Systems)、抗β8(20μg/ml、37E1B5)または抗β6(150μg/ml、10D5)の存在下または非存在下で行う。
本発明は、インテグリンαvβ8と特異的に結合するが、他のインテグリン(例えば、αvβ6、αvβ3など)とは顕著には結合しない抗体を提供する。本発明の抗体は、αvβ8中の特定のエピトープまたはエピトープ領域と結合する。エピトープは立体構造(非直線的)エピトープであっても非立体構造エピトープであってもよい。そのような抗体はβ8のみと結合することができ、すなわち、そのエピトープはβ8の内部に位置する。本発明の抗体の結合が、β8の外側のエピトープ領域、例えば立体構造エピトープ、またはαv内部およびβ8内部の両方に由来するエレメントに依存するものを必要としてもよい。
天然性または合成性である、インテグリンαvβ8のさまざまなアンタゴニストを用いうることも想定している。そのようなアンタゴニストには、例えばペプチドまたは低分子が含まれる。アンタゴニストには、例えば、医薬品、治療薬、環境物質、農業用または産業用物質、汚染物質、薬用化粧品、薬剤、有機化合物、脂質、グルココルチコイド、抗生物質、ペプチド、タンパク質、糖、糖質およびキメラ分子が含まれうる。いくつかの態様において、インテグリンαvβ8のアンタゴニストは、TGFβ特異的ペプチド、例えばTGFβ1特異的ペプチドまたはTGFβ3特異的ペプチドである。TGFβ特異的ペプチドの例には、GRRGDLATIHを含むペプチド(Mu et al. (2002) Journal of Cell Biology 157:493-507)およびHGRGDLGRLKを含むペプチドが非限定的に含まれる。いくつかの態様において、アンタゴニストは、TGFβ活性化を低減させるが、TGFβに対するαvβ8媒介性の細胞接着を大きくは阻害しない。
本発明の抗αvβ8アンタゴニスト、抗αvβ8抗体またはイムノコンジュゲート、組成物および方法は、慢性閉塞性肺疾患(COPD)および喘息を検出、治療または予防するために用いることができる。
検出可能なモイエティーを、直接的に、または例えばキレート剤もしくはリンカーを介して間接的に、本発明の抗体に付随させることができる。続いて、意図する治療法の適用可能性を判定するために、標識化抗体を個体に与える。例えば、標識化抗体を用いて罹患部におけるインテグリンβ8密度を検出することができ、その密度は典型的には非罹患組織に比して高い。また、標識化抗体は、罹患部に治療法が到達しうることも指し示すことができる。このようにして、患者を撮像結果に基づいて治療法に関して選択することができる。癌の正確な境界を判定するというような解剖学的特徴決定は、古典的な撮像手法(例えば、CT スキャニング、MRI、PETスキャニングなど)を用いて達成することができる。
抗αvβ8アンタゴニスト、抗αvβ8抗体またはイムノコンジュゲートは、ヒト患者に対して、公知の方法に従って、例えば、ボーラスとしてもしくは一定期間にわたる連続注入による静脈内投与、筋肉内、腹腔内、脳脊髄内(intracerobrospinal)、皮下、関節内、滑膜内、髄腔内、経口、局部(例えば、経皮的)または吸入経路などによって投与される。抗体の静脈内投与または皮下投与が好ましい。投与は局所性でも全身性でもよい。
トランスフォーミング増殖因子-β(TGF-β)は、炎症性反応および線維形成反応に関与するサイトカインである。本発明者らは以前に、IL-1βがβ8の発現をアップレギュレートすること、およびCOPD患者の気道内ではβ8発現が増大していることを示した。しかし、β8、TGF-βおよびIL-1βの相互作用はインビボではほとんど解明されていないことから、本発明者らはβ8媒介性気道リモデリングのマウスモデルを開発することにした。本明細書において、本発明者らは、IL-1-β誘発性でβ8媒介性のTGF-β活性化が、気道リモデリングにおいて決定的な役割を果たすことを示す。
本発明者らは、ヒトインテグリンαvβ8とそのリガンドであるトランスフォーミング増殖因子-β(TGF-β)との相互作用を選択的に阻止するマウスモノクローナル抗体(クローン37E1と命名、アイソタイプIgG2a)を作製した。TGF-βは、哺乳動物において3種のアイソフォーム(TGF-β 1〜3)として遍在性に発現されるが、そのプロペプチドであるTGF-βの潜在性関連ドメイン(LAP)とのその非共有結合性相互作用によって、不活性形態に維持される。インテグリンαvβ8はTGF-βのLAPと結合して、TGF-β1および3の活性化を媒介する。生殖細胞遺伝子欠失試験または条件的遺伝子欠失試験により、インテグリンαvβ8媒介性のTGF-β活性化がTGF-βのインビボ活性化のためには必須であり、それ故にαvβ8はTGF-β機能の「ゲートキーパー」であることが明らかになっている。特に、インテグリンαvβ8媒介性のTGF-β活性化は、COPD、肺線維症、腎線維症、炎症性脳自己免疫疾患(多発性硬化症および脱髄性疾患)、神経炎症、腎疾患、ならびに癌の増殖および転移の病態に関与する可能性が高い。一般に、インテグリンは接着分子であり、細胞外マトリックスタンパク質に対する細胞の接着を媒介する。クローン37E1は、それがαvβ8媒介性のTGF-β活性化を選択的に擾乱させ、固定化または分泌されたTGF-βに対するαvβ8の結合に対してはそうでないという点で特徴的である。このことは、インテグリンαvβ8媒介性のTGF-β活性化のみを擾乱させ、阻害することが望ましくない可能性のある細胞接着性は擾乱させないという高度の選択性をもたらす。加えて、TGF-βは必須なホメオスタシス性の上皮および免疫エフェクターであるため、TGF-βの全般的不活性化は望ましくない副作用を伴う可能性が高い。
本発明者らは、クローン37E1の重鎖および軽鎖の可変領域を操作し、さらに酵母ディスプレイシステムにおけるランダム突然変異誘発および鎖シャッフリングを用いて、より親和性の高い抗体を作り出した。本発明者らは同じ抗原に対してより高度の親和性を付与する特異的なアミノ酸置換を同定し、本発明者らはこれらの突然変異を機能に応じて大きく分類した。それらの突然変異体の1つは37E1B5と命名された。これはインビトロで親和性の増大を示し、培養細胞におけるインテグリンαvβ8媒介性のTGF-β活性化を阻害する効果がより強かった。インビトロでの37E1B5抗体の有効治療用量はピコモル濃度の範囲であった。より優れた診断用および治療用の用途のために、本発明者らは、37E1B5の以下の3種のバージョンを作製した:マウスIgG1、マウスIgG2aおよび部分的ヒト化IgG1。いずれも形質転換CHO細胞において産生させた。
本発明者らは、ヒトβ8を発現するヒト化BACトランスジェニックマウスを作出し、マウスインテグリンαvβ8欠失の致死効果のレスキューを目的として、それをβ8 koマウスと交雑させた。このヒト化マウスは、肺疾患、脳疾患、肝疾患および腎疾患のモデルにおける高親和性クローンの毒性および有効性を試験するために用いうると考えられる。
ECM産生の増大および線維芽細胞収縮性の増大は、気道壁肥厚における線維化反応で認められる顕著な特徴であり、I型コラーゲン(Col I)の増加およびSMA(αSMA)の増加はその反応の重要な生化学マーカーである。線維形成促進性の線維芽細胞表現型に対する自己分泌αvβ8媒介性のTGF-β活性化の寄与を評価するために、本発明者らは、中和性抗β8を用いた。β8阻止抗体による気道線維芽細胞の処理はαSMA発現およびCol I分泌を阻害したことから、自己分泌αvβ8媒介性のTGF-β活性化は筋線維芽細胞の表現型に影響を及ぼした。気道線維芽細胞と扁平化生ヒト気管支上皮細胞との共培養は、気道線維芽細胞によるCol I転写およびタンパク質産生の増加を導いた。コラーゲンの産生増加はIL-1β依存性および線維芽細胞β8依存性であった。扁平化生ヒト気管支上皮細胞との共培養によるCol I発現の増大は、IL-1 RAとの共培養処理によって、またはβ8 siRNAによる気道線維芽細胞のトランスフェクションによって、ほぼ完全に阻害することができた。
マウス配列をヒトITGB8にスワッピングしたキメラ性インテグリンβ8構築物を、37E1B5結合エピトープの位置決定のために用いた。エピトープの位置決定は、抗体結合、細胞表面染色、およびフローサイトメトリーによる検出によって行った。37E1B5エピトープはヒトインテグリンβ8のアミノ酸74〜180の範囲に含まれる。37E1B5はヒトβ8と結合するが、マウスβ8とは結合しない。このため、9種の非保存的なアミノ酸の違い、または7種の軽微なアミノ酸の違い(配列の中心線に+で表示)のうち少なくとも1つを、結合エピトープに含めた。これらのドメインは、インテグリンβ8サブユニットのPsi、ハイブリッド(hybrid)、およびβ-Iドメインのα1ヘリックスとして知られる区域の部分を反映し、これらは分子の表面上に認められる。
本発明者らは、組織染色および初代培養によって実証されたように、ヒトCOPD患者の肺由来の線維芽細胞においてインテグリンβ8の発現が増大していることを見いだした。加えて、インテグリンβ8の発現は、特発性肺線維症の患者から単離した線維芽細胞でも、正常患者由来の線維芽細胞と比較して増大している。本発明者らはまた、COPD線維芽細胞では、IL-1β依存性のインテグリンαvβ8タンパク質発現が、正常肺線維芽細胞と比較して増大していることも見いだした。これらのデータは、αvβ8がIL-1βの効果の下流標的および病的メディエーターの両方であることを実証している。
本発明者らは、ヒトBACクローンRP11-431K20を用いて、BACトランスジェニックマウス3種の系統を作製した。これらのマウスを、マウスitgb8の機能性アレルを1つ有するマウスと交配させて、ヒトITGB8およびマウスitgb8の機能性コピー1つを有するマウスのF1世代を作製した。これらのマウスの交雑育種によってF2世代を作製したところ、その結果、生存能力のあるBAC ITGB8、すなわちその遺伝子のヒトコピーを有するitgb8 -/-マウスが得られ、これにより、itgb8 -/-致死性のレスキューが実証された。
慢性骨関節炎に対して膝の選択的修復術を受ける患者の膝の関節腔から、成人関節軟骨を採取した。初代軟骨細胞を集密度70%まで増殖させて、インテグリン受容体の発現を細胞染色およびフローサイトメトリーによって判定した。用いた抗体は抗β8(37E1B5)および抗β6(E7P6)であった。37E1B5では強い染色が検出され、E7P6では染色が全く認められなかった。TGF-βバイオアッセイ物において、抗β8(37E1B5)または中和性抗β6の存在下または非存在下で、初代軟骨細胞をTMLC TGF-βレポーター細胞(Annes et al. (2004) J. Cell Biol. 165:723)と共培養した。抗β8はTGF-β活性化の強い阻止を生じたが、一方、抗β6はそのような効果を全く生じなかった。
Claims (27)
- 活性のある成熟TGFβペプチドの放出を阻害するが、αvβ8発現細胞上のαvβ8に対する潜在型TGFβの接着を大きくは阻害しない、αvβ8と特異的に結合する単離された抗体。
- β8と特異的に結合する、請求項1記載の単離された抗体。
- SEQ ID NO:11のポリペプチド配列中にあるβ8上のエピトープと特異的に結合する、請求項1記載の単離された抗体。
- αvβ8に対する結合に関して、SEQ ID NO:5、SEQ ID NO:6およびSEQ ID NO:7の3種の軽鎖CDRを含む軽鎖可変領域ならびにSEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10の3種の重鎖CDRを含む重鎖可変領域を有する抗体と競合する、請求項1記載の単離された抗体。
- SEQ ID NO:5、SEQ ID NO:6およびSEQ ID NO:7の3種の軽鎖CDRを含む軽鎖可変領域ならびにSEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10の3種の重鎖CDRを含む重鎖可変領域を有する、請求項1記載の単離された抗体。
- SEQ ID NO:3または4の軽鎖可変領域およびSEQ ID NO:1または2の重鎖可変領域を有する、請求項1記載の単離された抗体。
- アイソタイプがIgG1、IgG2、IgG3またはIgG4である、請求項1記載の単離された抗体。
- モノクローナル抗体である、請求項1記載の単離された抗体。
- ヒト抗体、ヒト化抗体またはキメラ抗体である、請求項1記載の単離された抗体。
- 請求項1記載の抗体および薬学的に許容される添加剤を含む薬学的組成物。
- 請求項1記載の抗体をコードする、単離された核酸。
- 請求項11記載の核酸を含む、単離された発現ベクター。
- 請求項12記載のベクターを含む、単離された宿主細胞。
- 個体におけるTGFβ活性化を低減させる方法であって、請求項1〜9のいずれか一項記載の抗体をそれを必要とする個体に投与して、それにより、その個体におけるTGFβ活性化を低減させる段階を含む方法。
- 個体がヒトである、請求項14記載の方法。
- 個体が、慢性閉塞性肺疾患(COPD)、喘息、関節炎、線維性障害、炎症性脳自己免疫疾患、多発性硬化症、脱髄性疾患(例えば、横断性脊髄炎、デビック病、ギラン・バレー症候群)、神経炎症、腎疾患、腺癌、扁平上皮癌、神経膠腫、乳癌、ならびに癌の増殖および転移からなる群より選択される少なくとも1つの病状を有し、かつTGFβの低減が病状の改善をもたらす、請求項14記載の方法。
- 線維性障害が、気道線維症、特発性肺線維症、非特異的間質性肺炎、感染後肺線維症、びまん性肺胞障害、膠原血管病関連肺線維症、薬剤誘発性肺線維症、珪肺症、アスベスト関連肺線維症、呼吸細気管支炎、呼吸細気管支炎間質性肺疾患、剥離性間質性線維症、特発性器質化肺炎、慢性過敏性肺炎、薬剤関連肺線維症、腎線維症および肝線維症からなる群より選択される、請求項16記載の方法。
- 生物試料中のインテグリンβ8の存在を判定する方法であって、
生物試料を、標識化抗体を形成させるための検出可能な標識と結びつけられた請求項1〜9のいずれか一項記載の抗体と接触させる段階;および
標識化抗体の存在を検出して、それにより、インテグリンβ8の存在を判定する段階
を含む方法。 - 判定がインビトロにおいてである、請求項18記載の方法。
- 判定がインビトロにおいてである、請求項18記載の方法。
- 慢性閉塞性肺疾患(COPD)、喘息、関節炎、線維性障害、炎症性脳自己免疫疾患、多発性硬化症、脱髄性疾患(例えば、横断性脊髄炎、デビック病、ギラン・バレー症候群)、神経炎症、腎疾患、腺癌、扁平上皮癌、神経膠腫、乳癌、ならびに癌の増殖および転移からなる群より選択される病状を検出するために用いられる、請求項18記載の方法。
- 個体におけるTGFβ活性化を低減させる方法であって、インテグリンαvβ8のアンタゴニストをそれを必要とする個体に投与して、それにより、その個体におけるTGFβ活性化を低減させる段階を含む方法。
- アンタゴニストが、活性のある成熟TGFβペプチドの放出を阻害するが、αvβ8発現細胞上のαvβ8に対する潜在型TGFβの接着を大きくは阻害しない、請求項22記載の方法。
- 個体がヒトである、請求項22記載の方法。
- アンタゴニストがαvβ8と特異的に結合する抗体である、請求項22記載の方法。
- 個体が、慢性閉塞性肺疾患(COPD)、喘息、関節炎、線維性障害、炎症性脳自己免疫疾患、多発性硬化症、脱髄性疾患(例えば、横断性脊髄炎、デビック病、ギラン・バレー症候群)、神経炎症、腎疾患、腺癌、扁平上皮癌、神経膠腫、乳癌、ならびに癌の増殖および転移からなる群より選択される少なくとも1つの病状を有し、かつTGFβの低減が病状の改善をもたらす、請求項22記載の方法。
- 線維性障害が、気道線維症、特発性肺線維症、非特異的間質性肺炎、感染後肺線維症、びまん性肺胞障害、膠原血管病関連肺線維症、薬剤誘発性肺線維症、珪肺症、アスベスト関連肺線維症、呼吸細気管支炎、呼吸細気管支炎間質性肺疾患、剥離性間質性線維症、特発性器質化肺炎、慢性過敏性肺炎、薬剤関連肺線維症、腎線維症および肝線維症からなる群より選択される、請求項26記載の方法。
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