JP2016530223A - レクチン様酸化ldl受容体1抗体および使用法 - Google Patents
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Abstract
Description
血管疾患は依然として、全世界において、有病率および死亡率の主要原因のうちの1つである。従来の危険因子を標的とする薬物は、血管危険性の一部を低下させる。しかし、実験データおよび臨床データは、他の新規の因子が、冠動脈疾患、大脳動脈疾患、および末梢動脈疾患、ならびにそれらの臨床症状の危険性のより大きな部分を説明しうることを示唆する。
本発明は、ヒトレクチン様酸化LDL(低密度リポタンパク質)受容体1(以下、場合によって、「LOX−1」と称する)に結合するモノクローナル抗体、ならびにこれを含む医薬組成物および処置方法に関する。
別段に定義されない限り、本明細書で使用される全ての技術的および科学的用語は、本発明が関する技術分野の当業者により一般的に理解される意味と同じ意味を有する。
本発明は部分的に、LOX−1に特異的に結合し、その生物学的活性を阻害する抗体分子の発見に基づく。本発明は、完全IgGフォーマットの抗体、ならびにFab断片(例えば、抗体のE2E10、FF1、FF3、FF4、FF5、およびFF6)など、それらの抗原結合性断片の両方に関する。
本発明は、LOX−1に特異的に結合し、その酸化促進活性および炎症促進活性を含む、その生物学的活性を阻害する抗体を提供する。酸化修飾されたLDL(oxLDL)の受容体であるLOX−1は、血管細胞(内皮細胞および平滑筋細胞)、好中球、単球およびマクロファージ、および血小板の表面上で発現する。さらに、LOX−1は、ヒトおよび動物のアテローム性動脈硬化性病変を含む血管疾患において上方調節される(Kataoka H, et al., Circulation 99; 3110-3117)。LOX−1はまた、全身性炎症性疾患/全身性自己免疫疾患(例えば、関節リウマチ、ブドウ膜炎、加齢黄斑変性、および子癇前症)においても上方調節される。OxLDLは、血管疾患の発症機序に関与している。oxLDLに加えて、LOX−1は、アセチル化LDL、終末糖化産物(AGE)、熱ショックタンパク質70、(HSP70)、アポトーシス性細胞、老化赤血球、白血球、活性化血小板、細菌、ホスファチジルセリン、およびC反応性タンパク質(CRP)を含む他のリガンドにも結合する。
本発明は、LOX−1に特異的に結合する抗体を提供する。いくつかの実施形態では、本発明は、ヒト、およびカニクイザルLOX−1にも特異的に結合する抗体を提供する。本発明の抗体は、実施例で記載される通りに単離されたヒトモノクローナル抗体およびFabを含むがこれらに限定されない。
さらに別の実施形態では、本発明は、表1に記載されている配列と相同なアミノ酸配列を含む、抗体またはその抗原結合性断片を提供するが、抗体は、LOX−1タンパク質(例えば、ヒト、およびカニクイザルLOX−1)に結合し、表1に記載されている抗体の所望の機能的特性を保持する。
ある種の実施形態では、本発明の抗体は、CDR1配列、CDR2配列、およびCDR3配列を含む重鎖可変領域、ならびにCDR1配列、CDR2配列、およびCDR3配列を含む軽鎖可変領域を有し、この場合、これらのCDR配列のうちの1つまたは複数は、本明細書で記載される抗体またはそれらの保存的修飾に基づき指定されたアミノ酸配列を有し、抗体は、本発明のLOX−1結合性抗体の所望の機能的特性を保持する。
本発明は、表1に記載されているLOX−1結合性抗体と同じエピトープに結合する抗体を提供する。したがって、LOX−1結合アッセイ(実施例で記載されるLOX−1結合アッセイなど)において、本発明の他の抗体と競合する(例えば、本発明の他の抗体の結合を、統計学的に有意な形で競合的に阻害する)それらの能力に基づき、さらなる抗体を同定することができる。本発明の抗体の、LOX−1タンパク質への結合を阻害する被験抗体の能力により、被験抗体が、その抗体と、LOX−1への結合について競合することが可能であり、このような抗体は、非限定的な理論によれば、LOX−1タンパク質上の、それが競合する抗体と同じであるかまたは関連の(例えば、構造的に類似するか、または空間的に近接した)エピトープに結合しうることが裏付けられる。ある種の実施形態では、本発明の抗体と同じLOX−1上のエピトープに結合する抗体は、ヒトモノクローナル抗体である。このようなヒトモノクローナル抗体は、本明細書で記載される通りに、調製および単離することができる。本明細書で使用される通り、等モル濃度の競合抗体の存在下で、競合抗体が、本発明の抗体または抗原結合性断片のLOX−1との結合を、50%を超えて(例えば、80%、85%、90%、95%、98%、または99%)阻害するとき、抗体は、結合について「競合する」。
出発抗体から特性を改変した修飾抗体を操作する出発材料として、本明細書で示されるVH配列および/またはVL配列のうちの1つまたは複数を有する抗体を使用して、本発明の抗体をさらに調製することができる。抗体は、一方または両方の可変領域(すなわち、VHおよび/またはVL)内、例えば、1つもしくは複数のCDR領域内、および/または1つもしくは複数のフレームワーク領域内の1つまたは複数の残基を修飾することにより操作することができる。加えて、または代替的に、抗体は、定常領域内の残基を修飾して、例えば、抗体のエフェクター機能を改変することによっても操作することができる。
結果として得られるポリペプチドが、LOX−1に特異的に結合する少なくとも1つの結合性領域を含む限りにおいて、多種多様な抗体/免疫グロブリンのフレームワークまたは足場を援用することができる。このようなフレームワークまたは足場は、ヒト免疫グロブリンまたはそれらの断片の5つの主要なイディオタイプを含み、好ましくはヒト化側面を有する他の動物種の免疫グロブリンを含む。この点で、ラクダ科動物において同定される単一重鎖抗体などの単一重鎖抗体は、特に対象である。当業者により、新規のフレームワーク、足場、および断片が、発見および開発され続けている。
ラマ種(アルパカ(Lama paccos)、ラマ(Lama glama)、およびビクーニャ(Lama vicugna))などの新世界メンバーを含む、ラクダおよびヒトコブラクダ(dromedary)(フタコブラクダ(Camelus bactrianus)およびヒトコブラクダ(Calelus dromaderius))ファミリーのメンバーから得られる抗体タンパク質は、サイズ、構造的複雑性、およびヒト対象に対する抗原性に関して特徴付けられている。天然で見出されるこのファミリーの哺乳動物に由来するある種のIgG抗体は、軽鎖を欠き、したがって、他の動物に由来する抗体の場合の、2つの重鎖および2つの軽鎖を有する、典型的な4つの鎖の四次構造とは構造的に異なっている。PCT/EP93/02214(1994年3月3日に公表されたWO94/04678)を参照されたい。
別の態様では、本発明は、本発明のLOX−1結合性抗体またはその断片を含む二特異性分子または多特異性分子を特色とする。本発明の抗体またはその抗原結合性領域は、少なくとも2つの異なる結合性部位または標的分子に結合する二特異性分子を作り出すように誘導体化することもでき、別の機能的分子、例えば、別のペプチドまたはタンパク質(例えば、受容体に対する別の抗体またはリガンド)へと連結することもできる。本発明の抗体は実際、3つ以上の異なる結合性部位および/または標的分子に結合する多特異性分子を作り出すように誘導体化することもでき、他の2つ以上の機能的分子へと連結することもでき、このような多特異性分子はまた、本明細書で使用される「二特異性分子」という用語により包含されることも意図される。本発明の二特異性分子を創出するには、本発明の抗体を、二特異性分子が結果として得られるように、別の抗体、抗体断片、ペプチド、または結合性模倣体など、1つまたは複数の他の結合性分子へと機能的に連結する(例えば、化学的カップリング、遺伝子融合、非共有結合的会合により、またはこれら以外の形で)ことができる。
本発明は、in vivoにおける半減期を延長した、LOX−1タンパク質に特異的に結合する抗体を提供する。
本発明は、融合タンパク質を作り出すように、異種タンパク質または異種ポリペプチドへと(またはその断片、好ましくは、少なくとも10、少なくとも20、少なくとも30、少なくとも40、少なくとも50、少なくとも60、少なくとも70、少なくとも80、少なくとも90、または少なくとも100アミノ酸のポリペプチドへと)、組換えにより融合させるかまたは化学的にコンジュゲートさせた(共有結合的コンジュゲーションおよび非共有結合的コンジュゲーションの両方を含む)、LOX−1タンパク質に特異的に結合する抗体またはそれらの断片を提供する。特に、本発明は、本明細書で記載される抗体の抗原結合性断片(例えば、Fab断片、Fd断片、Fv断片、F(ab)2断片、VHドメイン、VH CDR、VLドメイン、またはVL CDR)と、異種タンパク質、異種ポリペプチド、または異種ペプチドとを含む融合タンパク質を提供する。当技術分野では、タンパク質、ポリペプチド、またはペプチドを、抗体または抗体断片と融合またはコンジュゲートさせる方法が知られている。例えば、米国特許第5,336,603号、同第5,622,929号、同第5,359,046号、同第5,349,053号、同第5,447,851号、および同第5,112,946号;欧州特許第EP307,434および同第EP367,166号;国際特許公開第WO96/04388号および同第WO91/06570号;Ashkenaziら、1991、Proc. Natl. Acad. Sci. USA 88:10535〜10539; Zhengら、1995、J. Immunol. 154:5590〜5600;およびVilら、1992、Proc. Natl. Acad. Sci. USA 89:11337〜11341を参照されたい。
抗体をコードする核酸
本発明は、上記で記載したLOX−1結合性抗体鎖のセグメントまたはドメインを含むポリペプチドをコードする、実質的に精製された核酸分子を提供する。本発明の核酸のいくつかは、配列番号15、35、55、75、または95に示される重鎖可変領域をコードするヌクレオチド配列、および/または配列番号25、45、65、85、または105に示される軽鎖可変領域をコードするヌクレオチド配列を含む。具体的な実施形態では、核酸分子は、表1において同定される核酸分子である。本発明の他のいくつかの核酸分子は、表1において同定される核酸分子のヌクレオチド配列と実質的に(例えば、少なくとも65、80%、95%、または99%)同一なヌクレオチド配列を含む。適切な発現ベクターから発現させるとき、これらのポリヌクレオチドによりコードされるポリペプチドは、LOX−1抗原結合能を呈示することが可能である。
モノクローナル抗体(mAb)は、従来のモノクローナル抗体法、例えば、Kohler and Milstein, 1975 Nature 256: 495による標準的な体細胞ハイブリダイゼーション法を含む、様々な技法により作製することができる。モノクローナル抗体を作製するための多くの技法、例えば、Bリンパ球のウイルス性形質転換または発がん性形質転換を援用することができる。
本発明の操作抗体は、例えば、抗体の特性を改善するように、VHおよび/またはVL内のフレームワーク残基へと修飾を施した操作抗体を含む。このようなフレームワーク修飾は、抗体の免疫原性を低下させるように施すことが典型的である。例えば、1つの手法は、1つまたは複数のフレームワーク残基を、対応する生殖細胞系列配列へと「復帰突然変異させる」ことである。より具体的には、体細胞突然変異を経た抗体は、抗体が由来する生殖細胞系列配列と異なるフレームワーク残基を含有しうる。このような残基は、抗体フレームワーク配列を、抗体が由来する生殖細胞系列配列と比較することにより同定することができる。フレームワーク領域配列を、それらの生殖細胞系列の立体配置へと戻すには、例えば、部位特異的突然変異誘発により、体細胞突然変異を、生殖細胞系列配列へと「復帰突然変異させる」ことができる。このような「復帰突然変異させた」抗体もまた、本発明により包含されることを意図する。
上記で論じた通り、本明細書で示されるVH配列およびVL配列または全長重鎖および全長軽鎖配列を有するLOX−1結合性抗体は、全長重鎖配列および/もしくは全長軽鎖配列、VH配列および/もしくはVL配列、またはこれらへと付着された定常領域を修飾することにより、新たなLOX−1結合性抗体を創出するのに使用することができる。したがって、本発明の別の態様では、本発明のLOX−1結合性抗体の構造特色を使用して、ヒトLOX−1に結合し、また、LOX−1の1つまたは複数の機能的特性も阻害すること(例えば、LOX−1とLOX−1受容体の結合を阻害する、LOX−1依存性の細胞増殖を阻害する)など、本発明の抗体の少なくとも1つの機能的特性を保持する、構造的に関連するLOX−1結合性抗体を創出する。
本明細書で記載されるLOX−1に結合する抗体は、それを必要とする対象へと、有効量の、本発明の抗体または抗原結合性断片を投与することにより、LOX−1レベルの上昇および/またはLOX−1活性の増大と関連する疾患または障害を処置するのに治療的に有用な濃度で使用することができる。本発明は、それを必要とする対象へと、有効量の、本発明の抗体を投与することにより、LOX−1関連心血管障害を処置する方法を提供する。本発明は、それを必要とする対象へと、有効量の、本発明の抗体を投与することにより、LOX−1関連心血管障害を処置する方法を提供する。
本発明は、薬学的に許容される担体と併せて製剤化されたLOX−1結合性抗体(インタクトなまたは結合性断片)を含む医薬組成物を提供する。組成物は加えて、例えば、心血管障害の処置または防止に適する1つまたは複数の他の治療剤も含有しうる。薬学的に許容される担体は、組成物を増強するかもしくは安定化させるか、または、組成物の調製を容易とするのに使用することもできる。薬学的に許容される担体は、生理学的に適合性の溶媒、分散媒、コーティング、抗菌剤および抗真菌剤、等張剤および吸収遅延剤などを含む。
ヒトCD33、精製タグ(EFHR)、およびBirAビオチニル化配列(GLNDIFEAQKIEWHE)に由来するN末端シグナルペプチド(配列番号144)を伴う、ヒトLOX−1ポリペプチドの細胞外ドメイン(アミノ酸残基61〜273)をコードする核酸配列を、哺乳動物細胞用発現ベクターである、pRS5aへとサブクローニングした。結果として得られるプラスミドである、pRS5a_APP−Avi−ヒト−sLOX−1(61〜273)を、HEK293T細胞へと、標準的なポリエチレンイミン(PEI)トランスフェクション法を使用して、一過性にトランスフェクトした。細胞は、Novartis培地M11V3(Bioconcept)中の懸濁培養液中で増殖させ、トランスフェクションは、Wave Bioreactorを使用して、培地5リットル中に、1ml当たり1.4×106個の細胞の最終細胞濃度で実行した。
抗LOX1特異的抗体の結合特異性および機能的活性について調べるために、ヒトLOX−1を安定的に過剰発現させるHEK293細胞を発生させた。標準的なLipofectamine 2000トランスフェクション法を使用して、HEK293−6E細胞に、全長ヒトLOX−1 cDNAおよびハイグロマイシン耐性をコードする哺乳動物用発現プラスミドをトランスフェクトした。トランスフェクトされた培養物を、トランスフェクション後3日目に、LOX−1の表面における発現について、フローサイトメトリーにより査定し、次いで、ハイグロマイシン選択(200μg/ml)にかけて、安定的発現細胞について濃縮した。クローン集団は、2ラウンドにわたる逐次的な限界希釈により得、発現は、フローサイトメトリーにより確認した。培養物中で、4週間を超えて安定的なLOX−1の発現を維持するクローンだけを選択し、後続の抗体特徴付けアッセイにおいて使用した。
組換えヒトLOX−1タンパク質は、実施例1で記載した通りに社内調製し、抗LOX−1ハイブリドーマクローンを作製するための免疫原として使用した。PBS中のLOX−1抗原を、等容量のフロイントアジュバントと混合して、Balb/cマウスにおける免疫応答を増強した。完全フロイントアジュバント(Sigma、F5881)を、初回の注射のために使用し、不完全フロイントアジュバント(Sigma、F5506)を、その後における免疫化のために使用した。
ハイブリドーマ細胞が、プレートウェル内で増殖して、ハーフコンフルエントとなり、上清がオレンジ色へと変化した、融合後2週目において、細胞ベースのLOX−1抗原についての免疫蛍光フローサイトメトリー、またはLOX−1タンパク質抗原についてのELISAなどのイムノアッセイによる抗体スクリーニングのために、ハイブリドーマ上清を、プレートからサンプリングした。一次スクリーニングのために、LOX−1をトランスフェクトされた293−6E細胞を、非トランスフェクト細胞と対比して使用するフローサイトメトリーにより、ハイブリドーマ上清について調べた。略述すると、ヒトLOX−1をトランスフェクトされた293−6E細胞、または非トランスフェクト細胞を、それぞれ、50μLのハイブリドーマ上清と共にインキュベートした後で、フルオレセイン−AffiniPure Fab断片ヤギ抗マウスIgG(H+L)コンジュゲート(Jackson ImmunoResearch Laboratories)により標識付けし、Becton Dickinson FACSCaliburを伴う自動式のフローサイトメトリーにより解析した。
LOX−1抗体は、標準的な方法(例えば、プロテインAアフィニティークロマトグラフィー)を使用して、ハイブリドーマ上清から精製した。
マウスモノクローナル抗体であるE2E10は、そのタンパク質配列を、ヒト生殖細胞系列配列へと近似させ、その免疫原性を低下させるように、Humaneer(商標)化されている。Humaneer(商標)化技術は、South San FranciscoのKaloBiosにより利用可能である。抗体をHumaneer(商標)化することにより、親抗体または基準抗体の特異性およびアフィニティーをなおも保持しながら、ヒト生殖細胞系列配列との相同性が大きなV領域配列により操作されたヒト抗体(米国特許公開第2005/0255552号および同第2006/0134098号)を作製する。工程ではまず、基準Fabの重鎖可変領域内および軽鎖可変領域内の最小の抗原結合特異性決定基(BSD)(重鎖CDR3内の配列および軽鎖CDR3内の配列であることが典型的である)を同定する。これらの重鎖BSDおよび軽鎖BSDは、Humaneer(商標)化工程において構築される全てのライブラリー内で維持されるので、各ライブラリーは、エピトープに焦点を合わせたものとなり、最終的な完全Humaneer(商標)化抗体は、元のマウス抗体のエピトープ特異性を保持する。
oxLDLの、LOX−1タンパク質への結合を阻害するLOX−1抗体の能力は、実施例4で記載した方法を使用して決定した。このアッセイでは、硫酸銅に媒介されたLDLの酸化により発生させた、Kalen Biomedical製の「high binding OxLDL」(型番770212−7)に加えて、他の2つの形態の修飾LDL:マロンジアルデヒドで修飾されたLDL(Academy Bio−Medical Co.;型番20P−MD−L105)、および次亜塩素酸で修飾されたLDLについても調べた。次亜塩素酸で修飾されたLDLは、以下の手順に従い調製した。ヒトLDL(Kalen Biomedical;型番770200−4)は、PBSで、0.25mg/mLの最終濃度まで希釈した。次いで、次亜塩素酸ナトリウム(NaOCl;JT Baker;型番9416−01)を、0.1mMの最終濃度まで添加した。溶液を、室温で4時間にわたりインキュベートし、次いで、200μlの総容量当たり100mMのメチオニン5μlを添加して、L−メチオニンを反応の最終濃度まで添加することにより、反応を停止させた。修飾LDLの、LOX−1への結合の、LOX−1抗体による阻害を示す代表的なデータを、図1A〜1Cに示し、表3に記載する。
huLOX−1/HEK293細胞は、10%のFBSおよび1%のペニシリン−ストレプトマイシンを、含有するDMEM中で、75cm2の表面積当たり20mlの培養培地を含有するT型フラスコ内の接着性単層として維持した。細胞は、加湿されたインキュベーター内に、5%のCO2および37℃でインキュベートし、2〜3日ごとに継代培養した。細胞を継代培養するために、培養培地を除去し、単層を、10〜20mlのあらかじめ加熱されたPBSで1回洗浄する。洗浄した後で、1mlのあらかじめ加熱されたTrypLE Expressを添加し、細胞を、37℃で5分間にわたりインキュベートした。次いで、あらかじめ加熱された新鮮な培養培地を添加した。
LOX−1抗体または非関与性の対照抗体を、単独または(Fab)2架橋剤(ポリクローナルヤギ抗ヒトIgG Fc(Fab)2;Abcam;型番ab98526))の存在下、0.05mLのアッセイ培地(DMEM+10%のFBS)中に2倍の最終濃度で、室温で15分間にわたりインキュベートした。(Fab)2架橋剤の、LOX−1抗体に対する比を変化させ、1:1および1:2の比を組み入れた。LOX−1抗体または対照抗体単独(架橋剤を伴わない)による用量応答実験では、0.005μg/mL〜20μg/mLの範囲の抗体濃度を使用した。抗体単独を、架橋剤を伴う抗体と比較する実験では、0.03μg/mL〜20μg/mLの範囲の抗体濃度を使用した。
Thermo Scientific製のキット(EZ−Link Micro NHS−PEO4−Biotinylation Kit;Thermo Scientific;型番21955)を使用して、LOX−1抗体を、ビオチニル化させた。0.5〜1.0mg/mLの濃度でPBS緩衝液中の抗体を、50倍モル過剰量のNHS−ビオチン試薬と共に、室温で60分間にわたりインキュベートした。次いで、PBS中で平衡化させ、製造元の指示書に従い使用される、脱塩スピンカラム(Zeba Desalt Spin Column 7K MWCO、Thermo Scientific;型番89882)を使用して、ビオチニル化させた抗体を、過剰量のビオチニル化試薬から分離した。ビオチニル化させた抗体の濃度は、280nmにおけるその吸光度の測定に基づき決定した。
質量分析(MS)と組み合わせた水素−重水素交換(HDx)(Woods, 2001)を使用して、抗体であるE2E10の結合部位を、LOX−1上にマッピングした。HDxでは、タンパク質の交換可能なアミド水素を、重水素で置きかえる。この工程は、タンパク質の構造/動態および溶媒との接近可能性に対して高感度であり、したがって、リガンドの結合について報告することが可能である。HDxMSの非侵襲的性質、高感度、大型のタンパク質に対する作動能力、および結合部位をマッピングしうる高分解度により、HDxMSは、他の方法から区別される。これらの実験の目的は、LOX1上の、E2E10のエピトープの同定であった。
カニクイザルLOX−1のヌクレオチド配列およびアミノ酸配列を決定するために、全RNAを、3匹の個別のサルから得られた臓器:Zyagen/GW製の1匹の個体に由来する3つの臓器、およびCovance,Inc製の2匹の個体に由来する12の臓器から抽出した。次いで、全RNAを、公開データベース(Uniprot;NCBI)に従いデザインされた、非翻訳領域に由来するプライマーを使用するPCR増幅のために使用した。標準的な配列決定法を使用して、増幅されたLOX−1 mRNAの核酸配列を決定した。カニクイザルLOX−1(アミノ酸61〜273に対応する)の細胞外ドメイン内で、3匹の個別のサルに由来するカニクイザルLOX−1のアミノ酸配列は同一であった。
Biacore結合アッセイによる抗体の解離定数の決定
ヒトおよびカニクイザルのLOX−1に結合するマウスLOX−1抗体であるE2E10について、Biacore T200を、未使用の濾過されたランニング緩衝液(1倍濃度のHBS−EP+(GE型番BR−1006−60))で準備した。マウス抗体捕捉キット(GE型番BR−1008−38)およびアミンカップリングキット(GE型番BR−1000−50)を使用して、CM5チップ(GE型番BR−1005−30)を調製した。略述すると、未使用のチップを、EDC/NHSにより、10ul/分で420秒間にわたり活性化した。抗マウスIgG抗体を、10mMの酢酸pH5.0中に30ug/ml、10ul/分で420秒間にわたり固定した。チップ表面を、1Mのエタノールアミン溶液で不活化し(10ul/分で420秒間にわたり)、次いで、10mMのグリシン−HCl、pH1.5(GE型番BR−1003−54)により、60ul/分で30秒間ずつ、3回にわたりコンディショニングした。
以下のSETプロトコールを使用して、ヒト可溶性LOX−1に結合する、ビオチニル化E2E10についてのKD値を決定した。96ウェルMSDプレート(Standard Bindプレート、MSD型番L15XA−3)を、4℃で一晩にわたるインキュベーションにより、PBS中に0.25ug/mLのヒト可溶性LOX−1 50uLでコーティングした。溶液相の試料は、ヒト可溶性LOX−1を、ポリプロピレン製のV型底96ウェルプレート内のSET希釈剤(PBS、0.5%のBSA、0.1%のTween−20、0.1%のTriton X−100)中で滴定することにより調製した。この希釈系列を、SET希釈剤中で希釈されたビオチニル化E2E10と、1:1で組み合わせ(合計100μL)、試料を、振とうしながら、室温で一晩にわたりインキュベートした。
Y=(Bmax/(CAb/2))×((CAb/2)−((((((CAg+CAb)+KD)/2)−((((((CAg+CAb)+KD)2)/4)−(CAg×CAb))0.5))2)/(2×CAb)))
[式中、Bmaxは、LOX−1タンパク質が溶液中に存在しない場合のシグナルであり、CAbは、溶液中のLOX−1抗体の一定の濃度であり、CAgは、溶液中の可溶性LOX−1の濃度であり、KDは、平衡結合定数である]へと当てはめることにより決定した。
Y=(Bmax/(CAb/2))×((CAb/2)−((((((CAg+CAb)+KD)/2)−((((((CAg+CAb)+KD)2)/4)−(CAg×CAb))0.5))2)/(2×CAb)))
[式中、Bmaxは、LOX−1タンパク質が溶液中に存在しない場合のシグナルであり、CAbは、溶液中のLOX−1抗体の一定の濃度であり、CAgは、溶液中の可溶性LOX−1の濃度であり、KDは、平衡結合定数である。FF1、FF3、FF4、FF5、FF6、およびE2E10についての結果を、表9および図6に示す]へと当てはめることにより決定した。
本明細書で引用される全ての参考文献であって、特許、特許出願、論文、教科書などを含む参考文献、およびそれらにおいて引用された参考文献は、それらについて既に言及した程度において、参照によりそれらの全体において本明細書に組み込まれる。
前出の明細書は、当業者が、本発明を実施することを可能とするのに十分であると考えられる。前出の記載および実施例は、本発明のある種の好ましい実施形態について詳述し、本発明者らにより企図される最良の方式について記載する。しかし、前出の記載および実施例が、本文中でいかに詳述されているように見えるとしても、本発明は、多くの様式で実施することができ、本発明は、添付の特許請求の範囲およびそれらの任意の同等物に従うとみなされるべきであることが察知されるであろう。
Claims (27)
- 単離抗LOX−1抗体またはその断片。
- LOX−1のリガンド結合性ドメインに結合する、単離抗LOX−1抗体またはその断片。
- LOX−1のエピトープに結合する単離抗体またはその断片であって、前記エピトープが、LOX−1のアミノ酸残基100〜109、207〜218、または228〜246を含む、単離抗体またはその断片。
- OxLDLの、LOX−1タンパク質への結合を遮断する、前記請求項のいずれかに記載の単離抗体または断片。
- oxLDL誘導活性酸素種(ROS)産生を阻害する、前記請求項のいずれかに記載の単離抗体または断片。
- Biacoreにより測定される34pM以下のKD、または溶液平衡滴定アッセイ(SET)により測定される4pM以下のKDで、ヒトLOX−1タンパク質に結合する、単離抗体またはその断片。
- 表1に列挙されたCDRのうちの少なくとも1つに対して少なくとも95%の同一性を有する少なくとも1つの相補性決定領域を含む、前記請求項のいずれかに記載の単離抗体または断片。
- 表1のCDR1、CDR2、およびCDR3を含む、前記請求項のいずれかに記載の単離抗体または断片。
- 表1のCDR1、CDR2、およびCDR3を含み、変異体が、CDR1、CDR2、またはCDR3のうちの1つにおいて、少なくとも1〜4カ所のアミノ酸変化を有する、前記請求項のいずれかに記載の単離抗体または断片。
- ヒトLOX−1に結合する単離抗体またはその断片であって、配列番号10、30、50、70、および90からなる群から選択される重鎖CDR3を含む、単離抗体またはその断片。
- ヒトLOX−1に結合する単離抗体またはその断片であって、配列番号14、34、54、74、または94からなる群から選択されるVH;ならびに配列番号24、44、64、84、または104からなる群から選択されるVLまたは97〜99%の同一性を有するそのアミノ酸配列を含む、単離抗体またはその断片。
- 配列番号14、34、54、74、または94からなる群から選択される可変重鎖配列を含む、単離抗体またはその断片。
- 配列番号24、44、64、84、または104からなる群から選択される可変軽鎖配列を含む、単離抗体またはその断片。
- 配列番号14、34、54、74、または94からなる群から選択される可変重鎖、ならびに配列番号24、44、64、84、または104からなる群から選択される可変軽鎖配列を含む、単離抗体またはその断片。
- 配列番号8、28、48、68、および88からなる群から選択される重鎖可変領域のCDR1、配列番号9、29、49、69、および89からなる群から選択される重鎖可変領域のCDR2、10、30、50、70、および90からなる群から選択される重鎖可変領域のCDR3、配列番号18、38、58、78、および98からなる群から選択される軽鎖可変領域のCDR1、配列番号19、39、59、79、および99からなる群から選択される軽鎖可変領域のCDR2、ならびに配列番号20、40、60、80、および100からなる群から選択される軽鎖可変領域のCDR3を含む、単離抗体またはその断片。
- 配列番号11、31、51、71、および91からなる群から選択される重鎖可変領域のCDR1、配列番号12、32、52、72、および92からなる群から選択される重鎖可変領域のCDR2、13、33、53、73、および93からなる群から選択される重鎖可変領域のCDR3、配列番号21、41、61、81、および101からなる群から選択される軽鎖可変領域のCDR1、配列番号22、42、62、82、および102からなる群から選択される軽鎖可変領域のCDR2、ならびに配列番号23、43、63、83、および103からなる群から選択される軽鎖可変領域のCDR3を含む、単離抗体またはその断片。
- 配列番号8の重鎖可変領域のCDR1、配列番号9のCDR2、配列番号10のCDR3、配列番号11の軽鎖可変領域のCDR1、配列番号12のCDR2、および配列番号13のCDR3を含む、単離抗体またはその断片。
- 配列番号28の重鎖可変領域のCDR1、配列番号29のCDR2、配列番号30のCDR3、配列番号31の軽鎖可変領域のCDR1、配列番号32のCDR2、および配列番号33のCDR3を含む、単離抗体またはその断片。
- 配列番号48の重鎖可変領域のCDR1、配列番号49のCDR2、配列番号50のCDR3、配列番号51の軽鎖可変領域のCDR1、配列番号52のCDR2、および配列番号53のCDR3を含む、単離抗体またはその断片。
- 配列番号68の重鎖可変領域のCDR1、配列番号69のCDR2、配列番号70のCDR3、配列番号71の軽鎖可変領域のCDR1、配列番号72のCDR2、および配列番号73のCDR3を含む、単離抗体またはその断片。
- 配列番号88の重鎖可変領域のCDR1、配列番号89のCDR2、配列番号90のCDR3、配列番号91の軽鎖可変領域のCDR1、配列番号92のCDR2、および配列番号93のCDR3を含む、単離抗体またはその断片。
- 上記請求項の一項に記載の抗体またはその断片と、薬学的に許容される担体とを含む、医薬組成物。
- LOX−1障害を処置する方法であって、有効量の、前記請求項のいずれかに記載の抗体または断片を含む医薬組成物を、LOX−1障害に罹患している対象へと投与するステップを含む、方法。
- 前記対象が、間欠性跛行およびラザフォード分類II/III跛行のうちの1つまたは複数に罹患している、請求項23に記載の方法。
- 前記対象が、狭心症に罹患している、請求項23に記載の方法。
- 前記請求項のいずれかに記載の単離抗体または断片と同じエピトープに結合する、単離抗体またはその断片。
- ヒトLOX−1タンパク質に結合し、前記請求項のいずれかに記載の単離抗体または断片と交差競合する、単離抗体またはその断片。
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