JP2010508819A - ヒト化抗d因子抗体 - Google Patents
ヒト化抗d因子抗体 Download PDFInfo
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- JP2010508819A JP2010508819A JP2009535444A JP2009535444A JP2010508819A JP 2010508819 A JP2010508819 A JP 2010508819A JP 2009535444 A JP2009535444 A JP 2009535444A JP 2009535444 A JP2009535444 A JP 2009535444A JP 2010508819 A JP2010508819 A JP 2010508819A
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Abstract
Description
さらに、本発明は、マウスMAb166−32のヒト化抗体にも関する。本発明は、この抗体の可変重鎖および軽鎖のアミノ酸配列および対応する核酸配列を含む。本発明の別の実施形態は、これらの抗体のCDR配列を含む。
本出願において使用する用語については、当業者に通常の一般的な意味で解釈すべきである。ただし、出願人は以下の用語を以下に規定するように詳細に定義したい。
ヒトVHサブグループIコンセンサスフレームワークマイナスKabatCDR(配列番号28);
ヒトVHサブグループIコンセンサスフレームワークマイナス伸長超可変領域(配列番号29〜31);
ヒトVHサブグループIIコンセンサスフレームワークマイナスKabatCDR(配列番号32);
ヒトVHサブグループIIコンセンサスフレームワークマイナス伸長超可変領域(配列番号33〜35);
ヒトVHサブグループIIIコンセンサスフレームワークマイナスKabatCDR(配列番号36);
ヒトVHサブグループIIIコンセンサスフレームワークマイナス伸長超可変領域(配列番号37〜39);
ヒトVHサブグループVIIコンセンサスフレームワークマイナスKabatCDR(配列番号55);
ヒトVHサブグループVIIコンセンサスフレームワークマイナス伸長超可変領域(配列番号56〜58);
ヒトVHアクセプターフレームワークマイナスKabatCDR(配列番号40);
ヒトVHアクセプターフレームワークマイナス伸長超可変領域(配列番号41〜42);
ヒトVHアクセプター2フレームワークマイナスKabatCDR(配列番号43);または
ヒトVHアクセプター2フレームワークマイナス伸長超可変領域(配列番号44〜45)
が挙げられる。
QVQLVQSGPELKKPGASVKVSCKAS(配列番号8のアミノ酸1〜25)を含むFR1、
WVRQAPGQGLE(配列番号8のアミノ酸36〜46)を含むFR2、
RFVFSLDTSVSTAYLQISSLKAEDTAVYYCER(配列番号8のアミノ酸67〜98)、
RFVFSLDTSVSTAYLQISSLKAEDTAVYYCE(配列番号8のアミノ酸67〜97)、
RFVFSLDTSVSTAYLQISSLKAEDTAVYYC(配列番号8のアミノ酸67〜96)、
RFVFSLDTSVSTAYLQISSLKAEDTAVYYCS(配列番号51)または
RFVFSLDTSVSTAYLQISSLKAEDTAVYYCSR(配列番号52)を含むFR3
WGQGTLVTVSS(配列番号8のアミノ酸105〜115または配列番号27のアミノ酸105〜115)を含むFR4
のフレームワーク配列のうち1つ、2つ、3つまたは全部を含む。
DIQX6TQSPSSLSX7SVGDRVTITC(配列番号26のアミノ酸1〜23)を含むFR1、配列中、X6はVまたはMであり、X7はMまたはAである;
WYQQKPGKX8PKLLIX9(配列番号26のアミノ酸35〜49)を含むFR2、配列中、X8はPまたはVであり、X9はSまたはYである;
GVPSRFSX10SGSGX11DFTLTISSLQPEDVATYYC(配列番号26のアミノ酸57〜88)を含むFR3、配列中、X10はSまたはGであり、X11はAまたはTである;
FGQGTKX12EIK(配列番号54)を含むFR4、配列中、X12はVまたはLである、
フレームワーク配列のうち1つ、2つ、3つまたは全部を含んでもよい。
ヒトVLκサブグループIコンセンサスフレームワーク(配列番号47);
ヒトVLκサブグループIIコンセンサスフレームワーク(配列番号48);
ヒトVLκサブグループIIIコンセンサスフレームワーク(配列番号49);または
ヒトVLκサブグループIVコンセンサスフレームワーク(配列番号50)
が挙げられる
一実施形態では、VLアクセプターヒトフレームワークは、
DIQVTQSPSSLSASVGDRVTITC(配列番号7のアミノ酸1〜23)を含むFR1、
WYQQKPGKVPKLLIS(配列番号7のアミノ酸35〜49)を含むFR2、
GVPSRFSGSGSGTDFTLTISSLQPEDVATYYC(配列番号7のアミノ酸57〜88)を含むFR3、
FGQGTKLEIK(配列番号7のアミノ酸98〜107)または
FGQGTKVEIK(配列番号53)を含むFR4
のフレームワーク配列のうち1つ、2つ、3つまたは全部を含んでもよい。
宿主細胞の選択および形質転換
本明細書においてベクター内のDNAのクローニングまたは発現に好適な宿主細胞は、原核生物細胞、酵母細胞または高等真核細胞である。この目的に好適な原核生物は、たとえば、E.coli、Enterobacter、Erwinia、Klebsiella、Proteus、Salmonella、SerratiaおよびShigellaなどの腸内細菌ならびにBacilli、PseudomonasおよびStreptomycesなど、グラム陰性生物とグラム陽性生物の両方を含む。好ましいE.coliクローニング宿主の1つにE.coli294(ATCC31,446)があるが、E.coli B、E.coli X1776(ATCC31,537)およびE.coli W3110(ATCC27,325)など、他の菌株も好適である。これらの例は例示的なもので、限定的なものではない。
組換え技法を用いる場合、抗体を細胞内、ペリプラズムに産生させてもよいし、培地に直接分泌させてもよい。抗体変異体を細胞内で産生させる場合、第1のステップとして、宿主細胞あるいは溶解フラグメントのいずれかである微粒子状の破片を、たとえば、遠心分離または除外濾過により除去してもよい。Carter et al.,Bio/Technology 10:163−167(1992)には、E.coliのペリプラズムに分泌させた抗体を単離する手順が記載されている。簡単に説明すると、酢酸ナトリウム(pH3.5)、EDTA(ethylenediaminetetraacetic acid)およびフッ化フェニルメチルスルホニル(PMSF:phenylmethylsulfonylfluoride)の存在下で約30分かけて細胞ペーストを解凍する。細胞残屑を遠心分離により除去してもよい。抗体変異体を培地に分泌させる場合、通常最初にこうした発現系の上清を、市販のタンパク質濃縮フィルター、たとえば、AmiconまたはMillipore Pelliconの除外濾過ユニットを用いて濃縮させる。前記のステップのいずれかにPMSFなどのプロテアーゼ阻害剤を加えてタンパク質分解を阻害してもよく、抗生物質を加えて外来性の汚染菌の増殖を防止しても構わない。
ポリペプチドまたは抗体の治療製剤を凍結乾燥製剤または水溶液として保存するため、純度が所望の程度のポリペプチドと、当該技術分野において通常用いられる任意の「薬学的に許容される」キャリア、賦形剤または安定剤(すべて「賦形剤」と呼ばれる)とを混合して調製してもよい。たとえば、緩衝剤、安定化剤、保存剤、等張剤、非イオン性洗浄剤、酸化防止剤およびこれ以外の各種添加剤がある。(Remington’s Pharmaceutical Sciences,16th edition,A.Osol,Ed.(1980)を参照)。こうした添加剤は、使用する投与量および濃度でレシピエントに無毒でなければならない。
本発明のヒト化抗体は、たとえば、特定の細胞、組織または血清中の目的標的の発現を検出する診断アッセイに有用である。診断用途では、一般に抗体変異体を検出可能な部分で標識する。多くの標識が利用可能である。蛍光の変化を定量する技法は、上述してある。化学発光基質は、化学反応により電子的に励起され、次いで(たとえばケミルミノメーターを用いて)測定できる光を発する場合があるか、蛍光アクセプターにエネルギーを供与する。酵素標識の例として、ルシフェラーゼ(ホタルルシフェラーゼおよび細菌ルシフェラーゼなど;米国特許第4,737,456号明細書)、ルシフェリン、2,3−ジヒドロフタラジンジオン、リンゴ酸デヒドロゲナーゼ、ウレアーゼ、西洋わさびペルオキシダーゼ(HRPO:horseradish peroxidase)などのペルオキシダーゼ、アルカリホスファターゼ、β−ガラクトシダーゼ、グルコアミラーゼ、リゾチーム、サッカライドオキシダーゼ(グルコースオキシダーゼ、ガラクトースオキシダーゼおよびグルコース−6−ホスファートデヒドロゲナーゼなど)、複素環式オキシダーゼ(ウリカーゼおよびキサンチンオキシダーゼなど)、ラクトペルオキシダーゼ、マイクロペルオキシダーゼおよび同種のものが挙げられる。酵素を抗体にコンジュゲートする技法については、O’Sullivan et al.,Methods for the Preparation of Enzyme−Antibody Conjugates for Use in Enzyme Immunoassay,in Methods in Enzym.(Ed.J.Langone & H.Van Vunakis),Academic press,New York,73:147−166(1981)に記載されている。
本発明の抗体については、哺乳動物の処置に使用してもよいことを意図している。一実施形態では、たとえば、前臨床データを取得するため、抗体をヒト以外の哺乳動物に投与する。ヒト以外の処置対象の例示的な哺乳動物として、非ヒト霊長類、イヌ、ネコ、齧歯類および前臨床試験が行われる他の哺乳動物が挙げられる。こうした哺乳動物については、抗体で処置する疾患の確立された動物モデルであってもよいし、目的の抗体の毒性を研究するために用いてもよい。これらの各実施形態では、哺乳動物に対して用量漸増研究を行っても構わない。
(実施例1)
D因子マウスMAb166−32のヒト化
マウスmAb166−32の重鎖可変領域(VH)および軽鎖可変領域(VL)の配列を公共データベースで入手可能なヒト抗体生殖系列配列と比較した。上記のステップ1に記載されているような鋳型を決定する際、全長、フレームワーク内の類似CDRの位置、全体の相同性、CDRの大きさなど、複数の判断基準を用いた。これらの判断基準をすべて総合して、図3および図4に示した166−32MAb重鎖および軽鎖配列とそれぞれのヒト鋳型配列との配列アライメントに示すような、最適なヒト鋳型の選択に適した結果を得た。
(実施例2)
ライブラリーのスクリーニング
一次スクリーニングには捕捉フィルターリフトを用いた。実際のスクリーニングサイズは、理論的なライブラリーサイズよりも3倍超大きくなる。シングルポイントELISAアッセイで候補をさらにスクリーニングした。最良のバインダーを、Fab濃度に基づきD因子を用いた抗原の直接滴定によりさらに確認した
捕捉リフトスクリーニング
D因子に対するFabの結合についての一次スクリーニングには捕捉フィルターリフトアッセイを用いた。高力価のファージを蒔いて、使用するまで(約6〜8時間)37℃でインキュベートした。ヤギ抗ヒトκを10mlのPBSTで10ug/mlに希釈し;標準的なプラークリフト手順に従ってプラークリフト用のニトロセルロースフィルターを調製し、次いでシェーカーの10mlのブロッキング緩衝液に2時間浸した。このフィルターをPBSTで3回すすいだ。フィルターをプラーク菌叢に置き、室温で約15〜24時間インキュベートした。その後、フィルターをプレートから除去し、TBSTで3回すすいだ。
(実施例3)
シングルポイントELISAによるスクリーニング
二次スクリーニングにはシングルポイントELISAによるアッセイを用いた。Immulon IIプレートをヤギ抗ヒトFab(1:12,000、50ul/ウェル)で室温にて一晩コートした。翌日、このプレートをプレートウォッシャーで4回洗浄した。ブロッキング緩衝液を1ウェル当たり100ulの容量で加え、プレートを室温で1時間インキュベートした。その後、プレートを4回洗浄した。
(実施例4)
ヒト化抗D因子クローンのシーケンシング
ヒトD因子に対する結合親和性に優れた16個のヒト化クローンを配列決定した(表1を参照)。この中で、軽鎖の2番目(100%ヒト)および49番目(100%マウス)と、重鎖の93番目(100%マウス)とが高度に保存されていることから、これらが抗体結合能力を保つ上で重要であることが示唆される。
(実施例5)
AP(alternative pathway)溶血アッセイ
溶血阻害アッセイおよびBIAcore解析を用いてヒト化クローンの生物学的機能を判定した(以下の実施例6を参照)。以下の手順に従って溶血アッセイを行った。1:20希釈ウサギ赤血球(RRBC:rabbit red blood cell)(0.5ml+9.5mlのGVB/Mg−EGTA緩衝液)20ulを20mlの食塩水(0.9%NaCl)で約1:2×104に希釈し、コールターカウンターでカウントした。次いで、細胞濃度を約2〜5×104細胞/mlに調節した。各プレートに約500×106/プレートRRBCまたは約1mlのRRBC/プレート(500×106/2〜5×104)を加えた。
(実施例6)
BiaCoreによる抗ヒトD因子Fabの速度論的解析
固定化−アミンカップリング法を用いてヒトD因子(Advanced Research Inc,0.1mg/ml)をCM5チップ(BiaCore)に直接固定化した。その手順を以下のとおり簡単に記載する:(1)流速(PBS)を5μl/分で一定にする。(2)35μlのEDC/NHS(1:1)を注入。(3)酢酸塩緩衝液(pH4.5)に溶かした35μlのヒトD因子を注入。(4)35μlのエトールアミンを注入して活性化基をブロックする。(5)5μlの10mMグリシン(pH1.5)で表面をクリーンアップする。リガンド(ヒトD因子)の固定化レベルは約1,000RUである。α−ヒトD因子(huDi、40μl、31.5μg/ml)を用いて行った試験では、900RU前後で相対感度を得た。
Claims (37)
- 配列番号1の重鎖可変ドメイン配列を含む、マウス抗体。
- 配列番号2の軽鎖可変ドメイン配列を含む、マウス抗体。
- 請求項1に記載の重鎖可変ドメイン配列および請求項2に記載の軽鎖可変ドメイン配列を含む、マウス抗体。
- 配列番号13、14、15、16、17および18を含む、抗体。
- 配列番号1および配列番号2を含む、キメラ抗体。
- 配列番号6;配列番号8;配列番号10;および配列番号12からなる群から選択される重鎖可変ドメインのアミノ酸配列を含む、ヒト化抗体の可変ドメイン。
- 配列番号5;配列番号7;配列番号9および配列番号11からなる群から選択される軽鎖可変ドメインのアミノ酸配列を含む、ヒト化抗体の可変ドメイン。
- 配列番号5の可変ドメイン配列および配列番号6の可変ドメイン配列を含む、ヒト化抗D因子抗体。
- 配列番号7の可変ドメイン配列および配列番号8の可変ドメイン配列を含む、ヒト化抗D因子抗体。
- 配列番号9の可変ドメイン配列および配列番号10の可変ドメイン配列を含む、ヒト化抗D因子抗体。
- 配列番号11の可変ドメイン配列および配列番号12の可変ドメイン配列を含む、ヒト化抗D因子抗体。
- 配列番号16の配列を持つCDR−L1;配列番号17、21または23の配列を持つCDR−L2および配列番号18、22または24の配列を持つCDR−L3を含む可変軽鎖を持つ、ヒト化抗D因子抗体。
- 配列番号13または25の配列を持つCDR−H1;配列番号14の配列を持つCDR−H2;および配列番号15または20の配列を持つCDR−H3を含む可変重鎖を持つ、ヒト化抗D因子抗体。
- 以下のアミノ酸配列:
QXIQLVQSGX2E LKKPGASVKV SCKASGYTFT SYGMNWVX3QA PGQGLEWMGW INTYTGETTYADDFKGRFVF SLDTSVSTAY LQISSLKAED TAX4YYCX5REG GVNNWGQGTL VTVSS(配列番号27)、を含むポリペプチドであって、
ここで配列中、X1はIまたはVであり;X2はPまたはSであり;X3はKまたはRであり;X4はTまたはVであり;X5はEまたはAである、ポリペプチド。
。 - 以下のアミノ酸配列:
DIQX6TQSPSSLSX7SVGDRVTITCITSTDIDDDMNWYQQKPGKX8PKLLIX9DGNTLRPGVPSRFSX10SGSGX11DFTLTISSLQPEDVATYYCLQSDSLPYTFGQ GTKLEIK(配列番号26)、を含むポリペプチドであって、
ここで配列中、X6はVまたはMであり;X7はMまたはAであり;X8はPまたはVであり;X9はSまたはYであり;X10はSまたはGであり、X11はAまたはTである、ポリペプチド。 - 配列番号6、8、10または12のアミノ酸配列を含む、ポリペプチド。
- 配列番号5、7、9または11のアミノ酸配列を含む、ポリペプチド。
- 請求項14に記載のポリペプチドを含む、ヒト化抗体。
- 請求項15または33に記載のポリペプチドをさらに含む、請求項18に記載のヒト化抗体。
- 請求項1〜13、18〜19、31または32のいずれか1項に記載の抗体フラグメント。
- 配列番号3の配列を含む、単離された核酸。
- 配列番号4の配列を含む、単離された核酸。
- 請求項1〜13、18〜19、31または32のいずれか1項に記載の抗体をコードする、単離された核酸。
- 請求項14〜17のいずれか1項に記載のポリペプチドをコードする、単離された核酸。
- 請求項23に記載の核酸を含む、ベクター。
- 請求項24に記載の核酸を含む、ベクター。
- 請求項25または26に記載のベクターを含む、細胞株。
- 請求項1〜13、18または19のいずれか1項に記載の抗体を含む、組成物。
- 補体による障害を処置する、請求項28に記載の組成物の使用。
- 前記障害は加齢黄斑変性症または糖尿病性網膜症などの眼疾患である、請求項29に記載の使用。
- 配列番号7の104番目のアミノ酸はバリンまたはロイシンである、請求項7に記載の可変ドメイン。
- 配列番号7の104番目のアミノ酸がバリンまたはロイシンである配列番号7の可変ドメイン配列および配列番号8の可変ドメイン配列を含む、請求項9に記載のヒト化抗D因子抗体。
- 配列番号26の104番目のアミノ酸はバリンまたはロイシンである、請求項15に記載のポリペプチド。
- 配列番号7の104番目のアミノ酸はバリンまたはロイシンである、請求項17に記載のポリペプチド。
- 請求項1〜13、18〜19、31または32のいずれか1項に記載のヒト化抗D因子抗体またはそのフラグメントを作製する、方法。
- マウス抗体166−32および/またはヒト化抗D因子抗体クローン#56、#111、#250もしくは#416および/またはヒト化抗D因子抗体クローン#56、#111、#250もしくは#416の可変ドメインまたはHVR配列を含む抗体と競合する、抗体。
- マウス抗体166−32および/またはヒト化抗D因子抗体クローン#56、#111、#250もしくは#416および/またはヒト化抗D因子抗体クローン#56、#111、#250もしくは#416の可変ドメインまたはHVR配列を含む抗体と同じエピトープに結合する、抗体。
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