JP4764334B2 - 高親和性抗ヒトIgE抗体 - Google Patents
高親和性抗ヒトIgE抗体 Download PDFInfo
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- JP4764334B2 JP4764334B2 JP2006503245A JP2006503245A JP4764334B2 JP 4764334 B2 JP4764334 B2 JP 4764334B2 JP 2006503245 A JP2006503245 A JP 2006503245A JP 2006503245 A JP2006503245 A JP 2006503245A JP 4764334 B2 JP4764334 B2 JP 4764334B2
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- PYIHTIJNCRKDBV-UHFFFAOYSA-L trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;dichloride Chemical compound [Cl-].[Cl-].C[N+](C)(C)CCCCCC[N+](C)(C)C PYIHTIJNCRKDBV-UHFFFAOYSA-L 0.000 description 1
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Description
(i) FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 (I)
のポリペプチド鎖を形成しており、ここでポリペプチド鎖はN末端から始まりC末端で終わるように記載している。VH及びVL鎖のCDRはそれぞれH1、H2、H3及びL1、L2、L3とも呼ばれる。何がFR又はCDRを構成しているかの決定は、通常同種内で作製された多数の抗体のアミノ酸配列を比較することによって行なわれ、同定のための一般的な規則はこの分野において公知である("Sequences of proteins of immunological interest", Kabat E. A. et al., US department of health and human service, Public health service, National Institute of Health)。
本明細書において用いられる語は、当業者が用いる一般的及び典型的な意味で解釈される。しかしながら、出願人は以下の語について下記の通りの特別な定義を与えることを望む。
起点となる又は「親」抗体は、この分野において利用可能なそのような抗体を作製するための技術を用いて調製することができる。これらの技術は周知である。出発抗体を作製するための典型的な方法は後段においてより詳細に記載する。これらの記載は親抗体を作製又は選択するための可能な代替技術であって、そのような分子を生成する方法を限定するものではない。
A. 標的の調製
可溶性の標的又はその断片を、抗体を作製するための免疫原として用いることができる。抗体は目的の標的に対して作製される。好ましくは、該標的は生物学的に重要なポリペプチドであり、疾病又は不調に悩まされる哺乳動物に該抗体を投与することでその哺乳動物に治療効果をもたらすことができる。しかしながら、抗体は非ポリペプチド性の標的に対しても作製され得る。標的がポリペプチドであれば、膜貫通分子(例えばレセプター)又は成長因子のようなリガンドであり得る。本発明の標的の1つはIgEである。細胞全体を抗体作製のための免疫原として用いることもできる。標的は組換えにより又は合成的方法を用いて生産してもよい。標的はまた天然源からも単離し得る。
ポリクローナル抗体は通常、非ヒト哺乳動物において適切な標的をアジュバントと組合わせて多重に皮下(sc)又は腹腔内(ip)注射することにより作製される。関連する標的を、例えばキーホールリンペットヘモシニアンのような、免疫対象の動物種において免疫原性のあるタンパク質と結合させることが有用であり得る。免疫応答を誘発できる多くの物質がこの分野において周知である。
モノクローナル抗体とは、単一の抗原部位を認識する抗体である。モノクローナル抗体は、その均一な特異性により、通常種々の異なる抗原部位を認識する抗体を包含するポリクローナル抗体よりもはるかに有用となっている。モノクローナル抗体は、Kohler et al., Nature, 256: 495 (1975) により初めて記載されたハイブリドーマ法を用いることにより、又は組換えDNA法により作製し得る。
ヒト化は、無傷のヒト可変領域よりも実質的に少ない部分が非ヒト種由来の相当する配列で置換されているキメラ抗体を作製するための技術である。ヒト化抗体は、非ヒト供給源から導入された1又は2以上のアミノ酸残基を有する。これらの非ヒトアミノ酸残基はしばしば「インポート」残基と言われ、典型的には「インポート」可変領域由来である。ヒト化は基本的にはWinter及び共同実験者(Jones et al, Nature 321: 522-525 (1986); Riechman et al., Nature 332: 323-327 (1988); Verhoeyens et al., Science 239: 1534-1536 (1988))の方法に倣って、非ヒトCDR又はCDR配列をヒト抗体中の相当する配列と置換することにより行なわれ得る(例えば米国特許第4,816,567号を参照)。本発明で実施した通り、ヒト化抗体はマウス抗体中の相同部位由来の残基で置換されたいくつかのCDR残基及びいくつかのFR残基を有し得る。
抗体断片の生産に関して種々の技術が開発されている。伝統的には、これらの断片は無傷の抗体のタンパク質分解を経て誘導された(例えばMorimoto et al., Journal of Biochemical and Biophysical Methods 24: 107-117 (1992) and Brennan et al., Science 229: 81 (1985)を参照)。しかしながら、これらの断片は現在では組換え宿主細胞により直接的に生産可能である。例えば、抗体断片は抗体ファージライブラリーから単離することができる。あるいは、F(ab')2-SH断片を大腸菌から直接回収し、化学的に結合させてF(ab')2断片を形成することができる(Carter et al., Bio/Technology 10: 163167 (1992))。他の方法では、組換え宿主細胞培養物から直接F(ab')2断片を単離することができる。抗体断片を生産するためのその他の技術が当業者に明らかになるだろう。他の具体例では、選択される抗体は一本鎖Fv断片(scFv)である(PCT特許出願WO 93/16185)。
一旦親抗体を同定及び単離したら、親抗体の1又は2以上の可変領域において1個又は2個以上のアミノ酸残基が改変される。あるいは、又はそれに加えて、フレームワーク残基の1個又は2個以上の置換が親抗体中に導入されてもよく、それにより抗体の結合親和性、例えばヒトIgEに対する抗体の結合親和性が改良される。修飾対象のフレームワーク領域残基の例には、直接非共有的に標的に結合するもの(Amit et al. Science 233: 747-753 (1986));CDRのコンフォメーションに相互作用/影響するもの(Chothia et al. J. Mol. Biol. 196: 901-917 (1987));及び/又はVL−VH接合部分に加わるもの(EP 239 400 B1)が包含される。ある具体例では、1個又は2個以上のそのようなフレームワーク領域残基の修飾により、目的とする標的に対する抗体の結合親和性が増大する。
本発明はまた、ここで開示されているような変異抗体をコードする単離核酸、該核酸を含むベクター及び宿主細胞、並びに該変異抗体を生産するための組換え技術を提供する。変異抗体の組換え体生産のために、それをコードする核酸が単離され、さらなるクローニング(DNAの増幅)のために又は発現のために複製可能なベクター中に挿入される。変異抗体をコードするDNAは、慣用法を用いて(例えば変異抗体の重鎖及び軽鎖をコードする遺伝子に特異的に結合し得るオリゴヌクレオチドプローブを用いることにより)容易に単離及び配列決定される。
本発明の変異抗体は組換えによって生産し得る。該変異体はまた、好ましくはシグナル配列又は成熟タンパク質若しくはポリペプチドのN末端に特異的切断部位を有する他のポリペプチドである異種ポリペプチドと融合した融合ポリペプチドとして発現し得る。選択された異種シグナル配列は好ましくは、宿主細胞によって認識及び加工される(すなわちシグナルペプチダーゼによって切断される)ものである。ネイティブな抗体シグナル配列を認識及び加工しない原核宿主細胞に対しては、シグナル配列を、例えばアルカリホスファターゼ、ペニシリナーゼ、Ipp、若しくは熱安定性エンテロトキシンIIリーダーの群から選択した原核生物のシグナル配列と置換してもよい。あるいは図1のベクターの場合には、選択したシグナル配列は遺伝子III由来のウイルス性シグナル配列とした。酵母の分泌に対しては、ネイティブなシグナル配列を、例えば酵母インベルターゼリーダー、α‐因子リーダー(Saccharomyces属及びKluyveromyces属α‐因子リーダー)、若しくは酸性ホスファターゼリーダー、C. albicansグルコアミラーゼリーダー、又は例えばWO 90/13646に記載されているシグナルで置換してもよい。哺乳動物細胞発現においては、哺乳動物シグナル配列及びウイルス性分泌リーダー、例えば単純ヘルペスgDシグナルが利用可能である。そのような前駆領域のDNAは、変異抗体をコードするDNAと読み枠を合わせて結合される。
ベクターは通常、当該ベクターが1又は2以上の選択宿主細胞内で複製可能となるようにする核酸配列を包含する。一般に、この配列は、ベクターが宿主染色体DNAとは独立して複製できるようにするものであり、複製開始点又は自律複製配列を包含する。そのような配列は種々の細菌、酵母、ウイルスにおいてよく知られている。プラスミドpBR322由来の複製開始点は大部分のグラム陰性細菌に適し、2μプラスミド開始点は酵母に適し、種々のウイルス開始点(SV40、ポリオーマ、アデノウイルス、VSV又はBPV)は哺乳動物細胞内のベクターに有用である。一般に、複製開始点構成物は哺乳動物発現ベクターに対しては必要とされない(SV40開始点は典型的には初期プロモーターを有しているという理由でのみ用いられ得る)。
ベクターは、選択マーカーとも呼ばれる選択遺伝子を含み得る。典型的な選択遺伝子は、(a)例えばアンピシリン、ネオマイシン、メトトレキセート、又はテトラサイクリンのような抗生物質又はその他の毒素に対する抵抗性を付与し、(b)栄養要求性欠損を相補し、又は(c)例えば桿菌のD-アラニンラセマーゼをコードする遺伝子のような天然培地からは利用できない重要な栄養素を供給するタンパク質をコードする。
発現及びクローニングベクターは通常、宿主生物に認識され抗体核酸と操作可能な状態で連結されるプロモーターを包含する。原核生物宿主に用いるために適したプロモーターは、phoAプロモーター、β‐ラクタマーゼ及びラクトースプロモーター系、アルカリホスファターゼ、トリプトファン(trp)プロモーター系、並びにtacプロモーターのようなハイブリッドプロモーターを包含する。しかしながら、他の公知の細菌プロモーターが適している。細菌系において用いるプロモーターはまた、抗体をコードするDNAと操作可能な状態で結合したシャイン−ダルガルノ(S.D.)配列も包含し得る。
本発明の抗体をコードするDNAの高等真核生物による転写は、多くの場合、ベクター中にエンハンサー配列を挿入することによって増大する。現在では哺乳動物遺伝子(グロビン、エラスターゼ、アルブミン、α‐インターフェロン、及びインシュリン)由来の多くのエンハンサー配列が知られている。しかしながら典型的には、真核生物細胞ウイルス由来のエンハンサーが用いられるであろう。例には、複製開始点の後期側のSV40エンハンサー(bp 100-270)、サイトメガロウイルス初期プロモーターエンハンサー、複製開始点の後期側のポリオーマエンハンサー、及びアデノウイルスエンハンサーが含まれる。真核生物プロモーターの活性化のための促進要素についてはYaniv, Nature 297: 17-18 (1982)も参照のこと。エンハンサーは、ベクター中で抗体コード配列に対して5'又は3'の位置につなげてよいが、好ましくはプロモーターより5'側の部位に設けられる。
真核生物宿主細胞(酵母、真菌、昆虫、植物、動物、ヒト、又は他の多細胞生物由来の有核細胞)内で用いる発現ベクターはまた、転写の終結及びmRNAの安定化のために必要な配列も含み得る。そのような配列は一般に、真核生物又はウイルスのDNA又はcDNAの5'及び、時には3'非翻訳領域から利用可能である。これらの領域は、抗体をコードするmRNAの非翻訳部位中にポリアデニル化断片として転写されるヌクレオチドセグメントを包含する。有用な転写終結構成物の1つは、ウシ成長ホルモンポリアデニル化領域である。例えばW094/11026を参照のこと。
ここでベクター中にDNAをクローニング又は発現するのに適した宿主細胞は、原核生物、酵母、又は高等真核生物細胞である。この目的に適した原核生物は、例えば大腸菌、エンテロバクター属(Enterobacter)、エルウィニア属(Erwinia)、クレブシエラ属(Klebsiella)、プロテウス属(Proteus)、サルモネラ属(Salmonella)、セラチア属(Serratia)、及び赤痢菌のような腸内細菌、並びに桿菌、シュードモナス属(Pseudomonas)、及びストレプトミセス属(Streptomyces)といった、グラム陰性及びグラム陽性生物の両方を包含する。好ましい大腸菌クローニング宿主の1つはE. coli 294 (ATCC 31,446)であるが、E. coli B、E. coli X1776 (ATCC 31,537)及びE. coli W3110 (ATCC 27,325)のような他の菌株も適している。これらの例は説明のために挙げたものであり、これらに限定されない。
組換え技術を用いる際には、変異抗体は細胞内若しくは細胞膜周辺腔で生産され、又は培地中に直接分泌され得る。変異抗体が細胞内で生産される場合、第一段階として、宿主細胞又は溶解した断片いずれかの粒子状の細片を、例えば遠心又は限外ろ過によって取り除いてよい。Carter et al., Bio/Technology 10: 163-167 (1992)には、大腸菌の細胞膜周辺腔に分泌された抗体を単離するための手法が記載されている。簡潔に言えば、細胞ペーストを酢酸ナトリウム(pH3.5)、EDTA及びフェニルメチルスルホニルフルオライド(PMSF)の存在下で約30分間以上融解させる。細胞片は遠心によって取り除くことができる。変異抗体が培地中に分泌される場合には、そのような発現系由来の上清を、一般的には先ず第一に、例えばAmicon又はMillipore Pellicon ultrafiltration unitのような市販のタンパク質濃縮フィルターを用いて濃縮する。タンパク分解を防止するために、いずれの先行工程にPMSFのようなプロテアーゼ阻害剤を含ませてもよく、外因性の汚染菌の増殖を防止するために抗生物質を含ませてもよい。
ポリペプチド又は抗体の治療製剤は、所望の純度を有するポリペプチドと、この分野で典型的に用いられる任意の「薬理学的に許容される」担体、賦形剤又は安定剤(これらは全て「賦形剤」と呼ばれる)とを混合することにより、凍結乾燥製剤又は水性溶液として保管するために調製され得る。例えば、緩衝剤、安定剤、防腐剤、等張化剤(isotonifier)、非イオン洗浄剤、酸化防止剤及び他の種々の添加物(Remington's Pharmaceutical Sciences, 16th edition, A. Osol, Ed. (1980)を参照のこと)。そのような添加物は、使用される用量と濃度において受容者に対し無毒でなければならない。
該発明の変異抗体はアフィニティー精製試薬として用いられ得る。この工程において、該抗体は、この分野で周知の方法を用いてSEPHADEX(商標)樹脂又はろ紙のような固相上に固定化される。固定化変異抗体は精製対象の標的を含んだ試料と接触し、その後、固定化変異抗体に結合した精製対象の標的を除く試料中の実質的に全ての物質を除去する適切な溶媒で支持体を洗浄する。最後に、グリシン緩衝液のような、変異抗体から標的を放出させる他の適切な溶媒で該支持体を洗浄する。
免疫沈降アッセイのような、どのような公知のアッセイにも用いることができる。Zola, Monoclonal Antibodies: A Manual of Techniques, pp. 147-158 (CRC Press, Inc. 1987)。
本発明の抗体は哺乳動物を治療するために用い得ると想定される。1つの具体例において、該抗体は、例えば前臨床データを得るために非ヒト哺乳動物に投与される。処置対象の模範的な非ヒト哺乳動物は、非ヒト霊長類、イヌ、ネコ、げっ歯類、及び前臨床研究が行なわれる他の哺乳動物である。そのような哺乳動物は、該抗体で治療する対象となる疾病の動物モデルを確立し得、又は目的の抗体の毒性を研究するために用いられ得る。これらの具体例それぞれでは、投与量の段階的増大の研究が哺乳動物において行なわれ得る。
マウスmAb TES-C21の重鎖可変領域(VH)及び軽鎖可変領域(VL)の配列を、公共のデータベースから利用可能なヒト抗体生殖系列配列と比較した。上記工程1に記載したとおり鋳型を決定する際に、全体長、フレームワーク内の類似のCDR位置、全体の相同性、CDRのサイズなどを含んだ、数種の判定基準を用いた。図3A及び3Bに表された、TES-C21 MAbの重鎖及び軽鎖配列とそれぞれのヒト鋳型配列との間の配列アラインメントで示されるとおり、一括して考慮されたこれらの基準の全てから最適なヒト鋳型を選択するための結果が得られた。
ハイブリダイゼーション変異誘発により、VH及びVLをファージ発現ベクター中にクローニングした。ウリジル化した鋳型は大腸菌CJ236株(dut- ung-)をM13ベースのファージ(ファージ発現ベクターTN003)に感染させることにより調製した。
A. ファージライブラリーのプレーティング
プレート当たりの所望のプラーク数を得るため、ファージライブラリーをLB培地中に希釈した。力価の高いファージを200μLのXL-1B細胞培養液と混合した。3mLのLBトップアガーを混合し、LBプレート上に注ぎ、室温に10分間放置した。該プレートを37℃で一晩インキュベートした。
滅菌U底96ウェルプレートの各ウェルに100μLのファージ溶出緩衝液(10mM Tris-Cl, pH 7.5, 10mM EDTA, 100mM NaCl)を加えた。フィルター付ピペットチップを用いて、一晩置いたライブラリープレートからウェルへ単一のファージプラークを移した。該ファージ溶出プレートを37℃で1時間インキュベートした。該プレートはインキュベーション後4℃で保存することができる。
50mLの培養液から得たXL1B細胞を1:100希釈となるように2×YT培地に加えた。該細胞は、A600が0.9から1.2の間になるまで振とう器中にて37℃で増殖させた。
細胞が適切なODに達した時に、XL1B培養液に1MのIPTG(1:2000)を加えた。IPTGの終濃度は0.5mMであった。750μLの細胞培養液を96ウェルの深型ウェルプレート(Fisher Scientific)の各ウェルに移した。各ウェルは25μLの溶出ファージと共にインキュベートした。深型ウェルプレートを振とう器(250rpm)中に置いて37℃で一晩インキュベートした。
インキュベーション後、該深型プレートをBeckman JA-5.3 plate rotorを用いて3,250 rpmで20分間遠心した。ELISAのために、各ウェルから50μLの上清を回収した。
A600=0.9〜1.2になるまで、10μg/mLのテトラサイクリンを含む2×YT中で、振とう器(250rpm)中にて37℃でXL-1を増殖させた。IPTGを終濃度0.5mMとなるように添加し、各クローンの性状解析をするために、15mLの該培養液を50mLのコニカルチューブに移した。該細胞を高力価ストック(力価=〜1011pfu/mL)由来のファージ10μLで接種し、37℃で1時間インキュベートした。該細胞は室温で振とうしながら一晩増殖させた。
該細胞をIEC遠心器にて4,500rpmで20分間遠心してペレットにした。培養培地を取り除き、ペレットを650μLの再懸濁緩衝液(1mM EDTAを含む50mMトリス, pH 8.0及び500mMスクロース)中に再懸濁し、ボルテックスし、穏やかに振とうさせながら1時間氷上に置いた。細胞片は9,000rpmで10分間4℃にて遠心して取り除いた。可溶性Fabを含む上清を回収し4℃に保存した。
上記した潜在的に重要な部位のフレームワーク内に、12個のマウス/ヒトゆらぎ残基が存在した。VH中の部位73は、ヒト化ライブラリー中でマウス残基であるスレオニンを維持した。なぜならこの部位は結合に影響するものと決定されたからである。しかしながら、VH73におけるスレオニンはヒト生殖系列VHサブグループ1及び2において共通のヒト残基であることが既に知られている。
プレートを、炭酸コーティング緩衝液中に溶解した2μg/mLのヒツジ抗ヒトFdで4℃にて一晩被覆した。コーティング溶液を取り除き、該プレートを200μL/ウェルの3% BSA/PBSで37℃にて1時間ブロッキングした。該プレートをPBS/0.1% TWEEN(登録商標)(PBST)で4回洗浄し、50μL/ウェルのFabサンプル(すなわち、高力価ファージ及び分泌Fab若しくはDMBブロック由来のペリプラズム標本を含んだ上清、又は15mLの標本)を加えた。プレートを室温にて1時間インキュベートし、PBSTで4回洗浄した。次いで、0.5% BSA/PBS及び0.05% TWEEN(登録商標)中に希釈して0.015μg/mLとしたビオチン化SE44を50μL/ウェル添加した。プレートを次いで室温にて2時間インキュベートしPBSTで4回洗浄した。0.5% BSA/PBS及び0.05% TWEEN(登録商標)中に1:2000希釈したストレプトアビジンHRPを50μL/ウェル添加し、プレートを室温にて1時間インキュベートした。該プレートをPBSTで6回洗浄した。50μL/ウェルのTMB基質(sigma)を添加して発色させ、次いで50μL/ウェルの0.2M H2SO4を加えて停止した。
プレートを、炭酸コーティング緩衝液中に溶解した0.25μg/mL(精製Fab 0.1μg/mLに対し)のSE44で4℃にて一晩被覆した。コーティング溶液を取り除き、該プレートを200μL/ウェルの3% BSA/PBSで37℃にて1時間ブロッキングした。
1日目
10mg/mLのテトラサイクリンを含む500mLの培養液(2×YT)2つに、5mLのオーバーナイトストックXL1Bを植菌し、A600=0.9〜1.2となるまで37℃で増殖させた。IPTGを0.5mMの濃度で添加した。該細胞培養液それぞれに200μLのファージを感染させ、37℃で1時間振とう培養した。その後、細胞を25℃で一晩振とうして増殖させた。
250mL遠心チューブを用いて3500×gで30分間4℃にて遠心し、細胞を沈殿させた。培養液を吸引し、ペレットを全量12〜15mLの溶解緩衝液(緩衝液A+プロテアーゼ阻害剤カクテル)中に再懸濁した。
50mM NaH2PO4 6.9g NaH2PO4H2O (又は 6g NaH2PO4)
300mM NaCl 17.54g NaCl
10mM イミダゾール 0.68g イミダゾール (MW 68.08)
NaOHでpH8.0に調整
溶解緩衝液:
25mLの緩衝液AとComplete Protease Inhibitor Cocktail (Roche, Basel, Switzerland) 1錠を混合
ELISAに適した96ウェルアッセイプレートを、0.05mLの0.5μg/mL FcεRIアルファ鎖レセプターコーティング緩衝液(50mM炭酸水素塩/炭酸水素塩、pH9.6)で4〜8℃にて12時間被覆した。ウェルを吸引し、250μLのブロッキング緩衝液(PBS, 1 % BSA, pH 7.2)を加えて37℃で1時間インキュベートした。別々のアッセイプレートを用いて、サンプルと引例のTES-C21 MAbの200〜0.001μg/mLの力価を、アッセイ緩衝液(0.5% BSA及び0.05% Tween 20, PBS, pH 7.2)で1:4希釈して測定し、等量の100ng/mLビオチン化IgEを添加して該プレートを25℃で2〜3時間インキュベートした。FcεRIで被覆されたウェルをPBS及び0.05% TWEEN20で3回洗浄し、該ウェルにサンプルウェルから50μLを移し入れて、25℃で30分間揺り動かしながらインキュベートした。アッセイ緩衝液で1:2000希釈した1mg/mLストレプトアビジン−HRPを50μL/ウェル加えて揺り動かしながら30分間インキュベートし、次いで該プレートを前記の通り洗浄した。50μL/ウェルのTMB基質を加えて発色させた。等量の0.2M H2SO4を加えて反応を停止し、450nmにおける吸光度を測定した。
FcεRIのアルファ−サブユニットと会合したヒトIgEへの抗体の結合を、10μg/mLヒトIgEで4℃にて30分間前インキュベートすることにより決定した。プレートを3回洗浄し、種々の濃度のマウス抗ヒトIgE mAb E-10-10又はヒト化Fab変異体のいずれかと共に1時間インキュベートした。Fabの結合はビオチン標識抗ヒトFd抗体で検出し、次いでSA-HRPを行なった。マウスab E10-10は、ヤギ抗マウスIg Fc HRP結合Abによって検出した。
各候補は結合親和性について分析し、陽性クローンを配列決定した。結合親和性の増大をもたらす有益な変異をCDR中に有する変異抗体はさらに性状解析した。アッセイはBiacore解析;IgEのレセプターへの結合阻害;及びIgEと結合したレセプターの架橋を包含する。
高親和性のMAb候補を作製した。無傷の抗IgE MAbを作製するため、重鎖及び軽鎖可変領域をファージベクター鋳型からPCR増幅し、H鎖及びL鎖発現ベクター中にCMVプロモーター下で別々にサブクローニングした。6つの全抗体クローンを構築した。それを図10A〜Fに示す。この分野で周知の技術によって、エレクトロポレーションを用いて適切な重鎖及び軽鎖プラスミドをマウスミエローマセルラインNSO中に共トランスフェクトした。例えばLiou et al. J Immunol. 143(12):3967-75 (1989)を参照のこと。プロテインA−セファロース(Pharmacia)を用いて、単一の安定セルライン上清から抗体を精製した。抗体濃度は分光光度計を用いて280nmにおいて、及びFCAアッセイ(IDEXX)を用いて決定した。
Claims (23)
- IgEに特異的に結合する単離された抗体又は抗体断片であって、配列番号61に記載されたアミノ酸配列を有する軽鎖可変領域及び配列番号62に記載されたアミノ酸配列を有する重鎖可変領域を含む抗体又は抗体断片。
- CDRL1、CDRL2、及びCDRL3を含む軽鎖可変領域と、CDRH1、CDRH2、及びCDRH3を含む重鎖可変領域とを含み、IgEに特異的に結合する、単離された抗体又は抗体断片であって、CDRL1は配列番号5からなり、CDRL2は配列番号8からなり、CDRL3は配列番号71からなり、CDRH1は配列番号16からなり、CDRH2は配列番号20からなり、CDRH3は配列番号26からなる抗体又は抗体断片。
- 軽鎖定常領域及び重鎖定常領域をさらに含む請求項1又は2記載の抗体又は抗体断片。
- 前記軽鎖定常領域が配列番号58に記載されたアミノ酸配列を有し、前記重鎖定常領域が配列番号60に記載されたアミノ酸配列を有する、請求項3記載の抗体又は抗体断片。
- ATCC寄託番号PTA-5678を有する細胞によって生産される請求項1又は2記載の抗体。
- IgEに特異的に結合する単離された抗体又は抗体断片であって、配列番号63に記載されたアミノ酸配列を有する軽鎖可変領域及び配列番号64に記載されたアミノ酸配列を有する重鎖可変領域を含む抗体又は抗体断片。
- 軽鎖定常領域及び重鎖定常領域をさらに含む請求項6記載の抗体又は抗体断片。
- 前記軽鎖定常領域が配列番号58に記載されたアミノ酸配列を有し、前記重鎖定常領域が配列番号60に記載されたアミノ酸配列を有する、請求項7記載の抗体又は抗体断片。
- ATCC寄託番号PTA-5680を有する細胞によって生産される請求項7記載の抗体。
- IgEに特異的に結合する単離された抗体又は抗体断片であって、配列番号65に記載されたアミノ酸配列を有する軽鎖可変領域及び配列番号66に記載されたアミノ酸配列を有する重鎖可変領域を含む抗体又は抗体断片。
- 軽鎖定常領域及び重鎖定常領域をさらに含む請求項10記載の抗体又は抗体断片。
- 前記軽鎖定常領域が配列番号58に記載されたアミノ酸配列を有し、前記重鎖定常領域が配列番号60に記載されたアミノ酸配列を有する、請求項11記載の抗体又は抗体断片。
- ATCC寄託番号PTA-5679を有する細胞によって生産される請求項10記載の抗体。
- 請求項1、2、6又は10記載の抗体又は抗体断片を含む組成物。
- 標識をさらに結合された請求項1、2、6又は10記載の抗体又は抗体断片。
- 請求項1、2、6又は10記載の抗体又は抗体断片を含む診断キット。
- 請求項1、2、6又は10記載の抗体又は抗体断片をコードする核酸を含むベクター。
- 請求項17記載のベクターを含む細胞。
- 前記細胞がATCC寄託番号PTA-5678, PTA-5679又はPTA-5680である、請求項18記載の細胞。
- 抗体の生産に適した条件下で請求項18記載の細胞を培養すること、及び生産された抗体を単離することを含む、抗体を生産するための方法。
- 被験者におけるIgEレベルを測定するための方法であって、IgE分子を含むサンプルである被験者のサンプルを請求項1、2、6又は10記載の抗体又は抗体断片と接触させること;及び該サンプルによる抗体又は抗体断片の保持のレベルを対照被験者のコントロールサンプルと比較して決定することを含み、コントロールサンプルに対して被験者のサンプルによる抗体又は抗体断片の保持のレベルが高い又は低いということが、該被験者が対照被験者よりも高い又は低いレベルのIgE分子を有しているということを示すものである方法。
- 被験者におけるIgE媒介疾患を検出するための方法であって、IgE分子を含むサンプルである被験者から分離されたサンプルを請求項1、2、6又は10記載の抗体又は抗体断片と接触させること;及び該サンプルによる抗体又は抗体断片の保持のレベルを対照被験者のコントロールサンプルと比較して決定することを含み、コントロールサンプルに対して被験者のサンプルによる抗体又は抗体断片の保持のレベルが高い又は低いということが、該被験者がIgE媒介疾患を有するということを示すものである方法。
- 前記のIgE媒介疾患が、喘息、アレルギー性鼻炎、湿疹、蕁麻疹、又はアトピー性皮膚炎である、請求項22記載の方法。
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