JP2008500024A - 新規抗il13抗体およびその使用 - Google Patents
新規抗il13抗体およびその使用 Download PDFInfo
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Abstract
Description
インターロイキン(IL)−13は、多形質発現性Tヘルパー細胞サブクラス2(Th2)サイトカインである。IL4と同様に、IL13は、4α−らせん疎水性バンドルコアによって規定される三次構造を共有するタイプIサイトカインのファミリーに属する。IL13は、IL4と約30%のアミノ酸配列相同性を有し、そしてIL4の多くの性質を共有する(非特許文献1)。IL4とIL13との機能的類似性は、IL13が、そのIL13レセプターα鎖−1(IL13Rα1)への結合に引き続き、IL4レセプターα鎖(IL4R−α)を結合し得るという事実に帰因する((非特許文献2)。IL4Rαは、IL4およびIL13によって活性化され、Jak1依存性SAT6リン酸化を生じる。IL4およびIL13の両方は、B細胞増殖を促進し、そしてCD40/CD40L同時刺激との組み合わせでIgG4およびIgEへのクラススイッチングを誘導する(非特許文献3および4)。
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本発明は、グリコシル化ヒトIL13および非グリコシル化ヒトIL13の両方に特異的かつ高親和性で結合し;マウスIL13を結合せず、そして約1:2のモル比(MAb:IL13)でヒトLI13活性を中和する抗体に、少なくとも部分的に関連する。本発明にまた含まれるのは、上記抗体の軽鎖可変領域および/または重鎖可変領域由来の抗原結合性領域を含む抗体である。本発明の抗体はモノクローナルであり得、そしてモノクローナル抗体は、ヒト抗体、キメラ抗体、またはヒト化抗体であり得る。
本発明は、本明細書中に記載される特定の方法、プロトコール、細胞株、ベクター、または試薬に限定されない。なぜなら、それらは変動し得るからである。さらに、本明細書中で用いられる用語法は、特定の実施形態のみを記載する目的のために用いられ、そして本発明の範囲を制限することは意図されない。本明細書および添付の請求項で用いられるとき、単数形「a」、「an」、および「the」は、文脈が明瞭にそうでないことを指示しなければ、複数の参照を含み、例えば、「宿主細胞」への参照は、複数のこのような宿主細胞を含む。
組換えIL13を用いてマウスを免疫化し、本発明のモノクローナル抗体を産生するハイブリドーマを生成した。組換えIL13は、多くの供給元から市販される(例えば、R&D Systems、Minneapolis、MN、PetproTech、Inc.、NJ、およびSanofi Bio−Industries、Inc.、Tervose、PA.を参照のこと)。あるいは、IL13をコードする遺伝子またはcDNAは、プラスミドまたはその他の発現ベクター中にクローン化され、そして当業者に周知の方法に従って、多くの発現システムのいずれかで発現され得る。IL13およびIL13の核酸配列をクローニングし、そして発現するする方法は周知である(例えば、米国特許第5,652,123号を参照のこと)。遺伝子コードの縮重のため、IL13ポリペプチドをコードする複数のヌクレオチド配列が産生され得る。可能なコドン選択に基づいて組み合わせを選択することにより、ヌクレオチド配列を改変し得る。これらの組み合わせは、天然に存在するIL13ポリペプチドをコードするヌクレオチド配列に適用されるような標準的なトリプレット遺伝子コードに従ってなされ得、そしてすべてのそのような改変が考慮されるべきである。これらポリペプチドの任意の1つが、IL13に結合する抗体を生成するために動物の免疫化において用いられ得る。
本発明の抗体は、当該分野で公知の任意の適切な方法によって生成され得る。本発明の抗体は、ポリクローナル抗体を含み得る。ポリクローナル抗体を調製する方法は、当業者に公知である(Harlowら、Antibodies:a Laboratory Manual、(Cold spring Harbor Laboratory Press、第2版(1988))、これは、その全体が参考として本明細書中に援用される)。
本発明は、IL13の作用を阻害および中和するアンタゴニストモノクローナル抗体を提供する。特に、本発明の抗体は、IL13に結合し、そしてIL13レセプターα鎖−1(IL13α1)の活性化を阻害する。本発明の抗体としては、228B/C−1、228A−4、227−26、および227−43と称される抗体が挙げられ、そして228B/C−1のヒト化クローンが開示される。本発明としてはまた、これらの抗体の1つと同じエピトープ、例えば、モノクローナル抗体228B/C−1のエピトープに結合する抗体が挙げられる。
別の局面では、本発明は、本発明の抗体をコードするヌクレオチド配列を含むベクター構築物、およびこのようなベクターを含む宿主細胞を提供する。クローニングおよび形質転換のための標準的な技法が、本発明の抗体を発現する細胞株の調製で用いられ得る。
本発明は、本発明の抗体およびそのフラグメントをコードするヌクレオチド配列を含む、ポリヌクレオチドまたは核酸(例えば、DNA)をさらに提供する。例示のポリヌクレオチドは、本明細書に記載のアミノ酸配列の1つ以上を含む抗体鎖をコードするポリヌクレオチドを含む。本発明はまた、本発明の抗体をコードするポリヌクレオチドに、ストリンジェントまたはより低いストリンジェンシーハイブリダイゼーション条件下でハイブリダイズするポリヌクレオチドを包含する。
本発明の抗体は、抗体の合成のための当該技術分野で公知の任意の方法、特に化学的合成または好ましくは、組換え発現技法により産生され得る。
本発明の抗体は、改変されている、すなわち、抗体への任意のタイプの分子の共有結合による誘導体を含み、この共有結合は、IL13への結合を妨害しない。例えば、制限するのではなく、この抗体誘導体としては、例えば、ビオチン化、HRP、または任意のその他の検出可能成分によって改変された抗体が挙げられる。
抗体に結合体化された治療成分と一緒にまたはなしで、抗体は、単独でまたは細胞傷害性因子(単数または複数)と組み合わせて、治療薬として用いられ得る。本発明は、抗体を基礎にした治療に関し、これは、本発明の抗体を、IL13が媒介する疾患、傷害、または状態を、動物、哺乳動物、またはヒトに投与する工程を含む。この動物または被験体は、特定の障害(例えば、IL13に関係する障害)をもつと診断された動物のような、特定の処置が必要な動物であり得る。IL13に対して惹起された抗体は、動物においてアレルギー反応を阻害するために有用であり、この動物としては、ウシ、ブタ、ウマ、ニワトリ、ネコ、イヌ、非ヒト霊長類など、およびヒトが挙げられるが、これらに限定されない。例えば、治療的に受容可能な用量の本発明の抗体(もしくは複数の抗体)または本発明の抗体のカクテル、または種々の供給源のその他の抗体との組み合わせを投与することにより、抗原に対するアレルギー応答が、処置された哺乳動物において減少またはなくされ得る。
本発明の別の局面において、抗体またはその機能的誘導体をコードする配列を含む核酸が、遺伝子治療により、IL13の異常発現および/または活性にともなう疾患または障害を処置、阻害または予防するために投与される。遺伝子治療は、発現されるかまたは発現可能な核酸の被験体への投与によって実施される治療をいう。本発明のこの実施形態では、上記核酸は、治療効果を媒介するそれらのコードされたタンパク質を生成する。利用可能な遺伝子治療のための任意の方法が、本発明に従って用いられ得る。例示的な方法は、以下に記載される。
(A.MT−IL13/Fcのための発現プラスミドのクローニングおよび構築)
等しいかまたはより高い親和性をもつ、IL13Rα1に結合したアミノ酸残基番号13における変異(グルタミン酸からリンジンへ)をもつヒトIL13は、しかし、IL13Rα1保持細胞を活性化する能力を失ったことが報告された(Thompsonら、J.Biol.Chem.、274:29944(1999))。この変異した不活性なIL13(MT−IL13と示される)を、ヒト胎児腎細胞293−T中で発現した。この精製された組換えタンパク質を、本発明における免疫原として用い、抗IL−13モノクローナル抗体を生成した。2つのオリゴヌクレオチドプライマーは:
MT−IL13遺伝子に対応するオリゴヌクレオチド配列を合成し、そしてポリメラーゼ連鎖反応(PCR)におけるテンプレートとして用い、このIL13遺伝子をヒト精巣cDNAライブラリー(BD Biosciences Clontech、Palo Alto、CA)からクローニングした。IL13の推定されたシグナルペプチド配列を欠いたPCRフラグメント(342塩基対)を、pSecTag/FRTベクター(Invitrogen、Carlsbad、CA)中に連結した。このpSecTag/FRTベクターは、5’末端に分泌シグナルペプチドを、そして3’末端にヒトFcγ1(ヒンジ領域および定常領域CH2およびCH3)配列を含んだ。この構築物の組成は、配列決定により確認した。
MT−IL13/Fcの一時的発現のために、精製されたプラスミドDNAを、製造業者のプロトコールに従って、Lipofectamine 2000(Invitrogen)によって293T細胞中にトランスフェクトした。トランスフェンション72時間後、トランスフェクトされた細胞からの培養上清液を精製のために収集した。MT−IL13/Fcの安定な発現のために、細胞株を、Flp−In 293T細胞株(Invitrogen)を用いて樹立した。発現を確認するために、細胞上清液を、ドデシル硫酸ナトリウムポリアクリルアミドゲル電気泳動(SDS−PAGE)によって分析した。分離されたタンパク質を、ニトロセルロースメンブレンに移し、そして西洋ワサビペルオキシダーゼ(HRP)結合体化マウス抗ヒトIgG(Fc)モノクローナル抗体(Sigma、St.Louis、MO)またはポリクローナルヤギ抗−IL13抗体(R&D Systems、Minneapolis、MN)との反応より検出し、これらは次いでHRP−ロバ抗ヤギIgG(Jackson ImmunoResearch Laboratories、West Grove、PA)で検出された。免疫反応性タンパク質を、増幅化学発光検出(Supersignal West Pico Chemiluminescent Substrate、Pierce、Rockford、IL)を用いて、フィルム上で同定した。
MT−IL13/Fcは、リン酸緩衝化生理食塩水(PBS)で平衡化されたハイパー−DプロテインAアフィニティーカラム(Invitrogen)で精製した。このカラムに細胞培養上清液を付与した後、樹脂を20カラム容量を超える量のPBSで洗浄した。次いで、この樹脂をSCC緩衝液(0.05Mクエン酸ナトリウム、0.5M塩化ナトリウム、pH6.0)で洗浄し、非結合のタンパク質を除去した。IL13融合タンパク質を、次いで、溶出し(005Mクエン酸ナトリウム、0.15M塩化ナトリウム、pH3.0)、そしてPBS中で透析した。
雄のA/Jマウス(Harlan、Indianapolis、IN)、8〜12週齢に、200μLのPBS(pH7.4)で完全フロイントアジュバント(Difco Laboratories、Detroit、MI)中の20μgのMT−IL13/Fcを皮下注射した。2週間の間隔で、マウスを、不完全フロイントアジュバント中の20μgのMT−IL13/Fcで2度皮下注射した。次いで、2週間後、そして屠殺の3日前に、マウスに、PBS中の20μgの同じ免疫原で腹腔内注射した。1匹以上の抗原免疫化マウスから単離された脾臓細胞を、融合のために用いた。免疫化および融合の類似の手順もまた、免疫原としてのE.coli発現ヒトIL13(R&D Systems)とともに用いた。
種々の抗IL13モノクローナル抗体の反応性を、ELISAによって試験した。96ウェルマイクロテストプレートの異なるウェルを、E.coli発現非グリコシル化ヒトIL13(R&D Systems)、293T細胞発現グリコシル化MT−IL13/Fc、またはE.coli発現マウスIL13(R&D Systems)のいずれかで、PBS中の100μLの0.1μg/mL IL13タンパク質の添加によりコーティングした。室温で一晩インキュベーション後、これらウェルを、PBSTB(2%BSAを含むPBST)で処理し、残りの結合部位を飽和した。これらウェルを次いでPBSTで洗浄した。
(JES10−5A2によるヒトIL13への228B/C−1−Hrp結合の競合の欠如)
JES10−5A2および228B/C−1が、ヒトIL13上の同じエピトープに結合するか否かを取り扱うために、競合ELISAを用いて、E.coli発現ヒトIL13への228B/C−1−HRP結合に対するJES10−5A2の影響を試験した。96ェルマイクロテストプレートの96ウェルの各ウェルを、100μLのPBS中0.1μg/mLのIL13タンパク質とともにインキュベートした。室温で一晩のインキュベーションの後、これらウェルを、PBSTB(2%BSAを含むPBST)で処理し、残りの結合部位を飽和した。これらウェルを、次いで、PBSTで洗浄した。50マイクロリットルの2倍系列希釈の228B/C−1およびJES10−5A2(最終濃度20μg/mL〜9.76ng/mL)を、50μLの予備滴定した228B/C−1−HRPと(1:6,400希釈で)混合した。その混合物を、次いで、ウェルに添加し、そして室温で1時間インキュベートした。次いで、上記のように、発色のためにペルオキシダーゼ基質溶液を添加した。OD450を、ELISAリーダーを用いて測定した。
(L−1236およびHDLM−2細胞を用いるIL13自己分泌依存性増殖アッセイによる抗IL13中和モノクローナル抗体のスクリーニング)
L−1236およびHDLM−2は、German Collection of Miroorganisms and Cell Culture(DSMZ、Brauschweig、Germany)から得られるホジキンリンパ腫細胞株である。これら細胞株はIL13を産生し、これは、次いで、自己分泌様式でそれらの細胞増殖を活性化する(Kapp Uら、J.Exp.Med.189:1939(1999))。
(原発性ヒト単球上のIL13制御CD14およびCD23発現に対するアッセイ)
IL13は、ヒト単球におけるCD14発現の抑制およびCD23発現の上方制御を誘導する(de Waal Malefytら、J.Immunol.、151:6370(1993)、Chomaratら、Int.Rev.Immunol.、17:1(1998))。末梢血白血球(PBL)を、健常なヒトドナーの新鮮に収集したヘパリン処理全血から、Histopaque−1077(Sigma)中の密度勾配遠心分離によって単離した。5%ウシ胎仔血清を含むRPMI−1640培地(Invitrogen)中に懸濁されたPBL(1.5×106)を、組換えIL13(最終10ng/mL=0.813nM)および抗IL13モノクローナル抗体または無関係の抗体(3倍系列希釈、最終12μg/mL=80nMから)を含む96ウェルの組織培養プレートの各ウェルに添加した。単球上のCD14発現またはCD23発現は、イキュベートする培地に0.813nMのヒトIL13の添加により、それぞれ抑制または上方制御された。培地のコントロールは、組換えIL13なしのRPMI−1640/FBS培地を含んだ。
(THP−1細胞におけるIL13誘導STAT6リン酸化アッセイ)
IL13は、骨髄細胞株THP−1(ATCC、Manassas、VA)を活性化し得、IL13のシグナル伝達経路における重要なステップであるSTAT6のリン酸化を誘導する(Murata Tら、Int.Immunol.10:1103〜1110(1998))。上記抗IL13MAbを、このアッセイでIL13の阻害について試験した。
(抗IL13モノクローナル抗体をコードする重鎖および軽鎖遺伝子の分子クローニング)
QIAGENキット(Valencia、CA)を用いて、総RNAをハイブリドーマ細胞から単離した。逆転写(第1鎖cDNA)反応を、以下のように実施した:1〜1.5mgの総RNAを、1mlの10mM dNTP、50ngのランダムヘキサマー、およびRNaseを含まない12mLの最終容量の水と混合した。
(クローン228B/Cのヒト化)
(A.一般的プロトコール)
マウス抗体228B/Cの可変領域をクローニングし、そして実施例8に記載のように配列決定した。ファージベクター中のキメラFabを、マウス228B/Cの可変領域、およびヒトκ鎖の定常領域、およびヒトIgGのCH1部分を組み合わせたコントロールとして構築した。
軽鎖(Vk)の可変領域のヒト化を最初に実施した。しかし、いずれかの鎖で開始し得るか、または両方の鎖を同時にヒト化し得る。選択されたヒトテンプレートは、ヒトテンプレート2であり、そしてそれらが機能的活性の損失なくしてヒト化され得るか否かを決定するために軽鎖内のCDRに近接する9残基に関する効果の研究に関与した。第2ラウンドのスクリーニングのために研究された軽鎖上の位置は、4、9、12、73、81、82、83、84、および109であった。
候補抗体の全体の機能に対する重鎖フレームワーク残基の寄与を評価するために、ライブラリーを、マウスの軽鎖を維持しながら、親マウスとは異なるヒトDP27テンプレートフレームワーク内の10の位置を変動して構築した。このライブラリーは、Vhについて合成された重複するオリゴヌクレオチド、およびPCRを用いるマウスVkの生成を用いて生成した。このVkおよびVhを、次いで、変異誘発を用いてFab発現ベクター中に挿入し、そしてこのライブラリーを、次いで、機能的Fabについてスクリーニングした。ライブラリーの複雑度は、(210/70%)×3=3840であった。
いずれのライブラリーのスクリーニングから選ばれた候補も完全にヒト化されなかったので、ヒト化を操作した。所望のヒト化レベルが得られた一連の候補を生成した。HT2ライブラリーからの最もヒト化されたVkを、上記NEWまたはDP27ライブラリーからの最もヒト化されたVhと組み合わせた。次いでこれらのコンビナトリアル候補をアッセイし、最も高いヒト化レベルを保持しながらどれが特異的機能を維持したかを決定した。HT2−NEWから選択された候補は、重鎖についてHT2−NEW番号73および軽鎖についてHT2−NEW番号115であった。HT2−DP27軽鎖から選択された候補は、HT2−DP27番号89およびHT2−DP27番号144であり、そして重鎖についての候補は、HT2−DP27番号123およびHT2−DP27番号276であった。HT2−DP27については、構築物を、以下のように作成した:番号276Vhとの番号89Vkおよび番号123Vhとの番号89Vk;番号276Vhとの番号144Vkおよび番号123Vhとの番号144Vk。さらに、1つの構築物を、番号73Vh NEWとの番号144Vk DP27で作製し、HT2軽鎖とのNEWおよびDP27相互作用が異なるか否かを決定した。
(CDR最適化)
候補の抗IL13抗体の最適フレームワーク配列を決定する際に、CDRの最適化を実施した。このプロセスのために、CDRアミノ酸配列をランダム化し、次いで上記ライブラリーをスクリーニングして親クローンと等しいか、親クローンより良好な機能的活性を有するような候補を同定した。このライブラリーについては、親の候補はRL−36(上記を参照のこと)であった。6つのCDRをランダム化し、一度に1つの位置を、そして上記ライブラリーを機能的ELISAを用いてスクリーニングした。強く反応する候補を、親CDRとの比較のために配列決定した。以下の表に列挙されるすべての特有の配列がまた、適切な配列番号識別子とともに図20に見られることに注意されたい。
CDR−L1は15アミノ酸を含んでいた。これらの位置の各々を、変異誘発反応中で用いられるべく、当モル量で混合された合成オリゴヌクレオチドを用いてランダム化した。変異誘発オリゴヌクレオチドの取り込みの効率は、40%であると決定された。この%を用い、スクリーニングされることが必要な候補の数は3600であった。これらクローンは、機能的ELISAを用いてアッセイし、そして匹敵し得る機能的活性を生じたようなクローンを配列決定した。スクリーニングされた多くの候補から、166の陽性クローンを同定した。このグループから、10の候補を配列決定し、CDR内の変化を決定した。以下に示される配列決定結果から、改良された親和性に至る位置11および14は、NからQおよびMからLであることを得る。
CDR−L2は7アミノ酸を含んでいた。このライブラリーは、上記に記載のように調製した。このライブラリーの効率は80%であり、そして840クローンがアッセイされた。このアッセイから同定された陽性クローンの番号75および11を配列決定した。以下に示される結果から、位置および置換アミノ酸はランダムのようであったが、このCDR内の数個の位置が改良された活性を生じた。この結果は、CDR−L2は、抗原結合部位から最も遠く、そしてそれ故、抗原結合の際に最も少ない影響を奏するという知見を支持する。
CDR−L3は9アミノ酸から構成されていた。このライブラリーは、生成に際し、50%の効率を生じ、約1700のクローンがスクリーニングされることが必要であった。このスクリーニングから、257の陽性候補を同定し、そして10を配列決定した。これらの結果から、1つの位置のみが、親配列からの変化を生じた。数個の候補が、この位置変化が高度に好ましかったこと(NからA)を示唆した同じ配列を実証した。
CDR−H1は5アミノ酸を含んでいた。このライブラリーの効率は80%であり、約600の候補のみがスクリーニングされることを必要とした。このクスリーニングから、138の陽性クローンが存在し、そしてこれらクローンの11を配列決定した。以下に列挙される結果から、このCDR内の第2の位置が、抗原結合の改良の最大の機会を与えるようであった。しかし、数個のアミノ酸が有利に結合に影響した。
CDR−H2は16のアミノ酸を含んでいた。このライブラリーの効率は70%であり、これは、2100を超える候補がスクリーニングされる必要があることを意味した。このスクリーニングから、192の陽性候補を同定し、そして13を配列決定して、このCDR内で生じた変化を決定した。以下に列挙する配列決定結果から、いくつかの位置が結合親和性を改良したが、親と有意に異なるように見えたアミノ酸変化はなかった。
CDR−H3は10アミノ酸を含んでいた。このCDRは、一般に、抗原結合に最も大きい影響を課す1つであると考えられている。なぜなら、このループは、結合部位のほぼ中央にあるからである。このライブラリーは40%の効率を有し、そして2400の候補がスクリーニングされる必要があった。これらのうち、174の陽性クローンを同定し、そして10を配列決定し、このCDR内の変化を決定した。以下に列挙される結果は、第3の位置におけるYからRへの変化が、結合における改善のために重要な1つであり得ることを示した。
一旦、抗原結合において最も大きい全体の改善を生じたCDR内の変化を決定すると、最良の候補が次に組み合わせられて、これらの変更が、結合を改善したか否かを見た。従って、候補は、すべての好ましいアミノ酸置換を組み合わせるように操作した。
(エピトープマッピング)
抗IL13 MAb 228B/C−1は、立体配座エピトープに結合し、そしてカニクイザルIL13に、それがヒトIL13に結合するのと同じ高い親和性で結合する。しかし、228B/Cは、マウスIL13には結合しない。そこで、エピトープマッピングのために工夫された戦略は、このサルIL13の小部分を、対応するマウスIL13配列と交換することであった。重複するオリゴヌクレオチドを図18に示されるように合成した。2ラウンドのPCRを実施し、IL13ハイブリッド構築物を、サルIL13の一部が、マウスIL13からの対応する配列によって置換されるようにアセンブルした(図18)。最終のPCR増幅されたIL13コード領域を、TOPOクローニングキット(Invitrogen)を用いて、pcDNA3.1ベクター中にV5タグとインフレームでクローニングした。すべてのPCR増幅された領域は、配列決定により、所望のドメインがスワップしている変異のみを含み、そしてこの発現ベクター中にさらなる所望されない変異が含まれないことが確認された。
以下の培養物は、American Type Culture Collection、10801 University Boulevard、Manassas Va.20110−2209 USA(ATCC)に寄託されている:
Claims (61)
- グリコシル化ヒトIL13および非グリコシル化ヒトIL13の両方に特異的かつ高親和性で結合し、マウスIL13を結合せず、そして約1:2のモル比(MAb:IL13)でヒトLI13活性を中和する、抗体またはその抗原結合性フラグメント。
- 前記抗体が228B/Cであり、そしてPTA−5657で指定されるハイブリドーマによって産生される、請求項1に記載の抗体。
- 請求項2に記載の抗体と同じエピトープに結合する抗体。
- 前記抗体が228A−4であり、そしてPTA−5656で指定されるハイブリドーマによって産生される、請求項1に記載の抗体。
- 前記抗体が227−26であり、そしてPTA−5654で指定されるハイブリドーマによって産生される、請求項1に記載の抗体。
- 前記抗体が227−43であり、そしてPTA−5655で指定されるハイブリドーマによって産生される、請求項1に記載の抗体。
- 抗体であって、請求項1に記載の抗体の軽鎖可変領域および重鎖可変領域由来の抗原結合性領域を含む、抗体。
- 前記抗体が配列番号3に提示される抗体に少なくとも95%相同であるVL配列、および配列番号4に提示される抗体に少なくとも95%相同であるVH配列を有する、請求項7に記載の抗体。
- 前記抗体が配列番号5に提示される抗体に少なくとも95%相同であるVL配列、および配列番号6に提示される抗体に少なくとも95%相同であるVH配列を有する、請求項7に記載の抗体。
- 前記抗体が配列番号7に提示される抗体に少なくとも95%相同であるVL配列、および配列番号8に提示される抗体に少なくとも95%相同であるVH配列を有する、請求項7に記載の抗体。
- 228B/C−1、228A−4、227−26、および227−43からなり、そしてそれぞれATTC寄託番号PTA−5657、PTA−5656、PTA−5654、およびPTA−5655から指定される群から選択されるモノクローナル抗体を産生する、ハイブリドーマ細胞株。
- 請求項1に記載の抗体をコードする核酸を含む、細胞株。
- 請求項1に記載の抗体をコードする核酸を含む、ベクター。
- 前記抗体が、モノクローナル抗体である、請求項1の抗体。
- 前記モノクローナル抗体が、ヒト抗体、キメラ抗体、またはヒト化抗体である、請求項14の抗体。
- 請求項1に記載の抗体、および生理学的に受容可能なキャリア、希釈剤、賦形剤、または安定化剤を含む、組成物。
- 式:FRL1−CDRL1−FRL2−CDRL2−FRL3−CDRL3−FRL4を有するアミノ酸配列を含む可変軽鎖領域であって、ここで、FRL1が配列番号20〜25のいずれか1つからなり;CDRL1が配列番号99〜103のいずれか1つからなり;FRL2が配列番号29からなり;CDRL2が配列番号104〜114のいずれか1つからなり;FRL3が配列番号30〜56のいずれか1つからなり;CDRL3が配列番号115〜116のいずれか1つからなり;そしてFRL4が配列番号57〜59からなる、可変軽鎖領域。
- 配列番号3、5、7、93、95、97、142、144、および150のいずれか1つを含む、可変軽鎖領域。
- 定常領域をさらに含む、請求項17に記載の可変軽鎖領域。
- 定常領域をさらに含む、請求項18に記載の可変軽鎖領域。
- 式:FRH1−CDRH1−FRH2−CDRH2−FRH3−CDRH3−FRH4を有するアミノ酸配列を含む可変軽鎖領域であって、ここで、FRH1が配列番号60〜66のいずれか1つからなり;CDRH1が配列番号117〜122のいずれか1つからなり;FRH2が配列番号67〜75のいずれか1つからなり;CDRH2が配列番号123〜134のいずれか1つからなり;FRH3が配列番号76〜90のいずれか1つからなり;CDRH3が配列番号135〜141のいずれか1つからなり;そしてFRL4が配列番号91〜92からなる、可変重鎖領域。
- 配列番号4、6、8、94、96、98、143、145、146、147、148および149のいずれか1つを含む、可変重鎖領域。
- 定常領域の少なくともCH1ドメインをさらに含む、請求項21に記載の可変重鎖領域。
- 定常領域のCH1ドメイン、CH2ドメインおよびCH3ドメインをさらに含む、請求項23に記載の可変重鎖領域。
- 前記定常領域が、IgG抗体由来である、請求項24に記載の可変重鎖領域。
- 前記IgG抗体が、IgG1抗体、IgG2抗体、IgG3抗体、またはIgG4抗体である、請求項25に記載の可変重鎖領域。
- 定常領域の少なくともCH1ドメインをさらに含む、請求項22に記載の可変重鎖領域。
- 請求項17の可変軽鎖領域を含む抗体またはその抗原結合性フラグルメントであって、ここで、該抗体がIL13に特異的に結合する、抗体またはその抗原結合性フラグメント。
- 請求項21の可変重鎖領域を含む抗体またはその抗原結合性フラグルメントであって、ここで、該抗体がIL13に特異的に結合する、抗体またはその抗原結合性フラグメント。
- 請求項21に記載の重鎖領域を含む、請求項28に記載の抗体。
- 配列番号142に提示されるアミノ酸配列を有する可変軽鎖領域、および配列番号143に提示されるアミノ酸配列を有する可変重鎖領域を含む、請求項30に記載の抗体。
- 配列番号150に提示されるアミノ酸配列を有する可変軽鎖領域、および配列番号151に提示されるアミノ酸配列を有する可変重鎖領域を含む、請求項30に記載の抗体。
- 前記抗体が、配列番号152に提示される配列を有する単鎖抗体である、請求項1に記載の抗体。
- 前記抗体が、単一ドメイン抗体である、請求項1に記載の抗体。
- 前記抗体が、抗原結合性フラグメントである、請求項1に記載の抗体。
- 前記抗原結合性フクラグメントが、Fabである、請求項35に記載の抗体。
- 喘息症状を患う被験体を処置するための方法であって、該喘息症状を低減するために有効な量の請求項1に記載の抗体を投与する工程を包含する、方法。
- 前記抗体が、前記患者におけるIL13の活性を下方制御する、請求項37に記載の方法。
- 前記抗体が、前記患者における気管支の応答性亢進を低減する、請求項38に記載の方法。
- 前記抗体が、前記被験体の肺における好酸球増加症を低減する、請求項37に記載の方法。
- 前記抗体が、静脈内、腹腔内、吸入、筋肉内、皮下および経口からなる群から選択される1つ以上の経路によって投与される、請求項37に記載の方法。
- 前記抗体が、吸入によって投与される、請求項41に記載の方法。
- 患者に、治療的に有効な量の請求項1に記載の抗体を送達する吸入デバイス。
- サンプル中のインターロイキン−13タンパク質を検出するための方法であって:請求項30に記載の抗体をサンプルに接触させる工程;および免疫反応の発生によりインターロイキン−13を検出する工程を包含する、方法。
- 前記サンプルが、患者から収集される、請求項44に記載の方法。
- 患者におけるIL13の過剰発現を診断するための方法であって:
(a)患者からサンプルを得る工程;(b)IL13との免疫反応を可能にし得る条件下で、該サンプルと、請求項1に記載の抗体とを組み合わせる工程;および(c)IL13が、IL13の通常レベルの発現に対して過剰発現されるか否かを決定する工程を包含する、方法。 - 請求項1に記載の抗体を産生する方法であって:a)グリコシル化IL13部分および免疫原性部分を含む免疫原性化合物を産生する工程;b)該免疫原性化合物を含む注射可能な溶液をリン酸緩衝化生理食塩水(PBS)およびアジュバント中に調製する工程;c)静脈内注射および腹腔内注射の組み合わせによって、該注射可能な溶液でマウスを免疫化する工程、d)該免疫化マウスからの脾臓細胞を骨髄腫細胞と融合することによりハイブリドーマを産生する工程;e)請求項1に記載の抗体の特徴を有する抗体を産生するハイブリドーマを選択する工程;およびf)該抗体を単離する工程、を包含する、方法。
- 組換え抗体分子、またはそのIL13結合性フラグメントであって:マウス抗−IL13抗体由来の位置31〜35(CDR1)、50〜65(CDR2)および95〜102(CDR3)(Kabat番号付け)にある非ヒトCDRを含み、ここで、位置27〜30が、アミノ酸Gly26、Phe27、Ser28、Leu29、Asn30を有する少なくとも1つの抗体重鎖、またはそのIL13結合性フラグメント;およびマウス抗−IL13抗体由来の位置24〜34(CDR1)、50〜56(CDR2)および89〜97(CDR3)にある非ヒトCDRを含む少なくとも1つの抗体軽鎖、またはそのIL13結合性フラグメント、ならびにモノクローナル抗体由来のフレームワーク領域を含む、組換え抗体分子、またはそのIL13結合性フラグメント。
- 請求項30の抗体をコードするDNA配列。
- 請求項49に記載のDNA配列を有するベクター。
- 請求項50に記載のベクターを含む宿主細胞。
- 患者においてIgE抗体産生を阻害するための方法であって、該患者にIgE抗体産生を阻害する有効量の請求項1に記載の抗体を投与する工程、を包含する、方法。
- 前記IgE抗体産生の阻害が、気管支喘息を予防すること、アレルギー性鼻炎を予防すること、アレルギー性皮膚炎を予防すること、気管支喘息を処置すること、アレルギー性鼻炎を処置すること、じんま疹を処置すること、アナフィラキシーを予防すること、またはアトピー性皮膚炎を処置することを意図される、請求項52に記載の方法。
- 患者におけるIL13媒介障害を処置する方法であって、該患者に、有効量の請求項1に記載の抗体またはその抗原結合性フラグメントを投与する工程を包含し、ここで、該抗体またはその抗原結合性フラグメントが、IL13のそのレセプターへの結合を阻害し、そして該インターロイキンの該レセプターへの結合にともなう1つ以上の機能を阻害する、方法。
- 前記障害が、アレルギー性喘息、非アレルギー性(内因性)喘息、アレルギー性鼻炎、アトピー性皮膚炎、アレルギー性結膜炎、湿疹、じんま疹、食物アレルギー、慢性閉塞性肺疾患、潰瘍性大腸炎、RSV感染、ブドウ膜炎、強皮症、または骨粗鬆症である、請求項54に記載の方法。
- 患者においてIgE媒介障害を処置する方法であって、該患者に有効量の請求項1に記載の抗体またはその抗原結合性フラグメントを投与する工程を包含し、ここで、該抗体またはその抗原結合性フラグメントが、IL13のそのレセプターへの結合を阻害し、そして該インターロイキンの該レセプターへの結合にともなう1つ以上の機能を阻害する、方法。
- 哺乳動物において喘息の重篤度を低減する方法であって、該哺乳動物に、以下の特徴の少なくとも1つを有する抗IL13モノクローナル抗体;約1×109と約1×1012Mとの間のKDでヒトIL13を結合する能力;インターロイキンIL13のIL13レセプターへの結合にともなう1つ以上の機能を阻害する能力;および該抗体のマウスIL13を結合しない能力;の治療的に有効な量を投与する工程を包含する、方法。
- 前記抗IL13抗体が、吸入、全身的、ボーラス注射、または連続注入によって投与される、請求項52に記載の方法。
- 前記抗IL13抗体が、吸入、全身的、ボーラス注射、または連続注入によって投与される、請求項54に記載の方法。
- アミノ酸配列ESLINVSG(配列番号18)から本質的になるペプチド。
- アミノ酸配列YCAALESLINVS(配列番号19)から本質的になるペプチド。
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2012
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2013
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2014
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2017
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2019
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2020
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JP2007161724A (ja) * | 2003-12-23 | 2007-06-28 | Tanox Inc | 新規抗il13抗体およびその使用 |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8734801B2 (en) | 2003-12-23 | 2014-05-27 | Genentech, Inc. | Anti-IL13 antibodies and uses thereof |
JP2007161724A (ja) * | 2003-12-23 | 2007-06-28 | Tanox Inc | 新規抗il13抗体およびその使用 |
US8067199B2 (en) | 2003-12-23 | 2011-11-29 | Genentech, Inc. | Anti-IL13 antibodies and uses thereof |
US8088618B2 (en) | 2003-12-23 | 2012-01-03 | Genentech, Inc. | Anti-IL 13 antibodies and uses thereof |
JP4943161B2 (ja) * | 2003-12-23 | 2012-05-30 | ジェネンテック, インコーポレイテッド | 新規抗il13モノクローナル抗体での癌の処置 |
US8318160B2 (en) | 2003-12-23 | 2012-11-27 | Genentech, Inc. | Treatment of cancer with novel anti-IL13 monoclonal antibodies |
JP2007537146A (ja) * | 2003-12-23 | 2007-12-20 | タノックス インコーポレイテッド | 新規抗il13モノクローナル抗体での癌の処置 |
US8734797B2 (en) | 2003-12-23 | 2014-05-27 | Genentech, Inc. | Anti-IL13 antibodies and uses thereof |
US9605065B2 (en) | 2003-12-23 | 2017-03-28 | Genentech, Inc. | Anti-IL13 antibodies and uses thereof |
US11434287B2 (en) | 2003-12-23 | 2022-09-06 | Genentech, Inc. | Anti-IL13 antibodies and uses thereof |
US9067994B2 (en) | 2003-12-23 | 2015-06-30 | Genentech, Inc. | Anti-IL13 antibodies and uses thereof |
JP2017507939A (ja) * | 2014-02-21 | 2017-03-23 | ジェネンテック, インコーポレイテッド | 抗il−13/il−17二重特異性抗体及びその使用 |
JP2022531437A (ja) * | 2019-05-09 | 2022-07-06 | ジェネンテック, インコーポレイテッド | 抗体の作製方法 |
JP7397884B2 (ja) | 2019-05-09 | 2023-12-13 | ジェネンテック, インコーポレイテッド | 抗体の作製方法 |
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