JP2008054679A - 延長した半減期を有する分子ならびにその組成物および用途 - Google Patents
延長した半減期を有する分子ならびにその組成物および用途 Download PDFInfo
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Abstract
【解決手段】FcRnに対するIgG定常ドメインまたはそのFcRn結合性フラグメントの親和性を増加させる1以上のアミノ酸修飾を有するIgG定常ドメインまたはそのFcRn結合性部分。これらのアミノ酸修飾の1以上を有するIgG定常ドメインの全部または一部(FcRn結合性部分)と、そのような修飾IgG定常ドメインに結合した非IgGタンパク質または非タンパク質分子とを含有する融合タンパク質。
【選択図】なし
Description
本発明は、IgG定常ドメインまたはそのFcRn(Fc Receptor-neonate)結合性ドメインの修飾によりin vivo半減期が増加した分子に関する。より詳しくは、これらの分子は、FcRnに対する該定常ドメインまたはそのフラグメント(断片)の親和性を増加させるアミノ酸修飾を有する。本発明を用いた治療用および診断用のIgGおよび他の生物活性分子の半減期の増加は、例えばワクチン、受動免疫療法ならびに他の治療および予防方法におけるこれらの分子の投与量および/または投与頻度の減少を含む多数の利点を有する。本発明は更に、これらのアミノ酸修飾の1以上を有するIgG定常ドメインの全部または一部(FcRn結合性部分)と、そのような修飾IgG定常ドメインに結合した非IgGタンパク質または非タンパク質分子とを含有する融合タンパク質に関する。ここで、修飾IgG定常ドメインの存在は非IgGタンパク質または分子のin vivo半減期を増加させる。
治療剤としての免疫グロブリンの使用は近年劇的に増加しており、医学的治療の種々の領域に拡張されている。そのような使用は、無γグロブリン血症および低γグロブリン血症の治療、自己免疫疾患および移植片対宿主病を治療するための免疫抑制剤としての使用、リンパ性悪性疾患の治療、ならびに種々の全身性および感染性疾患を治療するための受動免疫療法を包含する。免疫グロブリンは、例えば診断イメージング法におけるin vivo診断ツールとしても有用である。
本発明は、FcRnに対するIgG分子の親和性を増加させるヒトIgG分子の定常ドメイン中のいくつかの突然変異の本発明者らによる同定に基づく。特に、本発明者らは、該定常ドメインの特定の領域中に導入されたランダムなアミノ酸突然変異を有するヒトIgG1定常ドメインのライブラリーを、FcRnに対する親和性の増加に関してスクリーニングした。そのようなランダム突然変異は、ヒトIgG1ヒンジ-Fc領域の残基251-256、285-290および308-314(これらのすべてはCH2ドメイン中に存在する)ならびに385-389および428-436(これらはCH3ドメイン中に存在する)の領域中に施された(残基は図2(配列番号83)に示すとおりであり、あるいは他のIgG分子のヒンジ-Fc領域中の類似残基は配列アライメントにより決定した)。本発明で用いるIgG定常ドメインの全残基はKabatら(Sequences of Proteins of Immunological Interest, U. S. Department of Health and Human Services, 1991(その全体を参照により本明細書に組み入れることとする))に従い番号づけされており、図2(配列番号83)に記載されているとおりであり、配列アライメントにより決定された他のIgG定常ドメイン中の対応残基を含む。抗体および他の治療剤および他の生物活性分子のin vivo半減期または被験者の血清もしくは他の組織中での維持は、抗体(または任意の他の医薬分子)の投与量および投与頻度を決定する重要な臨床的パラメーターである。したがって、増加した半減期を有するそのような分子(抗体を含む)は医薬上極めて重要である。
本明細書で用いる「IgG Fc領域」なる語は、IgG分子のパパイン消化により得られる結晶性フラグメントと関連するIgG分子の部分を意味する。該Fc領域は、ジスルフィド結合により連結された2つのIgG分子重鎖のC末端半分よりなる。それは抗原結合活性を有しないが、FcRn受容体を含むFc受容体および補体に対する結合部位および炭水化物部分を含有する(後記を参照されたい)。Fcフラグメントは、全第2定常ドメインCH2(Kabatの番号付け系によれば、ヒトIgG1の残基231-340)(例えば、配列番号80)および第3定常ドメインCH3(残基341-447)(例えば、配列番号81)を含有する。
図1は、FcRn受容体との相互作用に関与することが確認された残基の位置を示すIgGヒンジ-Fc領域の構造を示す(Ghetieら, Immunology Today 18(12): 592-598,1997)。
本発明は、野生型IgG定常ドメインに対して1以上のアミノ酸修飾(該修飾はFcRnに対する該IgG定常ドメインまたはそのフラグメントの親和性を増加させる)を含有するIgG定常ドメインまたはそのFcRn結合性フラグメント(すなわち、FcRnに結合するそのフラグメント)(好ましくはFcまたはヒンジ-Fcドメイン)を含む増加したin vivo半減期を有する分子、特にタンパク質、より詳しくは免疫グロブリンに関する。好ましい実施形態においては、本発明は、特に、ヒトにおける治療、予防および診断において特に有用である、ヒトまたはヒト化IgGおよびヒトIgGのFcRn結合性部分を含有する他の生物活性分子の修飾に関する。
本発明は、FcRnと相互作用するIgG定常ドメインの特定の部分におけるアミノ酸修飾(該修飾はFcRnに対するIgGまたはそのフラグメントの親和性を増加させる)の同定に基づくものである。したがって、本発明は、FcRnと相互作用する1以上の領域中に1以上のアミノ酸修飾(すなわち、置換、挿入または欠失)(該修飾はFcRnに対するIgGまたはそのフラグメントの親和性を増加させ、該分子のin vivo半減期をも増加させる)を含有するIgG定常ドメインまたはそのFcRn結合性フラグメント(好ましくはFcまたはヒンジ-Fcドメインフラグメント)を含む分子、好ましくはタンパク質、より好ましくは免疫グロブリンに関する。好ましい実施形態においては、前記の1以上のアミノ酸修飾は、IgG1ヒンジ-Fc領域の残基251-256、285-290、308-314、385-389および428-436(例えば、図4、配列番号83に記載のヒトIgG1ヒンジ-Fc領域におけるとおり)、または他のIgGヒンジ-Fc領域中の、アミノ酸配列アライメントにより決定されたそれらの類似残基の1以上において施される。好ましい実施形態においては、該アミノ酸修飾は、ヒトIgG定常ドメインまたはそのFcRn結合性ドメイン中に施される。ある実施形態においては、該修飾は、IgG定常ドメインの残基252、254または256においては施されない(すなわち、すべては、残基251、253、255、285-290、308-314、385-389、または428-436の1以上において施される)。より好ましい実施形態においては、該アミノ酸修飾は、残基252におけるロイシンによる置換、残基254におけるセリンによる置換、および/または256位におけるフェニルアラニンによる置換ではない。特に、好ましい実施形態においては、IgG定常ドメイン、ヒンジ-Fcドメイン、ヒンジ-Fcドメインまたは他のそのFcRn結合性フラグメントがマウスに由来する場合には、そのような修飾は施されない。
定常ドメインのアミノ酸残基251-256、285-290、308-314、385-389および428-436中の1以上の修飾は、当業者に公知の任意の技術を用いて導入することができる。アミノ酸残基251-256、285-290、308-314、385-389および428-436中の1以上の修飾を有する定常ドメインまたはそのフラグメントは、例えば、FcRn受容体に対する増加した親和性を有する定常ドメインまたはそのフラグメントを同定するための結合アッセイによりスクリーニングすることができる(例えば、後記第5.11節に記載のとおり)。FcRn受容体に対する定常ドメインまたはそのフラグメントの親和性を増加させる該ヒンジ-Fcドメインまたはそのフラグメント中の修飾を抗体中に導入して、該抗体のin vivo半減期を増加させることが可能である。さらに、FcRnに対する定常ドメインまたはそのフラグメントの親和性を増加させる定常ドメインまたはそのフラグメント中の修飾体を生物活性分子に融合して、該生物活性分子のin vivo半減期を増加させ、好ましくは、該分子のバイオアベイラビリティを改変(増強または減弱)する(例えば、粘膜表面(または他の標的組織)(例えば、肺)への輸送を増加または減少させる)ことができる。
突然変異誘発は、修飾される抗体の定常ドメインまたはそのフラグメント(例えば、CH2またはCH3ドメイン)の配列中の1以上の修飾を有するオリゴヌクレオチドの安定化を含む(それらに限定されるものではない)当技術分野で公知の技術のいずれかに従い行うことができる。部位特異的突然変異誘発は、所望の突然変異のDNA配列と、横断する欠失結合部の両側で安定な二本鎖を形成するのに十分なサイズおよび配列複雑度のプライマー配列を与えるのに十分な数の隣接ヌクレオチドとをコードする特異的オリゴヌクレオチド配列の使用により、突然変異体の産生を可能にする。典型的には、改変される配列の結合部の両側に約10〜約25以上の残基を有する約17〜約75ヌクレオチド以上の長さのプライマーが好ましい。突然変異体のライブラリーを作製するために、1以上の位置に種々の異なる突然変異を導入する多数のそのようなプライマーを使用することができる。
アミノ酸残基251-256、285-290、308-314、385-389および/または428-436中に1以上の修飾を有する定常ドメインまたはそのフラグメントを発現するベクター(特にファージ)をスクリーニングして、FcRnに対する増加した親和性を有する定常ドメインまたはそのフラグメントを同定して、ファージの集団から最高親和性結合体を選び出すことが可能である。アミノ酸残基251-256、285-290、308-314、385-389および/または428-436中に1以上の修飾を有する定常ドメインまたはそのフラグメントの、FcRnへの結合を分析するために使用しうるイムノアッセイは、ラジオイムノアッセイ、ELISA(酵素免疫検定法)、「サンドイッチ」イムノアッセイおよび蛍光イムノアッセイを包含するが、それらに限定されるものではない。そのようなアッセイは常套的なものであり、当技術分野で良く知られている(例えば、Ausubelら編, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York(その全体を参照により本明細書に組み入れることとする)を参照されたい)。典型的なイムノアッセイは後記で簡潔に説明される(がそれらに限定されるものではない)。また、アミノ酸残基251-256、285-290、308-314、385-389および/または428-436中に1以上の修飾を有する定常ドメインまたはそのフラグメントの、FcRnへの結合速度および解離速度を測定するために、BIAcore速度論的分析を用いることができる。BIAcore速度論的分析は、アミノ酸残基251-256、285-290、308-314、385-389および/または428-436中に1以上の修飾を有する定常ドメインまたはそのフラグメントの、チップからの結合および解離を、その表面上の固定化FcRnで分析することを含む(第5.1節および後記実施例を参照されたい)。
アミノ酸残基251-256、285-290、308-314、385-389および/または428-436中に1以上の修飾を有する定常ドメインまたはそのフラグメントをコードするヌクレオチド配列を直接的に配列決定するためには、当技術分野で公知の種々の配列決定反応のいずれかを用いることができる。配列決定反応の具体例は、MaximおよびGilbert(Proc. Natl. Acad. Sci. USA, 74: 560,1977)またはSanger(Proc. Natl. Acad. Sci. USA, 74: 5463,1977)により開発された技術に基づくものを包含する。また、マススペクトロメトリー(例えば、PCT公開WO 94/16101, Cohenら, Adv. Chromatogr., 36:127-162,1996およびGriffinら, Appl. Biochem. Biotechnol., 38:147-159,1993を参照されたい)を含む種々の自動配列決定法のいずれかを用いることも意図される(Bio/Techniques, 19: 448,1995)。
本発明の抗体またはそのフラグメントは、抗体の合成のための当技術分野で公知の任意の方法、特に、化学合成または好ましくは組換え発現技術により製造することができる。
本発明は、融合タンパク質を生成するよう異種ポリペプチド(すなわち、無関係なポリペプチドまたはその一部、好ましくは、該ポリペプチドの少なくとも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)に組換え的に融合した又は化学的に結合(コンジュゲーション)(共有結合および非共有結合の両方を含む)した抗体を含む。該融合は必ずしも直接的である必要はなく、リンカー配列を介して生じうる。また、異種ポリペプチドに融合または結合した抗体は、当技術分野で公知の方法を用いるin vitroイムノアッセイおよび精製方法において使用することができる。例えば、PCT公開番号WO 93/21232; EP 439,095; Naramuraら, Immunol. Lett., 39: 91-99, 1994; 米国特許第5,474,981号; Gilliesら, PNAS, 89: 1428-1432,1992; およびFellら,J. Immunol., 146: 2446-2452,1991(それらの全体を参照により本明細書に組み入れることとする)を参照されたい。
融合タンパク質は標準的な組換えDNA技法または、例えばペプチド合成機の使用によるタンパク質合成技法によって生産することができる。例えば、ある融合タンパク質をコードする核酸分子は、自動DNA合成機を含む従来の技法で合成することができる。あるいはまた、遺伝子断片のPCR増幅を、2つの連続的な遺伝子断片、それらは後にアニーリングされ再増幅されてキメラ遺伝子配列を生成することができるが、それらの遺伝子断片の間に相補的なオーバーハングを生ずるアンカープライマーを用いて行うことができる(例えば、Current Protocols in Molecular Biology, Ausubelら編, John Wiley & Sons, 1992を参照せよ)。さらに、生物活性分子をコードする核酸を、Fcドメインまたはそのフラグメントを含んでいる発現ベクター中にクローン化してその生物活性分子が定常ドメインまたはそのフラグメントとインフレームで連結するようにすることができる。
本発明は、疾患、障害、または感染に伴う症状を予防、治療、または改善するために、抗体を動物、好ましくは哺乳類、最も好ましくはヒトに投与することを含む、抗体に基づく治療を包含する。本発明の予防用および治療用化合物は、限定はされないが、抗体、および抗体をコードする核酸を含む。抗体は当業界では公知の、または本明細書に記載の製薬上許容される組成物で提供することができる。
本発明は融合タンパク質に基づくおよびコンジュゲート分子に基づく治療法を包含し、その治療法は融合タンパク質またはコンジュゲート分子を疾患、障害、または感染に伴う症状を予防、治療、または改善するために、動物、好ましくは哺乳類、最も好ましくはヒトに投与することを含むものである。本発明の予防用および治療用化合物には、限定はされないが、融合タンパク質および融合タンパク質をコードする核酸、ならびにコンジュゲート分子が含まれる。融合タンパク質およびコンジュゲート分子は、当業界では公知の、または本明細書に記載の製薬上許容される組成物で提供することができる。
本発明は、本発明の抗体、または本発明の抗体を含む医薬組成物の有効量を被験者に投与することによる、疾患、障害、または感染に伴う1種以上の症状を治療、予防、および改善する方法を提供する。本発明はまた、本発明の融合タンパク質もしくはコンジュゲート分子、または本発明の融合タンパク質もしくはコンジュゲート分子を含む医薬組成物の有効量を被験者に投与することによる、疾患、障害、または感染に伴う1種以上の症状を治療、予防、および改善する方法をも提供する。好ましい1態様においては、抗体または融合タンパク質もしくはコンジュゲート分子は実質的に精製されたものである(すなわち、その効果を制限する、または望ましくない副作用を生じる物質を実質的に含まない)。特定の1実施形態においては、該被験者は動物、好ましくは、非霊長類(例えば、ウシ、ブタ、馬、猫、イヌ、ラット、その他)および霊長類(例えばカニクイザルなどのサル、およびヒト)などの哺乳類である。好ましい1実施形態においては、該被験者はヒトである。
特定の1実施形態においては、抗体または融合タンパク質をコードする配列を含んでいる核酸は、疾患、障害、または感染に伴う1種以上の症状を治療、予防、または改善するために遺伝子治療によって投与することができる。遺伝子治療とは、被験者に発現された、または発現しうる核酸を投与することによって行われる治療法を意味する。本発明のこの実施形態においては、該核酸はそれがコードする、治療または予防効果を介在する抗体または融合タンパク質を産生する。
本発明の抗体、融合タンパク質、またはコンジュゲート分子は種々の方法で特徴を調べることができる。特に、本発明の抗体はある抗原に対しての免疫特異的な結合能をアッセイすることができる。そのようアッセイは、溶液中で(例えば、Houghten, Bio/Techniques, 13:412-421, 1992)、ビーズ上で(Lam, Nature, 354:82-84,1991)、チップ上で(Fodor, Nature, 364:555-556, 1993)、細菌で(米国特許第5,223,409号)、胞子で(米国特許第5,571,698号、第5,403,484号、および第5,223,409号)、プラスミドで(Cullら, Proc. Natl. Acad. Sci. USA, 89:1865-1869, 1992)、またはファージで(ScottとSmith, Science, 249:386-390, 1990; Devlin, Science, 249:404-406, 1990; Cwirlaら, Proc. Natl. Acad. Sci. USA, 87:6378-6382, 1990; およびFelici, J. Mol. Biol., 222:301-310, 1991)(これらの参照文献の各々はその全体を本明細書中に参照により組み入れる)行うことができる。ある抗原またはその断片と免疫特異的に結合することが判明している抗体については、その抗原に対する特異的親和性の程度をアッセイすることができる。
本発明の標識した抗体、融合タンパク質、およびコンジュゲート分子は、疾患、障害、または感染の検出、診断、またはモニターのための診断用途で用いることができる。本発明は、疾患、障害、または感染の検出または診断法であって、(a)被験者の細胞または組織サンプル中での抗原の発現を、その抗原と免疫特異的に結合する1種以上の抗体を用いてアッセイし、(b)その抗原のレベルを対照のレベル、例えば正常な組織サンプル中のレベルと比較し、アッセイした抗原のレベルが対照のレベルと比較して増加していれば疾患、障害、または感染を示すこととなることを含んでなる方法、を提供する。本発明はまた、疾患、障害、または感染の検出または診断法であって、(a)被験者の細胞または組織サンプル中での抗原の発現を、その抗原と結合する本発明の1種以上の融合タンパク質またはコンジュゲート分子を用いてアッセイし、(b)その抗原のレベルを対照のレベル、例えば正常な組織サンプル中のレベルと比較し、アッセイした抗原のレベルが対照のレベルと比較して増加していれば疾患、障害、または感染を示すこととなることを含んでなる方法、も提供する。従って、該融合タンパク質またはコンジュゲート分子は、リガンド、サイトカイン、もしくは増殖因子などの生物活性分子、およびヒンジ-Fc領域もしくはそれのフラグメントを含んでなり、そのような融合タンパク質またはコンジュゲート分子は検出される抗原と結合することができる。
本発明はまた、本発明の医薬組成物の1種以上の成分で満たされた1つ以上の容器を含んでなる医薬パックまたはキットをも提供する。任意でそのような容器には、一般医薬品または生物学的製剤の製造、使用、または販売を規制する薬事当局によって指定された形式の通知を添付することができ、その通知はヒトへの投与のための製造、使用、または販売のその薬事当局による承認内容を反映したものである。
修飾IgGおよびそれのFcRnフラグメントのIgG定常ドメインのFcRnとの結合能は、種々のin vitroアッセイで特徴を調べることができる。WardによるPCT公開WO 97/34631は、種々の方法を詳細に開示しており、その全体を本明細書中に参照により組み入れる。
下記の実施例はin vivoでの半減期が延長されている修飾ヒンジーFcフラグメントの作成、単離、および特性決定を説明するものである。
6.1.1. 試薬
化学物質は全て分析用グレードのものを用いた。制限酵素およびDNA修飾酵素はNew England Biolabs, Inc.(Beverly, MA)から購入した。オリゴヌクレオチドはNWG Biotech, Inc.(High Point, NC)で合成されたものである。pCANTAB5Eファージミドベクター,抗E-tag-西洋ワサビペルオキシダーゼコンジュゲート、TG1大腸菌(E.coli)株、IgG Sepharose 6 Fast FlowおよびHiTrap プロテインAカラムはAPBiotech, Inc.(Piscataway, NJ)から購入した。VCSM 13ヘルパーファージおよびQuick change mutagenesis kitはStratagene(La Jolla, CA)から入手した。CJ236大腸菌株はBio-Rad(Richmond, CA)から購入した。BCA Protein Assay Reagent KitはPierce(Rockford, IL)から入手した。Lipofectamine 2000はInvitrogen, Inc.(Carlsbad, CA)から購入した。
ヒトおよびマウスのFcRnのアミノ酸配列はそれぞれ配列番号84および85である(Firanら, Intern. Immunol., 13:993-1002, 2001およびPopovら, Mol. Immunol., 33:521-530, 1996も参照されたい、これら双方の文献はその全体を本明細書中に参照により組み入れる)。ヒトFcRnはまた、標準的なPCRプロトコールを用いてヒト胎盤cDNA(Clonetech, Palo Alto, CA)からのヒトβ2-ミクログロブリン(Kabatら, 1991, 「免疫学的興味深いタンパク質の配列」"Sequences of Proteins of Immunological Interest", U.S.Public Health Service, National Institute of Health, Washington, DC)とヒトα鎖のコドン23から267(Soryら, J. Exp. Med.,180:2377-2381, 1994)の単離後、得ることができる。軽鎖と重鎖はそれらの天然のシグナル配列(Kabatら, 1991, 上述の文献; Storyら, 上述の文献)とともにpFastBac DUALおよびpFastBac1 バクミド中にそれぞれクローン化し、ウイルスストックをSpodoptera frugiperda細胞(Sf9)中に製造者(Invitrogen, Carlbad, CA)の使用説明書に従って作成した。High-Five細胞は感染多重度を3として、市販のプロトコールを用いて(Invitrogen)、α鎖およびβ2鎖をコードするバキュロウイルスで感染させた。組換えヒトFcRnは下記のとおり精製した:感染させた昆虫細胞の上清を50mM MES(2-N-[モルホリノ]エタンスルホン酸)pH 6.0に対して透析し、10mLのヒトIgG Sepharose 6 Fast Flowカラム(APBiotech, Piscataway, NJ)にアプライした。樹脂を200mLの50mM MES pH6.0で洗い、FcRnを0.1M Tris-Cl pH8.0で溶出した。精製FcRnを50mM MES pH6.0に対して透析し、急速凍結し、−70℃で保存した。タンパク質の純度はSDS-PAGEおよびHPLCによって調べた。
ライブラリーの構築はKunkel法(Kunkelら, Methods Enzymol., 154:367-382, 1987)に由来する部位特異的突然変異誘発法に基づいて行った。MEDI-493 ヒトIgG1(Johnsonら, J. Infect. Disease, 176:1215-1224, 1997)由来のヒトヒンジ-Fc遺伝子のアミノ酸残基226-478(Kabatの番号付けによる、Kabatら, 1991, 上述の文献)をpCANTAB5Eファージミドベクター中にSfiI/NotI断片としてクローン化した。4種類のライブラリーは、251, 252, 254, 255, 256(ライブラリー1)、308, 309, 311, 312, 314(ライブラリー2)、385, 386, 387, 389(ライブラリー3)、および428, 433, 434, 436(ライブラリー4)の位置にランダムな変異を導入することによって作成した。簡潔に述べれば、4つの別々のヒンジ-Fc鋳型をオーバーラップ伸長法(Hoら, Gene, 15:51-59, 1989)によってPCRを用いて作成し、その各々には252(ライブラリー1)、310(ライブラリー2)、384(ライブラリー3)、および429(ライブラリー4)の位置に1個の停止コドンTAAを含んでおり、そのため、突然変異したファージミドのみがFcをディスプレイするファージを生ずる。
ライブラリー1:
5'-CATGTGACCTCAGGSNNSNNSNNGATSNNSNNGGTGTCCTTGGGTTTTGGGGGG-3'(配列番号120)
ライブラリー2:
5'-GCACTTGTACTCCTTGCCATTSNNCCASNNSNNGTGSNNSNNGGTGAGGACGC-3'(配列番号121)
ライブラリー3:
5'-GGTCTTGTAGTTSNNCTCSNNSNNSNNATTGCTCTCCC-3'(配列番号122)
ライブラリー4:
5'-GGCTCTTCTGCGTSNNGTGSNNSNNCAGAGCCTCATGSNNCACGGAGCATGAG-3'(配列番号122)
上記でN=A、C、T、またはG、 S=GまたはCである。
適切な縮重オリゴヌクレオチドを、標準的なプロトコールを用いてT4ポリヌクレオチドキナーゼの存在下でリン酸化した。10から30μgのssDNA U鋳型および0.6μgのリン酸化オリゴヌクレオチドを、10mM MgCl2, pH7.5を含有する50mM Tris-HClで最終容量を250μLとしてその中で結合させ、90℃で2分間、50℃で3分間、および20℃で5分間インキュベートした。ヘテロ二本鎖DNAの合成は、0.4mM ATP、1mM dNTP、および6mM DTTの存在下でT4 DNAリガーゼおよびT7 DNAポリメラーゼの双方を30ユニット添加して行い、その混合物を20℃で4時間インキュベートした。次いで、このようにして作成したヘテロ二本鎖DNAをQiagen Qiaquick DNA purification Kit(Qiagen, CA)を用いて精製および脱塩した。
電気穿孔法で取り込み可能な300μLのTG1大腸菌細胞を、1から5μgのヘテロ二本鎖DNAとともに、2.5kVの電場で200Ωと25μFキャパシタンスを用いて、ライブラリーのサイズが1 x 108(ライブラリー1および2)、または1 x 107(ライブラリー3および4)となるまで、電気的に穿孔させた。その細胞を2mLのSOC培地中に再懸濁し、この方法を6から10回反復した。多様性については組換え大腸菌の滴定によって評価した。電気パルスをあてた細胞を50mLのSOC培地中で37℃で30分間振盪しつつインキュベートし、遠心し、100μg/mLのアンピシリンおよび1010pfu/mLのVCSM 13ヘルパーファージを含んでいる500mLの2xYT中に再懸濁した。その培養物を37℃で一晩インキュベートし、細胞を遠心してペレットとした。変異したヒンジ-Fc部分をGIIIコートタンパク質上に発現している、上清中のファージを既に報告されているとおり(Sambrookら, 1989, 上述の文献)PEG6000で沈澱させ、5mLの20mM MES, pH6.0中に再懸濁した。
ファージをELISAをベースとするアプローチを用いてパニングした。96ウエルのELISAプレートを、炭酸ナトリウムバッファーpH9.0中に0.01mg/mLのマウスFcRnを含む液100μL/ウエルで、4℃で一晩コーティングし、次いで、4%脱脂粉乳で37℃で2時間ブロックした。そのコーティングしたプレートの各ウエルに、5%の粉乳および0.05%のTween 20含有の20mM MES, pH6.0中にファージを懸濁させた液(総計約1013個のファージ)の100-150μLを入れ、37℃で2〜3時間、振盪しつつインキュベートした。
各パニングプロセスの後、ファージを単離し、FcRnと結合した発現されたペプチドをコードする核酸を、ABI3000ゲノム分析機(Applied Biosystems, Foster City, CA)を用いるジデオキシヌクレオチド配列決定法(Sangerら, Proc. Natl. Acad. Sci. USA, 74:5463-5467, 1977)などの標準的な配列決定法で配列を調べた。
変異型のヒンジ-Fcフラグメントをコードする遺伝子を適切な制限酵素で切断し、発現ベクター、例えばVβpelBhis(Ward, J. Mol. Biol., 224:885-890, 1992)中に再クローン化した。その他のいずれかのタイプのタグ配列、例えばc-mycタグ、デカペプチドタグ(Huseら, Science, 246:1275-1281, 1989)、FlagTM(Immunex)タグなどを含むベクターを用いることができる。大腸菌などの組換えクローンを増殖させて、可溶性ヒンジ-Fcフラグメントの発現を誘導し、それは培地からまたは細胞溶解物に浸透圧ショックを与えた後該細胞溶解物から、用いたタグに基づいて単離することができ、または当業者にはよく知られた他の精製方法のいずれかで単離することができ、下記に列挙する方法によって特徴を調べることができる。
代表的なFc変異、例えばI253A、M252Y/S254T/T256E、M252W、M252Y、M252Y/T256Q、M252F/T256D、V308T/L309P/Q311S、G385D/Q386P/N389S、G385R/Q386T/P387R/N389P、H433K/N434F/Y436H、およびN434F/Y436などをヒトIgG1 MEDI-493(SYNAGIS(登録商標))(Johnsonら, 1997, 上述の文献)中に組み入れた。Quick Change Mutagenesis kit(Stratagene, La Jolla, CA)を製造者の使用説明書に従って用いて重鎖を部位特異的突然変異誘発にかけ、配列をABI3000(Applied Biosystems, Foster City, CA)シーケンサーを用いてジデオキシヌクレオチド配列決定法によって確認した。IgG1/VHがIgG1/VLと同時分泌されるヒト胎児腎細胞293でCMV前初期プロモーターおよびジシストロニックオペロンを用いて種々の構築物が一過性に発現された(Johnsonら, 1997, 上述の文献)。トランスフェクションはLipofectamine 2000(Invitrogen, Carlsbad, CA)と標準的なプロトコールを用いて行った。IgGはならし培地から直接的に1mLのHiTrapプロテインAカラムで製造者(APBiotech)の説明書に従って精製した。
6.6.1 in vitroでのHPLCおよびSDS-PAGEでの特徴の検討
精製後、修飾ヒンジ-Fcフラグメントの分子量および結合特性などの一般的な特徴については、SDS-PAGEおよびHPLCを含む当業者にはよく知られた方法で検討することができる。
修飾ヒンジ-Fcフラグメントの結合活性は、放射性標識した野生型ヒンジ-Fcまたは修飾ヒンジ-FcをマウスまたはヒトのFcRnを発現している細胞とインキュベートすることによって測定することができる。典型的には、SV40で形質転換させた内皮細胞(SVEC)(Kimら, J. Immunol., 40:457-465, 1994) などの内皮細胞系が用いられる。ヒンジ-Fcフラグメントと37℃で16-18時間インキュベートした後、細胞を培地で洗い、次いで50mM リン酸バッファー, pH7.5中に5mM Na2EDTAを含む液と5分間インキュベートして引き離す。107個の細胞あたりの放射能を測定する。
このアッセイはPCT公開 WO 97/34631で開示されているプロトコールに従ったものである。放射性標識した、修飾ヒンジ-Fcフラグメントの種々の濃度のもの(1μg/mL〜1mg/mL)をトランスウエルの片側に添加し、FcRnを発現している細胞単層が介在するそのフラグメントの移送を、そのトランスウエルのもう一方の側の放射能を測定することによって定量することができる。
修飾IgGヒンジ-Fcの半減期を測定するために、修飾ヒンジ-Fcフラグメントを125Iで放射性標識し(比活性は約107cpm/μg)、食塩水(pH7.2)中に溶解する。その溶液をBALB/Cマウス(Harlan, Indianapolis, IN)、このマウスはあらかじめ胸腺をブロックするためにNaI含有の水を与えておいたものであるが、そのマウスに液量を150μL以下で放射能は10 x 106〜50 x 106cpmのものを静脈内注射する。種々の時点、例えば注射後3分から72時間まででマウスの後眼窩洞から採血して血液をヘパリンを添加した毛細管に入れ、各サンプルから採取した血漿の放射能を計測する。
可溶性のマウスおよびヒトFcRnと固定化ヒトIgG1変異体との相互作用を、BIAcore 3000装置(Pharmacia Biosensor, Uppsala, Sweden)を用いて表面プラスモン共鳴の検出によってモニターした。ゲルろ過では親和性測定を妨害するような凝集物(van der Merweら, EMBO J., 12:4945-4954, 1993; van der Merweら, Biochemistry, 33:10149-10160, 1994)は検出されなかった。タンパク質濃度はヒトおよびマウスFcRnの双方についてはビシンコニン酸(BCA)法で計算し、IgG1の野生型および変異型については280nmでの1%減衰係数1.5を用いて計算した。IgG1は、Amine Coupling Kitを報告されているとおり用いて(Johnsonら, 上述の文献)、CM5センサーチップのデキストランマトリクス(Pharmacia Biosensor)に結合させた。10mM酢酸ナトリウム,pH5.0中でタンパク質濃度の範囲は3〜5μg/mLであった。活性化時間は流速を10μL/分として7分間とし、固定化時間は流速を10μL/分として10分間から20分間の間とした。過剰の反応性エステルは70μLの1.0 塩酸メタノールアミン, pH8.5を注射してクエンチした。このことによって、典型的には、500から4000共鳴ユニット(RU)の固定化がもたらされた。ヒトおよびマウスFcRnはバッファーを0.05% Tween20含有の50mM PBSバッファー, pH6.0に交換した。希釈はその同じバッファー中で行った。結合実験は全て25℃で濃度範囲を120から1μg/mLとし流速を5から10μL/分として行った;データは25から50分間収集し、表面を再生させるためにPBSバッファーpH7.2の1分間のパルスを3回行った。FcRnもコーティングされていない細胞上を流し、これらのブランクのランでのセンサーグラムをIgG1を結合させたチップで得られたものから差し引いた。各ランはソフトウエアBIAevaluation 3.1(Pharmacia)を用いて分析した。会合定数(KA)は、非特異的結合を補正した後、有利の反応体と複合体の平衡状態での濃度を測定することによるスキャッチャード分析から求めた。結合の平衡状態を見るBIAcore実験で(Karlssonら, 1991, 上述の文献; van der Merweら, 1993, 上述の文献; van der Merweら, 1994, 上述の文献; Raghavanら, Immunity, 1:303-315, 1994; Malchiodiら, J. Exp. Med., 182:1833-1845, 1995)、複合体の濃度は定常状態応答として直接測定することができる。遊離のアナライト(ヒトまたはマウスFcRn)の濃度はアナライト全体の濃度に等しいが、それはアナライトがサンプルの注入の際に常に補給されるからである。センサーチップ上の遊離のリガンドの濃度は複合体の濃度から、および表面の総結合能からKA=Req/C(Rmax−Req)として得ることができるが、この式でCは遊離アナライトの濃度、Reqは定常状態応答、Rmaxは表面の総結合能である。式を整理し直すとReq/C=KARmax−KAReqとなる。
Claims (50)
- 野生型IgG定常ドメインに対して、KabatのEU番号付けに基づくアミノ酸残基428での置換を含む、IgG定常ドメインまたはそのFcRn結合性フラグメントを含んでなる修飾されたIgGであって、該修飾IgGが、野生型IgG定常ドメインを有するIgGの半減期と比較して異なる半減期を有する、上記修飾IgG。
- アミノ酸残基428でのアミノ酸置換が、メチオニン、トレオニン、ロイシン、フェニルアラニンまたはセリンによる置換である、請求項1に記載の修飾IgG。
- 対応する野生型IgG定常ドメインに対して、KabatのEU番号付けに基づくアミノ酸残基251-256、285-290、308-314、385-389および429-436のうち1以上での1以上のアミノ酸置換をさらに含む、請求項1または2に記載の修飾IgG。
- アミノ酸残基251でのアミノ酸置換がロイシンまたはアルギニンによる置換であり、アミノ酸残基252でのアミノ酸置換がチロシン、フェニルアラニン、セリン、トリプチトファンまたはトレオニンによる置換であり、アミノ酸残基254でのアミノ酸置換がトレオニンまたはセリンによる置換であり、アミノ酸残基255でのアミノ酸置換がロイシン、グリシン、イソロイシンまたはアルギニンによる置換であり、アミノ酸残基256でのアミノ酸置換がセリン、アルギニン、グルタミン、グルタミン酸、アスパラギン酸、アラニン、アスパラギンまたはトレオニンによる置換であり、アミノ酸残基308でのアミノ酸置換がトレオニンによる置換であり、アミノ酸残基309でのアミノ酸置換がプロリンによる置換であり、アミノ酸残基311でのアミノ酸置換がセリンによる置換であり、アミノ酸残基312でのアミノ酸置換がアスパラギン酸による置換であり、アミノ酸残基314でのアミノ酸置換がロイシンまたはアラニンによる置換であり、アミノ酸残基385でのアミノ酸置換がアルギニン、アスパラギン酸、セリン、トレオニン、ヒスチジン、リシンまたはアラニンによる置換であり、アミノ酸残基386でのアミノ酸置換がトレオニン、プロリン、アスパラギン酸、セリン、リシン、アルギニン、イソロイシンまたはメチオニンによる置換であり、アミノ酸残基387でのアミノ酸置換がアルギニン、ヒスチジン、セリン、トレオニン、アラニンまたはプロリンによる置換であり、アミノ酸残基389でのアミノ酸置換がプロリンまたはセリンによる置換であり、アミノ酸残基433でのアミノ酸置換がリシン、アルギニン、セリン、イソロイシン、プロリン、グルタミンまたはヒスチジンによる置換であり、アミノ酸残基434でのアミノ酸置換がフェニルアラニン、チロシンまたはヒスチジンによる置換であり、アミノ酸残基436でのアミノ酸置換が、ヒスチジン、アスパラギン、アルギニン、トレオニン、リシンまたはメチオニンによる置換である、請求項3に記載の修飾IgG。
- 前記IgG定常ドメインがヒトIgG定常ドメインである、請求項1〜4のいずれか1項に記載の修飾IgG。
- 前記IgG定常ドメインがヒトIgG1、IgG2、IgG3またはIgG4定常ドメインである、請求項1〜5のいずれか1項に記載の修飾IgG。
- ヒトまたはヒト化IgGである、請求項5に記載の修飾IgG。
- 前記IgG定常ドメインが非ヒトIgG定常ドメインである、請求項1〜5のいずれか1項に記載の修飾IgG。
- ヒト化抗CD25モノクローナル抗体、キメラ抗CD25モノクローナル抗体、ヒト化抗αvβ3インテグリン抗体、またはヒト化抗CD3抗体である、請求項1〜8のいずれか1項に記載の修飾IgG。
- 呼吸器合胞体ウイルス(RSV)抗原に免疫特異的に結合する、請求項1〜8のいずれか1項に記載の修飾IgG。
- FcRnに対して、野生型IgG定常ドメインを含む対応するIgGよりも高い親和性を有する、請求項1〜10のいずれか1項に記載の修飾IgG。
- FcRnに対して、pH 7.4におけるよりもpH 6.0において野生型IgG定常ドメインを含む対応するIgGよりも高い親和性を有する、請求項1〜10のいずれか1項に記載の修飾IgG。
- 請求項1〜12のいずれか1項に記載の修飾IgGと製薬上許容される担体とを含んでなる医薬組成物。
- 容器に入れられた請求項1〜12のいずれか1項に記載の修飾IgGと使用説明書とを含んでなるキット。
- 修飾されたIgG定常ドメインまたはFcRnに結合するそのフラグメントと共有結合した非IgGポリペプチドを含んでなる融合タンパク質であって、該修飾IgG定常ドメインまたはそのフラグメントは、対応する野生型IgG定常ドメインに対して、KabatのEU番号付けに基づくアミノ酸残基428での置換を含む、上記融合タンパク質。
- アミノ酸残基428でのアミノ酸置換が、メチオニン、トレオニン、ロイシン、フェニルアラニンまたはセリンによる置換である、請求項15に記載の融合タンパク質。
- 前記修飾IgG定常ドメインまたはFcRn結合性フラグメントが、対応する野生型IgG定常ドメインに対して、KabatのEU番号付けに基づくアミノ酸残基251-256、258-290、308-314、385-389、および429-436のうち1以上での1以上のアミノ酸置換をさらに含む、請求項15または16に記載の融合タンパク質。
- アミノ酸残基251でのアミノ酸置換がロイシンまたはアルギニンによる置換であり、アミノ酸残基252でのアミノ酸置換がチロシン、フェニルアラニン、セリン、トリプチトファンまたはトレオニンによる置換であり、アミノ酸残基254でのアミノ酸置換がトレオニンまたはセリンによる置換であり、アミノ酸残基255でのアミノ酸置換がロイシン、グリシン、イソロイシンまたはアルギニンによる置換であり、アミノ酸残基256でのアミノ酸置換がセリン、アルギニン、グルタミン、グルタミン酸、アスパラギン酸、アラニン、アスパラギンまたはトレオニンによる置換であり、アミノ酸残基308でのアミノ酸置換がトレオニンによる置換であり、アミノ酸残基309でのアミノ酸置換がプロリンによる置換であり、アミノ酸残基311でのアミノ酸置換がセリンによる置換であり、アミノ酸残基312でのアミノ酸置換がアスパラギン酸による置換であり、アミノ酸残基314でのアミノ酸置換がロイシンまたはアラニンによる置換であり、アミノ酸残基385でのアミノ酸置換がアルギニン、アスパラギン酸、セリン、トレオニン、ヒスチジン、リシンまたはアラニンによる置換であり、アミノ酸残基386でのアミノ酸置換がトレオニン、プロリン、アスパラギン酸、セリン、リシン、アルギニン、イソロイシンまたはメチオニンによる置換であり、アミノ酸残基387でのアミノ酸置換がアルギニン、ヒスチジン、セリン、トレオニン、アラニンまたはプロリンによる置換であり、アミノ酸残基389でのアミノ酸置換がプロリンまたはセリンによる置換であり、アミノ酸残基433でのアミノ酸置換がリシン、アルギニン、セリン、イソロイシン、プロリン、グルタミンまたはヒスチジンによる置換であり、アミノ酸残基434でのアミノ酸置換がフェニルアラニン、チロシンまたはヒスチジンによる置換であり、アミノ酸残基436でのアミノ酸置換が、ヒスチジン、アスパラギン、アルギニン、トレオニン、リシンまたはメチオニンによる置換である、請求項17に記載の融合タンパク質。
- 修飾IgG定常ドメインまたはフラグメントがヒトIgG定常ドメインまたはそのフラグメントである、請求項15〜18のいずれか1項に記載の融合タンパク質。
- 前記IgG定常ドメインまたはフラグメントがヒトIgG1、IgG2、IgG3またはIgG4定常ドメインまたはそのフラグメントである、請求項15〜18のいずれか1項に記載の融合タンパク質。
- 前記IgG定常ドメインまたはフラグメントが非ヒトIgG定常ドメインまたはそのフラグメントである、請求項15〜18のいずれか1項に記載の融合タンパク質。
- 前記修飾IgG定常ドメインまたはフラグメントが、FcRnに対して、対応する野生型IgG定常ドメインまたはそのフラグメントよりも高い親和性を有する、請求項15〜21のいずれか1項に記載の融合タンパク質。
- 前記修飾IgG定常ドメインまたはフラグメントが、FcRnに対して、pH 7.4におけるよりもpH 6.0において対応する野生型定常ドメインまたはそのフラグメントよりも高い親和性を有する、請求項15〜21のいずれか1項に記載の融合タンパク質。
- 請求項15〜23のいずれか1項に記載の融合タンパク質と製薬上許容される担体とを含んでなる医薬組成物。
- 容器に入れられた請求項15〜23のいずれか1項に記載の融合タンパク質と使用説明書とを含んでなるキット。
- 修飾されたIgG定常ドメインまたはFcRnに結合するそのフラグメントと結合した非タンパク質物質を含んでなる分子であって、該修飾IgG定常ドメインまたはフラグメントは、対応する野生型IgG定常ドメインまたはそのフラグメントに対して、KabatのEU番号付けに基づくアミノ酸残基428でのアミノ酸置換を含む、上記分子。
- アミノ酸残基428でのアミノ酸置換が、メチオニン、トレオニン、ロイシン、フェニルアラニンまたはセリンによる置換である、請求項26に記載の分子。
- 前記修飾IgG定常ドメインまたはフラグメントが、対応する野生型IgG定常ドメインに対して、KabatのEU番号付けに基づくアミノ酸残基251-256、258-290、308-314、385-389、および429-436のうち1以上での1以上のアミノ酸置換をさらに含む、請求項26または27に記載の分子。
- 請求項26〜28のいずれか1項に記載の分子と製薬上許容される担体とを含んでなる医薬組成物。
- 容器に入れられた請求項26〜28のいずれか1項に記載の分子と使用説明書とを含んでなるキット。
- 修飾されたIgG定常ドメインまたはFcRnに結合する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核酸であって、該修飾IgG定常ドメインまたはフラグメントは、対応する野生型IgG定常ドメインまたはそのフラグメントに対して、KabatのEU番号付けに基づくアミノ酸残基428でのアミノ酸置換を含む、上記核酸。
- 請求項1〜12のいずれか1項に記載の修飾IgGの製造方法であって、(a) 該修飾IgGをコードするヌクレオチド配列に機能的に連結されたプロモーターを含んでなるベクターを宿主細胞に導入するステップ;および(b) 該宿主細胞を培養して該修飾IgGを産生させるステップを含む、上記方法。
- 請求項15〜23のいずれか1項に記載の融合タンパク質の製造方法であって、(a) 該融合タンパク質をコードするヌクレオチド配列に機能的に連結されたプロモーターを含んでなるベクターを宿主細胞に導入するステップ;(b) 該宿主細胞を培養して該融合タンパク質を産生させるステップを含む、上記方法。
- 請求項31に記載の核酸を含んでなる宿主細胞。
- 被験者での疾患もしくは障害を予防または治療するための医薬の製造における、請求項1〜9および11のいずれか1項に記載の修飾IgGの使用。
- 被験者での呼吸器合胞体ウイルス(RSV)感染を予防または治療するための医薬の製造における、請求項10に記載の修飾IgGの使用。
- 被験者がヒトである、請求項35または36に記載の使用。
- in vitroで疾患または障害を検出するための方法であって、(a) 請求項1〜9および11のいずれか1項に記載の修飾IgGを被験者由来のサンプルと接触させ、(b) 該修飾IgGと免疫特異的に結合する抗原のレベルを対照のレベルと比較し、該サンプル中の抗原のレベルが対照のレベルと比較して異なっていれば疾患または障害を示すこととなることを含んでなる、上記方法。
- in vitroでRSV感染を検出するための方法であって、(a) 請求項10に記載の修飾IgGを被験者由来のサンプルと接触させ、(b) 該修飾IgGと免疫特異的に結合するRSV抗原のレベルを対照のレベルと比較し、該サンプル中のRSV抗原のレベルが対照のレベルと比較して増加していればRSV感染を示すこととなることを含んでなる、上記方法。
- 疾患または障害を診断するための医薬の製造における、標識された形態の請求項1〜9および11のいずれか1項に記載の修飾IgGの使用であって、該医薬は、(a) 該医薬を被験者に投与し、(b) 該修飾IgGが免疫特異的に結合する抗原が発現されている被験者体内の部位へ標識された形態の該修飾IgGが優先的に濃縮されるまでの時間を待ち、(c) バックグラウンドレベルを測定し、(d) 被験者体内の標識された形態の該修飾IgGを検出して、バックグラウンドレベルを超える標識された形態の該修飾IgGが検出されれば、該被験者が疾患または障害を有していることが示されることを含んでなる方法において用いるためのものである、上記使用。
- RSV感染を診断するための医薬の製造における、標識された形態の請求項10に記載の修飾IgGの使用であって、該医薬は、(a) 該医薬を被験者に投与し、(b) 該修飾IgGが免疫特異的に結合するRSV抗原が発現されている被験者体内の部位へ標識された形態の該修飾IgGが優先的に濃縮されるまでの時間を待ち、(c) バックグラウンドレベルを測定し、(d) 被験者体内の標識された形態の該修飾IgGを検出して、バックグラウンドレベルを超える標識された形態の該修飾IgGが検出されれば、該被験者がRSV感染を有していることが示されることを含んでなる方法において用いるためのものである、上記使用。
- 被験者がヒトである、請求項38〜41のいずれか1項に記載の方法または使用。
- 被験者での疾患もしくは障害を予防または治療するための医薬の製造における、請求項15〜23のいずれか1項に記載の融合タンパク質の使用。
- in vitroで疾患または障害を検出するための方法であって、(a) 請求項15〜23のいずれか1項に記載の融合タンパク質を被験者由来のサンプルと接触させ、(b) 該融合タンパク質と免疫特異的に結合する抗原のレベルを対照のレベルと比較し、該サンプル中の抗原のレベルが対照のレベルと比較して異なっていれば疾患または障害を示すこととなることを含んでなる、上記方法。
- 疾患または障害を診断するための医薬の製造における、標識された形態の請求項15〜23のいずれか1項に記載の融合タンパク質の使用であって、該医薬は、(a) 該医薬を被験者に投与し、(b) 該融合タンパク質が免疫特異的に結合する抗原が発現されている被験者体内の部位へ標識された形態の該融合タンパク質が優先的に濃縮されるまでの時間を待ち、(c) バックグラウンドレベルを測定し、(d) 被験者体内の標識された形態の該融合タンパク質を検出して、バックグラウンドレベルを超える標識された形態の該融合タンパク質が検出されれば、該被験者が疾患または障害を有していることが示されることを含んでなる方法において用いるためのものである、上記使用。
- 被験者がヒトである、請求項43〜45のいずれか1項に記載の使用または方法。
- 被験者での疾患もしくは障害を予防または治療するための医薬の製造における、請求項26〜28のいずれか1項に記載の分子の使用。
- in vitroで疾患または障害を検出するための方法であって、(a) 請求項26〜28のいずれか1項に記載の分子を被験者由来のサンプルと接触させ、(b) 該分子と免疫特異的に結合する抗原のレベルを対照のレベルと比較し、該サンプル中の抗原のレベルが対照のレベルと比較して増加していれば疾患または障害を示すこととなることを含んでなる、上記方法。
- 疾患または障害を診断するための医薬の製造における、標識された形態の請求項26〜28のいずれか1項に記載の分子の使用であって、該医薬は、(a) 該医薬を被験者に投与し、(b) 該分子が免疫特異的に結合する抗原が発現されている被験者体内の部位へ標識された形態の該分子が優先的に濃縮されるまでの時間を待ち、(c) バックグラウンドレベルを測定し、(d) 被験者体内の標識された形態の該分子を検出して、バックグラウンドレベルを超える標識された形態の該分子が検出されれば、該被験者が疾患または障害を有していることが示されることを含んでなる方法において用いるためのものである、上記使用。
- 被験者がヒトである、請求項47〜49のいずれか1項に記載の使用または方法。
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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EXPY | Cancellation because of completion of term |