JP6192891B2 - 改善されたフィブロネクチンベースの結合分子およびそれらの使用 - Google Patents
改善されたフィブロネクチンベースの結合分子およびそれらの使用 Download PDFInfo
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Description
本願は、2008年5月2日に出願した米国仮出願第61/050,142号の優先権を主張し、その内容をそれらの全体において、参照により本明細書に組み込む。
関連情報
本明細書を通じて言及されているあらゆる特許、特許出願および文献の内容は、それらの全体において、参照により本明細書の一部とする。
所望の標的エピトープと特異的に結合することができる分子は、治療および医学的診断ツールとして極めて重要である。このクラスの分子の周知の例は、モノクローナル抗体である。ほぼあらゆる構造エピトープと特異的に、そして高い親和性で結合する抗体が、選択され得る。その結果、抗体は研究ツールおよびFDA承認治療薬として日常的に使用されており、治療用および診断用モノクローナル抗体の世界市場は現在約30,000,000,000ドルにも上る。
本発明は、標的抗原に特異的に結合し、したがって広範な治療および診断適用に用いることができる、フィブロネクチンタイプIII(Fn3)ベースの結合分子を提供する。本発明は、少なくとも1個の修飾底部ループを含むFn3が構造的および立体構造的安定性を保持しており、標的分子に結合できるという予期せぬ驚くべき発見に基づく。さらにまた、本発明は、Fn3の上部および底部ループの両方を用いることによって、1個のFn3分子が1種以上の標的分子に結合できる、新たな二重特異性なFn3ベースの結合分子の発見に基づく。本発明はまた、二重特異性および多重特異性なFn3ベースの結合分子を作成する単純な、効果的な方法も提供する。
本明細書および特許請求の範囲の理解を明確にするため、次の定義が簡便には提供される。
本明細書において使用するとき、用語「フィブロネクチンタイプIIIドメイン」または「Fn3ドメイン」は、いずれかの生物由来の野生型Fn3ドメインならびに2個以上の異なるFn3ドメイン由来のベータストランドから構築したキメラFn3ドメインを意味する。当該技術分野において知られているとおり、天然に生じるFn3ドメインはAB、BC、CD、DE、EFおよびFGループと称される6個のループで連結された、A、B、C、D、E、FおよびGと称される7個のベータストランドから成るベータサンドイッチ構造を有する(例えば、Bork and Doolittle, Proc. Natl. Acad. Sci. U.S.A 89:8990, 1992; Bork et al, Nature Biotech. 15:553, 1997; Meinke et al., J. Bacteriol. 175:1910, 1993; Watanabe et al., J. Biol. Chem. 265:15659, 1990; Main et al, 1992; Leahy et al., 1992; Dickinson et al., 1994; 米国特許第6,673,901号; PCT公報WO/03104418;および米国特許出願第2007/0082365号参照、これらの全教示を参照により本明細書の一部とする)。3個のループはドメインの上部に存在し(BC、DEおよびFGループ)、3個のループはドメインの底部に存在する(AB、CDおよびEFループ)(図1参照)。本発明の特定の態様において、該Fn3ドメインはヒトフィブロネクチンの第10Fn3ドメイン(10Fn3)に由来する(配列番号1)。
本発明は、標的抗原と特異的に結合するフィブロネクチンタイプIII(Fn3)ベースの結合分子を提供する。本発明は、1個以上の標的分子に結合する底部AB、CD、EFループ領域またはC末端の少なくとも1個以上の修飾を有する、単一特異性なFn3結合分子を提供する。本発明はさらに、2個の異なる結合節を有する同じ標的分子または2種以上の標的抗原に同時に結合する、二重特異性なFn3ベースの結合分子を提供する。本発明のFn3ベースの結合分子はまた、一体に(例えば数珠状に)連結して、多重特異性なFn3ベースの結合分子を形成するか、そして/または半減期および安定性を改善するためにヒト血清アルブミン(HSA)のような非Fn3部分と複合化されていてよい。Fn3ベースの結合分子は、抗体のような他の結合分子と同様に、多様な治療および診断適用に用いることができる。
一つの局面において、本発明は、野生型Fn3ドメインと比較して(例えば底部および/または上部ループ領域において)改変されて、特定の標的に結合する非Fn3結合配列が作成されている単一特異性なFn3ベースの結合分子を提供する。一つの態様において、単一特異性なFn3ベースの結合分子はAB、CD、EFループまたはC末端を用いて1個以上の標的分子に結合する。
一部は上記のとおり、別の局面において、本発明は、2個以上の標的に同時に結合できる二重特異性なFn3ベースの結合分子を提供する。かかる二重特異性なFn3ベースの結合分子は、同じタンパク質ドメイン内に2個以上の非Fn3結合配列を含む。これは、上部および底部AB、BC、CD、DE、EFまたはFGループ領域の2個以上を改変して非Fn3結合配列を含めることによって得られる(図1参照)。特定の態様において、二重特異性なFn3ベースの結合分子は、2個の別々の結合特異性を作成するために上部と底部ループ領域の両方において改変されている。
別の局面において、本発明は、2個以上の単一特異性なFn3ベースの結合分子または二重特異性なFn3ベースの結合分子を含み、それらが一体に(例えば遺伝子的または化学的に)連結されている多重特異性なFn3ベースの結合分子を提供する。多重特異性なFn3ベースの結合分子は、少なくとも1個の底部ループAB、CD、EFを用いて標的に結合する、少なくとも1個の単量体Fn3ベースの結合分子を含む。
別の局面において本発明は、1個以上の非Fn3部分と連結したFn3ベースの結合分子を含んでなる複合体を提供する。かかる非Fn3部分は、例えばFn3ベースの結合分子にさらなる機能的または物理化学的特性を与えることができる。一つの態様において、Fn3ベースの結合分子は、抗体Fcドメイン(またはその一部)に連結または融合する。分子とFcドメイン、例えばIgG1のFcドメインを融合する方法は、当該技術分野において既知である(例えばU.S. 5,428,130参照)。かかる複合体は、IgGホメオスタシスにおいて重要な機能を提供して、異化からそれと結合する分子を保護するFcRnと結合するFcの能力のため、延長された循環系半減期を有する。
1)核酸およびアミノ酸変化
1個以上のアミノ酸またはヌクレオチド修飾(例えば変化)を有する本発明のFn3ベースの結合分子は、多様な既知の方法によって作成することができる。典型的には、かかる修飾されたFn3ベースの結合分子は、例えば、組換え法によって作成することができる。さらに、遺伝子コードの縮重のため、多様な核酸配列を用いて各々所望の分子をコードすることができる。
多様なスクリーニングアッセイを使用して、本発明のFn3ベースの結合分子を同定することができる。所望の抗原との結合について選択するいずれかのインビトロまたはインビボスクリーニング方法が、本質的には、使用できる。
本発明のFn3ベースの結合分子は典型的には、組み換え発現によって作成する。該分子をコードする核酸を発現ベクターに挿入する。該分子をコードするDNAセグメントは、それらの発現を確実に行うため発現ベクターの調節配列と作動可能に連結している。発現調節配列は、プロモーター(例えば天然関連または異種プロモーター)、シグナル配列、エンハンサー要素および転写終止配列を含むが、これらに限定されない。好ましくは、発現調節配列は、真核宿主細胞を形質転換またはトランスフェクトすることができるベクター内の真核プロモーター系である。ベクターが適切な宿主に取り込まれると、ヌクレオチド配列の高レベル発現に適した条件下で該宿主を維持し、交叉反応するFn3ベースの結合分子を回収および精製する。
一つの局面において、本発明は、野生型Fn3ドメインと比較して改変されて、抗体の相補性決定領域(CDR)またはT細胞受容体の全部または一部を含むFn3ベースの結合分子を特徴とする。
本発明のFn3ベースの結合分子は、インビボでの治療上有用性を有する。したがって、本発明はまた、薬学的に許容される担体と共に製剤された、Fn3ベースの結合分子(またはその変異体、融合体および複合体)の1種または組合せを含む組成物、例えば医薬組成物を提供する。本発明の医薬組成物はまた、組合せ療法で、すなわち他の薬物と組み合わせて投与してもよい。例えば、組合せ療法は、本発明の組成物と少なくとも1種以上のさらなる治療薬物、例えば抗炎症剤、抗癌剤および化学療法剤を含んでいてもよい。
本明細書に記載のFn3ベースの結合分子は、いずれかの目的の抗原または標的に結合するように構築することがでる。かかる標的は、クラスタードメイン、細胞レセプター、細胞レセプターリガンド、増殖因子、インターロイキン、タンパク質アレルゲン、細菌またはウイルスを含むが、これらに限定されない(図1参照)。本明細書に記載のFn3ベースの結合分子は、増加した安定性および半減期、ならびにさらなる機能的部分を有するように修飾してもよい。したがって、これらの分子は、研究、治療および診断分野を含む、抗体が使用されているあらゆる領域において抗体の代わりに使用することができる。さらに、これらの分子は抗体よりも優れた溶解性および安定性を有するため、本明細書に記載の抗体模倣物はまた、抗体分子を破壊もしくは不活性化する条件下で使用することもできる。
フィブロネクチンベースの結合分子のライブラリーの作成
一般に、特に定めのない限り、本発明の実施は、化学、分子生物学、組換えDNA技術、免疫学(例えば特に抗体技術)およびポリペプチド調製における標準的な技術を使用する。例えば、Sambrook, Fritsch and Maniatis, Molecular Cloning: Cold Spring Harbor Laboratory Press (1989); Antibody Engineering Protocols (Methods in Molecular Biology), 510, Paul, S., Humana Pr (1996); Antibody Engineering: A Practical Approach (Practical Approach Series, 169), McCafferty, Ed., Irl Pr (1996); Antibodies: A Laboratory Manual, Harlow et al., C.S.H.L. Press, Pub. (1999); および Current Protocols in Molecular Biology, eds. Ausubel et al., John Wiley & Sons (1992)を参照されたい。本発明の実施に使用するのに好適な他の方法、技術および配列は、米国特許7,153,661; 7,119,171; 7,078,490; 6,703,199; 6,673,901; および 6,462,189に見出すことができる。
配列番号1の野生型Fn310配列を基礎として用いて、上部または底部ループを用いるバインダーのライブラリーを作成した。
VSDVPRDLEVVAATPTSLLISWDAPAVTVRYYRITYGETGGNSPVQEFTVPGSKSTATISGLKPGVDYTITVYAVTGRGDSPASSKPISINYRTEI (配列番号1)
ライブラリーA(溶媒に曝される上部ループBC、DEおよびFGを有するベータサンドイッチ):
ライブラリーB(溶媒に曝される底部ループAB、CE、EFおよびC末端を有するベータサンドイッチ):
単一特異性なフィブロネクチンベースの結合分子のスクリーニング
本実施例は、実施例1に記載のライブラリーAおよびBから作成した単一特異性なフィブロネクチンバインダーについてどのようにスクリーニングするかを説明する。ライブラリーAおよびBはいずれも独立して、pYD1 (Invitrogen)のような酵母ディスプレイベクターに、相同組換え法を用いてサブクローン化して、EBY100のような好適な株に、標準的な分子生物学的技術を用いて形質転換する。
全ての選択について、10Fn3ベースの分子のライブラリーAまたはライブラリーBを提示する酵母培養物をガラクトース含有培地(90% SG-CAA/10% SD-CAA、50 μg/mL カナマイシン、100 U/mL ペニシリンG、200 U/mL ストレプトマイシン)中、30℃で18時間誘導した。誘導された109個のライブラリーAまたはBの酵母細胞を25 mLの氷冷リン酸緩衝化食塩水(PBS)pH 7.4、2 mMのエチレンジアミンテトラ酢酸(EDTA)、0.5%のウシ血清アルブミン(BSA)で洗浄し、次いで1 μMのビオチニル化ニワトリ卵白リゾチーム(HEL-b、Sigma、St. Louis、MO)を含む同じバッファー 5mL中、室温で1時間、緩やかに振盪しながらインキュベートした。インキュベーションの後、サンプルを氷上で冷やし、25 mLの氷冷PBS pH 7.4、2 mMのEDTA、0.5%のBSAで洗浄し、2.5 mLの同じバッファーに再懸濁した。磁性Streptavidin MicroBeads (Miltenyi Biotec、Auburn、CA)の100 μLのアリコートを酵母に加え、氷上で10分間インキュベートした。氷冷PBS pH 7.4、2 mMのEDTA、0.5%のBSAをサンプルに加えて全量を25 mLとした後、すぐにこれをAutoMACS Cell Separator (Miltenyi Biotec)で、レア細胞のポジティブ選択のために予めセットされたプログラム(possel_s)を用いた分離に供した。選択した細胞を6 mLのSD-CAA、pH 4.5、50 μg/mLのカナマイシン、100 U/mLのペニシリンG、200 U/mLのストレプトマイシン中に回収し;連続希釈で定量した後、SD-CAA寒天プレートに播種し;50 mLの同じ培地中、30℃で2日間増殖させた。
2×106〜3×106個の誘導された酵母細胞で開始して、FACSによって続く選択ラウンドを行った。細胞を1 mLのPBS、pH 7.4、0.1% BSAで洗浄し、ビオチニル化ニワトリ卵白リゾチームを含む同じバッファー 100 μL中に再懸濁して、室温で緩やかに振盪しながら1時間インキュベートした。
二重特異性なフィブロネクチンベースの結合分子の作成
ヒトFn3のX線構造におけるランダム化領域のコンピューターモデリングは、ライブラリーAおよびBのそれぞれの単一特異性なバインダーを組み合わせて、二重特異性なフィブロネクチン結合分子を作成できることを示している。これらの結合分子は、それらが同じ標的分子の異なる領域を認識するか、あるいは二重特異性または多重特異性なフィブロネクチン分子の異なる結合部位が2種以上の異なる標的の異なる領域に結合できるように操作可能である。
ライブラリーAをスクリーニングして同定したバインダーA(溶媒に曝される上部ループBC、DE、FGを有するベータサンドイッチ):
あるいは、二重特異性なFn3ベースの結合分子は、2個以上の単一特異性なFn3ベースの結合分子を連結して作成できる。
底部ループを用いて標的に結合する単一特異性なフィブロネクチンベースの結合分子の作成
実施例2に記載の実験の詳細を反復して、フィブロネクチンの底部ループを用いて半減期エクステンダーであるHSAに結合する単一特異性なFn3ベースの結合分子を作成した。別のライブラリーを用いて、底部ループを用いてリゾチームに結合する単一特異性なフィブロネクチンベースの結合分子を作成した。
数ラウンドの選択の後、選択した集団の配列を決定した。各選択した酵母集団の飽和培養物1 mLからZymoprep キット(Zymo Research、Orange、CA)を用いてプラスミドDNAを抽出し、2 μLのプラスミドをエレクトロ・コンピテントなTop10 大腸菌(Invitrogen、Carlsbad、CA)に形質転換した。 プラスミドミニプレップを調製し、96コロニーについて配列決定した。
富化されたフィブロネクチンプールをコードする遺伝子を図6に示すpNAT40ベクターにクローン化して、構築物をエレクトロ・コンピテントなAcella大腸菌株(Gaithersburg、MD)に形質転換した。多数のクローンを選択肢、配列決定した。HSAに対する潜在的なFn3ベースのバインダーの選択したクローンのアミノ酸配列は、コンセンサス結合配列(配列番号42)と共に図7に示す。図8はリゾチームに対する潜在的なFn3ベースのバインダーの選択したクローンのアミノ酸配列を示す。
単一特異性なフィブロネクチンベースの結合分子の結合特性
この実施例は、Fn3の底部ループの少なくとも1個(例えばAB、CDおよび/またはEF)を改変してFn3ベースの結合分子を作成して、底部ループを用いて標的に結合するFn3ベースの分子の生産に成功した初めての例を示す。この実施例において、HSAに対する潜在的なFn3ベースのバインダーを試験した。
多重特異性なフィブロネクチンベースの結合分子の作成および特徴付け
この実施例は、2個の別個の単一特異性なFn3ベースの結合分子が、多重特異性、例えば二重特異性な分子を作成するためのリンカー配列を用いて数珠状に一体に連結されている、多重特異性なFn3ベースの結合分子の作成および特徴付けを示す。二重特異性な分子は次のとおりに設計した。図7において同定し、次に(配列番号8)示す底部側HSAバインダーに、短いGSリンカー配列GGGGSGGGGS(配列番号118)を用いて下記VEGFR2結合配列(配列番号117)を融合して、下記の配列番号119を有する多重特異性なFn3ベースの結合分子を作成した。この構築物はDNA2.0で合成し、発現ベクターpjExpress 401にサブクローン化した。クローニング、精製およびELISAは上記の標準的なプロトコールに従った。
二重特異性なフィブロネクチンベースの結合分子の作成および特徴付け
この実施例は、1個のフィブロネクチン分子が2個の別個の標的、例えばVEGFR2とHSAに結合するように改変された上部ループおよび底部ループを有する二重特異性なFn3ベースの結合分子の作成および特徴付けを示す。
VEGFR2/底部側配列番号8融合分子(クローン89)
実施例6および7の多重特異性および二重特異性なバインダーの結合特性を次のとおりに評価した。VEGFR2−Fc融合タンパク質を前処理したELISAプレート(NuncMultisorb)に不動化して、さらにPBSと1%のカゼインでブロックした。野生型Fn10(レーン1)、クローン87(多重特異性)(レーン2)、クローン89(二重特異性)(レーン3)およびPBSの澄明な溶解物のアリコートをウェルに加え、室温で1時間インキュベートした。これらは異なる濃度1、2および3で実行した。PBS/0.05%のTweenで5回洗浄し、該ウェルをPBS中 1 μg/mlのHSAと共にインキュベートした。HRP複合化ニワトリ抗ヒトhSA抗体(Abcam)で検出を行った。ELISAをTMP基質で現像し、OD値を450 nmで測定した。結果を図13に示す。
BIAcore T100 (GE)を用いて標的に結合するフィブロネクチンベースの足場タンパク質の結合カイネティクスを測定した。抗ヒトIgG(GE、ヒトIgG補足キット)。Fc特異的抗体をCM5センサーチップに不動化して、可溶性VEGFR2−huFc融合タンパク質をその表面に補足した。可溶性フィブロネクチンクローン87(多重特異性)をバッファー0(10 mMのHEPES、150 mMのNaCl、0.005%のTween 20、pH 7.4)中に100 nM(トップライン)および200 nM(ボトムライン)で注入した。各濃度でセンサーグラムを得て、速度定数ka(kon) および kd (koff)を決定した。アフィニティー定数KDを速度定数koff/konの比から計算した。
当業者は、常套未満の実験を用いて、本明細書に記載の本発明の具体的な態様の多様な均等を認識し、あるいは確認することができる。かかる均等は、特許請求の範囲に含まれることを意図する。
Claims (48)
- フィブロネクチンタイプIII(Fn3)ベースの結合分子であって、Fn3ドメイン
を含んでなり、ここで前記Fn3ドメインのEFループにおける少なくとも1個のアミノ
酸および底部ABループ領域、CDループ領域またはC末端の1個以上における少なくと
も1個のアミノ酸が配列番号1を含む野生型Fn3ドメインと比較して改変されて、特定
の標的に結合する非Fn3結合配列が作成されている、結合分子であって、前記EFルー
プにおける少なくとも2、3、4、5、6、または全てのアミノ酸が配列番号1を含む野
生型Fn3ドメインと比較して改変されている、結合分子。 - 少なくとも1個のアミノ酸が、配列番号1の15、16、38、39、40、41、42、43、44、45
、60、61、62、63、64、93、95および96番アミノ酸からなる群から選択される、請求項1
のFn3ベースの結合分子。 - 非Fn3結合配列が、抗体の相補性決定領域(CDR)もしくはT細胞受容体の全部ま
たは一部を含む、請求項1または2のFn3ベースの結合分子。 - 特定の標的がFn3ベースの結合分子の半減期を延長する部分である、請求項1のFn
3ベースの結合分子。 - Fn3ベースの結合分子の半減期を延長する部分がヒト血清アルブミンである、請求項
4のFn3ベースの結合分子。 - 特定の標的がリゾチームである、請求項1のFn3ベースの結合分子。
- 二重特異性なFn3ベースの結合分子であって、Fn3ドメインを含んでなり、ここで
前記Fn3ドメインのEFループにおける少なくとも1個のアミノ酸および底部ABルー
プ領域、CDループ領域またはC末端の1個以上における少なくとも1個のアミノ酸が、
配列番号1を含む野生型Fn3ドメインと比較して改変されて、第一の標的に結合する非
Fn3結合配列が作成されており、そして前記Fn3ドメインの上部BC、DEもしくは
FGループ領域の1個以上における少なくとも1個のアミノ酸が、配列番号1を含む野生
型Fn3ドメインと比較して改変されて、第二の標的に結合する非Fn3結合配列が作成
されている、結合分子であって、前記EFループにおける少なくとも2、3、4、5、6
、または全てのアミノ酸が配列番号1を含む野生型Fn3ドメインと比較して改変されて
いる、結合分子。 - 底部AB、CDまたはEFループ領域における少なくとも1個のアミノ酸が、配列番号
1の15、16、38、39、40、41、42、43、44、45、60、61、62、63、64、93、95および96番
アミノ酸からなる群から選択され、そして前記上部BC、DEまたはFGループ領域にお
ける少なくとも1個のアミノ酸が、配列番号1の21、22、23、24、25、26、27、28、29、
30、51、52、53、54、55、56、76、77、78、79、80、81、82、83、84、85、86、87および
88番アミノ酸からなる群から選択される、請求項7の二重特異性なFn3ベースの結合分
子。 - 非Fn3結合配列が抗体の相補性決定領域(CDR)またはT細胞受容体の全部または
一部を含む、請求項7または8の二重特異性なFn3ベースの結合分子。 - 第一および第二の標的が同一分子に存在する、請求項7〜9のいずれかの二重特異性
なFn3ベースの結合分子。 - 第一および第二の標的が異なる分子に存在する、請求項7または8に記載の二重特異
性なFn3ベースの結合分子。 - 二重特異性なFn3ベースの結合分子であって、Fn3ドメインを含んでなり、ここで
前記Fn3ドメインのEFループにおける少なくとも1個のアミノ酸および底部ABルー
プ領域、CDループ領域またはC末端の1個以上における少なくとも1個のアミノ酸が、
配列番号1を含む野生型Fn3ドメインと比較して改変されて、前記Fn3ベースの結合
分子の半減期を延長する部分に結合する非Fn3結合配列が作成されており、そして前記
Fn3ドメインの上部BC、DEもしくはFGループ領域の1個以上における少なくとも
1個のアミノ酸が、配列番号1を含む野生型Fn3ドメインと比較して改変されて、第二
の標的に結合する非Fn3結合配列が作成されている、結合分子であって、前記EFルー
プにおける少なくとも2、3、4、5、6、または全てのアミノ酸が配列番号1を含む野
生型Fn3ドメインと比較して改変されている、結合分子。 - Fn3ベースの結合分子の半減期を延長する部分がヒト血清アルブミンである、請求項
12の二重特異性なFn3ベースの結合分子。 - 第二の標的がVEGFR2である、請求項12の二重特異性なFn3ベースの結合分子
。 - 第二の標的がリゾチーム、細胞受容体、細菌およびウィルスからなる群から選択される
、請求項12の二重特異性なFn3ベースの結合分子。 - 第二の標的がヒトの疾患に関与している、請求項12の二重特異性なFn3ベースの結
合分子。 - 第二の標的が自己免疫疾患、がんまたは感染症に関与している、請求項12の二重特異
性なFn3ベースの結合分子。 - 上部ループにおける少なくとも21個のアミノ酸が配列番号1と比較して改変されてい
る、請求項7または12の二重特異性なFn3ベースの結合分子。 - 請求項1〜18のいずれかの2個以上のFn3ベースの結合分子を含んでなる、多重特
異性なFn3ベースの結合分子。 - Fn3ベースの結合分子がそれぞれ異なる標的に結合する、請求項19の多重特異性な
Fn3ベースの結合分子。 - 異なる標的が同一分子に存在する、請求項20の多重特異性なFn3ベースの結合分子
。 - 異なる標的が異なる分子に存在する、請求項20の多重特異性なFn3ベースの結合分
子。 - Fn3ベースの結合分子の半減期を延長する非Fn3部分に結合する、請求項1〜22
のいずれかのFn3ベースの結合分子。 - 多重特異性なFn3ベースの結合分子であって、2個以上の単一特異性なFn3ベースの結合分子を含んでなり、ここで少なくとも第一の単一特異性なFn3ベースの結合分子が、前記Fn3ドメインのEFループにおける少なくとも1個のアミノ酸、および底部ABループ領域、CDループ領域またはC末端の1個以上における少なくとも1個の、配列番号1を含む野生型Fn3ドメインと比較して改変され、第一の標的と結合する非Fn3結合配列が作成されている、改変されたアミノ酸を含み;そして第二の単一特異性なFn3ベースの結合分子が、前記Fn3ドメインの上部BC、DEもしくはFGループ領域の1個以上において、配列番号1を含む野生型Fn3ドメインと比較して改変され、第二の標的と結合する非Fn3結合配列が作成されている、少なくとも1個の改変されたアミノ酸を含み、第一および第二の単一特異性なFn3ベースの結合分子がリンカー配列によって連結されている、結合分子であって、前記EFループにおける少なくとも2、3、4、5、6、または全てのアミノ酸が配列番号1を含む野生型Fn3ドメインと比較して改変されている、結合分子。
- 配列番号1を含む野生型Fn3ドメインと比較して改変されて、1種以上の標的と結合
する非Fn3結合配列を作成されているFn3ドメインの上部BC、DEもしくはFGル
ープ領域の1個以上における少なくとも1個のアミノ酸を有する第三の単一特異性なFn
3ベースの結合分子をさらに含んでなり、第二の単一特異性なFn3ベースの結合分子と
第三の単一特異性なFn3ベースの結合分子がリンカー配列によって連結されている、請
求項24の多重特異性なFn3ベースの結合分子。 - 第一の標的がFn3ベースの結合分子の半減期を延長する部分である、請求項24の多
重特異性なFn3ベースの結合分子。 - Fn3ベースの結合分子の半減期を延長する部分がヒト血清アルブミンである、請求項
26の多重特異性なFn3ベースの結合分子。 - 第二の標的がVEGFR2である、請求項24の多重特異性なFn3ベースの結合分子
。 - リンカー配列がG−Sリンカー配列である、請求項24の多重特異性なFn3ベースの
結合分子。 - Fn3ベースの結合分子の半減期を延長する非Fn3部分に結合する、請求項24の多
重特異性なFn3ベースの結合分子。 - CDループにおける少なくとも4、5、6、7、8、9個または全てのアミノ酸が、配
列番号1を含む野生型Fn3ドメインと比較して改変されている、請求項1のFn3ベー
スの結合分子、請求項7または12の二重特異性なFn3ベースの結合分子、または請求
項24の多重特異性なFn3ベースの結合分子。 - C末端の少なくとも1、2、3個または全てのアミノ酸が、配列番号1を含む野生型F
n3ドメインと比較して改変されている、請求項1のFn3ベースの結合分子、請求項7
または12の二重特異性なFn3ベースの結合分子、または請求項24の多重特異性なF
n3ベースの結合分子。 - 底部ループおよびC末端の少なくとも8、11または12個のアミノ酸が、配列番号1
を含む野生型Fn3ドメインと比較して改変されている、請求項1のFn3ベースの結合
分子、請求項7または12の二重特異性なFn3ベースの結合分子、または請求項24の
多重特異性なFn3ベースの結合分子。 - BCループにおける少なくとも6個のアミノ酸が、配列番号1を含む野生型Fn3ドメ
インと比較して改変されている、請求項7または12の二重特異性なFn3ベースの結合
分子、または請求項24の多重特異性なFn3ベースの結合分子。 - DEループにおける少なくとも5個のアミノ酸が、配列番号1を含む野生型Fn3ドメ
インと比較して改変されている、請求項7または12の二重特異性なFn3ベースの結合
分子、または請求項24の多重特異性なFn3ベースの結合分子。 - FGループにおける少なくとも10個のアミノ酸が、配列番号1を含む野生型Fn3ド
メインと比較して改変されている、請求項7または12の二重特異性なFn3ベースの結
合分子、または請求項24の多重特異性なFn3ベースの結合分子。 - 第一または第二の標的がVEGFR2、Fn3ベースの結合分子の半減期を延長する部
分、リゾチーム、細胞受容体、細菌またはウィルスからなる群から選択される、請求項7
の二重特異性なFn3ベースの結合分子、または請求項24の多重特異性なFn3ベース
の結合分子。 - 配列番号119または1〜10個のアミノ酸の欠失を含む配列番号119を含む、Fn
3ベースの結合分子。 - 配列番号120または1〜10個のアミノ酸の欠失を含む配列番号120を含む、Fn
3ベースの結合分子。 - 1個以上の非Fn3部分に連結された請求項1〜39のいずれかのFn3ベースの結合
分子を含む、複合体。 - 非Fn3部分が、Fn3ベースの結合分子の半減期を延長する分子を含むかまたはそれ
と結合する、請求項40の複合体。 - 非Fn3部分が、抗体Fc領域、ヒト血清アルブミン(HSA)およびポリエチレング
リコール(PEG)からなる群から選択される分子を含む、請求項40または41の複合
体。 - 機能的部分を付加するために配列番号1を含む野生型Fn3ドメインと比較して少なく
とも1個の修飾アミノ酸残基をさらに含んでなる、請求項1〜42のいずれかのFn3ベ
ースの結合分子または複合体。 - 修飾アミノ酸残基が、システイン残基または非天然アミノ酸残基の付加または置換を含
む、請求項43のFn3ベースの結合分子または複合体。 - 請求項1〜44のいずれかのFn3ベースの結合分子または複合体と、担体を含む組成
物。 - 自己免疫疾患、がんおよび感染症からなる群から選択される疾患を処置するための医薬
組成物であって、請求項1〜45のいずれかのFn3ベースの結合分子、複合体または組
成物を含んでなる組成物。 - サンプル中のタンパク質を検出する方法であって、請求項1〜44のいずれかのFn3
ベースの結合分子または複合体を標識化し、前記標識化した結合分子または複合体を前記
サンプルと接触させ、そしてFn3ベースの結合分子または複合体と前記タンパク質間の
複合体形成を検出することを含んでなる方法。 - 請求項1、7、12、19および32のいずれか一つのFn3ベースの結合分子をコー
ドする、核酸ライブラリー。
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CN102076713A (zh) | 2011-05-25 |
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EP2274331B1 (en) | 2013-11-06 |
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JP2011522517A (ja) | 2011-08-04 |
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PL2439212T3 (pl) | 2017-06-30 |
ES2620285T3 (es) | 2017-06-28 |
EP2383292A1 (en) | 2011-11-02 |
US20110038866A1 (en) | 2011-02-17 |
PT2274331E (pt) | 2014-02-27 |
ES2445695T3 (es) | 2014-03-04 |
US9296810B2 (en) | 2016-03-29 |
US20160376345A1 (en) | 2016-12-29 |
WO2009133208A1 (en) | 2009-11-05 |
EP2439212B1 (en) | 2016-12-21 |
JP2017060481A (ja) | 2017-03-30 |
CN102076713B (zh) | 2015-03-25 |
JP2018118978A (ja) | 2018-08-02 |
AU2009242038B2 (en) | 2013-05-30 |
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