JP2014504265A - Fcドメイン中に突然変異を有する、安定したヘテロ二量体抗体の設計 - Google Patents
Fcドメイン中に突然変異を有する、安定したヘテロ二量体抗体の設計 Download PDFInfo
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- JP2014504265A JP2014504265A JP2013536966A JP2013536966A JP2014504265A JP 2014504265 A JP2014504265 A JP 2014504265A JP 2013536966 A JP2013536966 A JP 2013536966A JP 2013536966 A JP2013536966 A JP 2013536966A JP 2014504265 A JP2014504265 A JP 2014504265A
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Abstract
Description
本出願は、2011年11月4日に作成され、15キロバイトのサイズを有するテキストファイルZymeworks V84467WO.txtとして本出願と共に提出された配列表を参照により組み込む。
この複合体におけるFc−FcγRタンパク質間相互作用は、Fc分子中の2つの鎖がFcγR分子上の2つの異なる部位と相互作用することを示す。自然Fc分子では2つの重鎖において対称性があるが、一方の鎖上の残基のまわりの局所的なFcγR環境は、反対のFc鎖上の同じ残基位置を取り囲むFcγR残基とは異なる。2つの対称に関連する位置は、異なる選択のFcγR残基と相互作用する。
本発明のFc変異体(例えば抗体又は融合タンパク質)は、様々な方法において特徴付けられてもよい。一実施形態では、変異体Fcヘテロ二量体の純度が、SDS−PAGEゲル、ウェスタンブロット、濃度測定、又は質量分析法を含むが、これらに限定されない、当技術分野においてよく知られている技術を使用して評価される。タンパク質安定性は、サイズ排除クロマトグラフィー、紫外可視分光法及びCD分光法、質量分光法、示差光散乱(differential light scattering)、ベンチトップ安定性アッセイ(bench top stability assay)、他の特徴付け技術とつながれた凍結融解、示差走査熱量測定、示差走査蛍光分析(differential scanning fluorimetry)、疎水性相互作用クロマトグラフィー、等電点電気泳動、受容体結合アッセイ、又は相対的なタンパク質発現レベルに限定されない、多くの技術を使用して、特徴付けることができる。例示的な実施形態では、変異体Fcヘテロ二量体の安定性は、示差走査熱量測定又は示差走査蛍光分析などのような当技術分野においてよく知られている技術を使用して、野生型CH3ドメインと比較した、変異体CH3ドメインの融解温度によって評価される。
本発明は、疾患、障害、又は感染と関連する1つ又は複数の症状を予防する、治療する、又は回復させるために、動物、特に哺乳動物、具体的にはヒトに、本発明の1つ又は複数のFc変異体(例えば抗体)を投与することを包含する。本発明のFc変異体は、エフェクター細胞機能(例えばADCC、CDC)の効能の変化が所望される疾患又は障害の治療又は予防に特に有用である。Fc変異体及びその組成物は、原発性又は転移性新生物疾患(つまり癌)及び感染症の治療又は予防に特に有用である。本発明の分子は、当技術分野において知られている又は本明細書において記載される薬学的に許容される組成物中に提供されてもよい。下記に詳述されるように、本発明の分子は、癌(特に受動免疫療法において)、自己免疫疾患、炎症性障害、又は感染症を治療する又は予防するための方法において使用することができる。
抗体重鎖及び軽鎖をコードする遺伝子を、ヒト/哺乳動物発現のために最適化されたコドンを用いる遺伝子合成により構築した。Fab配列は公知のHer2/neu結合Abから生成され(Carter P.ら(1992)、Humanization of an anti P185 Her2 antibody for human cancer therapy、Proc Natl Acad Sci 89、4285頁)、FcはIgG1アイソタイプであった(配列番号1)。最終遺伝子産物を哺乳動物発現ベクターpTT5(NRC−BRI、Canada)(Durocher, Y.、Perret,S.& Kamen,A.、High−level and high−throughput recombinant protein production by transient trasfection of suspension−growing human HEK293−EBNA1 cells、Nucleic acids research 30、E9(2002))中にサブクローニングした。CH3ドメイン中の突然変異は、pTT5鋳型ベクターの部位特異的突然変異誘発により導入された。作製した変異体CH3ドメイン突然変異の一覧については、表1及び表6及び表7を参照されたい。
清澄化された培養培地を、MabSelect SuRe(GE Healthcare)プロテインAカラム上に充填し、pH7.2の10倍カラム容量のPBSバッファーで洗浄した。抗体をpH3.6の10倍カラム容量のクエン酸バッファーで溶出させ、抗体を含有するプールされた画分をpH11のTRISで中和した。Econo−Pac 10DGカラム(BioRad)を用いてタンパク質を最終的に脱塩した。抗体とエンテロキナーゼ(NEB)とを1:10,000の比率で、25℃でPBS中で一晩インキュベートすることにより、重鎖B上のC末端mRFPタグを除去した。ゲル濾過により混合物から抗体を精製した。ゲル濾過のために、3.5mgの抗体混合物を1.5mLに濃縮し、1mL/minの流速でAKTA Express FPLCを介してSephadex 200 HiLoad 16/600 200pgカラム(GE Healthcare)上に充填した。pH7.4のPBSバッファーを1mL/minの流速で用いた。精製された抗体に対応する画分を回収し、約1mg/mLに濃縮し、−80℃で保存した。
すべてのDSC実験を、GE VP−Capillary装置を用いて実行した。タンパク質をPBS(pH7.4)中でバッファー交換し、0.4〜0.5mg/mLに希釈し、0.137mLを試料セル中に充填し、20〜100℃で1℃/minの走査速度で測定した。PBSバッファーのバックグラウンドを差し引いて、Originソフトウェア(GE Healthcare)を用いてデータを分析した(図27を参照されたい)。試験した変異体及び決定された融解温度の一覧については表3を参照されたい。70℃以上の融解温度を有する変異体及びそれぞれの変異体に関する特定のTmの一覧については表4を参照されたい。
すべての結合実験を、10mM HEPES、150mM NaCl、3.4mM EDTA、及び0.05%Tween20(pH7.4)と共に25℃でBioRad ProteOn XPR36装置を用いて実行した。約3000共鳴単位(RU)が固定され、残りの活性基がクエンチされるまで、25μL/minで10mM NaOAc(pH4.5)中の4.0μg/mLを注入することにより、組換えHER−2/neu(p185、ErbB−2(eBiosciences,Inc.))を活性化GLMセンサーチップ上に捕捉した。安定なベースラインを確立するためのバッファー注入の後、25μL/minで240s注入した場合に(約500RUが得られる)Her−2/neuタンパク質に結合させることにより、変異体CH3ドメインを含む精製された抗HER−2/neu抗体40μg/mLをセンサーチップ上に間接的に捕捉した。FcガンマR(CD16a(fアロタイプ)及びCD32b)濃度(6000、2000、667、222及び74.0nM)を、60μL/minで120s注入し、180sの解離段階を行って、結合センサーグラムのセットを得た。得られたKD値を、平衡適合モデルを用いて結合等温線から決定し、3回の独立した実行の平均として値を報告した。野生型IgG1 Fcドメインとの比較を行い、変異体kDに対するWT kDの比率として結合を表す(表5を参照されたい)。
安定性及び純度に関する初期の負の設計のFc変異体AZ8を改善するために、上記の構造及びコンピューター戦略を用いた(図24を参照されたい)。例えば、AZ8の徹底的な構造機能分析により、野生型ヒトIgG1と比較したAZ8のそれぞれの導入された突然変異、L351Y_V397S_F405A_Y407V/K392V_T394Wに関する詳細な理解が提供され、重要なコアヘテロ二量体突然変異はL351Y_F405A_Y407V/T394Wであるが、V397S、K392Vはヘテロ二量体形成とは関連しないことが示された。このコア突然変異(L351Y_F405A_Y407V/T394W)を、本明細書では「足場1」突然変異と呼ぶ。分析はさらに、野生型(WT)ホモ二量体形成に関して失われる重要な境界面ホットスポットがWT−F405−K409、Y407−T366と、Y407−Y407及び−F405のパッキングとの相互作用であることを示した(図29を参照されたい)。これは、ループ領域D399〜S400〜D401(図30を参照されたい)及びK370で結合したβ−シートの大きいコンフォメーションの相違を示した、パッキング、空洞及びMD分析に反映された。これは鎖間相互作用K409−D399の喪失(図30を参照されたい)及びE357への強いK370水素結合の弱体化をもたらした(K370は最早S364及びE357と直接接触していないが、完全に溶媒に曝露している)。WT IgG1 CH3ドメインにおいて、これらの領域は、境界面を縁で繋ぎ、バルク溶媒競合(bulk solvent competition)からコア相互作用を保護し、好ましい疎水性van der Waals相互作用の動的発生を増加させる。その結果は、WTと比較してより少なく埋没したAZ8の表面積及び疎水性コアのより高い溶媒接近性であった。これは、WTの安定性と比較したAZ8のより低い安定性に関する最も重要な因子が、a)WT−F405−K409相互作用及びF405のパッキングの喪失、並びにb)Y407−Y407及びY407−T366の強いパッキング相互作用の喪失であることを示していた。図29を参照されたい。
AZ33は初期の出発変異体AZ8よりも有意な安定性及び特異性(又は純度)の改善を提供するが、本発明者らの分析は、Fc変異体ヘテロ二量体の安定性に対するさらなる改善を、AZ33の実験データ及び上記の設計方法を用いるさらなるアミノ酸改変と共に行うことができることを示唆する。異なる設計アイデアを発現及び安定性について独立に試験したが、独立した設計アイデアは移転可能であり、最も成功したヘテロ二量体は異なる設計の組合せを含む。具体的には、AZ8の最適化のために、K409−F405A−K392に近い空洞でのパッキング突然変異を、残基L366T〜L368でのコアパッキングを最適化する突然変異から独立に評価した。これらの2つの領域366〜368及び409〜405〜392は、互いに遠位で、独立していると考えられる。例えば、Fc変異体AZ33を、366〜368ではなく409〜405〜392でパッキングのために最適化したが、これは、これらの最適化突然変異を別々に評価したためであった。366〜368突然変異の比較は、T366LがT366及びまたFc変異体AZ33の開発において用いられた点突然変異であるT366Iよりも改善された安定性を有することを示唆する。結果として、提示された実験データは、例えば、T366Iの代わりにT366Lを導入することによるAZ33のさらなる最適化を直接示唆する。したがって、CH3ドメイン中のアミノ酸突然変異T366L_K392M_T394W/F405A_Y407Vを本明細書では「足場1b」突然変異と呼ぶ。
安定性及び純度に関して初期の負の設計段階のFc変異体AZ15を改善するために、上記の構造及びコンピューター戦略を用いた(図24を参照されたい)。例えば、Fc変異体AZ15の包括的構造機能分析により、野生型(WT)ヒトIgG1と比較したAZ15の導入された突然変異L351Y_Y407A/E357L_T366A_K409F_T411Nの各々に関する詳細な理解が提供され、重要なコアヘテロ二量体突然変異はL351Y_Y407A/T366A_K409Fであるが、E357L、T411Nはヘテロ二量体の形成及び安定性に関して直接関連しないことが示唆された。このコア突然変異(L351Y_Y407A/T366A_K409F)を本明細書では「足場2」突然変異と呼ぶ。分析はさらに、野生型(WT)ホモ二量体形成に関して失われる重要な境界面ホットスポットが塩架橋D399−K409、水素結合Y407−T366及びY407−Y407のパッキングであることを示した。以下に提供される本発明者らの詳細な分析は、本発明者らがどのように本発明者らの元のFc変異体AZ15の安定性を改善し、改善された安定性を有するこれらのFc変異体を達成するために位置及びアミノ酸改変を行ったかを記載する。
本発明者らのコンピューター分析は、Fc変異体AZ15突然変異K409F_T366A_Y407Aの最適でないパッキング及びWT−Y407−Y407相互作用の喪失に起因する疎水性コアの全体的なパッキングの低下を示した。その後の操作段階における正の設計の努力は、初期のFc変異体AZ15中のこれらのパッキング欠損を相殺するための点突然変異に集中した。標的化された残基はT366、L351及びY407位を含んでいた。これらの異なる組合せをコンピューターにより試験し、コンピューターツールを用いて最良に順位付けされたFc変異体(AZ63〜AZ70)を、例1〜4に記載のように発現及び安定性について実験的に検証した。
分子動力学シミュレーション(MD)及びパッキング分析により、WT塩架橋K409−D399の喪失におそらく起因するループ399〜400の好ましいより「開いた」コンフォメーションが示された。これはまた、満たされていないD399をもたらし、次いで、K392との相殺的相互作用を選択し、より「開いた」コンフォメーションのループを誘導した。このより「開いた」ループコンフォメーションは、コアCH3ドメイン境界面残基の全体として低下したパッキング及びより高い溶媒接近性をもたらし、次いで、ヘテロ二量体複合体を有意に脱安定化した。したがって、標的化された正の設計の努力の1つは、D399−K409塩架橋の喪失及びK409のパッキング相互作用の喪失を相殺するさらなる点突然変異による、より「閉じた」WT様のコンフォメーションにおけるこのループの連結であった。標的化された残基は、T411、D399、S400、F405、N390、K392位及びその組合せを含んでいた。異なるパッキング、疎水的及び静電的な正の操作戦略を、上記の位置に関してコンピューターにより試験し、コンピューターツールを用いて決定された最良に順位付けされたFc変異体(AZ71〜AZ101)を、例1〜4に記載のように発現及び安定性について実験的に検証した。
Fc変異体AZ70及びAZ94は両方とも、初期の負の設計のFc変異体AZ15よりも安定性及び純度における有意な改善を提供するが、本発明者らの分析並びにAZ70及びAZ94の比較は、Fc変異体ヘテロ二量体の安定性に対するさらなる改善をさらなるアミノ酸改変と共に行うことができることを直接示唆する。例えば、Fc変異体AZ70及びAZ94は、初期変異体AZ15中の2つの異なる非最適化領域を標的化するように設計され、これは、疎水性コアでのパッキングを改善し、399〜401位のループコンフォメーションを安定化するためのさらなる塩架橋及び水素結合をもたらすコア境界面残基の外側に突然変異を作製することによって達成された。Fc変異体AZ70及びAZ94のさらなる点突然変異は互いに遠位で、したがって、独立しており、2a及び2b突然変異などの同じ足場2のコア突然変異の周囲で設計された他のFc変異体に移行可能である。具体的には、AZ70のみが最適化されたコア突然変異L351Y_Y407A/T366A_K409Fを担持するが、さらなる塩架橋を担持せず、一方、AZ94は4個のさらなる静電突然変異(K392E_T411E/D399R_S400R)を含むが、疎水性コア境界面における1つ少ない突然変異を有する(Y407A/T366A_K409F)。これらの足場2b突然変異はAZ70よりも安定性が低い(例えば、AZ94と同等のコア突然変異を有し、72℃のTmを有するAZ63を参照されたい)が、K392E_T411E/D399R_S400R突然変異の付加によって相殺される。提示される安定性及び純度に関する実験データは、疎水性コアを最適化するAZ70の突然変異と、AZ94の静電突然変異との組合せが、Fc変異体ヘテロ二量体の安定性及び純度をさらに改善するべきであることを示唆する。同様の様式で、足場2のFc変異体(AZ63〜101)に関する完全な実験データを分析して、Fc変異体ヘテロ二量体AZ70及びAZ94をさらに改善するために用いることができる点突然変異を同定した。これらの同定された突然変異を上記のコンピューター手法によってさらに分析し、順位付けして、表7に示されるようなAZ70及びAZ94に基づくさらなるFc変異体ヘテロ二量体の一覧を得た。
FcgRを含むヘテロ二量体Fc活性の原型例として、本発明者らは、FcgR結合について例4に記載されたSPRアッセイにおいて、Her2結合Fabアームを用いて、ヘテロ二量体Fc領域A:K409D_K392D/B:D399K_D356K(対照1(図35中のhet1))及びA:Y349C_T366S_L368A_Y407V/B:S354C_T366W(対照4(図35中のhet2))を含む2つの変異体抗体を試験した。図35に示されるように、本発明者らは、両方のヘテロ二量体Fc領域は、野生型IgG1 Fc領域と同じ相対強度で異なるFcガンマ受容体に結合することを観察するが、全体として、ヘテロ二量体Fc領域は野生型抗体よりもわずかに良好にそれぞれのFcgRに結合した。これは、FcのCH3境界面での突然変異は、本発明者らの分子動力学シミュレーション及び分析において観察されたようにCH2ドメインにわたるFcガンマ受容体のFc領域の結合強度に影響し得ることを示唆する。
Fc領域のCH2ドメイン中の267位のセリンのアスパラギン酸への突然変異(S267D)は、CH2ドメインの2つの鎖中にホモ二量体様式で導入された場合、FcガンマIIbf、IIbY及びIIaR受容体への結合を増強することが知られている。この突然変異は、ヘテロ二量体Fc分子中のCH2ドメインの1つにのみ導入することができ、図36Aに提示されたデータが示す通り、ホモ二量体CH2 Fc中にこの突然変異が導入された場合と比較して結合強度のおおよそ半分の改善が得られる。他方、Fcのホモ二量体CH2ドメイン中のE269K突然変異は、FcgRへのFc領域の結合を阻害する。本発明者らは、FcのCH2ドメイン中の2つの鎖の1つへのこれらの好ましい及び好ましくない突然変異の非対称的導入によってFcg受容体に対するFc領域の結合強度の操作を増強するためのスキームを提示する。ヘテロ二量体Fc中の1つのCH2鎖への非対称様式でのE269K突然変異の導入は、それが存在する面でのFcgRの結合を遮断することによって極性ドライバーとして作用するが、Fcの他方の面は通常の様式でFcgRと相互作用させる。この実験からの結果を図36Aに提示する。独立した様式でのFcの両方の鎖を介する結合強度を選択的に変化させる機会は、FcとFcg受容体との間の結合強度及び選択性を操作する機会の増加を提供する。かくして、CH2ドメイン中の突然変異のそのような非対称設計により、特定の結合モデルを支持するか又は疎外する正及び負の設計を導入することが可能になり、選択性を導入するためのより大きな機会を提供する。
Claims (90)
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、安定性が増大したヘテロ二量体形成を促進するアミノ酸突然変異を含む変異体CH3ドメインを含み、変異体CH3ドメインが、約70℃以上の融解温度(Tm)を有する、上記単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、ヘテロ二量体形成を促進するアミノ酸突然変異を含む変異体CH3ドメインを含み、ヘテロ二量体Fc領域が、Fcガンマ受容体の選択的な結合を促進する非対称性のアミノ酸改変を含む変異体CH2ドメインをさらに含む、上記単離ヘテロ多量体。
- 変異体CH2ドメインが、野生型CH2ドメインと比較して、FcガンマIIIa受容体に選択的に結合する、請求項2に記載の単離ヘテロ多量体。
- 変異体CH3ドメインが、約70℃以上の融解温度(Tm)を有する、請求項2又は請求項3に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域が、野生型Fc領域に比べてCH3ドメイン中にさらなるジスルフィド結合を含まない、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- 約70℃以上の融解温度(Tm)がさらなるジスルフィド結合の非存在下におけるものであることを条件として、ヘテロ二量体Fc領域が、野生型Fc領域に比べて変異体CH3ドメイン中にさらなるジスルフィド結合を含む、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域が、野生型Fc領域に比べて、変異体CH3ドメイン中にさらなるジスルフィド結合を含み、変異体CH3ドメインが、約77.5℃以上の融解温度(Tm)を有する、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域が、約90%を超える純度を有する、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域が、約95%以上の純度を有する、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域が、約98%以上の純度を有する、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- Tmが、約71℃以上である、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- Tmが、約74℃以上である、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域が、約98%以上の純度を有し、Tmが、約73℃である、請求項1から3までのいずれか一項に記載のヘテロ多量体。
- ヘテロ二量体Fc領域が、約90%以上の純度を有し、Tmが、約75℃である、請求項1から3までのいずれか一項に記載のヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、アミノ酸改変L351Y及びY407Aを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366A及びK409Fを含む、請求項1に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチド又は第2のCH3ドメインポリペプチドが、T411、D399、S400、F405、N390、又はK392位にさらなるアミノ酸改変を含む、請求項15に記載の単離ヘテロ多量体。
- T411位のアミノ酸改変が、T411N、T411R、T411Q、T411K、T411D、T411E、又はT411Wから選択される、請求項16に記載の単離ヘテロ多量体。
- D399位のアミノ酸改変が、D399R、D399W、D399Y、又はD399Kから選択される、請求項16に記載の単離ヘテロ多量体。
- S400位のアミノ酸改変が、S400E、S400D、S400R、又はS400Kから選択される、請求項16に記載の単離ヘテロ多量体。
- F405位のアミノ酸改変が、F405I、F405M、F405T、F405S、F405V、又はF405Wから選択される、請求項16に記載の単離ヘテロ多量体。
- N390位のアミノ酸改変が、N390R、N390K、又はN390Dから選択される、請求項16に記載の単離ヘテロ多量体。
- K392位のアミノ酸改変が、K392V、K392M、K392R、K392L、K392F、又はK392Eから選択される、請求項16に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、アミノ酸改変L351Y及びY407Aを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366V及びK409Fを含む、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、アミノ酸改変Y407Aを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366A及びK409Fを含む、請求項1のいずれか一項に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチド又は第2のCH3ドメインポリペプチドが、さらなるアミノ酸改変K392E、T411E、D399R、及びS400Rを含む、請求項24に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、アミノ酸改変D399R、S400R、及びY407Aを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366A、K409F、K392E、及びT411Eを含む、請求項24に記載の単離ヘテロ多量体。
- 変異体CH3ドメインが、約74℃以上の融解温度(Tm)を有し、ヘテロ二量体が、約95%以上の純度を有する、請求項24から26までのいずれか一項に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、L351及びY407位にアミノ酸改変を含み、第2のCH3ドメインポリペプチドが、T366位のアミノ酸改変及びアミノ酸改変K409Fを含む、請求項1に記載の単離ヘテロ多量体。
- L351位のアミノ酸改変が、L351Y、L351I、L351D、L351R、又はL351Fから選択される、請求項28に記載の単離ヘテロ多量体。
- Y407位のアミノ酸改変が、Y407A、Y407V、又はY407Sから選択される、請求項28に記載の単離ヘテロ多量体。
- T366位のアミノ酸改変が、T366A、T366I、T366L、T366M、T366Y、T366S、T366C、T366V、又はT366Wから選択される、請求項28に記載の単離ヘテロ多量体。
- 変異体CH3ドメインが、約75℃以上の融解温度(Tm)を有し、ヘテロ二量体が、約90%以上の純度を有する、請求項28から31までのいずれか一項に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、F405位のアミノ酸改変並びにアミノ酸改変L351Y及びY407Vを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T394Wを含む、請求項1に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチド又は第2のCH3ドメインポリペプチドが、K392、T411、T366、L368、又はS400位にアミノ酸改変を含む、請求項33に記載の単離ヘテロ多量体。
- F405位のアミノ酸改変が、F405A、F405I、F405M、F405T、F405S、F405V、又はF405Wである、請求項33に記載の単離ヘテロ多量体。
- K392位のアミノ酸改変が、K392V、K392M、K392R、K392L、K392F、又はK392Eである、請求項34に記載の単離ヘテロ多量体。
- T411位のアミノ酸改変が、T411N、T411R、T411Q、T411K、T411D、T411E、又はT411Wである、請求項34に記載の単離ヘテロ多量体。
- S400位のアミノ酸改変が、S400E、S400D、S400R、又はS400Kである、請求項34に記載の単離ヘテロ多量体。
- T366位のアミノ酸改変が、T366A、T366I、T366L、T366M、T366Y、T366S、T366C、T366V、又はT366Wである、請求項34に記載の単離ヘテロ多量体。
- L368位のアミノ酸改変が、L368D、L368R、L368T、L368M、L368V、L368F、L368S、及びL368Aである、請求項34に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、アミノ酸改変L351Y、F405A、及びY407Vを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T394Wを含む、請求項1に記載の単離ヘテロ多量体。
- 第2のCH3ドメインポリペプチドが、アミノ酸改変T366L又はT366Iを含む、請求項41に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、アミノ酸改変F405A及びY407Vを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366I、K392M、及びT394Wを含む、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、アミノ酸改変F405A及びY407Vを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366L、K392M、及びT394Wを含む、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、アミノ酸改変F405A及びY407Vを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366L及びT394Wを含む、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、アミノ酸改変F405A及びY407Vを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366I及びT394Wを含む、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- 変異体CH3ドメインが、表4において列挙される変異体から選択されるアミノ酸突然変異を含む、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- 変異体CH3ドメインが、表6において列挙される変異体から選択されるアミノ酸突然変異を含む、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- 変異体CH3ドメインが、表7において列挙される変異体から選択されるアミノ酸突然変異を含む、請求項1から3までのいずれか一項に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、アミノ酸改変L351Y及びY407Aを含む第1のCH3ドメインポリペプチド並びにアミノ酸改変T366A及びK409Fを含む第2のCH3ドメインポリペプチドを含む、上記単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチド又は第2のCH3ドメインポリペプチドが、T411、D399、S400、F405、N390、又はK392位にさらなるアミノ酸改変を含む、請求項50に記載の単離ヘテロ多量体。
- T411位のアミノ酸改変が、T411N、T411R、T411Q、T411K、T411D、T411E、又はT411Wから選択される、請求項51に記載の単離ヘテロ多量体。
- D399位のアミノ酸改変が、D399R、D399W、D399Y、又はD399Kから選択される、請求項51に記載の単離ヘテロ多量体。
- S400位のアミノ酸改変が、S400E、S400D、S400R、又はS400Kから選択される、請求項51に記載の単離ヘテロ多量体。
- F405位のアミノ酸改変が、F405I、F405M、F405T、F405S、F405V、又はF405Wから選択される、請求項51に記載の単離ヘテロ多量体。
- N390位のアミノ酸改変が、N390R、N390K、又はN390Dから選択される、請求項51に記載の単離ヘテロ多量体。
- K392位のアミノ酸改変が、K392V、K392M、K392R、K392L、K392F、又はK392Eから選択される、請求項51に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、アミノ酸改変L351Y及びY407Aを含む第1のCH3ドメインポリペプチド並びにアミノ酸改変T366V及びK409Fを含む第2のCH3ドメインポリペプチドを含む、上記単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、アミノ酸改変Y407Aを含む第1のCH3ドメインポリペプチド並びにアミノ酸改変T366A及びK409Fを含む第2のCH3ドメインポリペプチドを含む、上記単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチド又は第2のCH3ドメインポリペプチドが、さらなるアミノ酸改変K392E、T411E、D399R、及びS400Rを含む、請求項59に記載の単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチドが、アミノ酸改変D399R、S400R、及びY407Aを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366A、K409F、K392E、及びT411Eを含む、請求項59に記載の単離ヘテロ多量体。
- 変異体CH3ドメインが、約74℃以上の融解温度(Tm)を有し、ヘテロ二量体が、約95%以上の純度を有する、請求項59から61までのいずれか一項に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、L351位のアミノ酸改変及びアミノ酸改変Y407Aを含む第1のCH3ドメインポリペプチドを含み、第2のCH3ドメインポリペプチドが、T366位のアミノ酸改変及びアミノ酸改変K409Fを含む、上記単離ヘテロ多量体。
- L351位のアミノ酸改変が、L351Y、L351I、L351D、L351R、又はL351Fから選択される、請求項63に記載の単離ヘテロ多量体。
- Y407位のアミノ酸改変が、Y407A、Y407V、又はY407Sから選択される、請求項63に記載の単離ヘテロ多量体。
- T366位のアミノ酸改変が、T366A、T366I、T366L、T366M、T366Y、T366S、T366C、T366V、又はT366Wから選択される、請求項63に記載の単離ヘテロ多量体。
- 変異体CH3ドメインが、約75℃以上の融解温度(Tm)を有し、ヘテロ二量体が、約90%以上の純度を有する、請求項63から66までのいずれか一項に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、F405位のアミノ酸改変並びにアミノ酸改変L351Y及びY407Vを含む第1のCH3ドメインポリペプチドを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T394Wを含む、上記単離ヘテロ多量体。
- 第1のCH3ドメインポリペプチド又は第2のCH3ドメインポリペプチドが、K392、T411、T366、L368、又はS400位にアミノ酸改変を含む、請求項68に記載の単離ヘテロ多量体。
- F405位のアミノ酸改変が、F405A、F405I、F405M、F405T、F405S、F405V、又はF405Wである、請求項68に記載の単離ヘテロ多量体。
- K392位のアミノ酸改変が、K392V、K392M、K392R、K392L、K392F、又はK392Eである、請求項69に記載の単離ヘテロ多量体。
- T411位のアミノ酸改変が、T411N、T411R、T411Q、T411K、T411D、T411E、又はT411Wである、請求項69に記載の単離ヘテロ多量体。
- S400位のアミノ酸改変が、S400E、S400D、S400R、又はS400Kである、請求項69に記載の単離ヘテロ多量体。
- T366位のアミノ酸改変が、T366A、T366I、T366L、T366M、T366Y、T366S、T366C、T366V、又はT366Wである、請求項69に記載の単離ヘテロ多量体。
- L368位のアミノ酸改変が、L368D、L368R、L368T、L368M、L368V、L368F、L368S、及びL368Aである、請求項69に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、アミノ酸改変L351Y、F405A、及びY407Vを含む第1のCH3ドメインポリペプチドを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T394Wを含む、上記単離ヘテロ多量体。
- 第2のCH3ドメインポリペプチドが、アミノ酸改変T366L又はT366Iを含む、請求項76に記載の単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、アミノ酸改変F405A及びY407Vを含む第1のCH3ドメインポリペプチドを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366I、K392M、及びT394Wを含む、上記単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、アミノ酸改変F405A及びY407Vを含む第1のCH3ドメインポリペプチドを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366L、K392M、及びT394Wを含む、上記単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、アミノ酸改変F405A及びY407Vを含む第1のCH3ドメインポリペプチドを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366L及びT394Wを含む、上記単離ヘテロ多量体。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、アミノ酸改変F405A及びY407Vを含む第1のCH3ドメインポリペプチドを含み、第2のCH3ドメインポリペプチドが、アミノ酸改変T366I及びT394Wを含む、上記単離ヘテロ多量体。
- 二重特異性抗体である、請求項1から3まで、50、58、59、63、68、76、78、79、80、又は81のいずれか一項に記載のヘテロ多量体。
- 多重特異性抗体である、請求項1から3まで、50、58、59、63、68、76、78、79、80、又は81のいずれか一項に記載のヘテロ多量体。
- 請求項1から3まで、50、58、59、63、68、76、78、79、80、又は81のいずれか一項に記載のヘテロ多量体並びに薬学的に許容される担体を含む組成物。
- 請求項1から3まで、50、58、59、63、68、76、78、79、80、又は81のいずれか一項に記載のヘテロ多量体をコードする核酸を含む宿主細胞。
- 少なくとも1つの治療用抗体を含む、請求項1から3まで、50、58、59、63、68、76、78、79、80、又は81のいずれか一項に記載の単離ヘテロ多量体。
- アバゴボマブ(abagovomab)、アダリムマブ、アレムツズマブ、アウログラブ(aurograb)、バピネオズマブ、バシリキシマブ、ベリムバブ(belimumab)、ベバシズマブ、ブリアキヌマブ(briakinumab)、カナキヌマブ(canakinumab)、カツマキソマブ、セルトリズマブペゴール、セツキシマブ、ダクリズマブ、デノスマブ、エファリズマブ、ガリキシマブ、ゲムツズマブオゾガマイシン、ゴリムマブ、イブリツモマブチウキセタン、インフリキシマブ、イピリムマブ、ルミリキシマブ、メポリズマブ、モタビズマブ(motavizumab)、ムロモナブ、ミコグラブ(mycograb)、ナタリズマブ、ニモツズマブ、オクレリズマブ、オファツムマブ、オマリズマブ、パリビズマブ、パニツムマブ、ペルツズマブ、ラニビズマブ、レスリズマブ(reslizumab)、リツキシマブ、テプリズマブ(teplizumab)、トシリズマブ/アトリズマブ、トシツモマブ、トラスツズマブ、Proxinium(商標)、Rencarex(商標)、ウステキヌマブ、及びザルツムマブからなる群から選択される少なくとも1つの治療用抗体を含む、請求項1に記載の単離ヘテロ多量体。
- 癌抗原によって特徴付けられる癌を有する患者における癌を治療する方法であって、治療有効量の請求項86に記載のヘテロ多量体を前記患者に投与することを含む、上記方法。
- 免疫抗原によって特徴付けられる免疫障害を有する患者における免疫障害を治療する方法であって、治療有効量の請求項86に記載のヘテロ多量体を前記患者に投与することを含む、上記方法。
- ヘテロ二量体Fc領域を含む単離ヘテロ多量体であって、ヘテロ二量体Fc領域が、増加した安定性が増大したヘテロ二量体形成を促進するアミノ酸突然変異を含む変異体CH3ドメインを含み、変異体CH3ドメインが、表1、表6、又は表7において列挙される変異体から選択される、上記単離ヘテロ多量体。
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