JP5926791B2 - 抗体Fc変種 - Google Patents
抗体Fc変種 Download PDFInfo
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- JP5926791B2 JP5926791B2 JP2014501573A JP2014501573A JP5926791B2 JP 5926791 B2 JP5926791 B2 JP 5926791B2 JP 2014501573 A JP2014501573 A JP 2014501573A JP 2014501573 A JP2014501573 A JP 2014501573A JP 5926791 B2 JP5926791 B2 JP 5926791B2
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Description
本発明は、Fc領域の変種を含むポリペプチドに関する。より具体的には、本発明は、ポリペプチドのFc領域における1つまたは複数のアミノ酸置換の結果としてエフェクター機能が変化した、Fc領域を含むポリペプチドに関する。
モノクローナル抗体は、大きな潜在的治療能力を有し、今日の医療ポートフォリオ(portfolio)において重要な役割を果たしている。この10年の間、製薬業界における重要な動向は、癌、喘息、関節炎、多発性硬化症などのいくつかの疾患を治療するための治療物質としてモノクローナル抗体(mAb)を開発することであった。モノクローナル抗体は、遺伝子操作された哺乳動物細胞の培養において組換えタンパク質として主に製造される。
本発明は、抗体変種の分野に関し、ADCCおよび/またはC1q結合の減少のようにエフェクター機能が低下したFc変種を含むポリペプチドを提供する。
[本発明1001]
野生型ヒトIgG Fc領域のFc変種を含むポリペプチドであって、
該Fc変種がPro329の位置のアミノ酸置換および少なくとも1つのさらなるアミノ酸置換を含み、残基がKabatのEU指標に従って番号付けられており、かつ前記ポリペプチドが、野生型IgG Fc領域を含むポリペプチドと比べて、ヒトFcγRIIIAおよび/またはヒトFcγRIIAおよび/またはヒトFcγRIに対して低い親和性を示し、かつ前記ポリペプチドによって誘導されるADCCが、野生型ヒトIgG Fc領域を含むポリペプチドによって誘導されるADCCの20%以下にまで低減する、
前記ポリペプチド。
[本発明1002]
野生型ヒトFc領域のPro329が、グリシンもしくはアルギニン、またはFc/Fcγ受容体境界面内のプロリンサンドイッチを消失させるのに十分な大きさのアミノ酸残基で置換されている、本発明1001のポリペプチド。
[本発明1003]
少なくとも1つのさらなるアミノ酸置換がS228P、E233P、L234A、L235A、L235E、N297A、N297D、またはP331Sである、本発明1001または1002のポリペプチド。
[本発明1004]
少なくとも1つのさらなるアミノ酸置換が、ヒトIgG1 Fc領域のL234AおよびL235AまたはヒトIgG4 Fc領域のS228PおよびL235Eである、本発明1001〜1003のいずれかのポリペプチド。
[本発明1005]
ヒト受容体FcγI、FcγIIA、およびC1qを含む群のうちの少なくとも1つのさらなる受容体に対する親和性が、野生型ヒトIgG Fc領域を含むポリペプチドと比べて低い、本発明1001〜1004のいずれかのポリペプチド。
[本発明1006]
ヒトIgG1 Fc領域またはヒトIgG4 Fc領域を含む、本発明1001〜1005のいずれかのポリペプチド。
[本発明1007]
抗体またはFc融合タンパク質である、本発明1001〜1006のいずれかのポリペプチド。
[本発明1008]
以下である、本発明1001〜1007のいずれかのポリペプチド:
該ポリペプチドによって誘導される栓球凝集が、野生型ヒトIgG Fc領域を含むポリペプチドによって誘導される栓球凝集と比べて低減する。
[本発明1009]
以下である、本発明1001〜1008のいずれかのポリペプチド:
該ポリペプチドによって誘導されるCDCが、野生型ヒトIgG Fc領域を含むポリペプチドによって誘導されるCDCと比べて大きく低減する。
[本発明1010]
医薬として使用するための、本発明1001〜1009のいずれかのポリペプチド。
[本発明1011]
野生型Fc領域を含むポリペプチドに重鎖可変領域としてSEQ ID NO: 9および可変軽鎖領域としてSEQ ID NO: 8が含まれることを特徴とする抗CD9抗体である、本発明1001〜1010のいずれかのポリペプチド。
[本発明1012]
ポリペプチドのエフェクター機能が、野生型ヒトIgG Fc領域を含むポリペプチドによって誘導されるエフェクター機能と比べて大きく低減していることが望まれる疾患を治療する際に使用するための、本発明1001〜1011のいずれかのポリペプチド。
[本発明1013]
野生型ヒトIgG Fc領域のFc変種を含むポリペプチドのエフェクター機能が、野生型ヒトIgG Fc領域を含むポリペプチドによって誘導されるエフェクター機能と比べて大きく低減していることが望まれる疾患を治療するための医薬を製造する際の、本発明1001〜1012のいずれかのポリペプチドの使用。
[本発明1014]
野生型ヒトIgG Fc領域のFc変種を含むポリペプチドのエフェクター機能が、野生型ヒトFcポリペプチドを含むポリペプチドによって誘導されるエフェクター機能と比べて大きく低減していることが望まれる疾患を有する個体を治療する方法であって、本発明1001〜1012のいずれかのポリペプチドの有効量を個体に投与する段階を含む前記方法。
[本発明1015]
野生型ヒトIgG Fc領域を含むポリペプチドによって誘導されるADCCの20%以下にまでADCCを下方調整するための、および/またはADCPを下方調整するための、野生型ヒトIgG Fc領域のFc変種を含むポリペプチドの使用であって、
該ポリペプチドにおいて、ヒトIgG Fc領域のPro329がグリシンで置換されており、残基がKabatのEU指標に従って番号付けられており、該ポリペプチドが、ヒトFcγRIIIAおよびヒトFcγRIIAに対して低い親和性を示す、
前記ポリペプチドの使用。
[本発明1016]
Fc変種がヒトIgG1 Fc領域のL234AおよびL235AまたはヒトIgG4 Fc領域のS228PおよびL235Eに少なくとも2つのさらなるアミノ酸置換を含む、本発明1015のポリペプチドの使用。
[本発明1017]
前記ポリペプチドによって誘導される栓球凝集が、野生型ヒトFc領域を含み血小板活性化抗体であるポリペプチドによって誘導される栓球凝集と比べて低減する、本発明1015または1016の使用。
[本発明1018]
有効量のポリペプチドを個体に投与する段階を含む、疾患を有する個体をポリペプチドで治療する方法であって、
該ポリペプチドにおいて、ヒトIgG Fc領域のPro329がGlyで置換されており、残基がKabatのEU指標に従って番号付けられており、該ポリペプチドが、野生型ヒトIgG Fc領域を含むポリペプチドと比べてFcγRIIIAおよびFcγRIIAへの結合が大きく低減していることを特徴とする、
前記方法。
[本発明1019]
前記ポリペプチドが、ヒトIgG1 Fc領域のL234AおよびL235AまたはヒトIgG4 Fc領域のS228PおよびL235Eに少なくとも2つのさらなるアミノ酸置換を含む、本発明1018の方法。
定義
本発明の明細書および特許請求の範囲において、免疫グロブリン重鎖中の残基の番号付与は、参照により本明細書に明確に組み入れられるKabat, et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)で示されているようなEU指標のものである。「KabatによるEU指標」とは、ヒトIgG1 EU抗体の残基への番号付与を意味する。
本明細書において、本発明は、Fc変種を含むポリペプチドを作製するための方法に関する。「親」、「出発」、「非変種」、または野生型のポリペプチドは、Fc領域を含むポリペプチドまたは抗体を作製するための当技術分野において利用可能な技術を用いて調製される。本発明の好ましい態様において、親ポリペプチドは抗体であり、抗体を作製するための例示的な方法は、以下のセクションでより詳細に説明する。しかしながら、親ポリペプチドは、Fc領域を含む他の任意のポリペプチド、例えばイムノアドヘシンでよい。イムノアドヘシンを作製するための方法は、本明細書において下記により詳細に述べる。
当業者は、本発明の抗体が、(未改変抗体と比べて)変化したFcγR結合特性および/またはC1q結合特性(結合特性の例には、結合特異性、平衡解離定数(KD)、解離速度および結合速度(それぞれkoffおよびkon)、結合親和性、および/または結合活性が含まれるがそれらに限定されるわけではない)を有し得ること、ならびに特定の変化がより望ましいか、または望ましくないことを理解するであろう。平衡解離定数(KD)が、koff/konと定義されることは、当技術分野において公知である。当業者は、どの動態パラメータが、所与の抗体用途にとって最も重要であるかを特定することができる。例えば、1つもしくは複数の正の調節因子(例えばFcγRIIIA)への結合を低減する、かつ/または抑制性Fc受容体(例えばFcγRIIB)への結合を増大する改変が、ADCC活性を低減させるのに適切であると考えられる。したがって、結合親和性の比(例えば平衡解離定数(KD))は、本発明の抗体のADCC活性が上昇しているか、または低下しているかを示唆することができる。さらに、C1qへの結合を低減させる改変は、CDC活性を低減するか、またはなくすのに適していると考えられる。リガンドに対するFc領域の親和性および結合特性は、Fc-FcγR相互作用、すなわち、FcγRに対するFc領域の特異的結合を測定するための当技術分野において公知の様々なインビトロアッセイ法(生化学または免疫学に基づくアッセイ法)(限定されるわけではないが、平衡法(例えば、酵素結合免疫吸着測定法(ELISA)もしくはラジオイムノアッセイ法(RIA))、または動態(例えば、BIACORE(登録商標)解析を含む)、ならびに他の方法、例えば、間接的結合アッセイ法、競合阻害アッセイ法、蛍光共鳴エネルギー転移(FRET)、ゲル電気泳動、およびクロマトグラフィー(例えばゲルろ過)によって測定することができる。これらの方法および他の方法は、検査される1種もしくは複数種の構成要素に関する標識を利用することができ、かつ/または発色性標識、蛍光標識、発光標識、もしくは同位元素標識を非限定的に含む様々な検出方法を使用することができる。結合親和性および動態に関する詳細な説明は、Paul, W.E., ed., Fundamental Immunology, 4th Ed., Lippincott-Raven, Philadelphia (1999)において確認することができる。
発明の一定の局面において、本発明によるFc変種を含むポリペプチドは、野生型Fcポリペプチドを含むポリペプチドと比べて、エフェクター機能を調節する。
インビトロおよび/またはインビボの細胞障害性アッセイ法を行って、CDC活性および/またはADCC活性の低減/減少を確認することができる。例えば、Fc受容体(FcR)結合アッセイ法を行って、抗体はFcγR結合を欠く(したがって、ADCC活性を欠く可能性が高い)がFcRn結合能を保持していることを確実にすることができる。ADCCを媒介する主な細胞であるNK細胞は、FcγRIIIのみを発現するが、単球は、FcγRI、FcγRII、およびFcγRIIIを発現する。造血細胞におけるFcR発現は、Ravetch, and Kinet, Annu. Rev. Immunol 9 (1991) 457-492の464頁の表3に要約されている。関心対象の分子のADCC 活性を評価するためのインビトロのアッセイ法の非限定的な例は、米国特許第5,500,362号(例えば、Hellstrom, I., et al., Proc. Nat'l Acad. Sci.USA 83 (1986) 7059-7063を参照されたい)およびHellstrom, I., et al., Proc. Nat'l Acad. Sci. USA 82 (1985) 1499-1502; US 5,821,337 (Bruggemann, M., et al., J. Exp. Med. 166 (1987) 1351-1361を参照されたい)において説明されている。あるいは、非放射性アッセイ方法を使用してもよい(例えば、フローサイトメトリー用のACTI(商標)非放射性細胞障害性アッセイ法(CellTechnology, Inc. Mountain View, CA);およびCytoTox 96(登録商標)非放射性細胞障害性アッセイ法(Promega, Madison, WI)を参照されたい)。このようなアッセイ法に有用なエフェクター細胞には、末梢血単核細胞(PBMC)およびナチュラルキラー(NK)細胞が含まれる。あるいは、またはさらに、関心対象の分子のADCC活性は、インビボで、例えば、Clynes, et al., Proc. Nat'l Acad. Sci. USA 95 (1998) 652-656で開示されているもののような動物モデルにおいて評価してもよい。また、C1q結合アッセイ法を実施して、抗体はC1qに結合することができず、したがって、CDC活性を欠くことを確認することもできる。例えば、WO 2006/029879およびWO 2005/100402におけるC1qおよびC3c結合ELISAを参照されたい。補体活性化を評価するために、CDCアッセイ法を実施してもよい(例えば、Gazzano-Santoro, et al., J. Immunol. Methods 202 (1996) 163; Cragg, M.S., et al., Blood 101 (2003) 1045-1052;およびCragg, M.S., and Glennie, M.J., Blood 103 (2004) 2738-2743を参照されたい)。FcRn結合およびインビボのクリアランス/半減期の測定はまた、当技術分野において公知の方法を用いて実施することもできる(例えば、Petkova, S.B., et al., Int'l. Immunol. 18(12) (2006) 1759-1769を参照されたい)。
補体活性化経路は、補体系の第1成分(C1q)が分子、例えば、同族抗原と複合体を形成した抗体に結合することによって開始される。補体活性化を評価するために、例えばGazzano-Santoro, et al, J. Immunol. Methods 202 (1996) 163において説明されているようなCDCアッセイ法を実施することができる。
生物学的療法には、望まれない細胞および/または標的を認識し攻撃するように免疫系に指示する複雑な性質に関連した有害な毒性の問題があり得ることが当技術分野において理解されている。認識および/または攻撃のためのターゲティングが、治療が必要とされる場所で起こらない場合、有害な毒性のような結果が生じ得る。例えば、非標的組織の抗体染色は、潜在的毒性という問題を示唆し得る。
本発明の1つの局面において、野生型ポリペプチドは、血小板活性化および/または血小板凝集を誘導し、その変種、すなわち、Fc変種を含むポリペプチドは、栓球活性化および/または栓球凝集の減少またはさらには消失さえも示す。本発明のさらに別の局面において、これらの野生型ポリペプチドは、血小板タンパク質を標的とする抗体である。さらに別の局面において、抗体はCD9抗体である。さらに別の態様において、このCD9抗体は、P329Gの位置および/またはL234A/L235AもしくはS228P/L235Eの位置に変異を有する(P329G/LALA、P329G/SPLE)。別の特定の態様において、抗体は、SEQ ID NO: 8〜14によって特徴付けられる。
本発明の変種は、内部移行して、さらに抗体を細胞中に運び得る細胞表面抗原に結合することができる。細胞内部に入った後、変種は、細胞質中に放出されるか、特定の区画に導かれるか、または細胞表面で再利用され得る。いくつかの態様において、本発明の変種は、内部移行する細胞表面抗原に結合する。他の態様において、本発明の抗体は、細胞の特定の細胞小器官または区画を標的とし得る。さらに別の態様において、本発明の変種は、内部移行後に細胞表面または末梢で再利用され得る。
本発明の好ましい態様において、本明細書の教示に従って改変される、Fc領域を含むポリペプチドは、抗体である。抗体を作製するための技術は下記のとおりである。
ポリペプチドが抗体である場合、それは、関心対象の抗原を対象とする。好ましくは、抗原は、生物学的に重要なポリペプチドであり、疾患または障害を患っている哺乳動物に抗体を投与すると、その哺乳動物に治療的利益が生じ得る。しかしながら、非ポリペプチド抗原(例えば、腫瘍関連糖脂質抗原;米国特許第5,091,178号を参照されたい)を対象とする抗体もまた、企図される。
好ましくは、ポリクローナル抗体は、関連する抗原およびアジュバントを複数回皮下(sc)注射または腹腔内(ip)注射することによって、動物において産生させる。二官能性物質または誘導体化物質、例えば、マレイミドベンゾイルスルホスクシンイミドエステル(システイン残基を介した結合)、N-ヒドロキシスクシンイミド(リジン残基を介する)、グルタルアルデヒド、無水コハク酸、SOCl2、またはカルボジイミド(RおよびR1が異なるアルキル基である)を用いて、免疫化しようとする種において免疫原性であるタンパク質、例えば、キーホールリンペットヘモシアニン、血清アルブミン、ウシチログロブリン、またはダイズトリプシンインヒビターに、関連する抗原を結合させることが有用である場合がある。
モノクローナル抗体は、Kohler, et al., Nature, 256 (1975) 495によって最初に説明されたハイブリドーマ法を用いて作製することができ、または組換えDNA法(米国特許第4,816,567号)によって作製することができる。
一定の態様において、本明細書において提供される抗体の解離定数(Kd)は、1μM以下、100nM以下、10nM以下、1nM以下、0.1nM以下、0.01nM以下、または0.001nM以下(例えば、10-8Mまたはそれ以下、例えば10-8M〜10-13M、例えば10-9M〜10-13M)である。
一定の態様において、本明細書において提供される抗体は、キメラ抗体である。いくつかのキメラ抗体が、例えば、米国特許第4,816,567号;およびMorrison, et al., Proc. Natl. Acad. Sci. USA, 81 (1984) 6851-6855において説明されている。1つの例において、キメラ抗体は、非ヒト可変領域(例えば、マウス、ラット、ハムスター、ウサギ、またはヒト以外の霊長類、例えばサルに由来する可変領域)およびヒト定常領域を含む。別の例において、キメラ抗体は、クラスまたはサブクラスが親抗体のものから変更された、「クラススイッチされた」抗体である。キメラ抗体には、その抗原結合断片が含まれる。
一定の態様において、本明細書において提供される抗体は、ヒト抗体である。ヒト抗体は、当技術分野において公知の様々な技術を用いて作製することができる。ヒト抗体は、van Dijk, and van de Winkel, Curr. Opin. Pharmacol. 5 (2001) 368-74およびLonberg, Curr. Opin. Immunol. 20 (2008) 450-459において一般的に説明されている。
本発明の抗体は、所望の1種または複数種の活性を有する抗体を求めてコンビナトリアルライブラリーをスクリーニングすることによって、単離することができる。例えば、ファージディスプレイライブラリーを作製し、所望の結合特徴を有する抗体を求めてそのようなライブラリーをスクリーニングするための様々な方法が、当技術分野において公知であるこのような方法は、例えば、Hoogenboom, H.R., et al., in Methods in Molecular Biology 178 (2002) 1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001)において概説されており、例えば、McCafferty, J., et al., Nature 348 (1990) 552-554; Clackson, et al., Nature 352 (1991) 624-628; Marks, et al., J. Mol. Biol. 222 (1992) 581-597; Marks, and Bradbury, in Methods in Molecular Biology 248 161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu, et al., J. Mol. Biol. 338(2) (2004) 299-310; Lee, et al., J. Mol. Biol. 340(5) (2004) 1073-1093; Fellouse, Proc. Natl. Acad. Sci. USA 101(34) (2004) 12467-12472;およびLee, et al., J. Immunol. Methods 284(1-2) (2004) 119-132においてさらに説明されている。
一定の態様において、本明細書において提供される抗体は、多重特異性抗体、例えば二重特異性抗体である。多重特異性抗体は、少なくとも2つの異なる部位に対する結合特異性を有するモノクローナル抗体である。一定の態様において、結合特異性のうちの1つは、ある特異的抗原に対するものであり、他は、他の任意の抗原に対するものである。一定の態様において、二重特異性抗体は、抗原の2つの異なるエピトープに結合し得る。また、二重特異性抗体は、抗体が結合する抗原を発現する細胞に細胞障害性物質を局在化させるのにも使用され得る。二重特異性抗体は、完全長抗体または抗体断片として調製することができる。
一定の態様において、抗体の抗原への結合親和性および/または他の生物学的特性を改善することが望ましい場合がある。抗体のアミノ酸配列変種は、抗体をコードするヌクレオチド配列に適切な改変を導入することによって、またはペプチド合成によって、調製することができる。このような改変には、例えば、抗体のアミノ酸配列内の残基からの欠失、ならびに/または残基中への挿入、および/もしくは残基の置換が含まれる。最終構築物が所望の特徴、例えば、抗原結合を示すことを条件として、欠失、挿入、および置換の任意の組合せを行って、最終構築物に到達することができる。
一定の態様において、Fc部分以外の部分に1つまたは複数のアミノ酸置換をさらに有する、Fc変種を含むポリペプチドが、提供される。対象となる置換変異誘発部位には、HVRおよびFRが含まれる。保存的置換は、表1の「保存的置換」という項目の下に示す。より実質的な変更は、表1の「例示的置換」という項目の下に提供し、アミノ酸側鎖のクラスに関してさらに後述する。アミノ酸置換を関心対象の抗体に導入し、その作製物を所望の活性、例えば、保持された/向上した抗原結合、または低下した免疫原性についてスクリーニングすることができる。
(1)疎水性:Ile、Met、Ala、Val、Leu、Ile;
(2)中性で親水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)塩基性:His、Lys、Arg;
(5)鎖の向きに影響する残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe。
一定の態様において、本明細書において提供される抗体は、抗体がグリコシル化される程度を大きくするか、または小さくするように変化させられる。抗体へのグリコシル化部位の付加または欠失は、1つまたは複数のグリコシル化部位が作り出されるかまたは取り除かれるようにアミノ酸配列を変化させることによって、簡便に達成することができる。
一定の態様において、システインで操作された抗体、例えば、抗体の1つまたは複数の残基がシステイン残基で置換されている「チオMAb」を作り出すことが望ましい場合がある。特定の態様において、置換される残基は、抗体の接近可能な部位に存在する。それらの残基をシステインで置換することにより、反応性チオール基が、その結果、抗体の接近可能な部位に位置づけられ、本明細書においてさらに説明するように、薬物部分またはリンカー-薬物部分などの他の部分に抗体を結合させて免疫結合体を作り出すために使用され得る。一定の態様において、次の残基の任意の1つまたは複数をシステインで置換してよい:軽鎖のV205(Kabatの番号付与);重鎖のA118(EU番号付与);および重鎖Fc領域のS400(EU番号付与)。システインで操作された抗体は、例えば、米国特許第7,521,541号において説明されているようにして作製することができる。
一定の態様において、本明細書において提供される抗体は、当技術分野において公知であり、容易に入手可能である付加的な非タンパク性部分を含むようにさらに改変され得る。抗体の誘導体化に適した部分には、水溶性ポリマーが含まれるがそれに限定されるわけではない。水溶性ポリマーの非限定的な例には、ポリエチレングリコール(PEG)、エチレングリコール/プロピレングリコールの共重合体、カルボキシメチルセルロース、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリ-1,3-ジオキソラン、ポリ-1,3,6-トリオキサン、エチレン/無水マレイン酸共重合体、ポリアミノ酸(ホモポリマーまたはランダム共重合体のいずれか)、およびデキストランまたはポリ(n-ビニルピロリドン)ポリエチレングリコール、プロプロピレン(propropylene)グリコールホモポリマー、プロリプロピレン(prolypropylene)オキシド/エチレンオキシド共重合体、ポリオキシエチル化ポリオール(例えばグリセロール)、ポリビニルアルコール、ならびにそれらの混合物が含まれるが、それらに限定されるわけではない。ポリエチレングリコールプロピオンアルデヒドは、水中で安定であるため、製造の際に有利であり得る。ポリマーは、任意の分子量のものでよく、分枝状または非分枝状でよい。抗体に結合されるポリマーの数は変動してよく、複数のポリマーが結合される場合、それらは同じ分子または異なる分子でよい。通常、誘導体化のために使用されるポリマーの数および/またはタイプは、限定されるわけではないが、改善しようとする抗体の特定の特性または機能、その抗体誘導体が所定の条件下で治療法において使用されるかなどを含む考慮すべき事柄に基づいて決定することができる。
抗体は、例えば、米国特許第4,816,567号において説明されているようにして、組換え法および組換え組成物を用いて作製することができる。1つの態様において、本明細書において説明する抗体変種をコードする単離された核酸が提供される。このような核酸は、抗体のVLを含むアミノ酸配列および/またはVHを含むアミノ酸配列(例えば、抗体の軽鎖および/または重鎖)をコードし得る。さらなる態様において、このような核酸を含む1つまたは複数のベクター(例えば発現ベクター)が提供される。さらなる態様において、このような核酸を含む宿主細胞が提供される。1つのこのような態様において、宿主細胞は、(1)抗体のVLを含むアミノ酸配列および抗体のVHを含むアミノ酸配列をコードする核酸を含むベクター、または(2)抗体のVLを含むアミノ酸配列をコードする核酸を含む第1のベクターおよび抗体のVHを含むアミノ酸配列をコードする核酸を含む第2のベクターを含む(例えば、それらで形質転換されている)。1つの態様において、宿主細胞は、真核生物性、例えばチャイニーズハムスター卵巣(CHO)細胞またはリンパ系細胞(例えば、Y0細胞、NS0細胞、Sp20細胞)である。1つの態様において、抗体変種を作製する方法が提供され、この方法は、抗体の発現に適した条件下で、上記に提供されるような抗体をコードする核酸を含む宿主細胞を培養する段階、および任意で、宿主細胞(または宿主細胞培地)から抗体を回収する段階を含む。
本明細書において提供される抗体は、当技術分野において公知の様々なアッセイ法によって、同定し、物理的/化学的特性および/または生物学的活性についてスクリーニングし、またはそれらに関して特徴付けることができる。
1つの局面において、例えば、ELISA、ウェスタンブロットなどの公知の方法によって、本発明の抗体の抗原結合活性を試験する。
本発明はまた、1種または複数種の細胞障害性物質、例えば、化学療法剤または化学療法薬、増殖抑制剤、毒素(例えば、タンパク毒素、細菌、真菌、植物、もしくは動物に由来する酵素的に活性な毒素、またはそれらの断片)、または放射性同位元素に結合された本明細書の抗体を含む免疫結合体も提供する。
一定の態様において、本明細書において提供される抗体変種のいずれかは、生物試料においてその抗体に結合する抗原の存在を検出するのに有用である。本明細書において使用される「検出する」という用語は、定量的検出または定性的検出を包含する。一定の態様において、生物試料は、細胞または組織を含む。
本明細書において説明する抗体変種の薬学的製剤は、所望の程度の純度を有するそのような抗体を1種または複数種の任意の薬学的に許容される担体(Remington's Pharmaceutical Sciences 16th edition, Osol, A.Ed.(1980))と混合することによって、凍結乾燥製剤または水性液剤の形態で調製される。通常、薬学的に許容される担体は、使用される投与量および濃度において受容者に非毒性であり、限定されるわけではないが、次のものが含まれる:リン酸、クエン酸、および他の有機酸などの緩衝剤;アスコルビン酸およびメチオニンを含む抗酸化剤;保存剤(オクタデシルジメチルベンジルアンモニウムクロリド;塩化ヘキサメトニウム;塩化ベンザルコニウム;塩化ベンゼトニウム;フェノール、ブチルアルコールもしくはベンジルアルコール;メチルパラベンもしくはプロピルパラベンなどのアルキルパラベン;カテコール;レソルシノール;シクロヘキサノール;3-ペンタノール;およびm-クレゾールなど);低分子量(約10残基未満の)ポリペプチド;血清アルブミン、ゼラチン、もしくは免疫グロブリンなどのタンパク質;ポリビニルピロリドンのような親水性ポリマー;グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン、もしくはリジンなどのアミノ酸;単糖類、二糖類、および他の炭水化物(グルコース、マンノース、もしくはデキストリンを含む);EDTAのようなキレート剤;スクロース、ショ糖、マンニトール、トレハロース、もしくはソルビトールなどの糖;ナトリウムのような塩を形成する対イオン;金属複合体(例えばZn-タンパク質複合体);ならびに/またはポリエチレングリコール(PEG)のような非イオン系界面活性剤。本明細書における例示的な薬学的に許容される担体には、さらに、可溶性の中性活性ヒアルロニダーゼ糖タンパク質(sHASEGP)のような間質(insterstitial)薬物分散剤、例えば、rHuPH20(HYLENEX(登録商標), Baxter International, Inc.)のようなヒト可溶性PH-20ヒアルロニダーゼ糖タンパク質が含まれる。rHuPH20を含む、いくつかの例示的なsHASEGPおよび使用方法は、米国特許公報第2005/0260186号および同第2006/0104968号において説明されている。1つの局面において、sHASEGPは、コンドロイチナーゼのような1種または複数種の追加のグリコサミノグリカナーゼと組み合わせられる。
本明細書において提供されるポリペプチドのいずれかを治療方法で使用することができる。
本発明の別の局面において、前述の障害の治療、予防、および/または診断に有用な材料を含む製品が提供される。製品は、容器、および容器の上または容器に伴うラベルまたは添付文書を含む。適切な容器には、例えば、瓶、バイアル、シリンジ、IV溶液バッグなどが含まれる。容器は、ガラスまたはプラスチックなど様々な材料から形成されてよい。容器は、単独であるか、または病態を治療、予防、および/もしくは診断するのに有効な別の組成物と組み合わせられた組成物を含み、無菌取出口を有してよい(例えば、容器は、皮下注射針によって突き刺すことができる栓を有する静注液バッグまたはバイアルでよい)。組成物中の少なくとも1種の活性物質は、本発明の抗体である。ラベルまたは添付文書は、その組成物が、選ばれた病態を治療するのに使用されることを示す。さらに、製品は、(a)本発明の抗体を含む組成物がその中に含まれる第1の容器;および(b)別の細胞障害性物質またはそうでなければ治療物質を含む組成物がその中に含まれる第2の容器を含んでよい。本発明のこの態様の製品は、それらの組成物を用いて特定の病態を治療できることを示す添付文書をさらに含んでよい。あるいはまたはさらに、製品は、注射用静菌水(BWFI)、リン酸緩衝化生理食塩水、リンガー溶液、およびデキストロース溶液などの薬学的に許容される緩衝液を含む第2の(または第3の)容器をさらに含んでよい。これは、他の緩衝剤、希釈剤、フィルター、針、およびシリンジを含む、商業的観点および使用者の観点から望ましい他の材料もさらに含んでよい。
本発明の抗体変種は、アフィニティー精製剤として使用され得る。このプロセスにおいて、抗体変種は、当技術分野において周知の方法を用いて、Sephadex樹脂またはろ紙などの固相上に固定される。固定されたポリペプチド変種を、精製されるべき抗原を含む試料と接触させ、その後、固定された抗体変種に結合している精製されるべき抗原を除いて試料中の実質的にすべての材料を除去する適切な溶媒で支持体を洗浄する。最後に、ポリペプチド変種から抗原を遊離させるグリシン緩衝液pH5.0のような別の適切な溶媒で、支持体を洗浄する。
(a)35S、14C、125I、3H、および131Iなどのラジオアイソトープ;ポリペプチド変種は、例えば、Coligen, et al., Current Protocols in Immunology, Volumes 1 and 2, Ed.Wiley-Interscience, New York, N.Y., Pubs. (1991)において説明されている技術を用いてラジオアイソトープで標識することができ、放射能は、シンチレーション計数を用いて測定することができる。
(b)希土類キレート(ユーロピウムキレート)またはフルオレセインおよびその誘導体、ローダミンおよびその誘導体、ダンシル、リサミン、フィコエリトリンおよびテキサスレッド(Texas red)などの蛍光性標識が利用可能である。蛍光性標識は、例えば、上記のCurrent Protocols in Immunologyで開示されている技術を用いて、ポリペプチド変種に結合させることができる。蛍光は、蛍光計を用いて定量することができる。
(c)様々な酵素-基質標識が利用可能であり、米国特許第4,275,149号が、これらのうちのいくつかの概要を提供している。一般に、酵素は、様々な技術によって測定することができる発色基質の化学的変化を触媒する。例えば、酵素は、基質の色の変化を触媒する場合があり、この変化を分光光度的に測定することができる。あるいは、酵素は、基質の蛍光または化学発光を変化させる場合もある。蛍光の変化を定量するための技術は前述した。化学発光性基質は、化学反応によって電子的に励起され、次いで、(例えばケミルミノメーター(chemiluminometer)を用いて)測定できる光を発し得るか、または蛍光アクセプターにエネルギーを供与する。酵素標識の例には、ルシフェラーゼ(例えば、ホタルルシフェラーゼおよび細菌ルシフェラーゼ;米国特許第4,737,456号)、ルシフェリン、2,3-ジヒドロフタラジンジオン、リンゴ酸デヒドロゲナーゼ、ウレアーゼ、西洋ワサビペルオキシダーゼ(HRPO)のようなペルオキシダーゼ、アルカリホスファターゼ、β-ガラクトシダーゼ、グルコアミラーゼ、リゾチーム、糖類酸化酵素(例えば、グルコースオキシダーゼ、ガラクトースオキシダーゼ、およびグルコース-6-リン酸デヒドロゲナーゼ)、複素環系酸化酵素(ウリカーゼおよびキサンチンオキシダーゼなど)、ラクトペルオキシダーゼ、ならびにミクロペルオキシダーゼなどが含まれる。酵素を抗体に結合させるための技術は、O'Sullivan, et al., Methods for the Preparation of Enzyme-Antibody Conjugates for use in Enzyme Immunoassay, in Methods in Enzym. (ed J.Langone & H.Van Vunakis), Academic press, New York, 73:147-166 (1981)で説明されている。
(i)西洋ワサビペルオキシダーゼ(HRPO)と基質としての水素ペルオキシダーゼ。水素ペルオキシダーゼは色素前駆体(例えば、オルトフェニレンジアミン(OPD)または3,3',5,5'-テトラメチルベンジジンヒドロクロリド(TMB))を酸化する);
(ii)アルカリホスファターゼ(AP)と発色基質としてのパラ-ニトロフェニルホスファート;および
(iii)β-D-ガラクトシダーゼ(β-D-Gal)と発色基質(例えばp-ニトロフェニル-β-D-ガラクトシダーゼ)または蛍光原基質4-メチルウンベリフェリル-β-D-ガラクトシダーゼ。
SEQ ID NO: 1 ヒトκ軽鎖
SEQ ID NO: 2 ヒトλ軽鎖
SEQ ID NO: 3 ヒトIgG1(コーカサス人アロタイプ)
SEQ ID NO: 4 ヒトIgG1(アフリカ系アメリカ人アロタイプ)
SEQ ID NO: 5 ヒトIgG1 LALA変異体(コーカサス人アロタイプ)
SEQ ID NO: 6 ヒトIgG4
SEQ ID NO: 7 本発明による変種を作製するためのベースとなり得るκ軽鎖、λ軽鎖、IgG1、およびIgG4の例示的なヒト配列を表す、ヒトIgG4 SPLE変異体。
ヒトIgG1アロタイプの配列である配列番号3〜5において、KabatのEU指標に従うP329領域は212位に位置しているのに対し、配列番号6および7の該P329領域は209位に見出すことができる。
SEQ ID NO:8 mAb 40A746.2.3のκ軽鎖
SEQ ID NO:9 mAb 40A746.2.3の野生型IgG1の重鎖
SEQ ID NO:10 mAb 40A746.2.3のIgG1 P329Gの重鎖
SEQ ID NO:11 mAb 40A746.2.3のIgG1 LALA/P329Gの重鎖
SEQ ID NO:12 mAb 40A746.2.3のIgG4 SPLEの重鎖
SEQ ID NO:13 mAb 40A746.2.3のIgG4 SPLE/P329Gの重鎖
SEQ ID NO:14 mAb 40A746.2.3のIgG1 LALAの重鎖
抗体
後述する実験のために、CD9に対する抗体(SEQ ID 8〜14を参照されたい)、P-セレクチンに対する抗体 (WO 2005/100402で説明されている配列)、およびCD20に対する抗体(異名:GA101、EP1692182で説明されている配列)を使用した。
免疫グロブリンに対する様々なFcγ受容体の結合親和性の測定
25℃でBiacore T100機器(GE Healthcare)を用いて、表面プラズモン共鳴(SPR)により、免疫グロブリンに対する様々なFcγRの結合親和性を測定した。
P-セレクチン、CD20抗体、およびCD9抗体のFcポリペプチド中にP329G変異、P329A変異、SPLE変異、およびLALA変異を導入し、Biacoreシステムを用いて、FcγRIに対する結合親和性を測定した。P329G変異を有する抗体は引き続きFcγR1に結合する(図1aおよび図1b)のに対し、三重変異P329G/LALAおよびP329G/SPLEそれぞれの導入の結果、結合がほぼ検出できない抗体が生じた(図1b)。LALA変異またはSPLE変異は、P329Gのみの場合よりも受容体への結合を減少させたが、P329Gと組み合わせた場合よりも減少の程度は低かった(図1aおよび図1b)。したがって、P329GとLALA変異またはSPLE変異いずれかとの組合せの方が、P329G変異または二重変異LALAもしくはSPLEのみよりはるかに効果的である。CD20 IgG1野生型抗体のkd値は4.6nMであり、同じ抗体のP329G変異体のkd値は5.7nMであったが、三重変異体P329G/LALAの場合、FcγRI受容体に対する抗体の結合がほとんど検出不可能であるため、kd値を測定することができなかった。抗体それ自体は、すなわちCD9もしくはCD20またはP-セレクチンを試験したかを問わず、結合親和性には少ししか影響しない。
CD9抗体のFcポリペプチド中にP329G変異、SPLE変異、およびLALA変異をそれぞれ導入し、Biacoreシステムを用いて、FcγRIIA-R131受容体に対する結合親和性を測定した。捕捉されたmAbが100RUに相当するように、結合レベルを標準化する。したがって、1:1化学量論の場合、約20RU以下が予想される。図1cは、Fc変種にLALA変異、SPLE/P329G変異、P329G変異、およびLALA/P329G変異を導入することによって、FcγRIIA受容体に対する結合が大きく低減することを示す。FcγR1受容体への結合とは対照的に、P329G変異のみの導入により、該受容体への結合を極めて強く、三重変異P329G/LALAとほとんど同じ程度まで、妨害することができる(図1c)。
CD9抗体およびP-セレクチン抗体のFcポリペプチド中にSPLE変異、LALA変異、SPLE/P329G変異、およびLALA/P329G変異をそれぞれ導入し、Biacoreシステムを用いて、FcγRIIB受容体に対する結合親和性を測定した。図1dは、LALA変異体および三重変異体P329G/LALA、P329G/SPLEにおいて、FcγRIIB受容体に対する結合が大きく低減していることを示す。
CD9のFcポリペプチド中にP329G変異、LALA変異、SPLE変異、P329G/LALA変異、およびSPLE/P329G変異を導入し、Biacoreシステムを用いて、FcγRIIIA-V158受容体に対する結合親和性を測定した。P329G変異および三重変異P329G/LALAは、FcγRIIIA受容体に対する結合を最も大幅に、ほとんど検出不可能なレベルまで低減させた。P329G/SPLEもまた、結合親和性の大きな低減をもたらし、変異SPLEおよびLALAはそれぞれ、FcγRIIIA受容体に対する結合親和性を少ししか減少させなかった(図1e)。
C1Q ELISA
Fc変種を含む様々なポリペプチドのC1qに対する結合特性を、ELISAサンドイッチ型イムノアッセイ法によって解析した。各変種を、10μg/ml〜0μg/mlの間の8種類の濃度で疎水性Maxisorp 96ウェルプレートに結合させる。この結合は、抗体の複合体をシミュレートし、これはC1q分子の高親和性結合のための前提条件である。洗浄後、試料をインキュベートしてC1q結合を起こさせる。さらに洗浄した後、ポリクローナルウサギ抗hC1q抗体を用いて、結合されたC1q分子を検出する。次の洗浄段階の後に、酵素標識した抗ウサギFcγ特異的抗体を添加する。色の付いた生成物に酵素によって変換される基質を添加することによって、免疫学的反応を可視化する。測光法で測定して得られる吸光度は、調査する抗体に結合したC1qの量に比例している。変種-C1q相互作用のEC50値を算出した。発色反応に起因する吸光単位を抗体濃度に対してプロットする。最大反応の半分を示す抗体濃度が、EC50値を決定する。この測定値は、同じプレート上で測定される参照標準品に対する相対的差異として、試料および参照の変動係数と共に報告される。
標的細胞を伴わないADCC、BLTアッセイ法
試験する抗体(CD20(GA101)およびCD9)を、適切な96平底ウェルプレートにおいて4℃で一晩、PBSでコーティングした。プレートをPBSで洗浄した後、残っている結合部位を室温で1時間、PBS/1%BSA溶液でブロックした。その間に、エフェクター細胞(低親和性または高親和性のヒトFcγRIIIを発現するようにランスフェクトされたNK-92 細胞株)を採取し、ブロッキング緩衝液を廃棄した後、100μl/ウェルのAIM V培地を入れたウェルに200000生細胞/ウェルを播種した。100μl/ウェルのサポニン緩衝液(PBS中0.5%サポニン+1%BSA)を用いて、エフェクター細胞によるエステラーゼ放出の最大量を測定した。インキュベーター中で、37℃、5%CO2で3時間、細胞をインキュベートした。3時間後、20μl/ウェルの上清を180μl/ウェルのBLT基質(0.1M Tris-HCL中0.2mM BLT+0.11mM DTNB、pH8.0)と混合し、マイクロプレートリーダーにおいて405nmでプレートを読み取る前に37℃で30分間インキュベートした。最大放出(サポニンで処理した細胞)を100%に、刺激されていない細胞(抗体でコーティングされていない)を0%放出に設定して、エステラーゼ放出率(%)を決定した。
標的細胞を伴うADCC
ヒト末梢血単核球(PBMC)は、エフェクター細胞として使用し、Histopaque-1077(Sigma Diagnostics Inc., St.Louis, MO63178 USA)を用い、製造業者の取扱い説明書に基本的に従って、調製した。手短に言えば、ヘパリン処理したシリンジを用いて、ボランティアから静脈血を採取した。血液をPBS(Ca++もMg++も含有していない)で1:0.75〜1.3に希釈し、Histopaque-1077上に積み重ねた。室温(RT)、400xgで30分間、中断せずに勾配を遠心分離した。PBMCを含む中間相(interphase)を集め、PBS(2つの勾配に由来する細胞当たり50ml)で洗浄し、室温、300xgで10分間の遠心分離によって回収した。沈殿物をPBSで再懸濁した後、PBMCを計数し、室温、200xgで10分間の遠心分離によって2回目の洗浄を行った。次いで、その後の処置のために、適切な培地中に細胞を再懸濁した。ADCCアッセイ法のために使用したエフェクターと標的の比は、PBMC細胞およびNK細胞の場合、それぞれ25:1および10:1であった。丸底96ウェルプレートのウェル当たり50mlを添加するために、適切な濃度にてAIM-V培地中でエフェクター細胞を調製した。標的細胞は、10%FCSを含むDMEM中で増殖させたヒトBリンパ腫細胞(例えばRaji細胞)であった。標的細胞をPBS中で洗浄し、計数し、マイクロウェル当たり100ml中に細胞30'000個を添加するために、30万個/mlの濃度でAIM-V中に再懸濁した。抗体をAIM-V中で希釈し、予め播種した標的細胞に50mlを添加し、室温で10分間、標的に結合させた。次いで、エフェクター細胞を添加し、5% CO2を含む加湿された環境において37℃で4時間、プレートをインキュベートした。標的細胞の殺傷は、細胞障害性検出キット(Roche Diagnostics, Rotkreuz, Switzerland)を用いて、損傷した細胞からの乳酸デヒドロゲナーゼ(LDH)放出を測定することによって評価した。4時間インキュベーションした後、プレートを800xgで遠心分離した。各ウェルから得た100mlの上清を、新しい透明の平底96ウェルプレートに移した。キットの着色基質緩衝液をウェル1つにつき100ml添加した。SOFTmax PROソフトウェア(Molecular Devices, Sunnyvale, CA94089, USA)を用いて、少なくとも10分間、490nmにて、ELISAリーダーで呈色反応のVmax値を測定した。自発的LDH放出は、標的細胞およびエフェクター細胞のみを含み抗体を含まないウェルにおいて測定した。標的細胞のみおよび1% Triton X-100を含むウェルにおいて、最大放出を測定した。特異的抗体に媒介された殺傷の比率(%)を次のようにして算出した:((x-SR)/(MR-SR)×100(式中、xは特定の抗体濃度におけるVmaxの平均値であり、SRは、自発的放出のVmaxの平均値であり、MRは、最大放出のVmaxの平均値である)。
補体活性
標的細胞を計数し、PBSで洗浄し、100万細胞/mlの濃度でAIM-V(Invitrogen)中に再懸濁した。平底96ウェルプレートに50ml/ウェルの細胞を播種した。AIM-V中で抗体希釈物を調製し、50mlを細胞に添加した。室温で10分間、抗体を細胞に結合させた。ヒト血清補体(Quidel)を新たに解凍し、AIM-Vで3倍に希釈し、50mlをウェルに添加した。製造業者によって説明されているようにして、ウサギ補体(Cedarlane Laboratories)を調製し、AIM-Vで3倍に希釈し、50mlをウェルに添加した。対照として、アッセイ法に添加する前に、補体源を56℃で30分間加熱した。アッセイ用プレートを37℃で2時間インキュベートした。LDH放出を測定することによって、細胞の殺傷を測定した。簡単に説明すると、プレートを300×gで3分間遠心分離した。50ml/ウェルの上清を新しい96ウェルプレートに移し、細胞障害性キット(Roche)のアッセイ用試薬50mlを添加した。ELISAリーダーを用いた動力学的測定により、上清中のLDH濃度と対応するVmaxを測定した。1% Triton X-100の存在下で細胞をインキュベートすることによって、最大放出を測定した。
ヒトIgG1の炭水化物プロファイル
Fcγ受容体への結合を抑制することを狙いとする変異をFc内に含むヒトIgG1抗体の炭水化物プロファイルを、陽イオンモードのMALDI/TOF-MSによって解析した(中性オリゴ糖)。
全血における抗体誘導性血小板凝集アッセイ法
Dynabyte製のMultiplate機器を用いた全血血小板凝集解析。最初に、正常なヒトドナーに由来する血液20mlを採取し、ヒルイジン(hiruidin)入りチューブ(Dynabyte Medical, MP0601番)に移した。ミニセルインピーダンス器具(minicell impedance device)(Dynabead MP0021番)をMultiplate機器に差し込み、アッセイ法に使用した。次いで、0.9% NaCl 175μlをミニセルに添加した。抗体をミニセルに添加して、最終的な試験濃度を得た。次いで、ヒト血液175μlを添加し、37℃で3分間、インキュベートした。37℃でさらに6分間のインピーダンス解析を自動的に開始させた。血小板凝集の指標として曲線下面積を定量することによって、データを解析した。
Claims (12)
- 野生型ヒトIgG1 Fc領域のFc変種を含むポリペプチドであって、
該Fc変種がPro329の位置のアミノ酸置換および少なくとも1つのさらなるアミノ酸置換を含み、ここで野生型ヒトFc領域のPro329が、グリシンで置換されており、前記少なくとも1つのさらなるアミノ酸置換が、該ヒトIgG1 Fc領域のL234AおよびL235Aであり、残基がKabatのEU指標に従って番号付けられている、
前記ポリペプチド。 - 前記野生型ヒトIgG1ポリペプチドがADCCを誘導し、ここで前記IgG1 Fc変異体ポリペプチドによって誘導されるADCCが、野生型ヒトIgG1 Fc領域を含むポリペプチドによって誘導されるADCCの0〜20%にまで低減する、
請求項1記載のポリペプチド。 - 前記Fc変異体を含むポリペプチドが、野生型ヒトIgG1 Fc領域を含むポリペプチドと比べて、エフェクター機能に関与するFc受容体への低減または除去された親和性を示す、請求項1または2記載のポリペプチド。
- 抗体またはFc融合タンパク質である、請求項1〜3のいずれか一項記載のポリペプチド。
- 前記野生型ヒトIgG1ポリペプチドが栓球凝集を誘導し、ここで該IgG1 Fc変異体ポリペプチドにより誘導される該栓球凝集が、野生型ヒトIgG1 Fc領域を含むポリペプチドによって誘導される栓球凝集と比べて低減している、請求項1〜4のいずれか一項記載のポリペプチド。
- 前記野生型ヒトIgG1ポリペプチドがCDCを誘導し、ここでIgG1 Fc変異体ポリペプチドによって誘導される該CDCが、野生型ヒトIgG1 Fc領域を含むポリペプチドによって誘導されるCDCと比べて大きく低減している、請求項1〜5のいずれか一項記載のポリペプチド。
- 医薬として使用するための、請求項1〜6のいずれか一項記載のポリペプチド。
- 該ポリペプチドが抗CD9抗体であって、重鎖可変領域としてSEQ ID NO: 9および可変軽鎖領域としてSEQ ID NO: 8を含む野生型Fc領域を含むことを特徴とする、請求項1〜7のいずれか一項記載のポリペプチド。
- ポリペプチドのエフェクター機能が、野生型ヒトIgG Fc領域を含むポリペプチドによって誘導されるエフェクター機能と比べて大きく低減していることが望まれる疾患を治療する際に使用するための、請求項1〜8のいずれか一項記載のポリペプチド。
- 野生型ヒトIgG Fc領域のFc変種を含むポリペプチドのエフェクター機能が、野生型ヒトIgG Fc領域を含むポリペプチドによって誘導されるエフェクター機能と比べて大きく低減していることが望まれる疾患を治療するための医薬を製造する際の、請求項1〜9のいずれか一項記載のポリペプチドの使用。
- 野生型ヒトIgG Fc領域を含むポリペプチドによって誘導されるADCCの0〜20%にまでADCCを下方調整するための、および/またはADCPを下方調整するための、野生型ヒトIgG Fc領域のFc変種を含むポリペプチドのインビトロにおける使用であって、
該ポリペプチドにおいて、ヒトIgG Fc領域のPro329がグリシンで置換されており、および少なくとも1つのさらなるアミノ酸置換を含み、ここで該Fc変種がヒトIgG1 Fc領域のL234AおよびL235Aに少なくとも2つのさらなるアミノ酸置換を含み、残基がKabatのEU指標に従って番号付けられており、該ポリペプチドが、ヒトFcγRIIIAおよびヒトFcγRIIAに対して低い親和性を示す、
前記ポリペプチドの使用。
- 前記ポリペプチドによって誘導される栓球凝集が、野生型ヒトFc領域を含み血小板活性化抗体であるポリペプチドによって誘導される栓球凝集と比べて低減する、請求項11記載の使用。
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