JP2020529410A - Nkg2d、cd16及びflt3と結合するタンパク質 - Google Patents
Nkg2d、cd16及びflt3と結合するタンパク質 Download PDFInfo
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Abstract
Description
本出願は、2017年7月31日出願の米国特許仮出願第62/539,421号明細書の利益及びその優先権を主張し、その内容全体が、あらゆる目的のために参照によって本明細書に組み込まれる。
本出願は、ASCII形式で電子的に提出された配列表を含有し、その全体が参照によって本明細書に組み込まれる。2018年7月30日に作成されたASCIIコピーは、DFY−027WO_SL.txtという名称であり、103,731バイトのサイズである。
本発明は、ナチュラルキラー細胞上のNKG2D受容体及びCD16受容体、ならびに腫瘍関連抗原FLT3に結合する多重特異性結合タンパク質を提供する。多重特異性結合タンパク質は、本明細書に記載される医薬組成物及び治療方法に有用である。多重特異性結合タンパク質と、ナチュラルキラー細胞上のNKG2D受容体及びCD16受容体との結合は、FLT3を発現する腫瘍細胞の破壊に対するナチュラルキラー細胞の活性を増強する。多重特異性結合タンパク質とFLT3発現細胞との結合は、がん細胞をナチュラルキラー細胞に近接させ、これにより、ナチュラルキラー細胞による直接的かつ間接的ながん細胞の破壊が促進される。いくつかの例示的な多重特異性結合タンパク質のさらなる記載が以下に提供される。
本明細書に記載される多重特異性タンパク質は、NKG2D結合部位、CD16結合部位、及びFLT3結合部位を含む。いくつかの実施形態では、多重特異性タンパク質は、NK細胞などの、NKG2D及び/またはCD16を発現する細胞、ならびにFLT3を発現する腫瘍細胞に同時に結合する。多重特異性結合タンパク質とNK細胞との結合は、腫瘍細胞の破壊に対するNK細胞の活性を増強し得る。
本発明は、本明細書に記載される多重特異性結合タンパク質及び/または本明細書に記載される医薬組成物を使用して、がんを処置する方法を提供する。本方法は、FLT3を発現する様々ながんを処置するために使用されてよい。いくつかの実施形態では、がんは白血病、例えば、急性骨髄性白血病、T細胞白血病、急性リンパ性白血病、慢性リンパ性白血病、慢性骨髄性白血病、または有毛細胞白血病である。
本発明の別の態様は、併用療法をもたらす。本明細書に記載される多重特異性結合タンパク質は、がんを処置するために追加の治療剤と組み合わせて使用され得る。
本開示はまた、治療有効量の本明細書に記載されるタンパク質を含有する医薬組成物を特徴とする。組成物は、様々な薬物送達システムで使用するために製剤化され得る。1つ以上の生理学的に許容される賦形剤または担体も、適切な製剤化のために組成物に含まれ得る。本開示での使用に好適な製剤は、Remington’s Pharmaceutical Sciences,Mack Publishing Company,Philadelphia,Pa.,17th ed.,1985に見出される。薬剤送達の方法の簡単な概説については、例えば、Langer(Science 249:1527−1533,1990)を参照のこと。
NKG2D結合ドメインは、精製した組換えNKG2Dに結合する
ヒト、マウスまたはカニクイザルNKG2Dエクトドメインの核酸配列を、ヒトIgG1Fcドメインをコードする核酸配列と融合し、発現される哺乳動物細胞内に導入した。精製後、NKG2D−Fc融合タンパク質をマイクロプレートのウェルに吸着させた。非特異的結合を防止するためにウシ血清アルブミンでウェルをブロックした後、NKG2D結合ドメインを滴定し、NKG2D−Fc融合タンパク質を予め吸着させたウェルに添加した。一次抗体の結合を、西洋ワサビペルオキシダーゼと複合化させた、Fc交差反応を回避するためにヒトカッパ軽鎖を特異的に認識する二次抗体を使用して検出した。3,3’,5,5’−テトラメチルベンジジン(TMB)、すなわち、西洋ワサビペルオキシダーゼの基質をウェルに添加して結合シグナルを可視化し、その吸光度を450nMで測定して540nMで補正した。NKG2D結合ドメインクローン、アイソタイプ対照または陽性対照(配列番号:101〜104から選択される重鎖及び軽鎖可変ドメインを含む、もしくはeBioscienceで入手可能な抗マウスNKG2DクローンのMI−6及びCX−5)を各ウェルに添加した。
EL4マウスリンパ腫細胞株を操作して、ヒトまたはマウスNKG2D−CD3ゼータシグナル伝達ドメインキメラ抗原受容体を発現させた。NKG2D結合クローン、アイソタイプ対照または陽性対照を100nMの濃度で使用して、EL4細胞上に発現した細胞外NKG2Dを染色した。抗体結合を、フルオロフォア複合化抗ヒトIgG二次抗体を使用して検出した。細胞をフローサイトメトリーによって分析し、バックグラウンドに対する倍率(FOB)を、親EL4細胞と比較したNKG2D発現細胞の平均蛍光強度(MFI)を使用して算出した。
ULBP−6との競合
組換えヒトNKG2D−Fcタンパク質をマイクロプレートのウェルに吸着させ、非特異的結合を減少させるためにウシ血清アルブミンでウェルをブロックした。飽和濃度のULBP−6−His−ビオチンをウェルに添加し、続いてNKG2D結合ドメインクローンを添加した。2時間のインキュベーション後、ウェルを洗浄し、NKG2D−Fcでコーティングしたウェルに結合したままであったULBP−6−His−ビオチンを、西洋ワサビペルオキシダーゼと複合化したストレプトアビジン及びTMB基質によって検出した。吸光度を450nMで測定し、540nMで補正した。バックグラウンドを差し引いた後、NKG2D−Fcタンパク質に対するNKG2D結合ドメインの特異的結合を、ウェル中でNKG2D−Fcタンパク質に対する結合からブロックされたULBP−6−His−ビオチンのパーセンテージから算出した。陽性対照抗体(配列番号:101〜104から選択される重鎖及び軽鎖可変ドメインを含む)ならびに様々なNKG2D結合ドメインが、NKG2Dに結合するULBP−6をブロックした一方で、アイソタイプ対照は、ULBP−6との競合をほとんど示さなかった(図8)。
組換えヒトMICA−Fcタンパク質をマイクロプレートのウェルに吸着させ、非特異的結合を減少させるためにウシ血清アルブミンでウェルをブロックした。NKG2D−Fc−ビオチンをウェルに添加し、続いてNKG2D結合ドメインを添加した。インキュベーション及び洗浄後、MICA−Fcでコーティングしたウェルに結合したままであったNKG2D−Fc−ビオチンを、ストレプトアビジン−HRP及びTMB基質を使用して検出した。吸光度を450nMで測定し、540nMで補正した。バックグラウンドを差し引いた後、NKG2D−Fcタンパク質に対するNKG2D結合ドメインの特異的結合を、MICA−Fcでコーティングしたウェルに対する結合からブロックされたNKG2D−Fc−ビオチンのパーセンテージから算出した。陽性対照抗体(配列番号:101〜104から選択される重鎖及び軽鎖可変ドメインを含む)ならびに様々なNKG2D結合ドメインが、NKG2Dに結合するMICAをブロックした一方で、アイソタイプ対照は、MICAとの競合をほとんど示さなかった(図9)。
組換えマウスRae−1デルタ−Fc(R&D Systemsから購入した)をマイクロプレートのウェルに吸着させ、非特異的結合を減少させるためにウシ血清アルブミンでウェルをブロックした。マウスNKG2D−Fc−ビオチンをウェルに添加し、続いてNKG2D結合ドメインを添加した。インキュベーション及び洗浄後、Rae−1デルタ−Fcでコーティングしたウェルに結合したままであったNKG2D−Fc−ビオチンを、ストレプトアビジン−HRP及びTMB基質を使用して検出した。吸光度を450nMで測定し、540nMで補正した。バックグラウンドを差し引いた後、NKG2D−Fcタンパク質に対するNKG2D結合ドメインの特異的結合を、Rae−1デルタ−Fcでコーティングしたウェルに対する結合からブロックされたNKG2D−Fc−ビオチンのパーセンテージから算出した。陽性対照(配列番号:101〜104から選択される重鎖及び軽鎖可変ドメインを含む、またはeBioscienceで入手可能な抗マウスNKG2DクローンのMI−6及びCX−5)ならびに様々なNKG2D結合ドメインクローンが、マウスNKG2Dに結合するRae−1デルタをブロックした一方で、アイソタイプ対照抗体は、Rae−1デルタとの競合をほとんど示さなかった(図10)。
ヒト及びマウスNKG2Dの核酸配列を、CD3ゼータシグナル伝達ドメインをコードする核酸配列に融合し、キメラ抗原受容体(CAR)構築物を得た。次いで、NKG2D−CAR構築物を、ギブソンアセンブリを使用してレトロウイルスベクターにクローニングし、レトロウイルス産生のためにexpi293細胞にトランスフェクトした。EL4細胞を、8μg/mLのポリブレンと共にNKG2D−CARを含有するウイルスに感染させた。感染から24時間後、EL4細胞中のNKG2D−CARの発現レベルをフローサイトメトリーによって分析し、細胞表面上で高レベルのNKG2D−CARを発現するクローンを選択した。
初代ヒトNK細胞
末梢血単核細胞(PBMC)を、密度勾配遠心分離法を使用して、ヒト末梢血バフィーコートから単離した。NK細胞(CD3−CD56+)を、磁気ビーズを用いたネガティブセレクションを使用してPBMCから単離し、単離したNK細胞の純度は通常、>95%であった。次いで、単離したNK細胞を、100ng/mLのIL−2を含有する培地中で24〜48時間培養してから、それらを、NKG2D結合ドメインを吸着させたマイクロプレートのウェルに移し、フルオロフォア複合化抗CD107a抗体、ブレフェルジン−A、及びモネンシンを含有する培地中で培養した。培養後、NK細胞を、フローサイトメトリーによってCD3、CD56及びIFN−γに対するフルオロフォア複合化抗体を使用してアッセイした。CD107a及びIFN−γ染色を、CD3−CD56+細胞中で分析し、NK細胞活性化を評価した。CD107a/IFN−γ二重陽性細胞の増加は、1つの受容体ではなく、2つの活性化受容体の結合による良好なNK細胞活性化を示している。NKG2D結合ドメインならびに陽性対照(例えば、配列番号:101または配列番号:103で表される重鎖可変ドメイン、及び配列番号:102または配列番号:104で表される軽鎖可変ドメイン)は、アイソタイプ対照よりも高いパーセンテージの、CD107a+及びIFN−γ+となるNK細胞を示した(図13及び図14は、2つの独立した実験からのデータを表し、各々でNK細胞調製のために異なるドナーのPBMCを使用した)。
脾臓をC57Bl/6マウスから入手し、70μmのセルストレーナーによって破砕して単一の細胞懸濁液を得た。細胞をペレットにし、ACK溶解緩衝液(Thermo Fisher Scientificから購入した#A1049201、155mMの塩化アンモニウム、10mMの重炭酸カリウム、0.01mMのEDTA)中に再懸濁して赤血球を除去した。残存する細胞を100ng/mLのhIL−2と共に72時間培養してから、採取してNK細胞単離のために調製した。次いで、NK細胞(CD3−NK1.1+)を、磁気ビーズを用いたネガティブ除去技術を使用して脾臓細胞から単離し、通常は>90%の純度であった。精製したNK細胞を、100ng/mLのmIL−15を含有する培地中で48時間培養してから、それらを、NKG2D結合ドメインを吸着させたマイクロプレートのウェルに移し、フルオロフォア複合化抗CD107a抗体、ブレフェルジン−A、及びモネンシンを含有する培地中で培養した。NKG2D結合ドメインでコーティングしたウェル中での培養後、NK細胞を、フローサイトメトリーによってCD3、NK1.1及びIFN−γに対するフルオロフォア複合化抗体を使用してアッセイした。CD107a及びIFN−γ染色を、CD3−NK1.1+細胞中で分析し、NK細胞活性化を評価した。CD107a/IFN−γ二重陽性細胞の増加は、1つの受容体ではなく、2つの活性化受容体の結合による良好なNK細胞活性化を示している。NKG2D結合ドメインならびに陽性対照(eBioscienceで入手可能な抗マウスNKG2DクローンのMI−6及びCX−5から選択される)は、アイソタイプ対照よりも高いパーセンテージの、CD107a+及びIFN−γ+となるNK細胞を示した(図15及び図16は、2つの独立した実験からのデータを表し、各々でNK細胞調製のために異なるマウスを使用した)。
ヒト及びマウス初代NK細胞活性化アッセイは、NKG2D結合ドメインとのインキュベーション後における、NK細胞上での細胞傷害性マーカーの増加を実証した。このことが腫瘍細胞溶解の増加につながるかを確認するために、細胞に基づくアッセイを利用し、各NKG2D結合ドメインを単一特異性抗体とした。Fc領域を1つの標的化アームとして使用した一方で、Fab領域(NKG2D結合ドメイン)は、NK細胞を活性化させるための別の標的化アームとして機能した。THP−1細胞はヒト起源であり、高レベルのFc受容体を発現し、これらを腫瘍標的として使用して、Perkin Elmer DELFIA細胞傷害性キットを使用した。THP−1細胞をBATDA試薬で標識し、105/mLで培養培地中に再懸濁させた。次いで、標識したTHP−1細胞をNKG2D抗体と組み合わせ、マウスNK細胞をマイクロタイタープレートのウェル中において37℃で3時間単離した。インキュベーション後、20μLの培養上清を除去し、200μLのユウロピウム溶液と混合して15分間暗所で振盪しながらインキュベートした。蛍光を、時間分解蛍光モジュールを備えたPheraStarプレートリーダーによって経時的に測定し(励起337nm、発光620nm)、特異的溶解をキットの説明書に従って算出した。
NKG2D結合ドメインの融解温度を、示差走査蛍光定量法を使用してアッセイした。外挿した見かけの融解温度は、典型的なIgG1抗体と比較して高い(図18)。
初代ヒトNK細胞活性化アッセイ
末梢血単核細胞(PBMC)を、密度勾配遠心分離法を使用して、ヒト末梢血バフィーコートから単離した。NK細胞を、ネガティブ磁気ビーズ(StemCell#17955)を使用してPBMCから精製した。NK細胞は、フローサイトメトリーによって決定した場合、>90%のCD3−CD56+であった。次いで、細胞を、活性化アッセイでの使用前に100ng/mLのhIL−2(Peprotech#200−02)を含有する培地中で48時間増殖させた。抗体を96ウェル平底プレート上に、2μg/mL(抗CD16、Biolegend#302013)及び5μg/mL(抗NKG2D、R&D#MAB139)の濃度で、100μLの滅菌PBS中において一晩4℃でコーティングし、続いてウェルを完全に洗浄して過剰な抗体を除去した。脱顆粒の評価のために、IL−2活性化NK細胞を5×105細胞/mLで、100ng/mLのヒトIL−2(hIL2)及び1μg/mLのAPC複合化抗CD107a mAb(Biolegend#328619)を補充した培養培地中に再懸濁させた。次いで、1×105細胞/ウェルを抗体でコーティングしたプレート上に添加した。タンパク質輸送阻害剤のブレフェルジンA(BFA、Biolegend#420601)及びモネンシン(Biolegend#420701)を、それぞれ1:1000及び1:270の最終希釈で添加した。播種した細胞を、4時間37℃で5%CO2中においてインキュベートした。IFN−γの細胞内染色のために、NK細胞を抗CD3(Biolegend#300452)及び抗CD56mAb(Biolegend#318328)で標識し、その後、固定して透過処理し、抗IFN−γ mAb(Biolegend#506507)で標識した。生CD56+CD3−細胞上でゲーティングした後、NK細胞を、CD107a及びIFN−γの発現についてフローサイトメトリーによって分析した。
EL4マウスリンパ腫細胞株を操作して、ヒトNKG2Dを発現させた。多重特異性結合タンパク質、例えば、三重特異性結合タンパク質(TriNKET)は、その各々がNKG2D結合ドメイン、FLT3結合ドメイン、及びCD16に結合するFcドメインを含有し、EL4細胞上に発現した細胞外NKG2Dに結合するそれらの親和性について試験した。TriNKETを20μg/mLに希釈し、次いで段階的に希釈した。TriNKETとNKG2Dとの結合を、フルオロフォア複合化抗ヒトIgG二次抗体を使用して検出した。次いで、細胞をフローサイトメトリーによって分析し、平均蛍光強度(MFI)を、二次抗体対照を基準として正規化してバックグラウンドに対する倍率(FOB)値を得た。
FLT3を発現するヒトAML細胞株(Molm−13及びEOL−1)を使用して、FLT3標的化TriNKETと腫瘍関連抗原との結合をアッセイした。TriNKETを細胞と共にインキュベートし、結合を、フルオロフォア複合化抗ヒトIgG二次抗体を使用して検出した。細胞をフローサイトメトリーによって分析し、平均蛍光強度(MFI)を、二次抗体対照を基準として正規化してバックグラウンドに対する倍率(FOB)値を得た。
ヒトAML細胞株のMolm−13及びEOL−1を使用して、細胞表面上に発現したFLT3に結合した後のFLT3標的化TriNKETの内在化を評価した。TriNKETまたはモノクローナル抗体のリンツズマブを20μg/mLに希釈し、これを使用して細胞を染色した。染色後、試料の3分の2を37℃で一晩置いて内在化を促進させ、試料の残り3分の1を、フルオロフォア複合化抗ヒトIgG二次抗体を使用して検出し、ベースラインMFIを得た。37℃での2時間及び20時間のインキュベーション後、試料をインキュベーターから取り出し、細胞の表面上にある結合した抗体を、フルオロフォア複合化抗ヒトIgG二次抗体を使用して検出し、試料MFIを得た。内在化を算出した:%内在化=(1−(試料MFI/ベースラインMFI))*100%。
FLT3標的化TriNKETの存在下においてFLT3発現がん細胞を溶解させるヒトNK細胞の能力を試験するために、末梢血単核細胞(PBMC)を単離し、NK細胞単離のために調製した。PBMCを、密度勾配遠心分離法を使用して、ヒト末梢血バフィーコートから単離した。単離したPBMCを洗浄し、NK細胞単離のために調製した。NK細胞を、磁気ビーズを用いたネガティブセレクション技術を使用して単離し、単離したNK細胞の純度は通常、>90%のCD3−CD56+であった。単離したNK細胞を、100ng/mLのIL−2を含有する培地中で培養したか、またはサイトカインを入れずに一晩置いた。IL−2活性化または置いたNK細胞を、細胞傷害性アッセイで翌日使用した。
本明細書で言及される特許文献及び科学論文の各々の開示全体は、あらゆる目的のために参照によって組み込まれる。
本発明は、その趣旨または本質的特徴から逸脱することなく、他の特定の形態で具現化されてよい。したがって、前述の実施形態は、本明細書に記載される本発明を限定するのではなく、あらゆる点において例示的であると見なされるべきである。したがって、本発明の範囲は、前述の記載によってではなく、添付の特許請求の範囲によって示され、特許請求の範囲と等価の意味及び範囲内に入る全ての変更が、本明細書に包含されること意図する。
Claims (38)
- タンパク質であって、
(a)NKG2Dと結合する第1抗原結合部位と、
(b)FLT3と結合する第2抗原結合部位と、
(c)抗体FcドメインもしくはCD16と結合するのに十分なその一部分、またはCD16と結合する第3抗原結合部位とを含む、前記タンパク質。 - 前記第1抗原結合部位が、ヒトのNKG2Dに結合する、請求項1に記載のタンパク質。
- 前記第1抗原結合部位が、重鎖可変ドメイン及び軽鎖可変ドメインを含む、請求項1または2に記載のタンパク質。
- 前記重鎖可変ドメイン及び前記軽鎖可変ドメインが、同じポリペプチド上に存在する、請求項3に記載のタンパク質。
- 前記第2抗原結合部位が、重鎖可変ドメイン及び軽鎖可変ドメインを含む、請求項3または4に記載のタンパク質。
- 前記第2抗原結合部位の前記重鎖可変ドメイン及び前記軽鎖可変ドメインが、同じポリペプチド上に存在する、請求項5に記載のタンパク質。
- 前記第1抗原結合部位の前記軽鎖可変ドメインが、前記第2抗原結合部位の前記軽鎖可変ドメインのアミノ酸配列と同一のアミノ酸配列を有する、請求項5または6に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:1、配列番号:41、配列番号:49、配列番号:57、配列番号:59、配列番号:61、配列番号:69、配列番号:77、配列番号:85、及び配列番号:93から選択されるアミノ酸配列と少なくとも90%同一の重鎖可変ドメインを含む、先行請求項のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:41と少なくとも90%同一の重鎖可変ドメイン及び配列番号:42と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:49と少なくとも90%同一の重鎖可変ドメイン及び配列番号:50と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:57と少なくとも90%同一の重鎖可変ドメイン及び配列番号:58と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:59と少なくとも90%同一の重鎖可変ドメイン及び配列番号:60と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:61と少なくとも90%同一の重鎖可変ドメイン及び配列番号:62と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:69と少なくとも90%同一の重鎖可変ドメイン及び配列番号:70と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:77と少なくとも90%同一の重鎖可変ドメイン及び配列番号:78と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:85と少なくとも90%同一の重鎖可変ドメイン及び配列番号:86と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:93と少なくとも90%同一の重鎖可変ドメイン及び配列番号:94と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:101と少なくとも90%同一の重鎖可変ドメイン及び配列番号:102と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、配列番号:103と少なくとも90%同一の重鎖可変ドメイン及び配列番号:104と少なくとも90%同一の軽鎖可変ドメインを含む、請求項1〜7のいずれか1項に記載のタンパク質。
- 前記第1抗原結合部位が、単一ドメイン抗体である、請求項1または2に記載のタンパク質。
- 前記単一ドメイン抗体が、VHH断片またはVNAR断片である、請求項20に記載のタンパク質。
- 前記第2抗原結合部位が、重鎖可変ドメイン及び軽鎖可変ドメインを含む、請求項1〜2または20〜21のいずれか1項に記載のタンパク質。
- 前記第2抗原結合部位の前記重鎖可変ドメイン及び前記軽鎖可変ドメインが、同じポリペプチド上に存在する、請求項22に記載のタンパク質。
- 前記第2抗原結合部位がFLT3と結合し、前記第2抗原結合部位の前記重鎖可変ドメインが、配列番号:109と少なくとも90%同一のアミノ酸配列を含み、前記第2抗原結合部位の前記軽鎖可変ドメインが、配列番号:113と少なくとも90%同一のアミノ酸配列を含む、請求項1〜23のいずれか1項に記載のタンパク質。
- 前記第2抗原結合部位がFLT3と結合し、前記第2抗原結合部位の前記重鎖可変ドメインが、配列番号:117と少なくとも90%同一のアミノ酸配列を含み、前記第2抗原結合部位の前記軽鎖可変ドメインが、配列番号:121と少なくとも90%同一のアミノ酸配列を含む、請求項1〜23のいずれか1項に記載のタンパク質。
- 前記第2抗原結合部位がFLT3と結合し、前記第2抗原結合部位の前記重鎖可変ドメインが、配列番号:125と少なくとも90%同一のアミノ酸配列を含み、前記第2抗原結合部位の前記軽鎖可変ドメインが、配列番号:129と少なくとも90%同一のアミノ酸配列を含む、請求項1〜23のいずれか1項に記載のタンパク質。
- 前記第2抗原結合部位が、単一ドメイン抗体である、請求項1〜4または8〜21のいずれか1項に記載のタンパク質。
- 前記第2抗原結合部位が、VHH断片またはVNAR断片である、請求項27に記載のタンパク質。
- 前記タンパク質が、CD16と結合するのに十分な抗体Fcドメインの一部分を含み、前記抗体Fcドメインがヒンジ及びCH2ドメインを含む、先行請求項のいずれか1項に記載のタンパク質。
- 前記抗体Fcドメインが、ヒトIgG1抗体のヒンジ及びCH2ドメインを含む、請求項29に記載のタンパク質。
- 前記Fcドメインが、ヒトIgG1抗体のアミノ酸234〜332と少なくとも90%同一のアミノ酸配列を含む、請求項29または30に記載のタンパク質。
- 前記Fcドメインが、ヒトIgG1の前記Fcドメインと少なくとも90%同一のアミノ酸配列を含み、Q347、Y349、L351、S354、E356、E357、K360、Q362、S364、T366、L368、K370、N390、K392、T394、D399、S400、D401、F405、Y407、K409、T411、K439からなる群から選択される1つ以上の位置で異なる、請求項31に記載のタンパク質。
- 先行請求項のいずれか1項に記載のタンパク質と、薬学的に許容される担体とを含む、製剤。
- 請求項1〜32のいずれか1項に記載のタンパク質を発現する1つ以上の核酸を含む、細胞。
- 腫瘍細胞死の増強方法であって、腫瘍細胞及びナチュラルキラー細胞を、有効量の請求項1〜32のいずれか1項に記載の前記タンパク質に曝露することを含み、前記腫瘍細胞がFLT3を発現する、前記方法。
- がんの処置方法であって、前記方法が、有効量の請求項1〜32のいずれか1項に記載の前記タンパク質または請求項33に記載の前記製剤を患者に投与することを含む、前記方法。
- 前記がんが白血病である、請求項36に記載の方法。
- 前記白血病が、急性骨髄性白血病、T細胞白血病、急性リンパ性白血病、慢性リンパ性白血病、慢性骨髄性白血病、及び有毛細胞白血病からなる群から選択される、請求項37に記載のがんの処置方法。
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