JP2021523913A - Nkg2d、cd16、及び線維芽細胞活性化タンパク質と結合するタンパク質 - Google Patents
Nkg2d、cd16、及び線維芽細胞活性化タンパク質と結合するタンパク質 Download PDFInfo
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Abstract
Description
本出願は、2018年5月16日に出願された米国仮特許出願第62/672,299号の利益及び優先権を主張する。
本出願は、ASCIIフォーマットで電子的に提出された配列表を含有し、本明細書に参照することによってその全体が援用される。2019年5月13日に作成された前記ASCIIコピーはDFY_056WO_SL25.txtと命名され、121,670バイトのサイズである。
本発明は、上で言及されたがんの治療を改善するための特定の利点を提供する。
本発明は、ナチュラルキラー細胞上のNKG2D受容体及びCD16受容体ならびにがん細胞上のFAPへ結合する、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、本明細書において記載される医薬組成物及び治療方法において有用である。ナチュラルキラー細胞上のNKG2D受容体及びCD16受容体への多重特異性結合タンパク質の結合は、FAP抗原を発現する腫瘍細胞の破壊に向けたナチュラルキラー細胞の活性を促進する。FAP発現細胞への多重特異性結合タンパク質の結合は、がん細胞をナチュラルキラー細胞と接近させ、それにより、ナチュラルキラー細胞によるがん細胞の直接的及び間接的な破壊を容易にする。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、以下で提供される。
配列番号101
QVQLVESGGGLVKPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIRYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDRGLGDGTYFDYWGQGTTVTVSS
配列番号102
QSALTQPASVSGSPGQSITISCSGSSSNIGNNAVNWYQQLPGKAPKLLIYYDDLLPSGVSDRFSGSKSGTSAFLAISGLQSEDEADYYCAAWDDSLNGPVFGGGTKLTVL
配列番号103
QVHLQESGPGLVKPSETLSLTCTVSDDSISSYYWSWIRQPPGKGLEWIGHISYSGSANYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCANWDDAFNIWGQGTMVTVSS
配列番号104
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK
配列番号130
MKTWVKIVFGVATSAVLALLVMCIVLRPSRVHNSEENTMRALTLKDILNGTFSYKTFFPNWISGQEYLHQSADNNIVLYNIETGQSYTILSNRTMKSVNASNYGLSPDRQFVYLESDYSKLWRYSYTATYYIYDLSNGEFVRGNELPRPIQYLCWSPVGSKLAYVYQNNIYLKQRPGDPPFQITFNGRENKIFNGIPDWVYEEEMLATKYALWWSPNGKFLAYAEFNDTDIPVIAYSYYGDEQYPRTINIPYPKAGAKNPVVRIFIIDTTYPAYVGPQEVPVPAMIASSDYYFSWLTWVTDERVCLQWLKRVQNVSVLSICDFREDWQTWDCPKTQEHIEESRTGWAGGFFVSTPVFSYDAISYYKIFSDKDGYKHIHYIKDTVENAIQITSGKWEAINIFRVTQDSLFYSSNEFEEYPGRRNIYRISIGSYPPSKKCVTCHLRKERCQYYTASFSDYAKYYALVCYGPGIPISTLHDGRTDQEIKILEENKELENALKNIQLPKEEIKKLEVDEITLWYKMILPPQFDRSKKYPLLIQVYGGPCSQSVRSVFAVNWISYLASKEGMVIALVDGRGTAFQGDKLLYAVYRKLGVYEVEDQITAVRKFIEMGFIDEKRIAIWGWSYGGYVSSLALASGTGLFKCGIAVAPVSSWEYYASVYTERFMGLPTKDDNLEHYKNSTVMARAEYFRNVDYLLIHGTADDNVHFQNSAQIAKALVNAQVDFQAMWYSDQNHGLSGLSTNHLYTHMTHFLKQCFSLSD
本明細書において記載される多重特異性結合タンパク質は、NKG2D結合部位、CD16結合部位、及びFAPについての結合部位を含む。ある特定の実施形態において、多重特異性結合タンパク質は、NKG2D及び/またはCD16を発現する細胞(NK細胞等)、ならびにFAPを発現する腫瘍細胞に同時に結合する。NK細胞への多重特異性結合タンパク質の結合は、がん細胞の破壊に向けたNK細胞の活性を促進し得る。
本発明は、本明細書において記載される多重特異性結合タンパク質及び/または本明細書において記載される医薬組成物を使用して、がんを治療するための方法を提供する。当該方法を使用して、FAPを発現する様々ながんを治療することができる。治療される例示的ながんは、胃癌、結腸直腸癌、膵臓癌、乳癌、子宮内膜癌、肺癌、前立腺癌、膀胱癌、子宮頸癌、頭頸部癌、卵巣癌、食道癌、腎癌、肝臓癌、精巣癌、ならびに口腔癌、多発性骨髄腫、白血病、急性骨髄性白血病、黒色腫、皮膚の基底細胞癌及び有棘細胞癌、神経膠腫、ユーイング肉腫、カポジ肉腫、ならびに中皮腫であり得る。
本発明の別の態様は、併用療法を提供する。本明細書において記載される多重特異性結合タンパク質は、がんを治療するための追加の治療剤と組み合わせて使用され得る。
本開示は、本明細書において記載されるタンパク質の治療有効量を含有する医薬組成物も特色とする。組成物は、様々な薬物送達系における使用のために製剤化され得る。1つまたは複数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中に含まれ得る。本開示における使用に好適な製剤は、Remington’s Pharmaceutical Sciences,17th Ed.Mack Publishing Company,Easton,PA(1985)中で見出される。薬物送達のための方法の短い総説については、例えばLanger T.,Science;249(4976):1527−1533を参照されたい。
NKG2D結合ドメインは精製された組換えNKG2Dへ結合する
ヒト、マウス、またはカニクイザルのNKG2Dエクトドメインの核酸配列を、ヒトIgG1 Fcドメインをコードする核酸配列と融合させ、発現させる予定の哺乳動物細胞の中へ導入した。精製後に、NKG2D−Fc融合タンパク質をマイクロプレートのウェルへ吸着させた。非特異的結合を防止するためにウシ血清アルブミンによりウェルをブロッキングした後に、NKG2D結合ドメインを力価測定し、NKG2D−Fc融合タンパク質により前吸着させたウェルへ添加した。一次抗体の結合を、ホースラディシュペルオキシダーゼへコンジュゲートさせ、ヒトκ軽鎖を特異的に認識してFc交差反応性を回避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)(ホースラディシュペルオキシダーゼのための基質)をウェルへ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、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可変ドメイン及び軽鎖可変ドメイン、または抗マウスNKG2DクローンのMI−6及びCX−5(eBioscience、San Diego、CA)を含む)を、各々ウェルへ添加した。
EL4マウスリンパ腫細胞株を、ヒトまたはマウスのNKG2D−CD3ζシグナル伝達ドメインキメラ抗原受容体を発現するように操作した。EL4細胞上で発現した細胞外NKG2Dを染色するために、NKG2D結合クローン、アイソタイプ対照または陽性対照を100nMの濃度で使用した。抗体結合を、フルオロフォアコンジュゲート抗ヒト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細胞に比較したNKG2D発現細胞の平均蛍光強度(MFI)を使用して計算した。
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へ吸着させ、ウェルをウシ血清アルブミンによりブロッキングして非特異的結合を低減させた。飽和濃度のULBP−6−His−ビオチンをウェルへ添加し、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に、ウェルを洗浄し、NKG2D−Fcコーティングウェルへ結合されたままのULBP−6−His−ビオチンを、ホースラディシュペルオキシダーゼへコンジュゲート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に、NKG2D結合ドメインのNKG2D−Fcタンパク質への特異的結合を、ウェル中のNKG2D−Fcタンパク質への結合がブロックされたULBP−6−His−ビオチンのパーセンテージから計算した。陽性対照抗体(配列番号101〜104から選択される重鎖可変ドメイン及び軽鎖可変ドメインを含む)及び様々なNKG2D結合ドメインは、ULBP−6のNKG2Dへの結合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)。
MAAAAIPALLLCLPLLFLLFGWSRARRDDPHSLCYDITVIPKFRPGPRWCAVQGQVDEKTFLHYDCGNKTVTPVSPLGKKLNVTMAWKAQNPVLREVVDILTEQLLDIQLENYTPKEPLTLQARMSCEQKAEGHSSGSWQFSIDGQTFLLFDSEKRMWTTVHPGARKMKEKWENDKDVAMSFHYISMGDCIGWLEDFLMGMDSTLEPSAGAPLAMSSGTTQLRATATTLILCCLLIILPCFILPGI(配列番号150)
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へ吸着させ、ウェルをウシ血清アルブミンによりブロッキングして非特異的結合を低減させた。NKG2D−Fcビオチン、続いてNKG2D結合ドメインをウェルへ添加した。インキュベーション及び洗浄後に、MICA−Fcコーティングウェルへ結合されたままのNKG2D−Fc−ビオチンを、ストレプトアビジン−HRP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に、NKG2D結合ドメインのNKG2D−Fcタンパク質への特異的結合を、MICA−Fcコーティングウェルへの結合がブロックされたNKG2D−Fc−ビオチンのパーセンテージから計算した。陽性対照抗体(配列番号101〜104から選択される重鎖可変ドメイン及び軽鎖可変ドメインを含む)及び様々なNKG2D結合ドメインは、MICAのNKG2Dへの結合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−1δ−Fc(R&D Systems、Minneapolis、MN)をマイクロプレートのウェルへ吸着させ、ウェルをウシ血清アルブミンによりブロッキングして非特異的結合を低減させた。マウスNKG2D−Fcビオチン、続いてNKG2D結合ドメインをウェルへ添加した。インキュベーション及び洗浄後に、Rae−1δ−Fcコーティングウェルへ結合されたままのNKG2D−Fc−ビオチンを、ストレプトアビジン−HRP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に、NKG2D結合ドメインのNKG2D−Fcタンパク質への特異的結合を、Rae−1δ−Fcコーティングウェルへの結合がブロックされたNKG2D−Fc−ビオチンのパーセンテージから計算した。陽性対照(配列番号101〜104から選択される重鎖可変ドメイン及び軽鎖可変ドメイン、または抗マウスNKG2DクローンのMI−6及びCX−5(eBioscience、San Diego、CA)を含む)及び様々なNKG2D結合ドメインクローンは、Rae−1δのマウスNKG2Dへの結合をブロックした一方で、アイソタイプ対照抗体は、Rae−1δとの競合をほとんど示さなかった(図10)。
ヒト及びマウスのNKG2Dの核酸配列をCD3ζシグナリングドメインをコードする核酸配列へ融合して、キメラ抗原受容体(CAR)コンストラクトを得た。次いでNKG2D−CARコンストラクトを、Gibsonアセンブリを使用してレトロウイルスベクターの中へクローニングし、レトロウイルス産生のためにexpi293細胞の中へトランスフェクションした。EL4細胞を、NKG2D−CARを含有するウイルスに8μg/mLのポリブレンと一緒に感染させた。感染の24時間後に、EL4細胞における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
密度勾配遠心分離を使用してヒト末梢血バフィーコートから末梢血単核細胞(PBMC)を単離した。磁気ビーズによるネガティブ選択を使用してPBMCからNK細胞(CD3−CD56+)を単離し、単離したNK細胞の純度は典型的には>95%であった。次いで単離したNK細胞を、100ng/mLのIL−2を含有している培地中で24〜48時間培養し、その後に、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へ移し、フルオロフォアコンジュゲート抗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。培養に続いて、CD3、CD56、及びIFN−γに対するフルオロフォアコンジュゲート抗体を使用して、フローサイトメトリーによって、NK細胞をアッセイした。CD3−CD56+細胞におけるCD107a染色及びIFN−γ染色を分析して、NK細胞の活性化を査定した。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係合を介するより良好なNK細胞の活性化を表す。NKG2D結合ドメイン及び陽性対照(例えば配列番号101または配列番号103によって表わ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によって表わ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NK細胞がCD107a+及びIFN−γ+になることを示した(図13及び図14は2つの独立した実験からのデータを表わし、各々は、NK細胞の調製のために異なるドナーのPBMCを使用した)。
C57Bl/6マウスから脾臓を得、70μmのセルストレーナーを介して破砕して単一細胞懸濁液を得た。細胞をペレットにし、ACK溶解緩衝液(Thermo Fisher Scientific#A1049201、Carlsbad、CA;155mMの塩化アンモニウム、10mMの重炭酸カリウム、0.01mMのEDTA)中で再懸濁して、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、その後に、収集し、NK細胞単離のために調製した。次いでNK細胞(CD3−NK1.1+)を、磁気ビーズによるネガティブ涸渇技法を使用して脾臓細胞から単離し、それにより典型的には>90%の純度を有するNK細胞集団を得た。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、その後に、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へ移し、フルオロフォアをコンジュゲートする抗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結合ドメインコーティングウェル中での培養に続いて、CD3、NK1.1、及びIFN−γに対するフルオロフォアコンジュゲート抗体を使用して、フローサイトメトリーによって、NK細胞をアッセイした。CD3−NK1.1+細胞におけるCD107a染色及びIFN−γ染色を分析して、NK細胞の活性化を査定した。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係合を介するより良好なNK細胞の活性化を表す。NKG2D結合ドメイン及び陽性対照(抗マウスNKG2DクローンのMI−6及びCX−5、eBioscience、San Diego、CA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NK細胞がCD107a+及びIFN−γ+になることを示した(図15及び図16は2つの独立した実験からのデータを表わし、各々は、NK細胞の調製のために異なるマウスを使用した)。
ヒト及びマウスの初代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のNK細胞上の細胞傷害性マーカーの増加を実証する。このことが腫瘍細胞溶解の増加へとつながるかどうかを検討するために、各々のNKG2D結合ドメインを単一特異性抗体へと発展させた細胞ベースのアッセイを利用した。Fc領域を1つの標的化アームとして使用する一方で、Fab領域(NKG2D結合ドメイン)を別の標的化アームとして作用させて、NK細胞を活性化した。THP−1細胞(ヒト起源であり、高レベルのFc受容体を発現する)を腫瘍標的として使用し、Perkin Elmer DELFIA(登録商標)Cytotoxicity Kit(Waltham、MA)を使用した。THP−1細胞をBATDA試薬により標識し、105/mLで培養培地中に再懸濁した。次いで標識したTHP−1細胞を、NKG2D抗体及び単離したマウスNK細胞と37℃で3時間マイクロタイタープレートのウェル中で組み合わせた。インキュベーション後に、20μlの培養液上清を除去し、200μlのユウロピウム溶液と混合し、暗所で振盪しながら15分間インキュベーションした。蛍光を、時間分解蛍光モジュール(励起337nm、発光620nm)を装備したPHERAStar(登録商標)プレートリーダーによって経時的に測定し、比溶解(specific lysis)をキットの指示に従って計算した。
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。NKG2D結合ドメインの推測された外挿の融解温度は、典型的なIgG1抗体に比べて高かった(図18)。
初代ヒトNK細胞活性化アッセイ
末梢血中単核細胞(PBMC)を、密度勾配遠心分離を使用して、末梢ヒト血液バフィーコートから単離した。NK細胞を、ネガティブ選択磁気ビーズ(StemCell Technologies、Vancouver、Canada;カタログ番号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されるように、>90%がCD3−CD56+であった。次いで細胞を、100ng/mLのhIL−2(PeproTech,Inc.、Rocky Hill、NJ、カタログ番号200−02)を含有する培地中で48時間増幅させ、その後に、活性化アッセイにおいて使用した。抗体を、100μlの滅菌リン酸緩衝生理食塩水(PBS)中で、2μg/ml(抗CD16、BioLegend、San Diego、CA;カタログ番号302013)及び5μg/mL(抗NKG2D、R&D Systems、Minneapolis、MN;カタログ番号MAB139)の濃度で、96ウェルの平底プレートの上へ4℃で一晩コーティングし、続いて、ウェルを完全に洗浄して過剰な抗体を除去した。脱顆粒の査定のために、IL−2活性化NK細胞を、100ng/mLのhIL2及び1μg/mLのAPCコンジュゲート抗CD107a mAb(BioLegend、San Diego、CA;カタログ番号328619)を補足した培養培地中で5×105細胞/mlで、再懸濁した。次いで1×105細胞/ウェルを、抗体コーティングプレートの上へ添加した。タンパク質輸送阻害物質のブレフェルジンA(BFA、BioLegend、San Diego、CA;カタログ番号420601)及びモネンシン(BioLegend、San Diego、CA;カタログ番号420701)を、1:1000及び1:270の最終希釈でそれぞれ添加した。プレーティングした細胞を、5%のCO2中で37℃で4時間インキュベーションした。IFN−γの細胞内染色のために、NK細胞を、抗CD3(BioLegend、San Diego、CA;カタログ番号300452)及び抗CD56 mAb(BioLegend、San Diego、CA;カタログ番号318328)により標識し、後続して、固定及び透過化を行い、抗IFN−γ mAb(BioLegend、San Diego、CA、カタログ番号506507)により標識した。NK細胞を、生存CD56+CD3−細胞に対してゲーティングした後に、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。
FAP発現を、3つのヒト細胞株:骨原性肉腫を有する患者からの正常な組織に由来したLL86線維芽細胞;COLO829黒色腫癌細胞;及び神経膠芽細胞腫からのU−87 MG上皮癌細胞上で確認した。FAP発現を、フルオロフォアコンジュゲート抗ヒトFAP抗体(R&D Systems、Minneapolis、MN)により細胞を染色することによって、フローサイトメトリー分析を使用して、測定した。
FAP発現ヒト細胞株(LL86、COLO 829及びU−87MG)を使用して、配列番号118に同一の軽鎖可変ドメイン配列とペアになる配列番号114に同一の重鎖可変ドメイン配列(FAP多重特異性BPシブロツズマブ);配列番号135に同一の軽鎖可変ドメイン配列とペアになる配列番号131に同一の重鎖可変ドメイン配列(FAP多重特異性BP 4G8);または配列番号143に同一の軽鎖可変ドメイン配列とペアになる配列番号139に同一の重鎖可変ドメイン配列(FAP多重特異性BP 29B11)を含む、FAP結合部位を有する多重特異性結合タンパク質の腫瘍抗原結合を査定した。同じFAP結合部位を有する多重特異性結合タンパク質または対応するモノクローナル抗体(mAb)を希釈し、細胞とインキュベーションした。結合を、フルオロフォアコンジュゲート抗ヒト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、ヒト組換えIgG1染色対照に対して正規化した平均蛍光強度(MFI)として表現して、バックグラウンドに対する倍率(FOB)値を得た。
密度勾配遠心分離を使用してヒト末梢血バフィーコートからPBMCを単離した。単離したPBMCを洗浄し、NK細胞の単離のために調製した。磁気ビーズを用いたネガティブ選択を使用してNK細胞を単離した。NK細胞は、フローサイトメトリーによって決定されるように、>90%がCD3−CD56+であった。単離したNK細胞をサイトカイン無しの培地中で一晩インキュベーションし、その後に、細胞傷害性アッセイにおいて使用した。
FAP発現ヒトがん細胞株を培養から収集した。細胞をPBSにより洗浄し、106細胞/mLで増殖培地中で再懸濁して、製造者の指示に従ってBATDA試薬(Perkin Elmer、Waltham、MA、カタログ番号AD0116)により標識した。標識後に、細胞をHEPES緩衝食塩水により3×洗浄し、5×104細胞/mLで培養培地中で再懸濁し、100μlのBATDA標識細胞を96ウェルプレートの各々のウェルへ添加した。指定したウェルを標的細胞からの自然放出のために取っておき、他のすべてのウェルを1%のTriton−Xの添加によって標的細胞の最大溶解のために調製した。
%比溶解=[(実験的放出−自然放出)/(最大放出−自然放出)]×100%
本明細書において参照される特許文書及び科学論文の各々の開示全体は、すべての目的のために参照することによって援用される。
本発明は、その趣旨または本質的特徴から逸脱せずに、他の具体的な形態で実施され得る。したがって、前述の実施形態は、本明細書において記載される本発明を限定するのではなく、すべての点で例証と見なされるべきである。よって、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、該特許請求の範囲の均等性の意味及び範囲内に入るすべての変化がその中に包含されることが意図される。
Claims (43)
- 以下の:
(a)NKG2Dと結合する第1の抗原結合部位と;
(b)線維芽細胞活性化タンパク質(FAP)と結合する第2の抗原結合部位と;
(c)CD16と結合するのに十分な抗体Fcドメインもしくはその一部、またはCD16と結合する第3の抗原結合部位と、
を含む、タンパク質。 - 前記第1の抗原結合部位が、ヒトにおけるNKG2Dへ結合する、請求項1に記載のタンパク質。
- 前記第1の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の抗原結合部位が、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の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の抗原結合部位の前記軽鎖可変ドメインが、前記第2の抗原結合部位の前記軽鎖可変ドメインのアミノ酸配列に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の抗原結合部位が、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、配列番号167、配列番号171、配列番号175、配列番号179、配列番号183、配列番号187、及び配列番号93から選択されるアミノ酸配列に少なくとも90%同一の重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の抗原結合部位が、配列番号41に少なくとも90%同一の重鎖可変ドメイン及び配列番号42に少なくとも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の抗原結合部位が、配列番号49に少なくとも90%同一の重鎖可変ドメイン及び配列番号50に少なくとも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の抗原結合部位が、配列番号57に少なくとも90%同一の重鎖可変ドメイン及び配列番号58に少なくとも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の抗原結合部位が、配列番号59に少なくとも90%同一の重鎖可変ドメイン及び配列番号60に少なくとも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の抗原結合部位が、配列番号61に少なくとも90%同一の重鎖可変ドメイン及び配列番号62に少なくとも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の抗原結合部位が、配列番号69に少なくとも90%同一の重鎖可変ドメイン及び配列番号70に少なくとも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の抗原結合部位が、配列番号77に少なくとも90%同一の重鎖可変ドメイン及び配列番号78に少なくとも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の抗原結合部位が、配列番号85、配列番号167、配列番号171、配列番号175、配列番号179、配列番号183、または配列番号187に少なくとも90%同一の重鎖可変ドメイン、及び配列番号86に少なくとも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の抗原結合部位が、配列番号93に少なくとも90%同一の重鎖可変ドメイン及び配列番号94に少なくとも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の抗原結合部位が、配列番号101に少なくとも90%同一の重鎖可変ドメイン及び配列番号102に少なくとも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の抗原結合部位が、配列番号103に少なくとも90%同一の重鎖可変ドメイン及び配列番号104に少なくとも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の抗原結合部位が、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の抗原結合部位が、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の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の抗原結合部位の前記重鎖可変ドメインが、配列番号114に少なくとも90%同一のアミノ酸配列を含み、前記第2の抗原結合部位の前記軽鎖可変ドメインが、配列番号118に少なくとも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の抗原結合部位の前記重鎖可変ドメインが、配列番号131に少なくとも90%同一のアミノ酸配列を含み、前記第2の抗原結合部位の前記軽鎖可変ドメインが、配列番号135に少なくとも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の抗原結合部位の前記重鎖可変ドメインが、配列番号139に少なくとも90%同一のアミノ酸配列を含み、前記第2の抗原結合部位の前記軽鎖可変ドメインが、配列番号143に少なくとも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の抗原結合部位の前記重鎖可変ドメインが、配列番号122に少なくとも90%同一のアミノ酸配列を含み、前記第2の抗原結合部位の前記軽鎖可変ドメインが、配列番号126に少なくとも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の抗原結合部位が、配列番号114及び118、131及び135、139及び143、ならびに122及び126からなる群から選択される、重鎖可変ドメイン及び軽鎖可変ドメインのCDR1、CDR2、及びCDR3の配列をそれぞれ含む、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の抗原結合部位が、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の抗原結合部位が、VHH断片またはVNAR断片である、請求項29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ドメインの一部を含み、前記抗体Fcドメインが、ヒンジドメイン及びCH2ドメインを含む、請求項1〜30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抗体のヒンジドメイン及びCH2ドメインを含む、請求項31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に少なくとも90%同一のアミノ酸配列を含む、請求項31または32に記載のタンパク質。
- 前記Fcドメインが、ヒトIgG1の前記Fcドメインに少なくとも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つまたは複数の位置で異なる、請求項33に記載のタンパク質。
- 請求項1〜34のいずれか1項に記載のタンパク質及び薬学的に許容される担体を含む、製剤。
- 請求項1〜34のいずれか1項に記載のタンパク質をコードする1つまたは複数の核酸を含む、細胞。
- 腫瘍細胞死を促進する方法であって、腫瘍細胞及びナチュラルキラー細胞を有効量の請求項1〜34のいずれか1項に記載のタンパク質へ曝露することを含む、前記方法。
- がんを治療する方法であって、有効量の請求項1〜34のいずれか1項に記載のタンパク質または請求項35に記載の製剤を患者へ投与することを含む、前記方法。
- 前記治療されるがんが、浸潤性乳管癌、膵管腺癌、胃癌、子宮癌、子宮頸癌、結腸直腸癌、乳癌、卵巣癌、膀胱癌、肺癌、中皮腫、胃癌、膵臓癌、頭頸部癌、肝臓癌、子宮内膜癌、神経内分泌癌、線維肉腫、悪性線維性組織球腫、平滑筋肉腫、骨肉腫、軟骨肉腫、脂肪肉腫、滑膜肉腫、神経鞘腫、黒色腫、及び神経膠腫からなる群から選択される、請求項38に記載の方法。
- 自己免疫疾患を治療する方法であって、有効量の請求項1〜34のいずれか1項に記載のタンパク質または請求項35に記載の製剤を患者へ投与することを含む、前記方法。
- 前記自己免疫疾患が、関節リウマチ、グレーヴス病、シェーグレン症候群、原発性胆汁性肝硬変症、原発性硬化症胆管炎、及び炎症性破壊性関節炎からなる群から選択される、請求項40に記載の方法。
- 線維症を治療する方法であって、有効量の請求項1〜34のいずれか1項に記載のタンパク質または請求項35に記載の製剤を患者へ投与することを含む、前記方法。
- 前記線維症が、特発性肺線維症、腎線維症、肝線維症、及び心臓線維症からなる群から選択される、請求項42に記載の方法。
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