JP2018505154A - 単量体Fcドメイン - Google Patents
単量体Fcドメイン Download PDFInfo
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- JP2018505154A JP2018505154A JP2017535678A JP2017535678A JP2018505154A JP 2018505154 A JP2018505154 A JP 2018505154A JP 2017535678 A JP2017535678 A JP 2017535678A JP 2017535678 A JP2017535678 A JP 2017535678A JP 2018505154 A JP2018505154 A JP 2018505154A
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Abstract
Description
本出願は、全ての図面を含め、参照にその全内容が本明細書に組み入れられる、2015年1月5日出願の米国仮特許出願第62/099,634号明細書の利益を主張するものである。
本出願は、電子形式の配列表と合わせて出願されている。この配列表は、2015年12月31日に作成された100KBサイズの「NTECH2 PCT_ST25 txt」という名称のファイルとして提供される。この配列表の電子形式の情報は、参照によりその全内容が本明細書に組み入れられる。
−CH3−リンカー−CH3−
(ECD)−CH2−CH3−リンカー−CH3
を含むポリペプチドである。
(P)−CH2−CH3−リンカー−CH3、
(ABD)−CH2−CH3−リンカー−CH3、
又は
(scFv)−CH2−CH3−リンカー−CH3。
(P1)−CH2−CH3−リンカー−CH3−(P2)
に従いポリペプチド鎖に含まれることができる。
(ABD1)−CH2−CH3−リンカー−CH3−(ABD2)
a)本明細書に記載されるとおりの直列型CH3ドメインを含むポリペプチド鎖をコードする第1の核酸を用意するステップ、
b)任意選択により、本明細書に記載されるさらなるポリペプチド鎖(例えば非共有結合性及び/又は共有結合性の相互作用によって(a)の鎖と結合する鎖)をコードするさらなる核酸を用意するステップ、及び
c)前記第1の(及び任意選択によりさらなる)核酸を宿主細胞で発現させて、それぞれ前記第1の(及び任意選択によりさらなる)ポリペプチド鎖を含むタンパク質を産生し、且つ単量体(又は任意選択によりヘテロ二量体、ヘテロ三量体、ヘテロ四量体又は五量体)タンパク質を回収するステップ
を含む。任意選択により、ステップ(c)は、産生されたタンパク質を、アフィニティー精製支持体、任意選択によりアフィニティー交換カラム、任意選択によりプロテインA支持体又はカラムにローディングし、且つヘテロ二量体タンパク質を収集するステップ;及び/又は産生されたタンパク質(例えば、アフィニティー交換又はプロテインAカラムにローディングした後に収集されたタンパク質)をイオン交換カラムにローディングし、且つ単量体(又は任意選択によりヘテロ二量体、ヘテロ三量体、ヘテロ四量体又は五量体)画分を収集するステップを含む。
本明細書で使用される「1つの(a)」又は「1つの(an)」は1つ以上を意味し得る。請求項において「含む(comprising)」という語と共に使用される場合、「1つの(a)」又は「1つの(an)」という語は1つ又は2つ以上を意味し得る。
本明細書の発明は、直列型CH3ドメイン及び直列型CH3ドメインを含むポリペプチドに関する。直列型CH3ドメインは単一のポリペプチド鎖内に構成することができ、従って2つのCH3ドメインはCH3−CH3二量体を形成することによって相互作用する。かかるCH3ドメインは、従って、他のCH3ドメイン含有ポリペプチド、特にFcドメイン含有ポリペプチドとのさらなる二量体化には利用できない。目的とする任意のアミノ酸配列、ポリペプチドドメイン又はポリペプチド、例えば「親」、「出発」又は「非変異」ポリペプチドを出発点として、又は当該技術分野でポリペプチドの作成に利用可能な技術を用いて直列型CH3ドメイン含有ポリペプチドに組み込むアミノ酸配列の供給源として使用することができる。直列型CH3ドメイン含有ポリペプチドは、例えば、CH3ドメインに連結したCH2ドメインを含むヒトFc領域を含むことができ、ここで、このCH3ドメインは直列型CH3ドメインのうちの一方である。
(ECD)−CH2−CH3−リンカー−CH3、
(ECD)−CH1−CH2−CH3−リンカー−CH3、
(VH又はVL)−CH2−CH3−リンカー−CH3、
(VH又はVL)−CH1−CH2−CH3−リンカー−CH3、
(ABD1)−CH1−CH2−CH3−リンカー−CH3、
又は
(ABD1)−CH2−CH3−リンカー−CH3。
(目的のドメイン1)−CH2−CH3−リンカー−CH3−(目的のドメイン2)、
(目的のドメイン1)−CH1−CH2−CH3−リンカー−CH3−(目的のドメイン2)、
(ABD1)−CH2−CH3−リンカー−CH3−(ABD2)、
(ABD1)−CH1−CH2−CH3−リンカー−CH3−(ABD2)、
(ECD)−CH2−CH3−リンカー−CH3−(ABD)、
(ECD)−CH1−CH2−CH3−リンカー−CH3−(ABD)、
(ABD)−CH2−CH3−リンカー−CH3−(ECD)、
又は
(ABD)−CH1−CH2−CH3−リンカー−CH3−(ECD)。
(ABD1)−(ABD2)−CH2−CH3−リンカー−CH3、
(ABD1)−(ABD2)−CH1−CH2−CH3−リンカー−CH3、
又は
(scFv1)−(scFv2)−CH2−CH3−リンカー−CH3。
(scFv1)−CH2−CH3−リンカー−CH3−(scFv2)
又は
(scFv1)−CH1−CH2−CH3−リンカー−CH3−(scFv2)。
一態様では、それを必要としている哺乳動物の処置又は診断用の医薬製剤の製造における本明細書で定義される任意の化合物の使用が提供される。また、薬剤として、又は薬剤中の活性成分若しくは活性物質として上記定義された任意の化合物の使用も提供される。さらなる態様では、経口投与、局所投与、又は注射用の固体又は液体製剤を提供するために、上記定義された化合物を含む医薬組成物を調製する方法が提供される。このような方法又はプロセスは、少なくとも化合物を薬学的に許容され得る担体と混合するステップを含む。
材料及び方法
ヒト腫瘍抗原CD19に特異的なscFv(抗CD19 scFv)及びNK細胞上のヒト活性化受容体NKp46に特異的なscFV(抗NKp46 scFv)をベースとする二重特異的Fcポリペプチドの調製に使用する種々の構築物を作製した。
コード配列を、直接合成及び/又はPCRによって構築した。PCRは、PrimeSTAR MAX DNAポリメラーゼ(Takara,#R045A)を用いて行い、PCR産物を、NucleoSpinゲル及びPCR clean−upキット(Macherey−Nagel,#740609.250)を用いて1%アガロースゲルから精製した。精製した後、PCR産物を定量してから、製造者のプロトコル(ClonTech,#ST0345)に記載されているようにIn−Fusion連結反応を行った。プラスミドは、Nucleospin 96プラスミドキット(Macherey−Nagel,#740625.4)を用いてEVO200(Tecan)で行われたミニプレップ調製後に得た。次いで、CHO細胞株のトランスフェクションの前に、プラスミドを配列の確認のために配列決定した。
F3ポリペプチドのドメイン構造が図1Aに示されている。Fc部分のDNA及びアミノ酸配列は、同じポリペプチド鎖上の2つのCH3ドメインが互いに結合し、それにより、異なる二重特異的タンパク質間の二量体化が防止される直列型CH3ドメインを含んでいた。
(VK−VH)抗CD19−CH2−CH3−CH3−(VH−VK)抗NKp46
図1Aに「形態4」として示すドメイン配置scFvCD19−CH2(N297S)−CH3−CH3−scFvNkp46−3を有するタンパク質を構築した。Fc部分のDNA及びアミノ酸配列は、形態F3と同じく直列型CH3ドメインを含んだが、それに加え、N結合型グリコシル化を防止し且つFcγR結合を無効にするためにN297S突然変異を含んだ。上記のとおりタンパク質をクローニングし、産生し、精製した。細胞培養上清からprot−Aビーズを使用したアフィニティークロマトグラフィーによって二重特異的タンパク質を精製し、SECによって分析及び精製した。タンパク質は1mg/Lの良好な産生収率を示し、単純なSECプロフィールを有した。NKp46−3可変ドメインを含むF4タンパク質のアミノ酸配列は、配列番号11に示す。
F9ポリペプチドは、中心ポリペプチド鎖、及びそれぞれCH1−CKの二量体化によって中心鎖に結合された2つのポリペプチド鎖を有する三量体ポリペプチドである。三量体F9タンパク質のドメイン構造が図1Bに示されており、CH1とCKドメインとの間の結合は、鎖間ジスルフィド結合である。2つの抗原結合ドメインは、抗体がscFv形態で機能を支持するか否かにかかわらず、この抗体の使用を可能にするF(ab)構造を有する。Fc部分のDNA及びアミノ酸配列は、形態F4と同様の直列型CH3ドメイン及びN297S置換を含むCH2ドメインを含んでいた。F9タンパク質の3つの変異体を作製した:(a)ヒンジ領域のシステイン残基が完全なままである(野生型、F9Aと呼ばれる)、(b)ヒンジ領域のシステイン残基がセリン残基によって置換されている(F9B)、及び(c)リンカー配列GGGSSがヒンジの残基DKTHTCPPCPを置換している(F9C)。変異型F9B及びF9Cは、中心鎖のホモ二量体の形成を防止することによって作製に利点を提供した。このヘテロ三量体は、以下から構成される。
(1)以下のように(N末端からC末端に)配置されたドメインを有する第1(中心)のポリペプチド鎖:
VH抗CD19−CH1−CH2−CH3−CH3−VH抗NKp46−CK、及び
(2)以下のように(N末端からC末端に)配置されたドメインを有する第2のポリペプチド鎖:
VK抗NKp46−CH1、及び
(3)以下のように(N末端からC末端に)配置されたドメインを有する第3のポリペプチド鎖:
VK抗CD19−CK
タンパク質を上記と同様にクローニングし、産生し、且つ精製した。二重特異的タンパク質を、prot−Aビーズを用いるアフィニティークロマトグラフィーによって細胞培養上清から精製し、分析し、且つSECによって精製した。このタンパク質は、8.7mg/L(F9A)及び3.0mg/L(F9B)の高い産生収率を示し、単純なSECプロフィールを有していた。
F10ポリペプチドは、中心ポリペプチド鎖、及びCH1−CKの二量体化によって中心鎖に結合された第2のポリペプチド鎖を有する二量体タンパク質である。二量体F10タンパク質のドメイン構造が図1Bに示され、CH1とCKドメインとの間の結合は、鎖間ジスルフィド結合である。2つの抗原結合ドメインの一方はFab構造を有し、且つ他方はscFvである。Fc部分のDNA及びアミノ酸配列は、形態F4と同様の直列型CH3ドメイン及びN297S置換を有するCH2ドメインを含んでいた。加えて、F10タンパク質の3つの変異体を作製した:(a)ヒンジ領域のシステイン残基が完全なままである(野生型、F10Aと呼ばれる)、(b)ヒンジ領域のシステイン残基がセリン残基によって置換されている(F10B、及び(c)リンカー配列GGGSS(配列番号28)がヒンジの残基DKTHTCPPCP(配列番号29)を置換している(F10C)。変異型F10B及びF10Cは、中心鎖のホモ二量体の形成を防止することによって作製に利点を提供した。(VK−VH)単位は、VHドメイン、リンカー、及びVK単位(scFv)から構成されていた。ヘテロ二量体は、以下から構成される。
(1)以下のように(N末端からC末端に)配置されたドメインを有する第1(中心)のポリペプチド鎖:
VH抗CD19−CH1−CH2−CH3−CH3−(VH−VK)抗NKp46、及び
(2)以下のように(N末端からC末端に)配置されたドメインを有する第2のポリペプチド鎖:
VK抗CD19−CK。
F11ポリペプチドのドメイン構造が図1Cに示されている。このヘテロ二量体タンパク質は、F10に類似しているが、抗原結合ドメインの構造が逆である。2つの抗原結合ドメインの一方はFab様構造を有し、且つ他方はscFvである。このヘテロ二量体は、以下から構成される。
(1)以下のように(N末端からC末端に)配置されたドメインを有する第1(中心)のポリペプチド鎖:
(VK−VH)抗CD19−CH2−CH3−CH3−VH抗NKp46−CK、及び
(2)以下のように(N末端からC末端に)配置されたドメインを有する第2のポリペプチド鎖:
VK抗NKp46−CH1。
二量体F12ポリペプチドのドメイン構造が図1Cに示されており、CH1とCKドメインとの間の結合は、ジスルフィド結合である。このヘテロ二量体タンパク質は、F11に類似しているが、F(ab)構造内のCH1とCKドメインが逆である。このヘテロ二量体は、以下から構成される。
(1)以下のように(N末端からC末端に)配置されたドメインを有する第1(中心)のポリペプチド鎖:
(VK−VH)抗CD19−CH2−CH3−CH3−VH抗NKp46−CH1、及び
(2)以下のように(N末端からC末端に)配置されたドメインを有する第2のポリペプチド鎖:
VK抗NKp46−CK。
三量体F17ポリペプチドのドメイン構造が図1Cに示されており、CHとCKドメインとの間の結合はジスルフィド結合である。ヘテロ二量体タンパク質は、F9と同様であるが、VH及びVKドメイン、並びにC末端F(ab)構造内のCH1及びCKドメインは、それぞれ、それらのパートナーと逆である。このヘテロ二量体は、以下から構成される。
(1)以下のように(N末端からC末端に)配置されたドメインを有する第1(中心)のポリペプチド鎖:
VH抗CD19−CH1−CH2−CH3−CH3−VK抗NKp46−CH1、及び
(2)以下のように(N末端からC末端に)配置されたドメインを有する第2のポリペプチド鎖:
VH抗NKp46−CK、及び
(3)以下のように(N末端からC末端に)配置されたドメインを有する第3のポリペプチド鎖:
VK抗CD19−CK
加えて、F17タンパク質の3つの変異体を作製した:(a)ヒンジ領域のシステイン残基が完全なままである(野生型、F17Aと呼ばれる)、(b)ヒンジ領域のシステイン残基がセリン残基によって置換されえいる(F10B、及び(c)リンカー配列GGGSS(配列番号28)がヒンジの残基DKTHTCPPCP(配列番号29)を置換している(F17C)。タンパク質を上記と同様にクローニングし、産生し、且つ精製した。F17Bタンパク質の3つの鎖のアミノ酸配列は、配列番号25、26、及び27に示されている。
表面プラズモン共鳴(SPR)による、二重特異的タンパク質によるNKp46結合親和性
Bacore T100の一般的な手順及び試薬
SPR測定を、Biacore T100装置(Biacore GE Healthcare)で、25℃で行った。全てのBiacore実験では、HBS−EP+(Biacore GE Healthcare)及びNaOH 10mMは、それぞれ泳動用緩衝液及び再生緩衝液としての役割を果たした。センサーグラムを、Biacore T100 Evaluationソフトウェアで分析した。プロテインAを(GE Healthcare)から購入した。ヒトNKp46組換えタンパク質を、クローニングし、産生し、且つInnate Pharmaで精製した。
プロテインAタンパク質を、Sensor Chip CM5上のデキストラン層のカルボキシル基に共有結合により固定した。チップ表面を、EDC/NHS(N−エチル−N’−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩及びN−ヒドロキシスクシンイミド(Biacore GE Healthcare))で活性化した。プロテインAを、結合緩衝液(10mM酢酸、pH5.6)で10μg/mlに希釈し、適切な固定化レベル(即ち、2500RU)に達するまで注入した。残りの活性化基の不活性化を、100mMエタノールアミン pH8(Biacore GE Healthcare)を用いて行った。
NKp46−3抗体由来の抗NKp46可変領域を有する種々の形態F3、F4、F9、F10、F11としての二重特異的タンパク質を試験し、完全長ヒトIgG1としてのNKp46−3抗体と比較した。
一価親和性試験を、製造者(Biacore GE Healthcare kinetic wizard)が推奨する正規のCapture−Kineticプロトコルに従って行った。62.5〜400nMの範囲のヒトNKp46組換えタンパク質の7段階希釈物を、捕捉した二重特異的抗体に連続的に注入し、再生の10分前に解離させた。全てのセンサーグラムのセットを、1:1動態結合モデルを用いてフィッティングした。
SPRから、形態F3、F4、F9、F10及びF11の全ての二重特異的ポリペプチドがNKp46との結合を維持したことが示された。一価親和性及び動力学的結合及び解離速度定数を以下の表3に示す。
NKp46作用機序
CD16−/NKp46+ NK細胞株がCD19陽性腫瘍標的細胞を溶解するように仕向ける機能的能力に関して、実施例1に記載するF3形態に従う配置を有するNKp46×CD19二重特異的タンパク質をリツキシマブ(抗CD20 ADCC誘導抗体)及びヒトIgG1アイソタイプ対照抗体と比較した。
KHYG−1 hNKp46 NK実験モデルにおいて、各NKp46×CD19二重特異的タンパク質は、ヒトKHYG−1 hNKp46 NK細胞株によるDaudi又はB221細胞の特異的溶解を誘導し、一方、リツキシマブ及びヒトIgG1アイソタイプ対照(IC)抗体はそれを誘導しなかった。
様々な二重特異的形態のFcRnに対する結合性
様々な抗体形態のヒトFcRnに対する親和性について、表面プラズモン共鳴(SPR)により、組換えFcRnタンパク質をセンサーチップCM5上のデキストラン層のカルボキシル基に共有結合的に固定化することによって調べた。ヒトIgG1定常領域を有するキメラ完全長抗CD19抗体、及び実施例1に記載するF3、F4、F9、F10、又はF11形態に係る配置を有するNKp46×CD19二重特異的タンパク質を試験した。各分析物について、定常状態又は1:1 SCK結合モデルを用いてセンサーグラム全体をフィッティングした。
SPR測定をBiacore T100装置(Biacore GE Healthcare)において25℃で実施した。全てのBiacore実験において、酢酸塩緩衝液(50mM酢酸塩 pH5.6、150mM NaCl、0.1%界面活性剤p20)及びHBS−EP+(Biacore GE Healthcare)をそれぞれランニング緩衝液及び再生緩衝液として用いた。センサーグラムはBiacore T100 Evaluationソフトウェアで分析した。組換えマウスFcRnはR&D Systemsから購入した。
組換えFcRnタンパク質をセンサーチップCM5上のデキストラン層のカルボキシル基に共有結合的に固定化した。チップ表面をEDC/NHS(N−エチル−N’−(3−ジメチルアミノプロピル)カルボジイミド塩酸塩及びN−ヒドロキシスクシンイミド(Biacore GE Healthcare))で活性化した。FcRnタンパク質をカップリング緩衝液(10mM酢酸塩、pH5.6)中10μg/mlに希釈し、適切な固定化レベル(即ち2500RU)に達するまで注入した。100mMエタノールアミンpH8(Biacore GE Healthcare)を使用して、残りの活性化基の不活性化を実施した。
シングルサイクルキネティクス(SCK)プロトコルに従い一価親和性試験を行った。41.5〜660nMの範囲の可溶性分析物(抗体及び二重特異的分子)の5段階希釈物をFcRn上に注入し(再生なし)、10分間解離させた後、再生した。各分析物について、1:1 SCK結合モデルを用いてセンサーグラム全体をフィッティングした。
結果を以下の表4に示す。単量体Fcドメインを含む二重特異的タンパク質(F3、F4、F9、F10、F11)はFcRnとの結合性を示した。二量体Fcドメインを有するヒトIgG1/K抗CD19抗体は7.8のKD(nM)を示した。
Claims (36)
- 可動性リンカーによって分離されている第1及び第2のCH3ドメインを含むポリペプチド鎖。
- 前記第1及び第2のCH3ドメインが、前記第1及び第2のCH3ドメインが非共有相互作用により互いの結合することを許容するのに十分な長さのリンカーによって分離されている、請求項1に記載のポリペプチド鎖。
- 前記第1及び第2のCH3ドメインを分離するアミノ酸配列が10〜30残基を有するペプチドリンカーである、請求項1又は2に記載のポリペプチド鎖。
- 前記第1及び第2のCH3ドメインを分離する前記アミノ酸配列が式(G4S)x(式中、xは、2、3、4、5又は6である)を有するペプチドリンカーである、請求項1〜3のいずれか一項に記載のポリペプチド鎖。
- ポリペプチドが、前記第1のCH3ドメインに融合したCH2ドメインを含むFcポリペプチドである、請求項1〜4のいずれか一項に記載のポリペプチド鎖。
- 前記ポリペプチドが、N末端からC末端に、目的のポリペプチド、CH2ドメイン、第1のCH3ドメイン、可動性ペプチドリンカー、及び第2のCH3ドメインを含む、請求項1〜5のいずれか一項に記載のポリペプチド鎖。
- 前記ポリペプチドが、N末端からC末端に、目的の抗原に特異的に結合する抗原結合ドメイン(ABD)、CH2ドメイン、第1のCH3ドメイン、可動性ペプチドリンカー、及び第2のCH3ドメインを含む、請求項6に記載のポリペプチド鎖。
- 前記ポリペプチドがドメイン配置:(ABD)−リンカー−CH2−CH3−リンカー−CH3を有する、請求項6又は7に記載の組成物。
- 前記ポリペプチドが、N末端からC末端に、目的の第1の抗原に特異的に結合する第1の抗原結合ドメイン(ABD1)、CH2ドメイン、第1のCH3ドメイン、可動性ペプチドリンカー、第2のCH3ドメイン、及び目的の第2の抗原に特異的に結合する第2の抗原結合ドメイン(ABD2)を含む、請求項1〜8のいずれか一項に記載のポリペプチド鎖。
- 前記ポリペプチドがドメイン配置:(ABD1)−リンカー−CH2−CH3−リンカー−CH3−リンカー−(ABD2)を有する、請求項9に記載のポリペプチド。
- 前記ポリペプチドがドメイン配置:(ABD1)−リンカー−CH1−CH2−CH3−リンカー−CH3−リンカー−(ABD2)を有する、請求項10に記載のポリペプチド。
- 請求項1〜11のいずれか一項に記載のポリペプチド鎖、及びそれと結合している1つ以上のさらなるポリペプチド鎖を含むタンパク質。
- (a)目的の第1のポリペプチド、
(b)前記目的の第1のポリペプチドのC末端に作動可能に連結している、アミノ酸残基の配列によって分離されている第1及び第2のCH3ドメインを含むFc由来部分、及び
(c)前記(b)のFc由来部分のC末端に作動可能に連結した目的のポリペプチド
を含む多機能タンパク質であって、前記多重特異的ポリペプチドがヒト新生児Fc受容体(FcRn)との結合能を有する、多機能タンパク質。 - 前記目的の第1のポリペプチドが、第1の抗原に結合する第1の抗原結合ドメイン(ABD1)である、請求項13に記載の組成物。
- 前記目的の第2のポリペプチドが、第2の抗原に結合する第2の抗原結合ドメイン(ABD2)である、請求項13又は14に記載の組成物。
- 前記ポリペプチドが、第1及び第2の抗原と一価の様式で結合する多重特異的ポリペプチドである、請求項13〜15のいずれか一項に記載の組成物。
- 前記(b)のFc由来部分が、N末端からC末端に、CH2ドメイン、第1のCH3ドメイン、ペプチドリンカー及び第2のCH3ドメインを含む、請求項13〜16のいずれか一項に記載の組成物。
- 前記ポリペプチドが、CD16、CD32A、CD32B及びCD64からなる群から選択される1つ以上のヒトFcγ受容体とのそのFcドメインを介した結合を実質的に欠いている、請求項1〜17のいずれか一項に記載の組成物。
- 前記多重特異的ポリペプチドがヒト新生児Fc受容体(FcRn)との結合能を有する、請求項1〜18のいずれか一項に記載の組成物。
- 前記CH2ドメインが、ヒトFcγ受容体との結合を低下させるアミノ酸置換を含む、請求項1〜19のいずれか一項に記載の組成物。
- 各ABDが抗体の超可変領域、任意選択により重鎖及び軽鎖CDRを含む、請求項1〜20のいずれか一項に記載の組成物。
- ABDが免疫グロブリン重鎖可変ドメイン及び軽鎖可変ドメインを含む、請求項1〜21のいずれか一項に記載の組成物。
- ABDがscFvである、請求項1〜22のいずれか一項に記載の組成物。
- 前記ポリペプチドが二重特異的ポリペプチドである、請求項1〜23のいずれか一項に記載の組成物。
- 前記抗原結合ドメインのうちの一方が癌抗原に結合する、請求項1〜24のいずれか一項に記載の組成物。
- 前記抗原結合ドメインのうちの一方がウイルス抗原又は細菌抗原に結合する、請求項1〜25のいずれか一項に記載の組成物。
- 前記抗原結合ドメインのうちの一方が免疫エフェクター細胞上の細胞表面受容体に結合する、請求項1〜26のいずれか一項に記載の組成物。
- 前記抗原結合ドメインのうちの一方が免疫エフェクター細胞上の細胞表面受容体に結合し、及び前記抗原結合ドメインのうちの他方が癌抗原、ウイルス抗原又は細菌抗原に結合する、請求項1〜27のいずれか一項に記載の組成物。
- 免疫エフェクター細胞上の前記細胞表面受容体が免疫グロブリンスーパーファミリーのメンバーである、請求項1〜28のいずれか一項に記載の組成物。
- 免疫エフェクター細胞上の前記細胞表面受容体が、ナチュラル細胞傷害性受容体ファミリー又はNK細胞レクチン様受容体ファミリーのメンバーである、請求項1〜29のいずれか一項に記載の組成物。
- 免疫エフェクター細胞上の前記細胞表面受容体が、活性化KIR、NKG2D、NKp30、NKp44、NKp46、CD8及びCD3からなる群から選択される、請求項1〜30のいずれか一項に記載の組成物。
- 前記抗体がヒトフレームワーク領域由来のフレームワーク残基を含む、請求項1〜31のいずれか一項に記載の組成物。
- 請求項1〜32のいずれか一項に記載のポリペプチド又はタンパク質と薬学的に許容可能な担体とを含む医薬組成物。
- 疾患の治療用医薬としての、請求項1〜33のいずれか一項に記載の組成物の使用。
- 対象の疾患を治療する方法であって、請求項1〜33のいずれか一項に記載の組成物を前記対象に投与するステップを含む方法。
- 前記疾患が癌、感染症又は炎症性若しくは自己免疫性疾患である、請求項34又は35に記載の方法又は使用。
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CN107428830A (zh) | 2017-12-01 |
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US20160196648A1 (en) | 2016-07-07 |
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