JP2019523017A - Cd3結合抗体 - Google Patents
Cd3結合抗体 Download PDFInfo
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- JP2019523017A JP2019523017A JP2019519970A JP2019519970A JP2019523017A JP 2019523017 A JP2019523017 A JP 2019523017A JP 2019519970 A JP2019519970 A JP 2019519970A JP 2019519970 A JP2019519970 A JP 2019519970A JP 2019523017 A JP2019523017 A JP 2019523017A
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Abstract
Description
本出願は、2016年6月21日に出願された米国仮特許出願第62/352,698号、2016年9月14日に出願された米国仮特許出願第62/394,360号、及び2017年4月28日に提出された米国仮特許出願第62/491,908号の利益を主張し、これらの出願は、その全体が本明細書に参考として援用される。
身体の免疫システムは、感染、傷害及びがんに対する防御の役割を果たす。2つの別々ではあるが、相互に関連したシステムである、体液性免疫システムと細胞性免疫システムは、身体を保護するために一緒に働く。体液性システムは、抗体と呼ばれる可溶性因子によって媒介され、体内で異物として認識される生成物を中和する。対照的に、細胞性システムは、外来の侵入物を除去し中和するT細胞及びマクロファージなどの細胞を含む。
CD3抗体は、例えば、米国特許第5,585,097号、5,929,212号、5,968,509号、6,706,265号、6,750,325号、7,381,803号、7,728,114号に開示されている。CD3結合特異性を有する二重特異性抗体は、例えば、米国特許第7,262,276号、7,635,472号、7,862,813号、及び8,236,308号に開示され、それぞれは本明細書に参照により具体的に組み込まれる。
その組成物及びその使用方法は、CD3に結合し、CD3を介してシグナル伝達を活性化(例えば、CD3+T細胞の活性化)する密接に関連した抗体のファミリーのために提供される。ファミリー内の抗体は、本明細書で定義されるCDR配列のセットを含む。抗体ファミリーは、臨床的治療剤(複数可)としての有用性に寄与する多くの利益を提供する。ファミリー内の抗体は、ある範囲の結合親和性を有するメンバーを含み、所望の親和性を有する特定の配列の選択を可能にする。親和性を微調整する能力は、治療される個体において、CD3活性化のレベルを管理し、それによって毒性を低減することが特に重要である。抗体ファミリーのメンバーは、約10−6〜約10−11Mの範囲のCD3に対する親和性(KD)を有し得る。本発明の抗体ファミリーの特定のメンバーは、カニクイザル(Cynomolgus macaque)のCD3タンパク質と交差反応性であり、この交差反応性に必要とされる特異的モチーフが同定され、これに基づいて、前臨床または臨床試験のための抗体の選択が可能となる。
X5は、任意のアミノ酸であってもよく、いくつかの実施形態において、X5は、SまたはRであり、
X7及びX8は、任意のアミノ酸であってもよく、いくつかの実施形態において、X7及びX8は、独立して、SまたはGである。いくつかの実施形態において、X7X8は、SSまたはGGであり、
X9は、任意のアミノ酸であってもよく、いくつかの実施形態において、X9は、HまたはYであり、いくつかの実施形態において、X9はHであり、X10は、任意のアミノ酸であってもよく、いくつかの実施形態においてX10は、YまたはFであり、いくつかの実施形態において、X10は、Yである。
X2’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X2’は、S、YまたはHであり、
X3’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X3’は、Y、HまたはRであり、
X6’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X6’は、S、NまたはIまたはRであり、
X7’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X7’は、TまたはPである。
X1’’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X1’’は、AまたはGである。
X8’’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X8’’は、LまたはFである。
X9’’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X9’’は、TまたはAである。
X10’’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X10’’は、G、AまたはRである。
本発明の理解を容易にするために、いくつかの用語を以下に定義する。
「含む」とは、列挙された要素が組成物/方法/キットにおいて必要とされることを意味するが、他の要素は、請求項の範囲内において組成物/方法/キットなどを形成するために含まれ得る。
本発明は、CD3に結合し、CD3を介してシグナル伝達を活性化(例えば、CD3+T細胞の活性化)する密接に関連する抗体のファミリーを提供する。ファミリー内の抗体は、本明細書で定義されるCDR配列のセットを含み、配列番号1〜68の提供されるVH配列、及び配列番号69の例示されるVL配列によって例示される。抗体のファミリーは、臨床的治療剤(複数可)としての有用性に寄与する多くの利益を提供する。ファミリー内の抗体は、ある範囲の結合親和性を有するメンバーを含み、所望の親和性を有する特定の配列の選択を可能にする。親和性を微調整する能力は、治療される個体におけるCD3活性化のレベルを管理し、それによって、毒性を低減することが特に重要である。例えば、小さく豊富な腫瘍抗原(細胞当たり10,000分子未満)が標的化される場合、高い親和性のCD3結合剤(<30nM)が存在することが予測される。大きく豊富な腫瘍抗原(細胞あたり50,000分子以上)が標的化される場合、低い親和性(>50nM)を有するCD3結合体が好ましい。
X7及びX8は、任意のアミノ酸であってもよく、いくつかの実施形態において、X7及びX8は、独立して、SまたはGである。いくつかの実施形態において、X7X8は、SSまたはGGであり、X9は、任意のアミノ酸であってもよく、いくつかの実施形態において、X9は、HまたはYであり、いくつかの実施形態において、X9はHであり、
X10は、任意のアミノ酸であってもよく、いくつかの実施形態においてX10は、YまたはFであり、いくつかの実施形態において、X10は、Yである。
X2’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X2’は、S、YまたはHであり、
X3’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X3’は、Y、HまたはRであり、
X6’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X6’は、S、NまたはIまたはRであり、
X7’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X7’は、TまたはPである。
X1’’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X1’’は、AまたはGである。
X8’’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X8’’は、LまたはFである。
X9’’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X9’’は、TまたはAである。
X10’’は、任意のアミノ酸であってもよく、いくつかの実施形態において、X10’’は、G、AまたはRである。
抗体は、化学合成によって調製され得るが、典型的には、例えば、単一の組み換え宿主細胞においてタンパク質を構成するすべての鎖の共発現、または重鎖ポリペプチド及び抗体(例えば、ヒト抗体)の共発現などの組換えDNA技術の方法によって産生される。さらに、抗体の重鎖及び軽鎖は、単一のポリシストロニック発現ベクターを用いて、発現させることもできる。個々のポリペプチドの精製は、親和性(プロテインA)クロマトグラフィー、サイズ排除クロマトグラフィー及び/または疎水性相互作用クロマトグラフィーなどの標準的なタンパク質精製技術を用いて達成される。二重特異性物質はサイズ及び疎水性において十分に異なり、精製は標準的な手順を用いて実施され得る。
本発明の別の態様は、適切な薬学的に許容される担体と混合した本発明の1つ以上のタンパク質を含む医薬組成物を提供することである。本明細書で使用される薬学的に許容される担体は、限定されるものではないが、アジュバント、固体担体、水、緩衝液、もしくは治療成分を保持するために当該技術分野で使用される他の担体、またはそれらの組み合わせを例示する。
特に、抗原結合性組成物が治療される状態に適した多重特異性抗体である場合、例えば、関連するがん細胞の治療のために、1つの結合部分(関連する感染症の治療のために、目的の病原体に対する特異的な結合部分など)が腫瘍関連抗原に特異的に結合する場合、標的細胞を本発明の抗原結合性組成物と接触させることを含むレジメンにおいて、限定されるものではないが、感染症、自己免疫疾患、原発性または転移性がんなどを含む疾患を治療または軽減するための方法が提供される。そのような方法は、治療有効量または本発明の有効量の薬剤を、治療を必要とする対象に投与することを含み、限定されるものではないが、試薬と化学療法剤、放射線療法、または手術との組合せを含む。
重鎖のみの抗体を発現する遺伝子操作されたラット
ヒトIgH遺伝子座を、ヒトVH6−D−JH領域の下流に連結したラットC領域遺伝子の改変及び連結を含むいくつかの部分で構築し、組み立てた。次いで、ヒトVH遺伝子の別々のクラスターを有する2つのBACを、組み立てられた(ヒトVH6−D−JH−ラットC)断片をコードするBACと同時に注入した。
固定された軽鎖抗体を発現する遺伝子操作されたラット
トランスジェニックヒト抗体レパートリーは、固有のL鎖と組み合わせて、多様な(VH−D−JH)n再編成を有するH鎖から生成された。このために、再編成したL鎖ヒトVk−Jk1−CkをDNAマイクロインジェクションによりラット生殖系列に組み込み、得られたトランスジェニック動物を、ヒトH鎖レパートリーを天然に発現する以前に記載されたラット株で飼育した(Osborn et al., 2013)。この新しいラット株は、OmniFlicと命名された。
トランスジェニックラットにおける抗原特異的抗体の生成
ラットにおける抗原特異的重鎖抗体の生成のために、遺伝子操作された発現ラットを2つの方法で免疫化した。
T細胞を活性化してサイトカインを産生し、その表面上のCD69をアップレギュレ−トするそれらの能力について、上記のようなキャンペーンから誘導された抗体をさらに特徴化した。Jurkat細胞または末梢血リンパ球によって産生されたIL−2の定量のために、BioLegendのELISA maxキットを使用した。ヒト末梢血T細胞及び異なる濃度のOmniFlic抗体を用いた実験の結果を図3に示す。
二重特異性の更なる開発のために、抗CD3 FlicAb ID304703(配列番号39)を選択した。このFlicAbは、カニクイザルのCD3と交差反応し、ヒトT細胞を強力に刺激する。二種類の二重特異性が産生された(模式図については図2を参照されたい)。二重特異性FlicAbを作製するために、Knobs−into−holes技術を用いた(Protein Engineering vol.9 no.7 pp.617−621, 1996,‘Knobs−into−holes’engineering of antibody CH3 domains for heavy chain heterodimerization. John B.B.Ridgway, Leonard G. Presta and Paul Carter)。ノブを有する重鎖のC末端をCタグでタグ付けし、ヘテロ二量体抗体をCaptureSelectのCタグアフィニティーマトリックス(Thermo Fischer Scientific)を用いて精製した。一方のアームがCD3(ID 304703)と反応し、他方がヒトPD−L1と反応する二重特異性FlicAbが産生され、PD−L1陽性腫瘍細胞の存在下でのみヒトCD8+T細胞を活性化することが示された(図3)。HDLM2は、多発性骨髄腫細胞株であり、表面上にPD−L1を発現する。Ramosは、バーキットリンパ腫の細胞株であり、これは、PD−L1に対して陰性である。CD69の発現を読み出シートとして使用した。指示された濃度で二重特異性抗体を使用した。
二重特異性殺傷活性とサイトカイン放出との相関
図6に示すように、それぞれ固有の抗CD3アーム(示されているとおり)及び共通の抗BCMAアームを有する4つのαCD3_fam1:aBCMA二重特異性抗体を、活性化した初代T細胞のリダイレクションを通して、U266 BCMA+腫瘍細胞を殺傷させる能力について試験した。この実験において、BCMAを発現するU266細胞を、二重特異性抗体の添加と共に、10:1 E:T比で活性化汎T細胞と混合した。X軸は、使用した抗体の濃度を示し、Y軸は、抗体を添加して6時間後の腫瘍細胞の%溶解を示す。殺傷活性は、IL−2の放出(図7)、IFNγの放出(図8)、及びCD3結合親和性(図9)と相関していた。IL−2の産生とU266腫瘍細胞の溶解との間の相関は、R2=0.37である。IFNγ産生とU266腫瘍細胞の溶解との間の相関は、R2=0.53である。U266殺傷EC50とタンパク質結合親和性との間の相関は、R2=0.93である。
本発明は、例えば、以下の項目を定要する。
(項目1)
ヒトVHフレームワークにおいてCDR1、CDR2及びCDR3配列を含む可変重鎖ドメインと、
可変軽鎖ドメインと、
を含むCD3に対して特異的な抗原結合タンパク質であって、
前記CDR1配列は、式
を有し、
X 5 、X 7 、X 8 、X 9 及びX 10 は、任意のアミノ酸であってもよく、
前記CDR2配列は、式
を有し、
X 2’ 、X 3’ 、X 6’ 及びX 7 ’は、任意のアミノ酸であってもよく、
前記CDR3配列は、式
を有し、
X 1’’ 、X 8’’ 、X 9’’ 及びX 10’’ は、任意のアミノ酸であってもよい、前記抗原結合タンパク質。
(項目2)
ヒトVHフレームワークにおいて、CDR1、CDR2及びCDR3配列を含む可変重鎖ドメインと、
可変軽鎖ドメインと、
を含むCD3に対して特異的な抗原結合タンパク質であって、
前記CDR1、CDR2またはCDR3は、任意の配列番号1〜68に見出される、前記抗原結合タンパク質。
(項目3)
ヒトVHフレームワークにおいて、CDR1、CDR2及びCDR3配列を含む可変重鎖ドメインと、
可変軽鎖ドメインと、
を含むCD3に対して特異的な抗原結合タンパク質であって、
前記CDR配列は、配列番号1〜68の任意の1つにおいて、CDR配列またはCDR配列のセットに対して少なくとも85%の同一性を有する配列である、前記抗原結合タンパク質。
(項目4)
ヒトVHフレームワークにおいて、CDR1、CDR2及びCDR3配列を含む可変重鎖ドメインと、
可変軽鎖ドメインと、
を含むCD3に対して特異的な抗原結合タンパク質であって、
前記CDR配列は、配列番号1〜68の任意の1つにおいて、CDR配列またはCDR配列のセットに対して3個までのアミノ酸置換を有する配列である、前記抗原結合タンパク質。
(項目5)
前記可変軽鎖ドメインは、ヒトVLフレームワークにおいて、CDR1、CDR2及びCDR3配列を含み、
前記CDR配列は、配列番号69において、CDR配列またはCDR配列のセットに対して3個までのアミノ酸置換を有する配列であるか、または、
前記CDR配列は、配列番号69において、CDR配列またはCDR配列のセットに対して少なくとも85%の同一性を有する配列である、項目1〜4のいずれかに記載の抗原結合タンパク質。
(項目6)
前記可変重鎖ドメインは、配列番号1〜68のいずれかに記載のアミノ酸配列を含む、項目1〜5のいずれかに記載の抗原結合タンパク質。
(項目7)
前記可変軽鎖ドメインは、配列番号69のアミノ酸配列を含む、項目1〜6のいずれかに記載の抗原結合タンパク質。
(項目8)
活性化アッセイにおいてT細胞と接触させた場合、前記抗原結合タンパク質は、参照抗CD3抗体と比較して、IL−2及びIL−10の一方または両方の低下したレベルの放出を誘導する、項目1〜7のいずれかに記載の抗原結合タンパク質。
(項目9)
Fc領域をさらに含む、項目1〜8のいずれかに記載の抗原結合タンパク質。
(項目10)
前記Fc領域は、エフェクター機能を低下させるように操作されている、項目9に記載の抗原結合タンパク質。
(項目11)
ヒトCD3デルタイプシロンに対する前記タンパク質の親和性(KD)は、約10 −6 Mから約10 −11 Mである、項目1〜10のいずれかに記載の抗原結合タンパク質。
(項目12)
前記タンパク質は、ヒト及びカニクイザルのCD3タンパク質と交差反応する、項目1〜10のいずれかに記載の抗原結合タンパク質。
(項目13)
前記タンパク質が一本鎖である、項目1〜12のいずれかに記載の抗原結合タンパク質。
(項目14)
前記タンパク質が二本鎖またはその倍数である、項目1〜12のいずれかに記載の抗原結合タンパク質。
(項目15)
前記タンパク質が三本鎖である、項目1〜12のいずれかに記載の抗原結合タンパク質。
(項目16)
前記タンパク質が三本鎖であり、両方の抗原結合性アームが抗体の重鎖及び軽鎖を含む、項目1〜12のいずれかに記載の抗原結合タンパク質。
(項目17)
前記タンパク質は、CD3以外のタンパク質に特異的な可変重鎖ドメインをさらに含む、項目1〜12のいずれかに記載の抗原結合タンパク質。
(項目18)
前記タンパク質は、CD3以外のタンパク質に特異的な可変重鎖ドメインをさらに含み、
活性化アッセイにおいてT細胞と接触させた場合、前記抗原結合タンパク質は、参照抗CD3抗体と比較して、IL−2及びIL−10の一方または両方の低下したレベルの放出を誘導し、
腫瘍細胞及びヒトT細胞を用いた標準インビトロアッセイにおいて、30%を超える腫瘍細胞傷害性を誘導する、項目1〜17のいずれかに記載の抗原結合タンパク質。
(項目19)
CD3以外のタンパク質に特異的な前記可変重鎖ドメインは、重鎖のみのドメインである、項目17に記載の抗原結合タンパク質。
(項目20)
CD3以外のタンパク質に特異的な可変重鎖ドメインは、軽鎖可変領域をさらに含む、項目19に記載の抗原結合タンパク質。
(項目21)
前記軽鎖可変領域は、前記CD3結合領域の軽鎖可変領域と同一である、項目19に記載の抗原結合タンパク質。
(項目22)
CD3以外の前記タンパク質は、腫瘍関連抗原である、項目17〜21のいずれかに記載の抗原結合タンパク質。
(項目23)
CD3以外の前記タンパク質は、病原体抗原である、項目17〜21のいずれかに記載の抗原結合タンパク質。
(項目24)
CD3以外の前記タンパク質は、免疫調節タンパク質である、項目17〜21のいずれかに記載の抗原結合タンパク質。
(項目25)
項目1〜24のいずれかに記載の抗原結合タンパク質を含む医薬組成物。
(項目26)
単位用量の製剤化における、項目25に記載の医薬製剤。
(項目27)
項目1〜24のいずれかに記載の抗原結合タンパク質をコードするポリヌクレオチド
。
(項目28)
項目27に記載のポリヌクレオチドを含むベクター。
(項目29)
項目28に記載のベクターを含む細胞。
(項目30)
前記タンパク質の発現を許容する条件下で、項目29に記載の細胞を増殖させ、前記タンパク質を前記細胞から単離することを含む、項目1〜24のいずれかに記載の抗原
結合タンパク質の製造方法。
(項目31)
有効量の項目1〜24のいずれかに記載の抗原結合タンパク質を個体に投与すること
を含む、治療方法。
(項目32)
前記個体がヒトである、項目31に記載の方法。
(項目33)
CD3に対して特異的な抗原結合タンパク質を作製する方法であって、
OmniFlicまたはUniRat動物をCD3で免疫すること、及び
抗原特異的な重鎖配列を同定することを含む、前記方法。
(項目34)
OmniFlicまたはUniRat動物をCD3以外の抗原で免疫すること、及び
項目1〜16のいずれかに記載の前記抗原結合タンパク質を含む分子において、組み合わせ得る抗原特異的な重鎖配列を同定すること、を含む項目17に記載の抗原結合タンパク質を作製する方法。
(項目35)
前記タンパク質は、CD3に対して特異的な結合ドメイン及びCD3以外の抗原に特異的な結合ドメインを含み、
活性化アッセイにおいてT細胞と接触させた場合、前記二重特異性抗原結合タンパク質は、参照抗CD3抗体と比較して、IL−2及びIL−10の一方または両方の低下したレベルの放出を誘導し、
腫瘍細胞及びヒトT細胞を用いた標準インビトロアッセイにおいて、30%を超える腫瘍細胞傷害性を誘導する、前記二重特異性抗原結合タンパク質。
(項目36)
(i)ヒトVHフレームワークにおいて、配列番号1のCDR1、CDR2及びCDR3配列を含むCD3結合可変領域と、
(ii)ヒトVLフレームワークにおいて、配列番号69のCDR1、CDR2及びCDR3配列を含む可変軽鎖ドメインと、
(iii)単一またはタンデムな構成において、配列番号70の26〜33位、51〜58位、97〜108位のそれぞれで、CDR1、CDR2及びCDR3配列を含む一本鎖抗BCMA可変領域含む二重特異性抗体。
(項目37)
Fc領域をさらに含む、項目36に記載の二重特異性抗体。
(項目38)
前記CD3結合可変領域は、配列番号1を含み、前記軽鎖可変領域は、配列番号69を含み、また、前記BCMA結合可変領域は、配列番号70または配列番号71を含む、項目37に記載の二重特異性抗体。
Claims (38)
- ヒトVHフレームワークにおいてCDR1、CDR2及びCDR3配列を含む可変重鎖ドメインと、
可変軽鎖ドメインと、
を含むCD3に対して特異的な抗原結合タンパク質であって、
前記CDR1配列は、式
X5、X7、X8、X9及びX10は、任意のアミノ酸であってもよく、
前記CDR2配列は、式
X2’、X3’、X6’及びX7’は、任意のアミノ酸であってもよく、
前記CDR3配列は、式
X1’’、X8’’、X9’’及びX10’’は、任意のアミノ酸であってもよい、前記抗原結合タンパク質。 - ヒトVHフレームワークにおいて、CDR1、CDR2及びCDR3配列を含む可変重鎖ドメインと、
可変軽鎖ドメインと、
を含むCD3に対して特異的な抗原結合タンパク質であって、
前記CDR1、CDR2またはCDR3は、任意の配列番号1〜68に見出される、前記抗原結合タンパク質。 - ヒトVHフレームワークにおいて、CDR1、CDR2及びCDR3配列を含む可変重鎖ドメインと、
可変軽鎖ドメインと、
を含むCD3に対して特異的な抗原結合タンパク質であって、
前記CDR配列は、配列番号1〜68の任意の1つにおいて、CDR配列またはCDR配列のセットに対して少なくとも85%の同一性を有する配列である、前記抗原結合タンパク質。 - ヒトVHフレームワークにおいて、CDR1、CDR2及びCDR3配列を含む可変重鎖ドメインと、
可変軽鎖ドメインと、
を含むCD3に対して特異的な抗原結合タンパク質であって、
前記CDR配列は、配列番号1〜68の任意の1つにおいて、CDR配列またはCDR配列のセットに対して3個までのアミノ酸置換を有する配列である、前記抗原結合タンパク質。 - 前記可変軽鎖ドメインは、ヒトVLフレームワークにおいて、CDR1、CDR2及びCDR3配列を含み、
前記CDR配列は、配列番号69において、CDR配列またはCDR配列のセットに対して3個までのアミノ酸置換を有する配列であるか、または、
前記CDR配列は、配列番号69において、CDR配列またはCDR配列のセットに対して少なくとも85%の同一性を有する配列である、請求項1〜4のいずれかに記載の抗原結合タンパク質。 - 前記可変重鎖ドメインは、配列番号1〜68のいずれかに記載のアミノ酸配列を含む、請求項1〜5のいずれかに記載の抗原結合タンパク質。
- 前記可変軽鎖ドメインは、配列番号69のアミノ酸配列を含む、請求項1〜6のいずれかに記載の抗原結合タンパク質。
- 活性化アッセイにおいてT細胞と接触させた場合、前記抗原結合タンパク質は、参照抗CD3抗体と比較して、IL−2及びIL−10の一方または両方の低下したレベルの放出を誘導する、請求項1〜7のいずれかに記載の抗原結合タンパク質。
- Fc領域をさらに含む、請求項1〜8のいずれかに記載の抗原結合タンパク質。
- 前記Fc領域は、エフェクター機能を低下させるように操作されている、請求項9に記載の抗原結合タンパク質。
- ヒトCD3デルタイプシロンに対する前記タンパク質の親和性(KD)は、約10−6Mから約10−11Mである、請求項1〜10のいずれかに記載の抗原結合タンパク質。
- 前記タンパク質は、ヒト及びカニクイザルのCD3タンパク質と交差反応する、請求項1〜10のいずれかに記載の抗原結合タンパク質。
- 前記タンパク質が一本鎖である、請求項1〜12のいずれかに記載の抗原結合タンパク質。
- 前記タンパク質が二本鎖またはその倍数である、請求項1〜12のいずれかに記載の抗原結合タンパク質。
- 前記タンパク質が三本鎖である、請求項1〜12のいずれかに記載の抗原結合タンパク質。
- 前記タンパク質が三本鎖であり、両方の抗原結合性アームが抗体の重鎖及び軽鎖を含む、請求項1〜12のいずれかに記載の抗原結合タンパク質。
- 前記タンパク質は、CD3以外のタンパク質に特異的な可変重鎖ドメインをさらに含む、請求項1〜12のいずれかに記載の抗原結合タンパク質。
- 前記タンパク質は、CD3以外のタンパク質に特異的な可変重鎖ドメインをさらに含み、
活性化アッセイにおいてT細胞と接触させた場合、前記抗原結合タンパク質は、参照抗CD3抗体と比較して、IL−2及びIL−10の一方または両方の低下したレベルの放出を誘導し、
腫瘍細胞及びヒトT細胞を用いた標準インビトロアッセイにおいて、30%を超える腫瘍細胞傷害性を誘導する、請求項1〜17のいずれかに記載の抗原結合タンパク質。 - CD3以外のタンパク質に特異的な前記可変重鎖ドメインは、重鎖のみのドメインである、請求項17に記載の抗原結合タンパク質。
- CD3以外のタンパク質に特異的な可変重鎖ドメインは、軽鎖可変領域をさらに含む、請求項19に記載の抗原結合タンパク質。
- 前記軽鎖可変領域は、前記CD3結合領域の軽鎖可変領域と同一である、請求項19に記載の抗原結合タンパク質。
- CD3以外の前記タンパク質は、腫瘍関連抗原である、請求項17〜21のいずれかに記載の抗原結合タンパク質。
- CD3以外の前記タンパク質は、病原体抗原である、請求項17〜21のいずれかに記載の抗原結合タンパク質。
- CD3以外の前記タンパク質は、免疫調節タンパク質である、請求項17〜21のいずれかに記載の抗原結合タンパク質。
- 請求項1〜24のいずれかに記載の抗原結合タンパク質を含む医薬組成物。
- 単位用量の製剤化における、請求項25に記載の医薬製剤。
- 請求項1〜24のいずれかに記載の抗原結合タンパク質をコードするポリヌクレオチド。
- 請求項27に記載のポリヌクレオチドを含むベクター。
- 請求項28に記載のベクターを含む細胞。
- 前記タンパク質の発現を許容する条件下で、請求項29に記載の細胞を増殖させ、前記タンパク質を前記細胞から単離することを含む、請求項1〜24のいずれかに記載の抗原結合タンパク質の製造方法。
- 有効量の請求項1〜24のいずれかに記載の抗原結合タンパク質を個体に投与することを含む、治療方法。
- 前記個体がヒトである、請求項31に記載の方法。
- CD3に対して特異的な抗原結合タンパク質を作製する方法であって、
OmniFlicまたはUniRat動物をCD3で免疫すること、及び
抗原特異的な重鎖配列を同定することを含む、前記方法。 - OmniFlicまたはUniRat動物をCD3以外の抗原で免疫すること、及び
請求項1〜16のいずれかに記載の前記抗原結合タンパク質を含む分子において、組み合わせ得る抗原特異的な重鎖配列を同定すること、を含む請求項17に記載の抗原結合タンパク質を作製する方法。 - 前記タンパク質は、CD3に対して特異的な結合ドメイン及びCD3以外の抗原に特異的な結合ドメインを含み、
活性化アッセイにおいてT細胞と接触させた場合、前記二重特異性抗原結合タンパク質は、参照抗CD3抗体と比較して、IL−2及びIL−10の一方または両方の低下したレベルの放出を誘導し、
腫瘍細胞及びヒトT細胞を用いた標準インビトロアッセイにおいて、30%を超える腫瘍細胞傷害性を誘導する、前記二重特異性抗原結合タンパク質。 - (i)ヒトVHフレームワークにおいて、配列番号1のCDR1、CDR2及びCDR3配列を含むCD3結合可変領域と、
(ii)ヒトVLフレームワークにおいて、配列番号69のCDR1、CDR2及びCDR3配列を含む可変軽鎖ドメインと、
(iii)単一またはタンデムな構成において、配列番号70の26〜33位、51〜58位、97〜108位のそれぞれで、CDR1、CDR2及びCDR3配列を含む一本鎖抗BCMA可変領域含む二重特異性抗体。 - Fc領域をさらに含む、請求項36に記載の二重特異性抗体。
- 前記CD3結合可変領域は、配列番号1を含み、前記軽鎖可変領域は、配列番号69を含み、また、前記BCMA結合可変領域は、配列番号70または配列番号71を含む、請求項37に記載の二重特異性抗体。
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