JP6585600B2 - C末端軽鎖ポリペプチド伸長を含有する抗体、ならびにその複合体及びその使用方法 - Google Patents
C末端軽鎖ポリペプチド伸長を含有する抗体、ならびにその複合体及びその使用方法 Download PDFInfo
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- JP6585600B2 JP6585600B2 JP2016543004A JP2016543004A JP6585600B2 JP 6585600 B2 JP6585600 B2 JP 6585600B2 JP 2016543004 A JP2016543004 A JP 2016543004A JP 2016543004 A JP2016543004 A JP 2016543004A JP 6585600 B2 JP6585600 B2 JP 6585600B2
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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Description
米国特許法第119条(e)の定めに従い、本出願は、2013年12月23日に出願された米国仮特許出願第61/920,425号の優先権を主張するものであり、当該開示は、参照により本明細書に援用される。
「抗体」及び「イムノグロブリン」という用語は、任意のアイソタイプの抗体またはイムノグロブリンである、完全抗体(たとえば、テトラマーから構成される抗体であり、当該テトラマーは同様に重鎖ポリペプチドと軽鎖ポリペプチドの2つのヘテロダイマーから構成され、完全IgG、IgA、IgD、IgEまたはIgM抗体を含む);半抗体(たとえば、重鎖ポリペプチドと軽鎖ポリペプチドの1つの二量体を含む抗体);限定されないが、Fab、F(ab’)2、Fab’、Fv、scFv、二特異性抗体、及びダイアボディを含む、対象抗原への特異的結合を保持している抗体断片(たとえば、IgG、IgA、IgD、IgEまたはIgM抗体等の完全抗体の断片);キメラ抗体;モノクローナル抗体;ヒト化抗体(たとえば、ヒト化モノクローナル抗体、またはヒト化抗体断片);または完全なヒト抗体(ヒトイムノグロブリンタンパク質配列のみを含有する抗体)を含む。また、体細胞変異ならびに/またはV−D−J再構成の結果としてNヌクレオチドもしくはPヌクレオチドの付加及び欠失を含むヒトモノクローナル抗体が含まれる。また、合成配列がCDRに挿入されているヒト抗体が含まれる(たとえば、Miersch S & Sidhu SS (2012)Synthetic antibodies:concepts,potential and practical considerations.Methods 57(4):486−98;及びKnappik et al.(2000)Fully synthetic human combinatorial antibody libraries (HuCAL)based on modular consensus frameworks and CDRs randomized with trinucleotides.J.Mol.Biol.296(1):57−86)を参照のこと)。ある態様において、本開示抗体は、IgG(たとえば、IgG1、IgG2、IgG3またはIgG4抗体)、Fab、F(ab’)2、及びFab’から選択される。
1つの態様において、本明細書は、抗体へのペイロード付加のためのペイロードアダプター(本明細書において、「C末端アミノ酸伸長」または「C末端伸長」とも呼称される)、ならびに当該ペイロードアダプターを含有する抗体を提示する。
(XaCb)c(X’dCe)f (I)
ここで、
X及びX’は、1以上のアミノ酸のスペーサーを表し、ここで、各X及びX’のアミノ酸配列は、独立して、本明細書に開示されるスペーサーアミノ酸配列の例のいずれかを含む、対象の任意のアミノ酸配列から選択され、
Cは、システイン残基を表し、
a、b、c、d、e及びfは、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、及び20から独立して選択される整数を表し、ここで、b及びeの総計は、少なくとも1であり、ならびにc及びfの総計は少なくとも1である。X及びX’は、同じであっても異なっていてもよい。cが1よりも大きい場合、(XaCb)cの各Xは、(XaCb)cの各反復単位内で、同じアミノ酸配列であっても異なるアミノ酸配列であってもよい。dが1よりも大きい場合、(X’dCe)fの各X’は、(X’dCe)fの各反復単位内で、同じアミノ酸配列であっても異なるアミノ酸配列であってもよい。
(XaCb)c(X’dCe)f(X”gCh)i (II)
ここで、
X、X’及びX’’は、1以上のアミノ酸のスペーサーを表し、ここで、各X、X’及びX’’のアミノ酸配列は、独立して、本明細書に開示されるスペーサーアミノ酸配列の例のいずれかを含む、対象の任意のアミノ酸配列から選択され、
Cは、システイン残基を表し:及び、
a、b、c、d、e、f、g、h及びiは、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、及び20から独立して選択される整数であり、ここで、b、e、及びhの総計は、少なくとも1であり、ならびにc、f及びiの総計は少なくとも1である。X、X’及びX’’は、同じであっても異なっていてもよい。cが1よりも大きい場合、(XaCb)cの各Xは、(XaCb)cの各反復単位内で、同じアミノ酸配列であっても異なるアミノ酸配列であってもよい。dまたはfが1よりも大きい場合、(X’dCe)fの各X’は、(X’dCe)fの各反復単位内で、同じアミノ酸配列であっても異なるアミノ酸配列であってもよい。gまたはiが1よりも大きい場合、(X’’gCh)iの各X’’は、(X’’gCh)iの各反復単位内で、同じアミノ酸配列であっても異なるアミノ酸配列であってもよい。
本発明により、C末端アミノ酸伸長(本明細書において、簡便性を目的として「改変軽鎖ポリペプチド」と呼称される)を有する軽鎖ポリペプチドをコードする核酸、ならびに、当該核酸を含有するベクター及び宿主細胞が開示される。当該核酸によりコードされる当該改変軽鎖ポリペプチドは、上述の特性のいずれかを任意の組み合わせで含有してもよい。たとえば、当該複合体の抗体部分のC末端伸長は、当該伸長の長さ、当該伸長のアミノ酸組成、当該伸長中のスペーサーの数、及びそのアミノ酸配列に関し、上述のC末端伸長の特性のいずれかを含有してもよく、1以上のスペーサー及び1以上のシステイン残基の組み合わせに基づいた伸長構成のいずれかを含有してもよく、ならびに上述及び本明細書の他の部分に記述されるC末端伸長の任意の他の態様を含有してもよい。
上述のように、本発明により、改変軽鎖ポリペプチド(すなわち、本発明のC末端伸長を有する軽鎖ポリペプチド)の作製方法、ならびに1つ以上の当該改変軽鎖ポリペプチドを含有する抗体の作製方法が開示される。
本発明は、C末端伸長を有する軽鎖ポリペプチドを少なくとも1つ有する抗体を開示するものであり、当該C末端伸長のうちの少なくとも1つのシステインは、剤(たとえば薬剤)に結合されている。
ある態様において、当該剤は、リンカーを介してシステイン残基に結合されている。本発明の複合体における用途が見いだされるリンカーとしては、マレイミド、またはマレイミドをベースとしたリンカー;バリン‐シトルリンリンカー;ヒドラゾンリンカー;N−スクシンイミジル−4−(2−ピリジルジチオ)酪酸塩(SPDB)リンカー;スクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボン酸塩(SMCC)リンカー;ビニルスルホンをベースとしたリンカー;システインに適合された金属原子(複数含む)を含有するリンカー;たとえば限定されないがテトラエチレングリコール等のポリエチレングリコール(PEG)を含有するリンカー;プロパン酸を含有するリンカー;カプロレイン酸を含有するリンカー;Fleximer(登録商標)ポリマー(Mersana Therapeutics,Cambridge,MA)を含有するリンカー、またはFleximerポリマーに薬剤を付加するために用いられるリンカー(たとえば、USPN 8,524,214(参照によりその全体で本明細書に援用される)を参照のこと);及びそれらの任意の組み合わせを含有するリンカーが挙げられる。
本発明の抗体複合体のペイロードとなる剤は、任意の適切な剤であってもよい。本発明の抗体複合体での使用に選択される剤は、当該複合体が用いられる応用法により変化しうる(たとえば、殺傷、細胞増殖阻害、ホルモン療法、標的画像化及び/または遺伝子治療等)。対象の剤としては、限定されないが、治療剤(たとえば、薬剤(たとえば、細胞毒性剤))、検出可能な剤(たとえば、in vivoイメージング剤)、及び/または対象の特定の抗体をベースにした応用法に有用な他の剤が挙げられる。
本発明はまた、抗体複合体の作製方法を開示するものである。当該方法は、C末端アミノ酸伸長を含有する軽鎖ポリペプチドを含有する抗体に剤を結合することを含み、当該伸長はシステイン残基を含有し、当該剤は、当該C末端アミノ酸伸長のシステイン残基に、直接、または間接的(たとえばリンカーを介して)に結合される。1つの実施形態において、当該方法は、当該C末端伸長の外側のシステインではなく、当該C末端アミノ酸伸長のシステイン残基に優先的に(または「偏向的に」)剤が結合することを含む。ある態様において、当該結合は、たとえばマレイミド化学反応、ハロアセチル化学反応、ピリジルジスルフィド化学反応、または本明細書に記述される他の任意の適切な化学反応を用いて、当該システイン残基のスルフヒドリル基にリンカーを結合させることを含む。当該複合体を作製する方法はさらに、結合工程の前に、たとえば上述の適切な還元剤及び反応条件を用いて、システイン残基をスルフヒドリル基(すなわちチオール)に還元することを含む。適切な還元剤としては、限定されないが、DTPA、システアミン、TCEP(トリス(2−カルボキシエチル)ホスフィン塩酸塩)、それらの組み合わせ等が挙げられる。ある実施形態において、当該複合体を作製する方法は、C末端伸長を含有する軽鎖ポリペプチドを含有する抗体と還元剤を接触させることを含む。ある実施形態において、当該複合体を作製する方法は、C末端アミノ酸伸長を含有する軽鎖ポリペプチドを含有する抗体と、第一の還元剤を接触させ、次いで、C末端アミノ酸伸長を含有する軽鎖ポリペプチドを含有する抗体と、第二の還元剤を接触させることを含む。本発明の別の実施形態では、当該軽鎖伸長内のシステインが合成産物としてすでに還元状態にあるため、還元工程を必要としない。ある実施形態において、還元抗体は、適切な酸化剤と接触させられてもよい。適切な酸化剤としては、限定されないが、デヒドロアスコルビン酸(DHAA)等が挙げられる。抗体に結合される剤は、任意の有用な剤であってもよい。ある態様において、当該剤は、治療剤または標識剤であり、当該剤は、本明細書の他の箇所に記述されている。
上記に要約されるように、本発明により、組成物が開示される。本発明の組成物は、上述のいずれかの抗体、複合体、核酸、ベクター及び/または宿主細胞を含有してもよい。本発明の態様には、医薬組成物が含まれる。ある実施形態において、当該医薬組成物は、本明細書のいずれかに記述される任意の抗体(たとえば、上述のシステイン残基を含有するC末端アミノ酸伸長を含有する軽鎖ポリペプチドを含有する抗体)、または本明細書のいずれかに記述される任意の複合体(たとえば、上述のシステイン残基を含有するC末端アミノ酸伸長を含有する軽鎖ポリペプチドを有する抗体構成要素を含有する複合体)、及び薬学的に受容可能な添加剤を含有する。当該医薬組成物中に存在する抗体または複合体は、本発明の抗体、または本発明の複合体に関し、任意の組み合わせで、上述の特性のいずれかを含有してもよい。たとえば、抗体のC末端伸長、または複合体の抗体部分は、伸長の長さ、伸長を構成するアミノ酸、伸長中のスペーサーの数、及びそのアミノ酸配列、1以上のスペーサーと1以上のシステインの組み合わせに基づいた伸長の構造、ならびに上述及び本明細書のいずれかに記述されるC末端伸長の任意の他の態様に関し、上述のC末端伸長の特性のいずれかを含有してもよい。
本発明は、疾患または障害の治療方法を開示するものである。当該方法は、本明細書のいずれかに記述される抗体、複合体、または医薬組成物のいずれかの治療有効量を、その必要のある対象に投与することを含んでもよい。当該抗体または複合体は、単独で投与されてもよく(たとえば、単剤療法)、または1以上の追加の治療剤と組み合わされて投与されてもよい(たとえば、併用療法)。
本発明はまた、キットを開示する。ある実施形態によると、当該キットは、本明細書のいずれかに記述される特性のいずれかを有する、本発明の抗体、複合体または医薬組成物のいずれかを含有しうる。あるいは、またはさらに、当該キットは、本発明抗体、またはその軽鎖ポリペプチド、または本発明の複合体のいずれかの作製に有用な任意の試薬を含有してもよい。たとえば、当該キットは、システイン含有C末端アミノ酸伸長を含有する抗体軽鎖ポリペプチドをコードする核酸を含有してもよい。そのようなキットは、たとえば、本発明抗体または複合体の作製に用途が見いだされるコンピテント細胞、または1以上の抗体軽鎖ポリペプチド及び/もしくは重鎖ポリペプチドをコードする核酸をすでに有している細胞、当該C末端軽鎖ポリペプチド伸長中のシステイン残基のスルフヒドリル基を還元するための還元剤、システイン残基の還元スルフヒドリル基に剤を結合させるためのリンカー、剤(リンカーに付加される、またはリンカーから分離される)、試薬、緩衝液、精製カラム等、またはその任意の組み合わせを含有してもよい。当該キットは、本発明方法(たとえば、疾患もしくは障害の治療方法、抗体軽鎖ポリペプチドの作製方法、及び/または抗体複合体の作製方法)の実施において、用途が見いだされる。
C末端軽鎖ポリペプチドシステイン含有伸長を有する抗体をコードする核酸のクローニング
ヒトIgG1C及びヒトIgGkCクローニングベクターを作製するために、ヒトIgGC及びIgkC領域をpTT5ベクターへとクローニングした(図1)。定常領域を伴う、インフレームでの可変領域のクローニングを容易にするために、制限酵素部位を定常領域の5’末端に導入した。重鎖定常領域配列を、GCC TCCからGCT AGCへと変え、元のアミノ酸配列を維持しながらNheI制限酵素部位を導入した。軽鎖ポリペプチド定常領域配列を、CGA ACTからCGT ACGへと変え、元のアミノ酸配列を維持しながらBsiWI制限酵素部位を作製した。当該変化は、Operon−Eurofinsから購入したミスマッチPCRプライマーを設計することにより導入した。pTT5ベクターはBsiWI部位を含有していなかったため、IgkC5’プライマーを、5’NheIオーバーハングを用いて設計し、当該ベクターへのクローニングを容易にした。3’プライマーは、ストップコドンのBamHI制限酵素部位3’を用いて設計した。
上述の実施例1で作製されたプラスミドのQiagenマキシプレップを行い、トランスフェクション用のプラスミドを単離した。HEK293細胞に、ハーセプチン重鎖及びハーセプチン軽鎖‐cys構築物を用いて、293フェクチン(Invitrogen)を用いて共トランスフェクトした。細胞をFreestyle293発現培地(Gibco)(0.1% Pluronic F68(Gibco)溶液を補充)中で5日間、増殖させた。トランスフェクションの24時間後、細胞に0.5%トリプトンを補充した。上清を回収し、プロテインAセファロースバッチ重力プロトコール(GEHealthcare)を用いて分泌抗体を精製し、次いで、Amicon(登録商標)Ultra15フィルター(30kDa MWカットオフ)(Millipore)を用いて、PBS PH7.4に緩衝液交換を行った。
PBSに溶解したハーセプチン及びハーセプチン‐VLCysX(X=1、2または4)の試料(1〜5mg)を、100mM リン酸、50mM NaCl、2mM DTPA、pH6.1に前調整したZeba(商標)スピンカラム(Pierce、カタログ#87767)にアプライし、メーカーの説明書に従い緩衝液交換を行った。タンパク質濃度を確立するための標準物としてハーセプチン、及び遊離チオール基の無い場合を確立するための標準物としてシステインを使用したEllman‘s試薬を用いて、ビシンコニン酸アッセイ(Pierce、#23225)により溶出物を解析した。
上述の実施例3の溶出物を氷上で冷却した後、マレイミド毒素(toxin1、またはtoxin2)が、10mM DMSOストック溶液(通常、チオール当たり2.0eqであり、等量が還元ハーセプチン対照に加えられている(ハーセプチン‐toxin2))から添加された。精製及び緩衝液交換(20mM クエン酸ナトリウム、pH5.5)の前に、氷上で30〜70分間、結合反応を進ませた。精製された複合体を滅菌ろ過(Costar(登録商標)Spin−X(登録商標)0.22um遠心フィルター、#8161)を行い、BCA試薬を用いて総タンパク質含量の解析を行った。
上述の実施例4で作製された抗体薬剤複合体を、Her2陽性ヒト乳がん細胞株HCC1954に対し、様々な濃度で検証を行った。化合物添加の前日、HCC1954細胞(100μL)を、不透明壁で、透明な底の96ウェル組織培養処置マイクロタイタープレートに、完全増殖培地を用いて、2500細胞/10μL培地の密度で添加した。HCC1954細胞は、一晩、37℃/5%CO2でインキュベートし、マイクロタイタープレート表面に細胞を付着させた。抗体薬剤複合体は、所望される最終最大濃度の5倍で完全増殖培地中に希釈され、次いで、化合物は、同じ培地、8工程で1:3に用量設定された。化合物がない対照(増殖培地のみ)は、6連で、各マイクロタイタープレートに含まれた。調製された化合物希釈を3連でHCC1954細胞に添加した(25μL/ウェル)。細胞及び化合物希釈は、3〜5晩、37℃/5%CO2でインキュベートした。インキュベーション後、CellTiter−Glo(登録商標)試薬を用いて、各アッセイウェルに調整済みのCellTiter−Glo(登録商標)を30μL添加することにより、細胞活性を測定した。マイクロプレートルミノメーターを用いて発光を測定する前に、最短で20分間、混合物をインキュベートした(500msの積分時間)。集められた相対発光単位(RLU)は、上述の増殖培地単独対照を用いて、細胞毒性%に転換された(細胞毒性%=1−[ウェルRLU/平均培地単独対照RLU])。Prism Graph Padソフトウェアで使用可能な非線形回帰法を用いて、データを曲線に適合させた。本実験から得られたデータを示すグラフは図3に示す。Her−VLCys2−toxin2、Her−VLCys1−toxin1、及びハーセプチン‐toxin2のEC50値は、表4に示す。
追加の軽鎖伸長を作製するために、IDT(登録商標)の合成gBlocks(登録商標)遺伝子断片を、所望の配列で注文し、Gibsonアセンブリクローニングキット(New England Biolabs)を用いて、ハーセプチンVKへインフレームでクローニングした。すべてのクローンは、配列を確認され、実施例1に記述されるように解析された。
実施例6で作製されたクローンのQiagenマキシプレップを行い、トランスフェクションの準備が整ったプラスミドを単離した。293フェクチン(Invitrogen)を用いて、HEK293細胞に、ハーセプチン重鎖とハーセプチン軽鎖‐cys構築物を共トランスフェクトした。細胞をFreestyle293発現培地(Gibco)(0.1% Pluronic F68(Gibco)溶液を補充)中で5日間、増殖させた。トランスフェクションの24時間後、細胞に0.5%トリプトンを補充した。上清を回収し、AKTAxpress装置及びHitrap Mab Select SuReカラム(カタログ#11−0034−93)を用いて上清から分泌抗体を精製し、次いで、30kDa MWカットオフのAmicon(登録商標)Ultra15フィルター(Millipore)を用いて、PBS PH7.4に緩衝液交換を行った。
ハーセプチン VLSpacerX(30μM、PBS)を、1.25mMジエチレントリアミンペンタ酢酸(DTPA)(2.5mM、pH6.7のストック溶液からのPBS溶液)を添加し、次いで、システアミン塩酸塩(最終濃度1mM)を1.0Mストックから添加することにより、還元した。試料を、37℃で120分間、インキュベートした。室温にまで冷却した後、PBS+1mM DTPA pH7.3で前調整したZeba(商標)スピンカラム(40KDa MWCO)を通すことにより、反応混合物からシステアミンを除去した。
軽鎖が伸長された全長モノクローナル抗体は、PBS及び1mM DTPA中で、2時間、37℃、約12倍のTCEP(トリス(2−カルボキシエチル)ホスフィン塩酸塩)を用いて還元された(最終抗体濃度は2.5mg/mL)。還元された軽鎖伸長抗体を、Zeba(商標)Spin Desalting Column、40K MWCOにロードし、PBSを用いて溶出した。溶出された還元抗体を、10等量の10mM デヒドロアスコルビン酸(DHAA)を用いて、室温で30分間、PBS中で処理した。
実施例9の再酸化された抗体を、抗体に対し3.5モル等量で組合せ、混合し、室温で約1時間反応させ、複合体化を行い、軽鎖伸長抗体‐薬剤複合体(ADC)(Tsp2−Toxin3、Tsp3−Toxin3、Tsp4−Toxin3、Tsp5−Toxin3、Tsp6−Toxin3、Tsp9−Toxin3、Tsp10−Toxin3、Tsp10−Toxin4、Tsp10−Toxin1、Tsp11−Toxin3、TVLCys1−Toxin3(DAR 1.06)、Bsp10−Toxin3、Bsp10−Toxin4、Bsp10−Toxin1、Bsp10−Toxin6、及びBsp10−MC−vc−PABC−MMAEを含む)を形成させた。複合体混合物は、Zeba(商標)Spin Desalting Column、40K MWCOにロードし、PBSで溶出した。
HER2発現MDA−MB−231細胞をトリプシン処理し、計数し、及び試料当たり50,000個の細胞を、非複合体化MAbまたは複合体化ADCとともに24時間、4℃、総量50μlでインキュベートした。10%ウシ胎児血清を補充したLeibovitz‘s L15培地において、20000、4000、800、160、32、6.4、1.28及び0.256ng/mlで抗体をアプライした。インキュベーション後、細胞を氷冷したPBS+1%FBS中で2回洗浄し、Alexa 647標識ヤギ抗ヒトIgGFc(2ug/mL)二次抗体+2.5ug/mL 7−アミノアクチノマイシンDとともにインキュベートした。細胞を30分間インキュベートし、2回洗浄し、50μl PBS+1%FBS中に再懸濁し、及びフローサイトメトリーにより解析した。非複合体化抗体に対する結合の結果を図4(パネルA及びB)に示し、ADCに対する結合の結果を図5(パネルA及びB)に示す。「TSP2」は、配列番号105の軽鎖ポリペプチドを有する抗体である。「TSP3」は、配列番号106の軽鎖ポリペプチドを有する抗体である。「TSP4」は、配列番号107の軽鎖ポリペプチドを有する抗体である。「TSP5」は、配列番号108の軽鎖ポリペプチドを有する抗体である。「TSP6」は、配列番号109の軽鎖ポリペプチドを有する抗体である。「TSP9」は、配列番号112の軽鎖ポリペプチドを有する抗体である。「TSP10」は、配列番号113の軽鎖ポリペプチドを有する抗体である。「TSP11」は、配列番号114の軽鎖ポリペプチドを有する抗体である。VLcys1は、C末端軽鎖伸長GGGSC(配列番号60)を有するトラスツズマブである。
示差走査熱量測定法(DSC)実験を、試料:伸長10を有するトラスツズマブ(TSP10)、及びトラスツズマブ(T)(PBS溶液、pH7.4)に対して行った。DSCセルに試料をロードする前に、試料は、室温で平衡化され、緩衝液で希釈され、及び攪拌しながら8分間、真空下で脱気された。試料は、VPCapillary−DSC、MicroCalを用いて、60℃/時のスキャン速度で、10℃から100℃までスキャンされた。対照細胞はPBS緩衝液を含有した。結果を図6に示す。
5−マレイミド‐Alexa488を、上述の還元/複合体化方法を用いてMAbに結合させた。抗体は、100μg/mlのPBS溶液から1:15〜1:40希釈された試料を用いて、各レーンに20μlロードされ、SDS−PAGEにより解析された。ゲルは、Alexa488の蛍光を測定するTyphoon Trio(商標)撮像装置(GE Healthcare Life Science)を用いて画像化された。結果を図7に示す。
7〜8週齢のメスのNOD/SCIDガンマ(NSG)マウス(Jackson)に、マトリゲルと1:1で混合された5*106 NCI−N87腫瘍細胞(ATCC Cat#CRL−5822)(総量は100μl)を接種した。腫瘍は、毎月曜日、水曜日、及び金曜日に測定された。腫瘍が150〜200mm3のサイズに到達した時点で、動物を以下の表6の処置群に割り当て、群間の平均腫瘍サイズの釣り合いをとった。「T」は、トラスツズマブの略語である。
抗体薬剤複合体のHIC解析を、TSKgel Butyl−NPRカラム(2.5uM、4.6mm x 3.5cm)を用いて、280nmで、DADを備えたHP1100Series HPLCで行った。当該方法は、95%から5%の線形勾配の移動相Aで、12分にわたり、1mL/分で泳動し、3分間、再平衡化し、95%Aに戻した(A:1.5M硫酸アンモニウム及び25mM第一リン酸ナトリウム、pH4.4;B:25%IPAの25mMリン酸ナトリウム溶液、pH4.73)。Chemistationソフトウェアを、データ回収、解析及びピーク面積定量に用いた。結果を図20〜41に示す。
組み換え抗体及び抗体複合体の非変性SEC解析を、Acquity UPLC BEH 200 SECカラム(1.7uM、4.6mm x 150cm)を用いて、280nmで、DADを備えたHP1100 Series HPLCで行った。解析は、25mMリン酸ナトリウム及び150mM塩化ナトリウム緩衝液(pH6.8)を用いて、0.2mL/分で20分にわたり、均一濃度溶離を用いて行われた。Chemistationソフトウェアをデータ回収、解析、及びピーク面積定量に用いた。
組み換え抗体及び抗体薬剤複合体の完全質量解析のために、変性SEC高分解能質量分析法(HRMS)を、Acquity UPLC BEH 200 SECカラム(1.7uM、4.6mm x 150cm)を用いて、280nmで、PDA検出器を備えたWaters Acquity H Class UPLCで行った。高分解能質量分析検出は、MicroMass Q−TOF Premierを用いて行われた(スキャン範囲は、250〜4900m/z)。解析は、0.1%TFA及び0.1%FAを用いて、70/30 H20/ACNで、11分にわたり、0.25ml/分で均一濃度溶離により行われた。データ回収及び解析は、MaxEnt1でデコンヴォルーションされたスペクトルで、MassLynx4.1を用いて行われた。
in vitro細胞増殖アッセイは、上述の実施例5に記述される方法と類似した方法を用いて行われ、様々なトラスツズマブ(「T」)ベースのADC及び対照を用いて、HER2発現HCC1954細胞、HER2発現N87細胞、及びHER2抗原陰性Jurkat細胞を処置した。「遊離Toxin1」は、上述のToxin3の遊離形態(すなわち、抗体に結合されていない)である。結果は図42〜53に示し、以下の表7及び8に要約する。
トラスツズマブ軽鎖伸長変異体は、固相化プロテインAで精製され、非還元変性または還元(+DTT)変性ポリアクリルアミドゲル電気泳動(PAGE)に供された。結果を図59〜62に示す。
ADCの安定性は、熱安定性試験を用いて評価された。TSp10、TSp10−Toxin3、TSp10−Toxin1、TSp10−Toxin4、TSp6−Toxin3、TSp9−Toxin3のPBS溶液(1mg/mL、pH7)の個々の分注物を調製した。非変性SEC−UV解析(前述)は、37℃でのインキュベーションの前、ゼロ時点で、10μLの注入体積で行われた。各試料の分注物は、インキュベーションの191時間後、及びインキュベーションの330時間後に、非変性SEC−UVにより解析された。各種の単量体ピーク面積の割合は、各ゼロ時点での測定値に対して調節された。結果を図63、パネルA及びBに示す。
Claims (34)
- システイン残基を含有するC末端アミノ酸伸長を含有する軽鎖ポリペプチドを含有する抗体又はその抗原結合断片であって、前記C末端アミノ酸伸長は、4〜50アミノ酸長を有し、ここで、
前記C末端アミノ酸伸長は、内因性ヒトアミノ酸配列又は修飾ヒトアミノ酸配列を含み、
前記ヒトアミノ酸配列は、ヒト抗体ヒンジ領域もしくは、その一部、又はT細胞受容体ヒンジ領域もしくはその一部を含み、
前記C末端アミノ酸伸長は抗原に特異的に結合しない、抗体又はその抗原結合断片。 - 前記C末端アミノ酸伸長は5〜50アミノ酸長である、請求項1に記載の抗体又はその抗原結合断片。
- 前記C末端アミノ酸伸長は5〜25アミノ酸長である、請求項1に記載の抗体又はその抗原結合断片。
- 前記C末端アミノ酸伸長は、システイン残基を含有しないアミノ酸スペーサーを含有する、請求項1〜3のいずれか1項に記載の抗体又はその抗原結合断片。
- 前記スペーサーは、3〜20のアミノ酸を含有する、請求項4に記載の抗体又はその抗原結合断片。
- 前記スペーサーは、1以上のグリシン(G)残基、及び1以上のセリン(S)残基を含む、請求項4又は5に記載の抗体又はその抗原結合断片。
- 前記スペーサーは、配列GGGS(配列番号1)を含有する、請求項4〜6のいずれか1項に記載の抗体又はその抗原結合断片。
- 前記抗体がIgGである、請求項1〜7のいずれか1項に記載の抗体又はその抗原結合断片。
- 前記抗原結合断片が、Fab、F(ab’)2、Fab’、Fv、又はscFvである、請求項1〜8のいずれか1項に記載の抗体又はその抗原結合断片。
- 前記内因性ヒトアミノ酸配列が、ヒト抗体ヒンジ領域の少なくとも2、3、4、5又は6個の連続アミノ酸を含む、請求項1〜9のいずれか1項に記載の抗体又はその抗原結合断片。
- 前記C末端アミノ酸伸長が、1又はそれ以上のシステイン残基が挿入又は置換によって導入されている内因性ヒトアミノ酸配列を含む、請求項1〜9のいずれか1項に記載の抗体又はその抗原結合断片。
- 前記C末端アミノ酸伸長は、配列番号32、33、34、35、36、37、38、39もしくは40のいずれか1つに記載の配列、又はその一部分を含む、請求項1〜9のいずれか1項に記載の抗体又はその抗原結合断片。
- 前記C末端アミノ酸伸長が、配列番号92、93、94、95、96、97、98、99、100、101、102、又は103のいずれか1つで表される配列を含む、請求項1〜9のいずれか1項に記載の抗体又はその抗原結合断片。
- 2つの軽鎖ポリペプチドであって、それぞれがシステイン残基を含むC末端アミノ酸伸長を含むポリペプチドを含有する、請求項1〜13のいずれか1項に記載の抗体又はその抗原結合断片。
- 抗体が、第1重鎖ポリペプチド及び第1軽鎖ポリペプチドを含む第1モノエピトープ性抗原結合ドメイン、並びに第2重鎖ポリペプチド及び第2軽鎖ポリペプチドを含む第2モノエピトープ性抗原結合ドメインを含み、第1軽鎖ポリペプチド及び第2軽鎖ポリペプチドのうちの1つがシステイン残基を含むC末端アミノ酸慎重を含む、請求項1〜13のいずれか1項に記載の抗体又はその抗原結合断片。
- 抗体が、第1重鎖ポリペプチド及び第1軽鎖ポリペプチドを含む第1モノエピトープ性抗原結合ドメイン、並びに第2重鎖ポリペプチド及び第2軽鎖ポリペプチドを含む第2モノエピトープ性抗原結合ドメインを含み、第1軽鎖ポリペプチド及び第2軽鎖ポリペプチドの両方がシステイン残基を含むC末端アミノ酸伸長を含む、請求項1〜13のいずれか1項に記載の抗体又はその抗原結合断片。
- 二重特異性抗体である、請求項1〜16のいずれか1項に記載の抗体又はその抗原結合断片。
- 請求項1〜17のいずれか1項に記載の抗体又はその抗原結合断片;及び
前記C末端アミノ酸伸長の前記システイン残基を介して前記抗体又はその抗原結合断片に結合されている剤、
を含有する複合体であって、当該剤が治療剤又は標識剤である、複合体。 - 前記剤が、リンカーを介して前記システイン残基に結合されている、請求項18に記載の複合体。
- 前記剤が、治療剤である、請求項18又は19に記載の複合体。
- 前記治療剤が、オーリスタチンもしくはそのアナログ、又はヘミアステリンもしくはそのアナログである、請求項20に記載の複合体。
- 前記剤が、標識剤である、請求項18又は19に記載の複合体。
- 前記標識剤が、in vivoイメージング剤である、請求項22に記載の複合体。
- 前記抗体又はその抗原結合断片が、前記C末端アミノ酸伸長のシステイン残基以外のシステイン残基に結合された剤を含有しない、請求項18〜23のいずれか1項に記載の複合体。
- 前記C末端アミノ酸伸長が、2以上のシステイン残基を含有し、及び、ここで、前記2以上のシステイン残基のうちの少なくとも2つは、治療剤及び標識剤から独立して選択される剤に結合されている、請求項18〜24のいずれか1項に記載の複合体。
- 請求項1〜17のいずれか1項に記載の抗体又はその抗原結合断片の軽鎖ポリペプチドをコードする核酸。
- 請求項26に記載の核酸を含有するベクター。
- 請求項26に記載の核酸、または請求項27に記載のベクターを含有する宿主細胞。
- 請求項1〜17のいずれか1項に記載の抗体又はその抗原結合断片、または請求項18〜25のいずれか1項に記載の複合体;及び
薬学的に受容可能な添加剤
を含有する医薬組成物。 - 請求項26に記載の核酸を宿主細胞中で発現することを含む、抗体又はその抗原結合断片の軽鎖を作製する方法。
- 請求項1〜17のいずれか1項に記載の抗体又はその抗原結合断片に剤を結合させることを含む、抗体複合体を作製する方法であって、ここで、前記剤は、前記C末端アミノ酸伸長の前記システイン残基に結合され、前記剤は治療剤又は診断剤である、方法。
- 前記抗体又はその抗原結合断片に前記剤を結合させる前に、前記C末端アミノ酸伸長の前記システイン残基の前記スルフヒドリル基を還元することをさらに含む、請求項31に記載の方法。
- 前記還元することが、
(a)前記C末端アミノ酸伸長中ではないシステイン残基ではなく、前記C末端アミノ酸伸長中のシステイン残基を優先的に1つ以上還元すること、又は
(b)前記C末端アミノ酸伸長中の1以上のシステイン残基を還元し、前記C末端アミノ酸伸長中でない任意のシステイン残基を還元しないこと、
を含む、請求項32に記載の方法。 - 前記結合することが、マレイミド化学反応、ハロアセチル化学反応、ビニルスルホン化学反応、またはピリジルジスルフィド化学反応を用いて、前記還元スルフヒドリル基に前記剤を架橋させることを含む、請求項32又は33に記載の方法。
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