JP5011277B2 - ホモダイマー、ホモテトラマーまたはダイマーのダイマーのからなる安定に連結された複合体を発生させるための方法および使用 - Google Patents
ホモダイマー、ホモテトラマーまたはダイマーのダイマーのからなる安定に連結された複合体を発生させるための方法および使用 Download PDFInfo
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Description
本発明は、多重機能または多重結合特異性またはその両方を有することができ、そしてin vitroおよびin vivo用途に適当な安定に拘束された構造体(stably tethered structures)を発生させるためのプラットホーム技術を開示する。1つの態様では、安定に拘束された構造体は、タンパク質または非タンパク質であることができる任意の有機物質のホモダイマーとして産生される。以後a2として示されるホモダイマーは、各サブユニットにおいて含有される二量体化およびドッキングドメイン(dimerization and docking domain)(DDD)と呼ばれる、別のペプチド結合を介して互いに連結された2つの同一なサブユニットからなる。このサブユニットは、DDD配列を関心のある前駆体にスペーサー基を介してリコンビナント工学またはケミカルコンジュゲーションにより連結することにより構築され、これは自己会合してダイマーを形成することができる構造体をもたらす。DDD1(図1a、配列番号1)と呼ばれるDDD配列で作られた代表的なa2構築物は、実施例2および3に記載されている。
1型: 同じmAbに由来する2つのFabまたはscFvフラグメントからなる二価a2構築物。選ばれた例について表1参照。
2型: 2つの同じ非免疫グロブリンタンパク質からなる二価a2構築物。選ばれた例について表2参照。
3型: 同じmAbに由来する4つのFabまたはscFvフラグメントからなる四価a4構築物。選ばれた例について表3参照。
4型: 4つの同じ非免疫グロブリンタンパク質からなる四価a4構築物。選ばれた例について表4参照。
5型: 同じmAbに由来する2つのFabまたはscFvフラグメントおよび異なるmAbに由来する2つのFabまたはscFvフラグメントからなる二重特異的四価a2a’2構築物。選ばれた例について表5参照。
6型: 同じmAbに由来する2つのFabまたはscFvフラグメントおよび2つの同じ非免疫グロブリンタンパク質からなる多機能性a2a’2構築物。選ばれた例について表6参照。
7型:異なる非免疫グロブリンタンパク質の2つの対からなる多機能性a2a’2構築物。選ばれた例について表7参照。
特許、特許出願、論文、本および専門書を含むがそれらに限定されない、本願で引用されたすべての文献または文献の一部は、そのまま参照により本明細書に明白に組み込まれる。
本明細書で使用された単数表現(“a”または“an”)は、1つまたは1つより多くの品目を意味することができる。
追加の部分が、上記した安定に拘束された構造体にコンジュゲーションされうる。例えば、薬物、毒素、放射性化合物、酵素、ホルモン、細胞傷害性タンパク質、キレート、サイトカインおよび他の機能的作用物質を、安定に拘束された構造体にコンジュゲーションさせることができる。コンジュゲーションは、例えば、側鎖にアミン、カルボキシル、チオールまたはヒドロキシル基を含有するアミノ酸残基への共有結合を介してであることができる。この目的で種々の慣用のリンカー、例えば、ジイソシアナート、ジイソチオシアナート、ビス(ヒドロキシスクシンイミド)エステル、カルボジイミド、マレイミド、ヒドロキシスクシンイミドエステル、グルタルアルデヒド等を使用することができる。安定に拘束された構造体への作用物質のコンジュゲーションは、好ましくは、改変されていない構造体に含まれた各サブユニットの活性に有意に影響を与えない。コンジュゲーションは、a4およびa’4構築物に別々に行うことができ、そして得られるコンジュゲートは、a2a’2構築物を調製するために使用される。更に、細胞傷害剤を最初にポリマー担体にカップリングさせることができ、次いでこれを安定に拘束された構造体にコンジュゲーションさせる。この方法については、Ryser et al.,Proc. Natl. Acad. Sci. USA, 75:3867-3870, 1978; U.S.4,699,784およびU.S.4,046,722を参照されたい。これらは参照により本明細書に組み込まれる。
特許請求の範囲に請求された方法および/または組成物の種々の態様は、被験体に投与されるべき1種以上のペプチドをベースとする安定に拘束された構造体に関する。投与は、鼻、頬側、吸入、直腸、膣、局所、同所(orthotopic)、皮膚内、皮下、筋肉内、腹腔内、動脈内、鞘内、または静脈内注射を含むがそれらに限定されない当技術分野で知られている任意の経路により行うことができる。
種々のポリペプチドまたはタンパク質は、特許請求の範囲で請求された方法および組成物の範囲内で使用されうる。ある態様では、タンパク質は、抗体または抗原結合部位を含有する抗体のフラグメントを含むことができる。本明細書で使用された、タンパク質、ポリペプチドまたはペプチドは、一般に約200アミノ酸より大きく、遺伝子から翻訳された完全長配列以下のタンパク質;約100アミノ酸より大きいポリペプチド;および/または約3〜約100アミノ酸のペプチドを指すが、これらに限定されない。便宜上、用語「タンパク質」、「ポリペプチド」および「ペプチド」は、本明細書では交換可能に使用される。従って、用語「タンパク質」または「ペプチド」は、天然に存在するタンパク質に見出された20種の普通のアミノ酸の少なくとも1種または少なくとも1種の改変されたもしくは格別のアミノ酸を含むアミノ酸配列を包含する。
ポリペプチドの調製のための他の態様は、ペプチド模倣体の使用である。模倣体は、タンパク質二次構造のエレメントを模倣するペプチド含有分子である。例えば、Johnson et al.,"Peptide Turn Mimetics"in BIOTECHNOLOGY AND PHARMACY, Pezzuto et al., Eds., Chapman and Hall, New York(1993)参照。これらは参照により本明細書に組みこまれる。ペプチド模倣体の使用の背景の論理は、タンパク質のペプチド主鎖が、分子相互作用、例えば抗体と抗原の相互作用、を促進するようにアミノ酸側鎖を配向するために主として存在するということである。ペプチド模倣体は、天然の分子に類似した分子相互作用を可能とすることが期待される。
種々の態様は融合タンパク質に関することができる。これらの分子は、一般にN末端またはC末端で、第2ポリペプチドもしくはタンパク質のすべてまたは一部に連結されたペプチドのすべてまたは実質的な部分を有する。融合タンパク質を発生させる方法は、当業者に周知されている。このようなタンパク質は、例えば、二官能性架橋試薬を使用する化学的結合により、完全な融合タンパク質のde novo合成により、または第2ペプチドもしくはタンパク質をコードするDNA配列への第1タンパク質もしくはペプチドをコードするDNA配列の結合、次いでインタクトな融合タンパク質の発現により製造することができる。
タンパク質またはペプチドは、全体的にせよ部分的にせよ、慣用の技術に従って溶液中でまたは固体支持体上で合成することができる。種々の自動合成装置が市販されておりそして既知のプロトコールに従って使用することができる。例えば、Stewart and Young,(1984, Solid Phase Peptide Synthesis, 2d. ed., Pierce Chemical co,); Tam et al.,(1983, J.Am. Chem. Soc., 105:6442); Merrifield, (1986,Science, 232:341-347); and Barany and Merrifield(1979, The peptides, Gross and Meienhofer, eds., Academic Press, New York, pp.1-284)参照。通常約6から約35〜50アミノ酸までの短いペプチド配列はこのような方法により容易に合成することができる。または、関心のあるペプチドをコードするヌクレオチド配列を発現ベクターに挿入し、適切なホスト細胞中にトランスフォーメーションまたはトランスフェクションしそして発現のために適当な条件下に培養する、リコンビナントDNA技術を使用することができる。
種々の態様は、ターゲットに対する抗体に関する。用語「抗体」は、本明細書では、抗原結合領域を有する任意の抗体様分子を指すのに使用され、そして抗体フラグメント、例えば、Fab’、Fab、F(ab’)2、単一ドメイン抗体(DABs)、Fv、scFv、(単一鎖Fv)等を含む。種々の抗体をベースとする構築物およびフラグメントを調製および使用するための技術は、当技術分野で周知されている。抗体を調製しそして特徴付けるための手段も当技術分野で周知である(例えば、Harlowe and Lane, 1988, Antibodies,1988,Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory参照)。使用される抗体は広い多様な既知のソースから商業的に得ることもできる。例えば、種々の抗体分泌ハイブリドーマ系統が、American Type Culture Collection(ATCC,Manassas,VA)から入手可能である。
特許請求の範囲に請求された方法および/または組成物のいくらかの態様は、抗体フラグメントに関することができる。このような抗体フラグメントは、慣用の方法による全体の抗体のペプシンもしくはパパイン消化により得ることができる。例えば、抗体フラグメントは、ペプシンにより抗体を酵素開裂させてF(ab’)2フラグメントを得ることにより産生することができる。このフラグメントは、チオール還元剤を使用して更に開裂させることができ、次いで場合によりジスルフィド結合の開裂から生じるスルフヒドリル基のためのブロッキング基によりブロッキングして、Fab’一価フラグメントを産生する。または、パパインnを使用する酵素による開裂は、2つの一価のFabフラグメントおよびFcフラグメントを産生する。抗体フラグメントを産生するための例示的方法は、U.S.Pat.No.4,036,945; U.S.Pat.No.4,331,647;Nisonoff et al., 1960, Arch. Biochem. Biophys., 89:230; Porter, 1959, Biochem. J., 73:119; Edelman et al., 1967, METHODS IN ENZYMOLOGY, page 422(Academic Press), and Coligan et al.(ends), 1991, CURRENT PROTOCOLS IN IMMUNOLOGY,(John Wiley & Sons)に開示されている。
キメラ抗体は、ヒト抗体の可変領域が、例えば、マウス抗体の相補性決定領域(CDRs)を含む、マウス抗体の可変領域により置換されているリコンビナントタンパク質である。キメラ抗体は、被験体に投与されるとき、減少した免疫原性および増化した安定性を示す。キメラ抗体を構築するための方法は、当技術分野で周知されている(例えば、Leung et al., 1994, Hybridoma 13:469)。
コンビナトリアルアプローチまたはヒト免疫グロブリンローカスでトランスフォーメーションされたトランスジェニック動物を使用して完全にヒト抗体を産生するための方法は、当技術分野で知られている(例えば、Mancini et al., 2004, New Microbiol. 27:315-28; Conrad and Scheller, 2005, Comb. Chem. High Throughput Screen. 8:117-26; Brekke and Loset, 2003, Curr. Opin. Pharmacol. 3:544-50; 各々は参照により本明細書に組み込まれる)。このような完全にヒト抗体は、キメラもしくはヒト化抗体より少なくすらある副作用を示しそして本質的に内在性ヒト抗体としてin vivoで機能することが予想される。ある態様では、特許請求の範囲に請求された方法および手順は、このような技術により産生されたヒト抗体を利用することができる。
二重特異的な安定に拘束された構築物の使用のための1つのストラテジーは、プレターゲティング法(pre-targeting methologies)を含み、この方法では、エフェクター分子は、二重特異的構築物が投与された後被験体に投与される。エフェクター、ハプテンまたは担体に対する結合部位および疾患に罹っている組織に対する結合部位を含む二重特異的構築物は、疾患のある組織に局在化しそして疾患のある組織へのエフェクターの局在化の特異性を増化させる(U.S.Patent Application No.20050002945)。エフェクター分子は二重特異的構築物よりもはるかに速く循環から除かれ得るので、正常な組織は、エフェクター分子が疾患ターゲティング抗体に直接連結されている場合よりも、プレターゲティングストラテジーが使用される場合にエフェクター分子への曝露が減少することができる。
ある態様では、構築物形成のための前駆体は、アプタマーを含むことができる。アプタマーの結合特徴を構築しそして決定する方法は、当技術分野に周知されている。例えば、このような技術は、U.S.Patent Nos. 5,582,981; 5,595,877; および5,637,459に記載されており、これらの各々は参照により本明細書に組みこまれる。
ある態様では、本明細書に記載された前駆体、成分および/または複合体は、1種以上のアビマー配列を含むことができる。アビマーは、種々のターゲット分子に対するそれらのアフィニティーおよび特異性において抗体に幾分類似した結合タンパク質のクラスである。それらは、in vitroエキソンシャフリングおよびファージディスプレーによりヒト細胞外レセプタードメインから開発された。(Silverman et al., 2005, Nat. Biotechnol. 23:1493-94; Silverman et al., 2006, Nat. Biotechnol.24:220)。得られる多重ドメインタンパク質は、単一エピトープ結合タンパク質と比較して、改良されたアフィニティー(ある場合にナノモル以下)および特異性を示すことができる多重独立結合ドメインを含むことができる。(同上)。種々の態様において、アビマーは、例えば、特許請求の範囲に請求された方法および組成物において使用するためのDDD配列に結合させることができる。アビマーの構築および使用の方法に関する追加の詳細は、例えば、U.S.Patenr Application Publication Nos. 20040175756, 20050048512, 20050053973, 20050089932および20050221384に開示されており、その各々の実施例の節は参照により本明細書に組みこまれる。
タンパク質をベースとするin vitro診断
本発明は、疾患関連抗原の存在についてin vitroおよび/またはin vivoで生物学的サンプルをスクリーニングするための安定に拘束された構造体の使用を意図する。例示的イムノアッセイでは、抗体、融合タンパク質またはそのフラグメントを含む安定に拘束された構造体は、下記するとおり、液相において利用することができまたは固相担体に結合させることができる。好ましい態様、特にin vivo投与を伴う態様では、抗体またはそのフラグメントはヒト化される。抗体またはそのフラグメントは完全にヒトであることも好ましい。なお更に好ましくは、融合タンパク質は、ヒト化抗体または完全にヒト抗体を含む。当業者は、特定の遺伝子の発現のレベルを決定するための広く多様な技術が知られておりそして任意のこのような既知の方法、例えば、イムノアッセイ、RT−PCR、mRNA精製および/またはcDNA作成、続く遺伝子発現アッセイチップへのハイブリダイゼーションを利用して、個々の被験体および/または組織における発現のレベルを決定することができることを認識するであろう。使用される例示的なin vitroアッセイは、RIA、ELISA、サンドイッチELISA、ウエスタンブロット、スロットブロット、ドットブロット等を含む。このような技術はインタクトな抗体を使用して開発されたけれども、抗体、抗体フラグメントまたは他の結合部分を組み込んだ安定に拘束された構造体を使用することができる。
安定に拘束された構造体は、ある態様では、核酸部分を組み込まれていることができる。特定の態様では、特に核酸増幅方法を使用して、核酸を分析して結合のレベルを決定することができる。種々の形態の増幅が当技術分野で周知されておりそして任意のこのような方法を使用することができる。一般に、増幅は増幅されるべきターゲット核酸配列に選択的にまたは特異的にハイブリダイゼーションする1つ以上のプライマーの使用を含む。
標識されたペプチドまたはMAbsにより診断画像化する方法は周知である。例えば、イムノシンチグラフィーの技術では、リガンドまたは抗体をγ放出放射性同位元素で標識しそして患者に導入する。γカメラを使用してγ放出放射性同位元素の位置および分布を検出する。例えば、Srivastava(ed.),RADIOLABELED MONOCLONAL ANTIBODIES FOR IMAGING AND THERAPY(Plenum Press 1988), Chase,"Medical Applications of Radioisotopes," in REMINGTONS PHARMACEUTICAL SCIENCES,18th Edition, Gennaro et al.(eds.),pp.624-652(Mack Publishing Co., 1990),and Brown, "Clinical Use of Monoclonal Antibodies," in BIOTECHNOLOGY AND PHARMACY 227-49, Pezzuto et al.(eds.)(Chapmann & Hall 1993)参照。例えば511keVのエネルギーを有するようなポジトロン放出放射性核種(PET同位元素)、例えば18F、68Ga、64Cuおよび124Iの使用も好ましい。このような画像化は、安定に拘束された構造体の直接標識によりまたは、Goldenberg et al,"Antibody Pre-targeting Advances Cancer Radioimmunodetection and Radioimmunotherapy,"(J Clin Oncol 2006;24:823-834)に記載のようにプレターゲティングされた画像化方法により行うことができる。U.S.Patenr Publication Nos.20050002945, 20040018557, 20030148409および20050014207も参照。これらの各々は、参照により本明細書に組み込まれる。
多くの適切な画像化剤が、タンパク質またはペプチドへのそれらの結合のための方法と同じく当技術分野で知られている(例えば、U.S.Patents 5,021,236および4,472,509参照、両方共参照により本明細書に組み込まれる)。ある結合方法は、例えばタンパク質またはペプチドに結合したDTPAのような有機キレート化剤を使用する金属キレート錯体の使用を含む(U.S.Patent.4,472,509)。タンパク質またはペプチドは、グルタルアルデヒドまたは過ヨウ素酸塩などのカップリング剤の存在下に酵素と反応させることもできる。フルオレセインマーカーとのコンジュゲートは、これらのカップリング剤の存在下にまたはイソチオシアナートとの反応により調製される。
医薬組成物
ある態様では、安定に拘束された構造体および/または1種以上の治療剤を被験体、例えば癌を有する被験体に投与することができる。このような作用物質は、医薬組成物の形態で投与することができる。一般に、これはヒトまたは動物に有害でありうる不純物を本質的に含まない組成物を調製することを伴うであろう。当業者は、医薬組成物は例えば経口的もしくは非経口的、例えば静脈内を含む種々の経路により被験体に投与することができることを知るであろう。
或る態様では、化学療法剤を投与することができる。使用される抗癌化学療法剤は、5−フルオロウラシル、ブレオマイシン、ブスルファン、カンプトテシン、カルボプラチン、クロラムブシル、シスプラチン(CDDP)、シクロホスファミド、ダクチノマイシン、ダウノルビシン、ドクソルビシン、エストロゲンレセプター結合剤、エトポシド(VP16)、ファルネシルタンパク質トランスフェラーゼ阻害剤、ゲムシタビン、イホスファミド、メクロレタミン、メルファラン、メトトレキセート、マイトマイシン、ナベルビン、ニトロソウレア、プリコマイシン、プロカルバジン、ラロキシフェン、タモキシフェン、タキソール、テマゾロミド(temazolomide)(DTICの水性形態)、トランスプラチナム(transplatinum)、ビンブラスチンおよびメトトレキセート、ビンクリスチンまたは前記のものの任意のアナログもしくは誘導体変異体を含むが、それらに限定されない。感染性生物に対して使用される化学療法剤は、アシクロビル、アルベンダゾール、アマンタジン、アミカシン、アモキシシリン、アムホテリシンB、アムピシリン、アズトレオナム、アジスロマイシン、バシトラシン、バクトリム、バトラフェン(Batrafen)(登録商標)、ビフォナゾール、カルベニシリン、カスポフンギン、セファクロル、セファゾリン、セファロスポリン、セフェピム、セフトリアクソン、セフォタキシム、クロラムフェニコール、シドフォビル、Cipro(登録商標)、クラリスロマイシン、クラブラン酸、クロトリマゾール、クロキサシリン、ドキシサイクリン、エコナゾール、エリスロサイクリン、エリスロマイシン、フラジル、フルコナゾール、フルシトシン、フォスカルネット、フラゾリドン、ガンシクロビル、ゲンタマイシン、イミペネム、イソニアジド、イトラコナゾール、カナマイシン、ケトコナゾール、リンコマイシン、リネゾリド、メロペネム、ミコナゾール、ミノサイクリン、ナフチフィン、ナリジクス酸、ネオマイシン、ネチルマイシン、ニトロフラントイン、ナイスタチン、オセルタミビル、オキサシリン、パロモマイシン、ペニシリン、ペンタミジン、ピペラシリン−タゾバクタム、リファブチン、リファンピン、リマンタジン、ストレプトマイシン、スルファメトキサゾール、スルファサラジン、テトラサイクリン、チオコナゾール、トブラマイシン、トルシクラート、トルナフタート、トリメトプリムスルファメトキサゾール、バラシクロビル、バンコマイシン、ザナミル(zanamir)およびジスロマイシンを含むが、それらに限定されない。
コルチコステロイドホルモンは、他の化学療法剤の有効性を増化させることができ、その結果としてそれらはしばしば組合わせ処置において使用される。プレドニゾンおよびデキサメタゾンは、コルチコステロイドホルモンの例である。プロゲスチン、例えば、ヒドロキシプロゲステロンカプロエート、メドロキシプロゲステロンアセタートおよびメゲストロールアセタートは、子宮内膜および胸の癌において使用された。エストロゲン、例えばジエチルスチルベストロールおよびエチニルエストラジオールは、癌、例えば前立腺癌において使用された。抗エストロゲン、例えばタモキシフェンは、癌、例えば乳癌において使用された。アンドロゲン、例えばテストステロンプロピオナートおよびフルオキシメステロンも乳癌を処置するのに使用された。
ある態様では、抗血管新生剤、例えばアンギオスタチン、バクロスタチン、カンスタチン、マスピン、抗VEGF抗体、抗PIGFペプチドおよび抗体、抗血管成長因子抗体、抗Flk−1抗体、抗Flt−1抗体およびペプチド、ラミニンペプチド、フィブロネクチンペプチド、プラスミノーゲンアクチベーター阻害剤、組織メタロプロテイナーゼ阻害剤、インターフェロン、インターロイキン12、IP−10、Gro−β、トロンボスポンジン、2−メトキシエストラジオール、プロリフェリン関連タンパク質、カルボキシアミドトリアゾール、CM101、マリマスタット、ペントサンポリサルフェート、アンギオポエチン−2、インターフェロンα、ハービマイシンA、PNU145156E、16Kプロラクチンフラグメント、リノマイド(Linomide)、サリドマイド、ペントキシフィリン、ゲニステイン、TNP−470、エンドスタチン、パクリタキセル、アキュチン(accutin)、アンギオスタチン、シドフォビル、ビンクリスチン、ブレオマイシン、AGM−1470、血小板因子4またはミノサイクリンを使用することができる。
本明細書で使用された、用語「イムノモデュレーター」は、サイトカイン、幹細胞成長因子、リンホトキシンおよび造血因子、例えば、インターロイキン、コロニー刺激因子、インターフェロン(例えば、インターフェロンα、インターフェロンβおよびインターフェロンγ)および「S1因子」と命名された幹細胞成長因子を含む。適当なイムノモデュレーター部分の例は、IL−2、IL−6、IL−10、IL−12、IL−18、IL−21、インターフェロンγ、TNFα等を含む。
ある態様では、ペプチドおよび/またはタンパク質は、放射性核種治療または放射免疫治療法に使用することができる(例えば、Govindan et al., 2005, Technology in Cancer Research&Treatment, 4:375-91; Sharkey and Goldenberg, 2005, J.Nucl.Med.46:115S-127S; Goldenberg et al.(J Clin Oncol 2006;24:823-834), "Antibody Pre-targeting Advances Cancer Radioimmunodetection and Radioimmunotherapy,"参照、これらの各々は参照により本明細書に組み込まれる)。特定の態様では、安定に拘束された構造体は、使用される放射性同位元素により直接タグ付けすることができ、そして被験体に投与されうる。別の態様では、放射性同位元素(1種または複数)は、放射性標識されそして疾患のある組織における高められた発現の部位に局在する二重特異的な安定に拘束された構造体の投与後に注射されるハプテンペプチドまたはリガンドを使用して、上記したプレターゲティング方法において投与されうる。
種々の態様は、患者の疾患のある組織を処置または診断するのに適当な化合物を含有するキットに関することができる。例示的キットは少なくとも1種の安定に拘束された構造体を含有することができる。投与用の成分を含有する組成物が、例えば経口送達などの消化管を経由する送達用に処方されていないならば、ある他の経路を経由してキット成分を送達することができる装置を含ませることができる。非経口送達などの用途のための1つのタイプの装置は、被験体の身体に組成物を注射するために使用される注射器である。吸入装置も使用することができる。
下記の実施例は、特許請求の範囲に請求された本発明を説明するために提供されるが 限定するために与えられるのではない。
Fd鎖のC末端またはN末端に結合されたDDD1配列(配列番号1)を有するFabをベースとするサブユニットは、融合タンパク質として産生される。プラスミドベクターpdHL2を使用して多数の抗体および抗体をベースとする構築物が産生された。Gillies et al., J Immunol Methods(1989), 125:191-202; Losman et al., Cancer(Phila)(1997),80:2660-6参照。このジシストロン哺乳動物発現ベクターは、IgGの重鎖および軽鎖の合成を指向する。ベクター配列は、多くの異なるIgG−pdHL2構築物について殆ど同じであり、唯一の差は可変ドメイン(VHおよびVL)配列に存在する。当業者に知られている分子生物学的ツール使用して、これらのIgG−pdHL2発現ベクターは、重鎖のヒンジ、CH2およびCH3ドメインのためのコード配列を、ヒンジの最初の4残基、14残基Gly−SerリンカーおよびヒトRIIαの最初の44残基をコードする配列で置換することにより、Fd−DDD1−pdHL2またはFd−DDD2−pdHL2発現ベクターに転換されうる。シャトルベクターCH1−DDD1−pGemTは、下記するとおり、IgG−pdHL2ベクター(図2a)のFd−DDD1−pdHL2ベクター(図2b)への転換を促進するようにデザインされた。
CH1の調製
CH1ドメインを、テンプレートとしてpdHL2プラスミドベクターを使用するPCRにより増幅した。左PCRプライマーは、CH1ドメインの上流(5’)およびCH1コード配列の5’であるSacII制限エンドヌクレアーゼ部位からなる。右プライマーは、ヒンジの最初の4残基(PKSC)をコードする配列、続いてBamHI制限部位を含む最後の2つのコドン(GS)を有するGGGGSからなる。
(G4S)2DDD1と命名された二重鎖オリゴヌクレオチドは、Sigma Genosys(Haverhill, UK)により合成されて、最初の2つのコドンがBamHI制限部位を含むリンカーペプチドの11残基により先行されたDDD1のアミノ酸配列(配列番号1)をコードする。停止コドンおよびEagI制限部位は3’端部に結合。コードされたポリペプチド配列は下記に示される。
DDD1配列をコードする190bpフラグメントをBamHIおよびNotI制限酵素によりpGemTから切り出し、次いでCH1−pGemTにおける同じ部位にライゲーションしてシャトルベクターCH1−DDD1−pGemTを発生させた。
CH1−DDD1をコードする配列を下記のとおりpdHL2ベクターにおける任意のIgG構築物に組み込むことができる。pdHL2からSacII/EagI制限フラグメント(CH1−CH3)を除去しそしてそれを、それぞれのpGemTシャトルベクターから切り出されるCH1−DDD1のSacII/EagIフラグメントで置換することにより、全体の重鎖定常ドメインをCH1−DDD1で置換する。
C−DDD1−Fd−hMN−14−pdHL2
C−DDD1−Fd−hMN−14−pdHL2は、柔軟性ペプチドスペーサーを介してFd鎖のC末端においてhMN−14FabにDDD1配列が連結されている融合タンパク質の2つのコピーを含むa2構築物を産生するための発現ベクターである(図3)。hMN−14IgGを産生するのに使用されたプラスミドベクターhMN14(I)−pdHL2は、SacIIおよびEagI制限エンドヌクレアーゼにより消化してCH1−CH3ドメインを除去し、そしてSacIIおよびEagIによりCH1−DDD1−SV3シャトルベクターから切り出されたCH1−DDD1フラグメントを挿入することにより、C−DDD1−Fd−hMN−14−pdHL2に転換された。
N−DDD1−Fd−hMN−14−pdHL2は、柔軟性ペプチドスペーサーを介してFd鎖のN末端においてhMN−14FabにDDD1配列が連結されている融合タンパク質の2つのコピーを含むa2構築物を産生するための発現ベクターである(図4)。
C−DDD1−Fd−hMN−14−pdHL2およびN−DDD1−Fd−hMN−14−pdHL2ベクターを、Sp2/0由来のミエローマ細胞にエレクトロポレーションによりトランスフェクションした。C−DDD1−hMN−14−pdHL2は、hMN−14κ軽鎖およびhMN−14Fd−DDD1の両方の合成および分泌を指向するジシストロン発現ベクターであり、hMN−14κ軽鎖およびhMN−14Fd−DDD1は組み合わさってC−DDD1−hMN−14Fabを形成する。N−DDD1−hMN−14−pdHL2は、hMN−14κ軽鎖およびN−DDD1−Fd−hMN−14の両方の合成および分泌を指向するジシストロン発現ベクターであり、hMN−14κ軽鎖およびN−DDD1−Fd−hMN−14は組み合わさってN−DDD1−Fab−hMN−14を形成する。各融合タンパク質は、DDD1ドメインの相互作用を介して安定なホモダイマーを形成する。
Rap−hPAM4−Fd−DDD1−pdHL2の構築
Rap−hPAM4−Fd−DDD1−pdHL2は、各々が、それぞれ、軽鎖のN末端およびFd鎖のC末端に連結されたランピルナーゼ(Rap)およびDDD1配列を含有する、2つの同じFab融合タンパク質を含むa2構築物を産生するための発現ベクターである。hPAM4は、MUC−1に対して特異的なヒト化モノクローナル抗体である。各々hPAM4の軽鎖のN末端に融合したRapの2つの分子からなる2L−Rap(N69Q)−hPAM4と呼ばれる免疫毒素を産生するために使用されたプラスミドベクターRap−hPAM4−γ1−pdHL2を、SacIIおよびNgoM4で消化して、CH1−CH3ドメインをコードするフラグメントを除去し、次いでSacIIおよびNgoM4でプラスミドベクターC−DDD1−Fd−hMN−14−pdHL2から切り出されたCH1−DDD1をライゲーションして、Rap−hPAM4−Fd−DDD1−pdHL2を発生させた。
Rap−hPAM4−Fd−DDD1−pdHL2ベクターを、エレクトロポレーションによりNS0ミエローマ細胞にトランスフェクションした。Rap−hPAM4−Fd−DDD1−pdHL2は、Rap融合したhPAM4軽鎖およびhPAM4−Fd−DDD1の両方の合成および分泌を指向するジシストロン発現ベクターであり、Rap融合したhPAM4軽鎖およびhPAM4Fd−DDD1は組み合わさってRap−Fab融合タンパク質を形成する。各融合タンパク質は、DDD1ドメインの相互作用を介して、Rap−hPAM4−Fab−DDD1と呼ばれる安定なホモダイマーを形成する。
N−DDD2−Fd−hMN−14−pdHL2の構築
N−DDD2−Fd−hMN−14−pdHL2は、DDD2配列が柔軟性ペプチドスペーサーを介してFd鎖のN末端においてhMN−14Fabに結合されている融合タンパク質の4つのコピーを含む、以後四価N−DDD2−Fab−hMN−14と呼ばれるa4構築物を産生するための発現ベクターである。
N−DDD2−Fd−hMN−14−pdHL2ベクターを、エレクトロポレーションによりSp/EEEミエローマ細胞にトランスフェクションした。このジシストロンベクターは、hMN−14κ軽鎖およびN−DDD2−Fd−hMN−14の両方の合成および分泌を指向し、これらは組み合わさってFabをベースとするサブユニットN−DDD2−Fab−hMN−14を形成する。エレクトロポレーションの後、細胞を96ウエル組織培養プレートにおいてプレートし、そしてトランスフェクタントクローンを0.05μM(MTX)で選択した。
C−DDD2−Fd−hMN−14−pdHL2の構築
C−DDD2−Fd−hMN−14−pdHL2は、DDD2配列が柔軟性ペプチドスペーサーを介してFd鎖のC末端においてhMN−14Fabに結合されている融合タンパク質の4つのコピーを含む、以後四価C−DDD2−Fab−hMN−14と呼ばれるa4構築物を産生するための発現ベクターである。
C−DDD2−Fd−hA20−pdHL2は、DDD2配列が柔軟性ペプチドスペーサーを介してFd鎖のC末端においてhA20−Fabに結合されている融合タンパク質の4つのコピーを含む、以後四価C−DDD2−Fab−hA20と呼ばれるa4構築物を産生するための発現ベクターである。
C−DDD2−Fd−hMN−3−pdHL2は、DDD2配列が柔軟性ペプチドスペーサーを介してFd鎖のC末端においてhMN3−Fabに結合されている融合タンパク質の4つのコピーを含む、以後四価C−DDD2−Fab−hMN−3と呼ばれるa4構築物を産生するための発現ベクターである。hMN−3は、CEA(CEACAM5)またはNCA−90(CEACAM6)のNドメインに対して特異的なヒト化モノクローナル抗体である。
C−DDD2−Fd−hLL2−pdHL2は、DDD2配列が柔軟性ペプチドスペーサーを介してFd鎖のC末端においてhLL2−Fabに結合している融合タンパク質の4つのコピーを含む、以後四価C−DDD2−Fab−hLL2と呼ばれるa4構築物を産生するための発現ベクターである。hLL2は、CD22に対して特異的なヒト化モノクローナル抗体である。
C−DDD2−Fd−hMN−14−pdHL2ベクターを、エレクトロポレーションによりSp/EEEミエローマ細胞にトランスフェクションした。このジシストロン発現ベクターは、hMN−14κ軽鎖およびC−DDD2−Fd−hMN−14の両方の合成および分泌を指向し、これらは組み合わさってC−DDD2−Fab−hMN14を形成する。エレクトロポレーションの後、細胞を96ウエル組織培養プレートにおいてプレートし、そしてトランスフェクタントクローンを0.05μMメトトレキセート(MTX)で選択した。
C−DDD2−Fd−hA20−pdHL2ベクターを、エレクトロポレーションによりNS0ミエローマ細胞にトランスフェクションした。このジシストロン発現ベクターは、hA20κ軽鎖およびC−DDD2−Fd−hA20の両方の合成および分泌を指向し、これらは組み合わさってC−DDD2−Fab−hA20を形成する。エレクトロポレーションの後、細胞を96ウエル組織培養プレートにおいてプレートしそしてトランスフェクタントクローンを0.05μMメトトレキセート(MTX)で選択した。
C−DDD2−Fd−hMN−3−pdHL2ベクターを、エレクトロポレーションによりNS0ミエローマ細胞にトランスフェクションした。このジシストロン発現ベクターは、hMN−3κ軽鎖およびC−DDD2−Fd−hMN−3の両方の合成および分泌を指向し、これらは組み合わさってC−DDD2−Fab−hMN−3を形成する。エレクトロポレーションの後、細胞を96ウエル組織培養プレート中にプレートしそしてトランスフェクタントクローンを0.05μMメトトレキセート(MTX)により選択した。
C−DDD2−Fd−hLL2−pdHL2ベクターをエレクトロポレーションによりSp2/0由来のミエローマ細胞にトランスフェクションした。このジシストロン発現ベクターは、hLL2κ軽鎖およびC−DDD2−Fd−hLL2の両方の合成および分泌を指向し、これらは組み合わさってC−DDD2−Fab−hLL2を形成する。エレクトロポレーションの後、細胞を96ウエル組織培養プレート中にプレートしそしてトランスフェクタントクローンを0.05μMメトトレキセート(MTX)により選択した。
二重特異的四価C−DDD2−Fab−hMN−3×C−DDD2−Fab−hA20の産生、精製および特徴付け
実施例5から得られた四価C−DDD2−Fab−hMN−3および四価C−DDD2−Fab−hA20を組みあわせそして、そして室温で1時間1mMグルタチオンで還元し、次いで酸化されたグルタチオンを2mMの最終濃度となるように加えた。テトラマー画分をSuperdex−200カラムでのゲルろ過により他の分子形態から精製した。二重特異的四価C−DDD2−Fab−hMN−3×C−DDD2−Fab−hA20の形成を、図26に示されたとおり、CEACAM5でコーティングされたプレートを使用しそしてWR2でプローブされるELISAにより証明した。
実施例5から得られた四価C−DDD2−Fab−hMN−3および四価C−DDD2−Fab−hMN−14を組みあわせそして、そして室温で1時間1mMグルタチオンで還元し、次いで酸化されたグルタチオンを2mMの最終濃度となるように加えた。テトラマー画分をSuperdex−200カラムでのゲルろ過により他の分子形態から精製した。二重特異的四価C−DDD2−Fab−hMN−3×C−DDD2−Fab−hMN−14の形成を、図27に示されたとおり、BXPC3細胞を使用するフローサイトメトリーにより証明した。
実施例5から得られた四価C−DDD2−Fab−hA20および四価C−DDD2−Fab−hLL2を組みあわせそして、そして室温で1時間1mMグルタチオンで還元し、次いで酸化されたグルタチオンを2mMの最終濃度となるように加えた。テトラマー画分をSuperdex−200カラムでのゲルろ過により他の分子形態から精製した。二重特異的四価C−DDD2−Fab−hA20×C−DDD2−Fab−hLL2の形成を、WN(hLL2に対するラット抗id)でコーティングされるプレートを使用しそしてWR2(hA20に対するラット抗id)でプローブされるELISAにより証明した。
Claims (34)
- ホモダイマーを含む組成物であって、該ホモダイマーの各モノマーが、ヒトタンパク質キナーゼA調節サブユニットRIIαの二量体化およびドッキングドメイン(DDD)を含み、ここで該DDDが、抗体、ヒト化抗体、ヒト抗体、キメラ抗体、抗体フラグメントまたはサイトカインからなる群より選択される前駆体に結合している、組成物。
- 前記DDDが、配列番号1(DDD1)または配列番号2(DDD2)の配列を含む、請求項1に記載の組成物。
- 前記モノマーが前記前駆体および前記DDDを含む融合タンパク質であるか、又は前記前駆体が前記DDDに化学的に連結されている、請求項1に記載の組成物。
- 前記前駆体と前記DDDとの間にリンカーペプチドを更に含む、請求項3に記載の組成物。
- 前記前駆体が抗体のFdフラグメントであり、そして前記Fdフラグメントが抗体の軽鎖に結合してFabフラグメントを形成する、請求項3に記載の組成物。
- 前記Fabフラグメントが、hMN−14、L19、hA20、hLL2、hL243、ヒト化CC49、7E3、hLL1、hPAM4、hRS7、hR1、L49、抗CD14、抗CD111、アダリムマブ、インフリキシマブ、オマリズマブ、パリビズマブおよびhMN−15、のFabフラグメントからなる群より選ばれる、請求項5に記載の組成物。
- 前記前駆体が、免疫グロブリン軽鎖(VL−CL)または免疫グロブリンFcドメイン(CH2−CH3)に融合したポリペプチドを含む、請求項1〜4のいずれか一項に記載の組成物。
- 前記CLをCH1に連結する前記CLのカルボキシル末端のシステインが、欠失しているかまたは非システインに突然変異している、請求項7に記載の組成物。
- 前記免疫グロブリン軽鎖または前記Fcドメインが、ヒト抗体またはヒト化抗体から選ばれる、請求項7に記載の組成物。
- 前記前駆体が、カルボニックアンヒドラーゼIX、αフェトプロテイン、A3、A33抗体に対する特異的抗原、Ba733、BrE3抗原、CA125、CD1、CD1a、CD3、CD5、CD15、CD16、CD19、CD20、CD21、CD22、CD23、CD25、CD30、CD33、CD38、CD45、CD74、CD79a、CD80、CD138、結腸特異的抗原p(CSAp)、CEA(CEACAM5)、CEACAM6、CSAp、EGFR、EGP−1、EGP−2、Ep−CAM、Flt−1、Flt−3、葉酸レセプター、HLA−DR、ヒト絨毛性性腺刺激ホルモン(HCG)およびそのサブユニット、HER2/neu、低酸素症誘導性因子(HIF−1)、Ia、IL−2、IL−6、IL−8、インスリン成長因子1(IGF−1)、KC4抗原、KS−1抗原、KS1−4、Le−Y、マクロファージ遊走抑制因子(MIF)、MAGE、MUC1、MUC2、MUC3、MUC4、NCA66、NCA95、NCA90、PAM−4抗体に対して特異的な抗原、胎盤成長因子、P53、前立腺酸性ホスファターゼ、PSA、PSMA、RS5、S100、TAC、TAG−72、テナシン、TRAILレセプター、Tn抗原、トムソン−フリーデンライヒ抗原、腫瘍壊死抗原、VEGF、ED−Bフィブロネクチン、17−1A抗原、血管新生マーカー、腫瘍遺伝子マーカーまたは腫瘍遺伝子産物、に対する少なくとも1つの結合部位を有する、請求項1〜4のいずれか一項に記載の組成物。
- 共有結合連結または非共有結合連結により前記ホモダイマーにコンジュゲーションされた1つ以上のエフェクターまたは担体を更に含む、請求項1に記載の組成物。
- 前記エフェクターが、診断剤、治療剤、化学療法剤、放射性同位元素、画像化剤、抗血管新生剤、サイトカイン、ケモカイン、成長因子、薬物、プロドラッグ、酵素、RNase、結合分子、アプタマー、ワクチン、細胞表面レセプターのためのリガンド、キレーター、イムノモデュレーター、オリゴヌクレオチド、ホルモン、光検出可能な標識、染料、ペプチド、毒素、コントラスト剤、常磁性標識、超音波標識、プロアポトーシス剤、リポソーム、ナノ粒子またはその組み合わせである、請求項11に記載の組成物。
- 前記ホモダイマーが、2つ以上のエフェクターまたは2つ以上の担体に結合している、請求項11に記載の組成物。
- 前記2つ以上の担体または2つ以上のエフェクターが、同じであるかまたは異なっている、請求項13に記載の組成物。
- 前記1種以上の担体が、少なくとも1種の診断剤または治療剤を含む、請求項11に記載の組成物。
- 2つのホモダイマーが、共有結合により結合してテトラマーを形成する、請求項1に記載の2つのホモダイマーを含む組成物。
- 前記DDDが、配列番号2(DDD2)の配列を含む、請求項16に記載の組成物。
- 前記2つのホモダイマーが、前記DDD2配列間のジスルフィド結合によって共有結合により結合している、請求項17に記載の組成物。
- 前記テトラマー中の2つのホモダイマーが、同じであるか又は異なる、請求項16に記載の組成物。
- 前記第1ホモダイマーが、第1前駆体に連結されたDDD配列を含む第1モノマーを含み、そして前記第2ホモダイマーが、第2前駆体に連結されたDDD配列を含む第2モノマーを含む、請求項16に記載の組成物。
- 前記2つのホモダイマーが、該ホモダイマーの各々のDDD部分間のジスルフィド結合により相互に保持されている、請求項20に記載の組成物。
- 前記第1前駆体がターゲット分子、複合体、集合体、細胞、抗原または組織に対する結合部位を有し、そして前記第2前駆体がハプテンに対する結合部位を有する、請求項20に記載の組成物。
- 前記第1前駆体が、疾患または医学的状態と関連した任意の細胞表面抗原に対するアフィニティーを有し、そして前記第2前駆体が、サイトカイン、成長因子、カルボキシペプチダーゼG2、ペニシリアミダーゼ、β−ラクタマーゼ、シトシンデアミナーゼ、ニトロレダクターゼ、β−ガラクトシダーゼ、緑色蛍光タンパク質(GFP)またはその種々の工学的に作成されたアナログ、アルカリホスファターゼ、セイヨウワサビペルオキシダーゼ、およびストレプトアビジンからなる群より選ばれる、請求項20に記載の組成物。
- 医療状態を処置する医薬の製造のための請求項1に記載のホモダイマーの使用。
- 前記状態が、癌、感染、炎症、過形成、糖尿病性網膜症、若年性糖尿病、黄班変性、炎症性腸疾患、クローン病、潰瘍性大腸炎、慢性関節リウマチ、サルコイドーシス、喘息、浮腫、肺高血圧、乾癬、角膜移植片拒絶、血管新生性緑内障、オスラー−ウエバーシンドローム、心筋血管新生、プラーク血管新生、再発狭窄症、血管外傷後の新生血管内膜形成、毛細血管拡張症、血友病関節症、血管繊維腫、慢性炎症と関連した線維症、肺線維症、深部静脈血栓症または創傷顆粒形成である、請求項24に記載の使用。
- 前記状態が、癌であり、そして前記前駆体が、カルボニックアンヒドラーゼIX、αフェトプロテイン、A3、A33抗体に対して特異的な抗原、Ba733、BrE3抗原、CA125、CD1、CD1a、CD3、CD5、CD15、CD16、CD19、CD20、CD21、CD22、CD23、CD25、CD30、CD33、CD38、CD45、CD74、CD79a、CD80、CD138、結腸特異的抗原p(CSAp)、CEA(CEACAM5)、CEACAM6、EGFR、EGP−1、EGP−2、Ep−CAM、Flt−1、Flt−3、葉酸レセプター、G250抗原、HLA−DR、ヒト絨毛性性腺刺激ホルモン(HCG)およびそのサブユニット、HER2/neu、低酸素症誘導性因子(HIF−1)、Ia、IL−2、IL−6、IL−8、インスリン成長因子1(IGF−1)、KC4抗原、KS−1抗原、KS1−4、LeY、マクロファージ遊走阻害因子(MIF)、MAGE、MUC1、MUC2、MUC3、MUC4、NCA66、NCA95、NCA90、PAM−4抗体に対して特異的な抗原、胎盤成長因子、P53、前立腺酸性ホスファターゼ、PSA、PSMA、RS5、S100、TAC、TAG−72、テナシン、TRAILレセプター、Tn抗原、トムソン−フリーデンライヒ抗原、腫瘍壊死抗原、VEGF、ED−Bフィブロネクチン、17−1A抗原、血管新生マーカー、腫瘍遺伝子マーカーおよび腫瘍遺伝子産物からなる群より選ばれる腫瘍関連抗原に対する結合アフィニティーを有する、請求項25に記載の使用。
- 医療状態を処置する医薬の製造のための、2つのホモダイマーを含むテトラマーの使用であって、第1ホモダイマーが第1前駆体に結合したDDD配列を含む第1モノマーを含み、そして第2ホモダイマーが第2前駆体に結合したDDD配列を含む第2モノマーを含む、使用。
- 前記第2前駆体が、ハプテンに結合する、請求項27に記載の使用。
- 前記ハプテンが、抗血管新生剤、化学療法剤、サイトカイン、薬物、プロドラッグ、毒素、酵素、RNase、オリゴヌクレオチド、放射性同位元素、イムノモデュレーター、抗生剤、抗ウイルス剤、抗真菌剤、ワクチン、ホルモン、結合分子、脂質、ポリマー、ミセル、リポソーム、ナノ粒子またはその組合せからなる群より選ばれる作用物質に結合している、請求項28に記載の使用。
- 前記状態が、自己免疫疾患であるか、又はウイルス、真菌又はバクテリアによって引き起こされる状態である、請求項29に記載の使用。
- 前記自己免疫疾患が、急性特発性血小板減少性紫斑病、慢性特発性血小板減少性紫斑病、皮膚筋炎、シデナム舞踏病、重症筋無力症、全身性エリテマトーデス、ループス腎炎、リウマチ熱、多腺性症候群、水泡性類天疱瘡、若年性糖尿病、ヘノッホ−シェンライン紫斑症、ポスト連鎖球菌腎炎、結節性紅班、タカヤス動脈炎、アジソン病、慢性関節リウマチ、多発性硬化症、サルコイドーシス、潰瘍性大腸炎、多形性紅班、IgA腎症、結節性多発性動脈炎、剛直性脊椎炎、グッドパスチャー症候群、閉塞性血栓血管炎(thromboangitis obliterans)、シェーグレン症候群、一次胆汁性肝硬変、ハシモト甲状腺炎、甲状腺中毒症、強皮症、慢性活動性肝炎、多発性筋炎/皮膚筋炎、多発性軟骨炎、尋常性天疱瘡、ウェグネル肉芽腫症、膜性腎症、筋萎縮性側索硬化症、脊髄ろう、巨細胞動脈炎/多発性筋肉痛、悪性貧血、急速進行性糸球体腎炎、乾癬または線維化肺胞炎である、請求項30に記載の使用。
- 前記状態が、心筋梗塞、虚血性心疾患、アテローム性動脈硬化症プラーク、移植片拒絶、アルツハイマー病、アトピー性組織、または活性化された顆粒球、単球、リンパ系細胞もしくはマクロファージの付着成長により引き起こされる炎症である、請求項29に記載の使用。
- 前記状態が、癌であり、そして前記第1前駆体が、カルボニックアンヒドラーゼIX、αフェトプロテイン、A3、A33抗体に対して特異的な抗原、Ba733、BrE3抗原、CA125、CD1、CD1a、CD3、CD5、CD15、CD16、CD19、CD20、CD21、CD22、CD23、CD25、CD30、CD33、CD45、CD74、CD79a、CD80、CD138、結腸特異的抗原p(CSAp)、CEA(CEACAM5)、CEACAM6、EGFR、EGP−1、EGP−2、Ep−CAM、Flt−1、Flt−3、葉酸レセプター、G250抗原、HLA−DR、ヒト絨毛性性腺刺激ホルモン(HCG)およびそのサブユニット、HER2/neu、低酸素症誘導性因子(HIF−1)、Ia、IL−2、IL−6、IL−8、インスリン成長因子1(IGF−1)、KC4抗原、KS−1抗原、KS1−4、LeY、マクロファージ遊走抑制因子(MIF)、MAGE、MUC1、MUC2、MUC3、MUC4、NCA66、NCA95、NCA90、PAM−4抗体に対して特異的な抗原、胎盤成長因子、P53、前立腺酸性ホスファターゼ、PSA、PSMA、RS5、S100、TAC、TAG−72、テナシン、TRAILレセプター、Tn抗原、トムソン−フリーデンライヒ抗原、腫瘍壊死抗原、VEGF、ED−Bフィブロネクチン、17−1A抗原、血管新生マーカー、腫瘍遺伝子マーカーおよび腫瘍遺伝子産物からなる群より選ばれる腫瘍関連抗原に結合する、請求項29に記載の使用。
- 前記テトラマーが、抗CD74X抗CD20、抗CD74X抗CD22、抗CD22X抗CD20、抗CD20X抗HLA−DR、抗CD19X抗CD20、抗CD20X抗CD80、抗CD2X抗CD25、抗CD8X抗CD25および抗CD2X抗CD147からなる群より選ばれる抗体または抗体フラグメントの組み合わせを含む、請求項27に記載の使用。
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AU2006232920B2 (en) | 2011-09-29 |
US20150050715A1 (en) | 2015-02-19 |
CN101484182B (zh) | 2014-06-11 |
US9540435B2 (en) | 2017-01-10 |
EP1874824A2 (en) | 2008-01-09 |
CA2604032C (en) | 2017-08-22 |
AU2006232920A1 (en) | 2006-10-12 |
US7521056B2 (en) | 2009-04-21 |
WO2006107617A3 (en) | 2008-08-14 |
CN101484182A (zh) | 2009-07-15 |
US7871622B2 (en) | 2011-01-18 |
WO2006107617A2 (en) | 2006-10-12 |
JP2008538747A (ja) | 2008-11-06 |
CA2604032A1 (en) | 2006-10-12 |
US8906377B2 (en) | 2014-12-09 |
EP1874824A4 (en) | 2009-12-30 |
US20090191225A1 (en) | 2009-07-30 |
US20060228300A1 (en) | 2006-10-12 |
US20110143417A1 (en) | 2011-06-16 |
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