JP2009536921A - アルファ5ベータ1アンタゴニストを含むコンビナトリアル療法 - Google Patents
アルファ5ベータ1アンタゴニストを含むコンビナトリアル療法 Download PDFInfo
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Abstract
Description
本発明は疾患における異常な血管新生を抑制することを包含する、癌の治療及び血管新生及び/又は抑制された血管透過性の抑制のためのVEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストの使用に関する。本発明は又、血管新生および血管透過性を促進するためのVEGFRアゴニスト及びアルファ5ベータ1アゴニストの使用に関する。本発明は又抗アルファ5ベータ1抗体、それらを含む組成物及びキット、及びそれらを製造および使用する方法に関する。
病理学的及び非病理学的な血管新生におけるVEGF−Aの重要な役割は、十分解明されている。インビボモデルにおけるVEGFの投与は強力な血管新生応答を誘導している(非特許文献1;非特許文献2)。単一のVEGF−A対立遺伝子の損失はマウスにおいて胚性致死を生じさせている(非特許文献3;非特許文献4)。VEGFは又、血管漏出性を誘導するその能力により血管透過性因子としても知られている(非特許文献5;非特許文献6)。即ち、VEGF−Aは発生、生殖及び骨の血管新生についても、他の非病理学的血管新生に加えて関与している。
Plouet,J等、EMBO J.(1989)8:3801−3808 Leung,D.W.等、Science(1989)246:1306−1309 Carmeliet,P.等、Nature(1996)380:435−439 Ferrara,N等、Nature(1996)380:439−442 Senger,D.R.等、Science(1995)219:983−985 Dvorak,H.F.等、Am.J.Pathol.(1995)146:1029−1039
本発明は低減された血管新生により利益を被る、異常な血管新生に罹患している、及び/又は新生物形成に罹患している患者を治療する医薬及び方法に関する。1つの実施形態によれば、本発明は治療有効量のVEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストを同時又は逐次的に対象に投与する工程を含む、対象における血管新生及び/又は血管透過性を抑制するための方法を提供する。他の実施形態によれば、本発明は、治療有効量のアルファ5ベータ1アンタゴニストを疾患に罹患した対象に投与する工程を含む、対象がVEGFアンタゴニストを用いた疾患に対する治療には応答性であったが、VEGFアンタゴニストに対して部分的に応答するか、またはもはや応答しない場合の、該対象を治療するための方法を提供する。別の実施形態によれば、本発明は治療有効量のVEGFアンタゴニストを疾患に罹患した対象に投与する工程を含む、疾患がアルファ5ベータ1アンタゴニスト療法に対し、単独又は化学療法との組み合わせにおいて、抵抗性又は難治性となっている場合の、該対象を治療するための方法を提供する。
理論に制約されないが、本発明者等は、増大した間質細胞のリクルートメントは、VEGFアンタゴニスト療法により治療された患者においてVEGFの活性の損失を補うことができる他の血管成長因子を運ぶことができることを提案する。抗a5b1抗体によるa5b1発現間質細胞のターゲティングは間質細胞の低減をもたらし、これにより潜在的に補償性の血管成長因子の生産を低減すると考えられる。或いは、又は追加的に、内皮−細胞外マトリックスの相互作用を抑制すること、特にアルファ5ベータ1の結合相互作用を抑制することが、VEGFアンタゴニスト療法による血管後退による細胞外マトリックストラック(extracellular matrix track)に沿った血管新生の復帰を抑制することによりVEGFアンタゴニスト療法を強化することを本発明者等は提案する。従って、何れかのVEGFアンタゴニスト治療と同時か、その後のアルファ5ベータ1アンタゴニストを用いた治療はVEGFアンタゴニスト治療からの血管の回復及びその結果としての新生血管成長の復帰を抑制すると考えられる。
/小胞状非ホジキンリンパ腫(NHL);小リンパ性(SL)NHL;中間等級/小胞状NHL;中悪性度びまん性NHL;高悪性度免疫芽球性NHL;高悪性度リンパ芽球性NHL;高悪性度小非分割細胞性NHL;バルキー疾患NHL;被膜細胞リンパ腫;エイズ関連リンパ腫;及びウォルデンストロムマクログロブリン血症);慢性リンパ性白血病(CLL);急性リンパ芽球性白血病(ALL);ヘアリー細胞白血病;慢性骨髄芽球性白血病;及び移植後のリンパ増殖性障害(PTLD)、並びに母斑症に伴う異常な血管の増殖、及びメイグズ症候群を包含する。
ヒトアルファ5ベータ1に結合し、そしてヒトアルファ5ベータ1への抗アルファ5ベータ1抗体の結合を競合的に抑制することができる新しい抗体を本明細書において提供する。1つの実施形態によれば、抗アルファ5ベータ1抗体は2006年3月7日にATCCにおいてアルファ5/ベータ1 7H5.4.2.8(ATCC No.PTA−7421)として寄託されたハイブリドーマ及びアルファ5/ベータ17H12.5.1.4(ATCC No.PTA−7420)として寄託されたハイブリドーマからなる群より選択されるハイブリドーマにより生産される。別の実施形態によれば、抗体は2006年3月7日にATCCにおいてアルファ5/ベータ1 7H5.4.2.8(ATCC No.PTA−7421)として寄託されたハイブリドーマ及びアルファ5/ベータ17H12.5.1.4(ATCC No.PTA−7420)として寄託されたハイブリドーマからなる群より選択されるハイブリドーマにより生産される。更に別の実施形態によれば、抗体は請求項1記載の抗体であって、抗体が2006年3月7日にATCCにおいてアルファ5/ベータ1 7H5.4.2.8(ATCC No.PTA−7421)として寄託されたハイブリドーマにより生産される抗体の可変重鎖(VH)及び可変軽鎖(VL)ドメイン配列を含む。別の実施形態においては、抗体は、2006年3月7日にATCCにおいてアルファ5/ベータ17H12.5.1.4(ATCC No.PTA−7420)として寄託されたハイブリドーマにより生産される抗体の可変重鎖(VH)及び可変軽鎖(VL)ドメイン配列を含む。寄託したハイブリドーマの抗体のヒト及びキメラ型も意図される。
疾患に罹患した対象における血管新生及び/又は血管透過性を抑制するための新しい組み合わせであり、その組み合わせはVEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストを含む。VEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストは同時又は逐次的な治療サイクルにおいて投与できる。そのような複合療法は異常な血管新生及び/又は血管透過性を有し、そして抗血管新生療法から利益を被る疾患を包含する疾患を治療するために有用である。そのような疾患は、限定しないが、癌、眼の疾患及び自己免疫疾患を包含する。或いは、対象はVEGFアンタゴニストで治療され、そして後にアルファ5ベータ1アンタゴニストを投与されることができ、例えば対象がVEGFアンタゴニスト治療に非応答性となるまでVEGFアンタゴニストで治療し、そして次に対象をアルファ5ベータ1アンタゴニストで治療する。1つの実施形態によれば、対象は癌が非侵襲性である場合にはVEGFアンタゴニストで治療し、癌が侵襲性である場合にはアルファ5ベータ1アンタゴニストで治療される。非疾患患者又は対照と比較して、天然に、又はVEGFアンタゴニスト療法に応答して、上昇したアルファ5ベータ1レベルを経験する一部の患者は、この複合治療に特に応答性となる場合がある。治療薬(例えば抗腫瘍剤、化学療法剤、増殖抑制剤及び細胞毒性剤)を更に含む組み合わせが意図される。例えば化学療法剤(例えばイリノテカン)及びアルファ5ベータ1アンタゴニストで治療される予定の、又は、化学療法及びアルファ5ベータ1アンタゴニストで治療されている患者は、VEGFアンタゴニスト療法から利益を被ることができる。或いは、化学療法及びVEGFアンタゴニストで治療されている患者は、アルファ5ベータ1アンタゴニスト療法から利益を被ることができる。1つの好ましい実施形態においては、抗VEGF抗体はAvastin(登録商標)抗体である。別の好ましい実施形態においては抗アルファ5ベータ1抗体は本明細書に記載した抗アルファ5ベータ1抗体である。VEGFアンタゴニスト、アルファ5ベータ1アンタゴニスト及び場合により化学療法剤を含むキットが意図される。
本発明により使用される抗体の治療用製剤は、凍結乾燥製剤又は水溶液の形態において、任意の生理学的に許容される担体、賦形剤又は安定化剤(Remington’s Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980))に所望の程度の純度を有する抗体を混合することにより保存用に製造される。許容される担体、賦形剤又は安定化剤は使用される用量及び濃度においてレシピエントに非毒性であり、そして、緩衝物質、例えばリン酸塩、クエン酸塩及び他の有機酸;抗酸化剤、例えばアスコルビン酸及びメチオニン;保存料(例えばオクタデシルジメチルベンジルアンモニウムクロリド;ヘキサメトニウムクロリド;塩化ベンザルコニウム、塩化ベンゼトニウム;フェノール、ブチル又はベンジルアルコール;アルキルパラベン、例えばメチル又はプロピルパラベン;セタノール;レゾルシノール;シクロヘキサノール;3−ペンタノール;及びm−クレゾール);低分子量(約10残基未満)のポリペプチド;蛋白、例えば血清アルブミン、ゼラチン又は免疫グロブリン;親水性重合体、例えばポリビニルピロリドン;アミノ酸、例えばグリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン又はリジン;単糖類、2糖類及び他の炭水化物、例えばグルコース、マンノース又はデキストリン;キレート剤、例えばEDTA;糖類、例えばスクロース、マンニトール、トレハロース又はソルビトール;塩形成対イオン、例えばナトリウム;金属複合体(例えばZn−蛋白複合体);及び/又は非イオン性界面活性剤、例えばTWEENTM、PLURONICSTM又はポリエチレングリコール(PEG)を包含する。例示される抗体製剤は参照により本明細書に組み込まれるWO98/56418に記載されている。皮下投与に適する凍結乾燥製剤はWO97/04801に記載されている。そのような凍結乾燥された製剤は適当な希釈剤で再構成して高蛋白濃度とし、そして再構成製剤を本明細書における治療すべき哺乳類に皮下投与してよい。
本発明の別の実施形態は腫瘍、眼の疾患又は自己免疫疾患及び関連の状態の治療のために有用な材料物質を含有する製造物品が提供される。製造物品は容器及び容器上又はそれに伴ったラベル又はパッケージインサートを含む。適当な容器は例えばビン、バイアル、シリンジ等を包含する。容器は種々の材料、例えばガラス又はプラスチックから形成してよい。一般的に容器は状態の治療に有効となる組成物を保持しており、そして滅菌された接触口を有してよい(例えば容器は静脈内投与用の溶液バッグ又は皮下注射針により穿刺可能な蓋つきのバイアルであってよい)。組成物中の少なくとも1つの活性剤は本発明のVEGFアンタゴニスト又はアルファ5ベータ1アンタゴニスト又はVEGFアゴニスト又はアルファ5ベータ1アゴニストである。ラベル又はパッケージインサートは、組成物が特定の状態を扱うために使用されることを示している。ラベル又はパッケージインサートは更に患者への抗体組成物の投与に関する説明書を含むことになる。本明細書に記載したコンビナトリアル療法を含む製造物品及びキットもまた意図される。
又はウエスタンブロットにおけるインビトロのアルファ5ベータ1及び/又はVEGFの検出及び定量のための抗体を含有するキットを提供できる。製造物品の場合と同様に、キットは容器及び容器上又はそれに付随したラベル又はパッケージインサートを含む。例えば、容器は本発明の抗アルファ5ベータ1抗体少なくとも1つを含む組成物を保持している。例えば希釈剤及び緩衝剤、対照抗体を含有する別の容器を包含させてよい。ラベル又はパッケージインサートは組成物の説明並びに意図されるインビトロ又は診断上の使用のための説明書を提示してよい。
モノクローナル抗体は例えばKohler and Milstein,Nature,256:495(1975)により記載されたもののようなハイブリドーマ法を用いて製造することができ、あるいは、組み換えDNA法(米国特許4,816,567)により作成することができ、あるいは実施例のセクションにおいて本明細書に記載した方法により製造することができる。ハイブリドーマ法においては、マウス、ハムスター又は他の適切な宿主動物を典型的には免疫化剤で免疫化することにより免疫化剤に特異的に結合することになる抗体を生産するか生産することができるリンパ球を生じさせる。或いは、リンパ球をインビトロで免疫化できる。
抗体はヒト化抗体又はヒト抗体であることができる。非ヒト(例えばマウス)抗体のヒト化型は典型的には非ヒト免疫グロブリンから誘導された最小配列を含有するキメラ免疫グロブリン、免疫グロブリン鎖、又はそのフラグメント(例えばFv、Fab、Fab’、F(ab’)2又は抗体の他の抗原結合サブ配列)である。ヒト化抗体はヒト免疫グロブリン(レシピエント抗体)を包含し、その場合レシピエントのCDR由来の残基は所望の特異性、親和性及び能力を有するマウス、ラット又はウサギのような非ヒト種(ドナー抗体)のCDR由来の残基により置き換えられている。一部の場合においては、ヒト免疫グロブリンのFvフレームワーク残基は相当する非ヒト残基により置き換えられている。ヒト化抗体は又レシピエント抗体中、又はインポートされたCDR又はフレームワーク配列中の何れにも存在しない残基を含むことができる。一般的にヒト化抗体は少なくとも1つ、そして典型的には2つの可変ドメインの実質的に全てを含むことができ、その場合、CDR領域の全て又は実質的に全てが非ヒト免疫グロブリンのものに相当し、そしてFR領域の全て又は実質的に全てがヒト免疫グロブリンコンセンサス配列のものとなる。ヒト化抗体は好ましくは又、免疫グロブリン定常領域の少なくとも一部分(Fc)、典型的にはヒト免疫グロブリンのものを含むことになる。Jones等、Nature,321:522−525(1986);Riechmann等、Nature,332:323−329(1988);Presta,Curr.Op.Struct.Biol.,2:593−596(1992)。
多重特異性抗体は2つ以上の異なる抗原に対して結合特異性を有するモノクローナルの、好ましくはヒト又はヒト化抗体(例えば少なくとも2つの抗原に対して結合特異性を有する二重特異性抗体)である。例えば、結合特異性の1つはアルファ5ベータ1抗体に対するものであることができ、そして他方は何れかの他の抗原に対するものであることができる。1つの好ましい実施形態によれば、他の抗原は細胞表面蛋白又は受容体又は受容体サブユニットである。例えば、細胞表面蛋白はナチュラルキラー(NK)細胞受容体であることができる。即ち、1つの実施形態によれば、本発明の二重特異性抗体はアルファ5ベータ1に結合でき、そしてVEGFに結合できる。
ヘテロ結合体抗体は2つの共有結合により連結された抗体を含む。そのような抗体は例えば望ましくない細胞に免疫系細胞をターゲティングするため(米国特許4,676,980)、及びHIV感染症を治療するために提案されている。WO91/00360;WO92/200373;EP 03089。抗体は合成蛋白化学における知られた方法、例えば交差結合剤を使用するものを用いてインビトロで製造できる。例えば免疫毒素をジスルフィド交換反応を用いて、又はチオエステル結合を形成することにより、構築することができる。この目的のための適当な試薬の例はイミノチオレート及びメチル−4−メルカプトブチルイミデート及び例えば米国特許4,676,980に開示されているものを包含する。
例えば癌の治療における抗体の有効性が増強されるようにエフェクター機能に関して本発明の抗体を修飾することが望ましい場合がある。例えばシステイン残基をFc領域に導入することにより、この領域における鎖間ジスルフィド結合形成を可能にすることができる。このようにして形成されたホモ2量体抗体は向上した内在化能力及び/又は増大した補体媒介細胞殺傷及び抗体依存性細胞性細胞毒性(ADCC)を有することができる。Caron等、J.Exp.Med.,176:1191−1195(1992)and Shopes,J.Immunol.,148:2918−2922(1992)を参照できる。増強され抗腫瘍活性を有するホモ2量体抗体はまた、Wolff等、Cancer Research,53:2560−2565(1993)に記載される通りヘテロ2官能性交差結合剤を用いて製造できる。或いは、二重のFc領域を有し、そしてこれにより増強された補体溶解及びADCC能力を有する抗体を操作することができる。Stevenson等、Anti−Cancer Drug Design,3:219−230(1989)を参照できる。
本発明は又細胞毒性剤、例えば化学療法剤、毒素(例えば細菌、カビ、植物又は動物期限の酵素的に活性な毒素又はそのフラグメント)又は放射性同位体(すなわちラジオコンジュゲート)に結合体化された抗体を含む免疫結合体に関する。
本明細書に開示した抗体は又イムノリポソームとして製剤できる。抗体を含有するリポソームは当該分野で知られた方法、例えばEpstein等、Proc.Natl.Acad.Sci.USA,82:3688(1985);Hwang等、Proc.Natl.Acad.Sci.USA,77:4030(1980);及び米国特許4,485,045及び4,544,545に記載される通り製造される。増強された循環時間を有するリポソームは米国特許5,013,556に記載されている。
本明細書に記載したポリペプチド並びに上記開示したスクリーニング試験により発見される他の分子に特異的に結合する抗体は医薬組成物の形態において上記及び後記する通り種々の疾患の治療のために投与できる。
ポリペプチドに特異的に結合する標識された抗体、及びその誘導体及び類縁体は、本発明のポリペプチドの発現、異常な発現及び/又は活性に関連する疾患及び/又は障害を検出、診断又はモニタリングするために使用できる。1つの好ましい実施形態によれば、本発明の抗体は対象内への抗体の注射を行う診断試験又は画像化試験において使用できる。本発明は(a)本発明の抗体1つ以上を用いて個体の細胞(例えば組織)又は体液中のポリペプチドの発現を試験すること、及び(b)遺伝子発現のレベルを標準的な遺伝子発現のレベルと比較することにより、標準的な発現レベルと比較した場合の試験した遺伝子発現のレベルの増大又は低下が異常発現を示すようにすること、を含むVEGF又はアルファ5ベータ1ポリペプチドの異常な発現の検出を可能とする。
無胸腺マウスにおいて抗VEGF抗体B20−4.1単独療法で治療されていたHT−29ヒト結腸直腸癌腫異種移植片の切片を抗アルファ5ベータ1発現に関して染色した。本試験において対照抗体(抗ブタクサ抗体)で治療されていた対照群と比較して、B20−4.1単独療法は活性が殆どないか、皆無であることに相当する終点までのメジアンの時間(TTE)を示した。腫瘍は58日の期間、週2回測定した。動物はその腫瘍が1000mm3の終点体積に到達した時点、又は第58日の何れか早い時点で安楽死させ、そして各マウスにつき(TTE)を計算した。治療の結果は対照マウスと比較した場合の治療マウスのメジアンTTEにおける増大のパーセントとして定義されるパーセント腫瘍成長遅延(%TGD)から求め、差はLogrank分析を用いて0.01≦P≦0.05で有意とみなし、そしてP<0.01で高度に有意とみなした。対照群のメジアンTTE値は20.6日であった。B20−4.1単独療法による治療は無活性に相当する20.1日のメジアンTTEを示した。
マウスに精製ヒトアルファ5ベータ1(Chemicon CC1027)を注射した。抗アルファ5ベータ1抗体を発現しているプラズマ細胞腫細胞を単離し、ハイブリドーマ細胞株に形質転換した。7H5.4.2.8及び7H12.5.1.4と命名された2つのハイブリドーマ細胞株をATCCに寄託した。上記参照。7H5.4.2.8ハイブリドーマから生産された抗体はmIgG2a Kappa抗体(本明細書においては「7H5抗体」とも称する)である。7H12.5.1.4ハイブリドーマから生産された抗体はmIgG2b Kappa抗体(本明細書においては「7H12抗体」とも称する)である。
成長中の人臍帯静脈内皮細胞(HUVEC)を含有する組織培養物をPBSで2回洗浄した。細胞を5mMEDTA/PBS溶液3〜4mlを用いて培養フラスコから脱離させた。新しい培地を細胞に添加して混合した。混合物中の細胞のアリコートを計数した。細胞を遠心分離し、洗浄緩衝液(50mM Tris、150mM NaCl、pH7.5)で1回洗浄した。細胞濃度は、細胞が384ウェルプレート上で25,000個/ウェル又は4,000個/ウェルとなるように96穴MSD高結合プレート(それぞれCat#L11XB−1又は#L11XB−2、Meso Scale Diagnostics、LLC)上にウェル当たり25uLで細胞が播種されるように調節した。細胞をプレート上室温で1時間インキュベートすることによりキャプチャーさせた。ウェルをブロックするために、25uLの保存緩衝液(TBS(50mM Tris,150mM NaCl)中30%ウシ胎児血清(FBS)+1mMCaCl2/1mM MgCl2,pH7.5)をウェルに添加し、30〜1時間室温でインキュベートした。
7H12又は7H5抗体を100uLにおいてRAJI細胞(アルファ5ベータ1mRNAを発現しない細胞株)又はHUVEC細胞(高レベルのアルファ5ベータ1mRNAを発現する細胞株)と共にインキュベートした。結合細胞を蛍光結合体二次抗体を用いて検出した。図3は7H12及び7H5がHUVEC細胞には結合するがRAJI細胞には結合しないことをFACS分析によって示している。同様の手法をウサギ滑膜細胞(HIG−82)及びアカゲザル細胞(CL−160アカゲザル線維芽細胞又はCRL−1780網膜内皮細胞)と共に使用した場合、本発明者等は7H12及び7H5がウサギ及びサルの細胞に結合することを観察した。
フィブロネクチン(Sigma F1141(ウシ)又はRoche 1080938(ヒト))を炭酸ナトリウム緩衝液で1ug/mlに希釈した。フィブロネクチン溶液100μlをNUNCマキシソープ96穴プレートのウェル当たりに添加し、4℃で一晩放置して結合させた(NUNC96穴平底イムノプレート、MaxiSorpN/Ster 439454(VWR62409−002))。次にウェルをリン酸緩衝生理食塩水(PBS)で洗浄し、少なくとも30分間1%BSA(Sigma A9418)でブロックした。次にプレートをPBSで3回洗浄した。20,000HUVEC細胞を各ウェルに添加し、1.4mM MgCl2及び1.4mM CaCl2を含有する生育培地中、7H5及び7H12の種々の濃度でインキュベートした。次にインキュベーション混合物をフィブロネクチンコーティングプレートに添加した。同じ生育培地中の約20,000個の細胞を、抑制性抗体を添加していない対照ウェル各々に添加した。
96穴プレートを一晩フィブロネクチン(1μg/kg)でコーティングした。次にプレートをPBSで洗浄した。3000〜5000個の内皮細胞(EC)を96穴当たり添加し、ウェルに完全に結合させた。抗アルファ5抗体を添加した(アイソタイプ対照を包含する)。各条件につき3ウェルを使用した。次に細胞を1〜24時間抗体と共にインキュベートした。抗インテグリンアルファ5ベータ1抗体を数種の濃度において試験した(例えば0μg/ml、4μg/ml、16μg/ml、60μg/ml、120μg/ml)。
HUVEC細胞をコンフルエントとなるまで5μg/mlフィブロネクチンコーティング24穴プレート上でEGM2+全補充物(Cloneticsより入手、Cat#CC−4176)中で生育させた。次に各ウェルの中央の細胞を2μlピペットの先端で剥離させ、剥離により除去された細胞を洗浄除去した。対照抗体、7H5又は7H12のいずれかを含有する細胞培養培地を異なるウェルに添加した。全被験抗体は20μg/mlで使用した。次に細胞を1〜2日間生育させた。創傷の生じた領域をモニタリングした。図6は0時間及び30時間におけるECM−2中20μg/ml抗アルファ5抗体(7H5)を含有する5μg/mlフィブロネクチン上のHUVEC移動の写真を示す。図7は7H5及び7H12抗体で処理した細胞に関する30時間における%移動のグラフである。
96穴プレートを一晩フィブロネクチン(1μg/ml)上でコーティングした。プレートをPBSで洗浄した。次に3000〜5000のHUVEC細胞を96穴当たりにプレーティングし、完全培地中で一晩生育させた(EBM−2培地(Cambrex CC−3156)+EGM−2、SingleQuots(Cambrex CC−4176))。2H−11マウスの内皮細胞をアポトーシス試験に使用する場合は、培地を10%FBSとの50/50培地とする。
カスパーゼ3/7活性試験を7H5及び7H12抗体を用いて実施した(Promegaより入手したApo−Oneカスパーゼ−3/7試験、標準的な96穴試験の説明書についてはTechnical Bulletin No.295参照)。
抗アルファ5ベータ1抗体が管形成を抑制する能力について試験できる。以下はNakatsu等、(2003)Microvascular Research 66(2003)102-112において記載されたHUVEC発芽及び管形成試験に基づいた管形成試験の例である。
アルファ5ベータ1アンタゴニスト療法及びVEGFアンタゴニスト療法の同時及び逐次的投与を異種移植片/自家移植片腫瘍モデルにいて評価することができる。好ましくは、モデルはVEGFアンタゴニスト単独療法に対しては殆ど又は全く応答しない。使用できるモデルの例は以下の通り、即ち(a)無胸腺ヌードマウスにおけるFo5自家移植片(mmtv−Her2トランスジェニックマウスから誘導した乳房腫瘍)(Finkle,D.等、(2004) Clin.Cancer Res.10:2499−2511);(b)無胸腺ヌードマウスにおけるHT29異種移植片(ヒト結腸直腸系統);及び(c)RIP−TbAg(Tgモデルにおける膵臓腫瘍)である。治療は典型的には腹腔内、皮下又は静脈内に投与し得る。例えば、抗VEGF抗体は10mg/kgにおいて週1回又は5mg/kgにおいて週2回投与してよい。投与すべき抗体のようなアルファ5ベータ1アンタゴニストの量はその親和性及び活性に基づいて推定できる。1つの実施形態において、VEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストを同日程において5〜6週間投与できる。或いは、又は追加的に、VEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストを逐次的に投与できる(例えば抗VEGF抗体を3週間、その後、抗アルファ5ベータ1抗体を3週間投与)。
HRLN雌性ヌードマウスの側腹部に5×106MDA−MB231ヒト乳癌細胞を皮下注射した(HRLNは株の名称)。腫瘍を平均80〜120mm3となるまで生育させた。次に腫瘍担持マウスを4群に分割し、群当たりの平均腫瘍体積が〜100mm3となった時点で治療を開始した。
(1)対照群:抗ブタクサ対照mab注射(10mg/kg、腹腔内(ip)、週1回)
(2)抗VEGF単剤群:抗VEGF mab B20.4.1注射(10mg/kg、ip、週1回)
(3)組み合わせ群:B20.41(10mg/kg、ip、週1回)+ハムスター抗マウスインテグリンアルファ5 mab 10E7(10mg/kg、ip、週2回)
(4)抗インテグリンアルファ5単剤群:ハムスター抗マウスインテグリンアルファ5 mab 10E7注射(10mg/kg、ip、週2回)
ニュージーランド白ウサギを計量し、イソフルオランで麻酔した。各ウサギにおいて、両方の耳介の内面から、そして辺縁に沿って剃毛した。脱毛ローションを用いて全ての残存する体毛を外科処置部位から除去した。外科処置部位はベタジンスクラブで浄化し、その後アルコールですすいだ。無菌的手法を用いて、環状8mmパンチ生検器具を用いて各耳介の耳軟骨の深さまで1つの創傷を作成した。根底にある軟骨膜を骨膜起子(periosteal elevator)及び精密鋏を用いて除去した。Opsite(登録商標)接着包帯を各創傷上に設置し、ウサギを麻酔から回復させた。
投与群は以下の通りである。
ベバシツマブ(抗VEGF抗体)100ug/30uLを各創傷に毎日(n=4)
7H12(抗アルファ5ベータ1抗体)100ug/30uLを各創傷に毎日(n=4)
ベバシツマブを100ug/15uL+7H12を100ug/15uL、各創傷に毎日(n=4)
トラスツズマブ(抗HER2抗体)100ug/30uLを各創傷に毎日(n=3)。
HRLN雌性nu/nuマウスの側腹部に1mm3のHT29腫瘍フラグメント(結腸腫瘍)を皮下注射した。腫瘍は治療薬投与前に80〜120mm3の平均の大きさに到達するまで生育させた。次に腫瘍担持マウスを4群に分割した。
HRLN雌性nu/nuマウスの側腹部に5×106HTC116腫瘍細胞(結腸腫瘍細胞)を皮下注射した。腫瘍は治療薬投与前に80〜120mm3の平均の大きさに到達するまで生育させた。次に腫瘍担持マウスを4群に分割した。
抗アルファ5ベータ1抗体を、Iodogen法を用いてヨウ素化し、放射標識した抗体を遊離の125I−NaからPD−10カラムを用いたゲル濾過により精製した。R9ab細胞、即ちウサギ線維芽細胞株(ATCCより購入、CCL−193)を24穴プレート中ウェル当たり〜50,000で播種し、48時間5%CO2中37℃でインキュベートした。細胞を結合緩衝液(50:50DMEM/F12培地、2%FBS及び50mMHEPES含有、pH7.2)で3回洗浄し、次に15分間氷上でインキュベートした。洗浄した細胞を4時間氷上において、3連で試験する13濃度について結合緩衝液中0.5uMから連続希釈した未標識抗アルファ5ベータ1モノクローナル抗体の漸減濃度を含有する125I−抗アルファ5ベータ1モノクローナル抗体約50pMでインキュベートした。細胞を結合緩衝液で3回洗浄し、次に200uLのSDS溶解緩衝液(1%SDS、8M尿素、100mMグリシン、pH 3.0)で可溶化した。細胞をWallac Wizard 1470ガンマカウンターで計数した。結合データは、抗体の結合親和性及び結合部位の濃度を測定するためにMunson and Robard(Munson,P.and Robard,D.(1980)Anal.Biochem.107:220−239)の曲線フィッティングアルゴリズムを使用しているGenentechのプログラムNewLigandを用いて評価した。図14及び15はこれらの結合試験においてそれぞれ、7H5抗体が0.10nMのKdを有し、そして7H12抗体が0.30nMのKdを有することを示している。
抗インテグリンα5β1IgGの3倍連続希釈物を室温で1〜2時間、PBST緩衝液(PBS及び0.5%(w/v)BSA及び0.05%(v/v)Tween20)中、ヒトインテグリンα5β1抗原(1ug/ml;R&D)でコーティングした96穴Nunc Maxisorpプレートと共にまずインキュベートし、その後、0.3nMビオチン化h7H5.v1 hIgG1(Genentech,Inc.の作成した7H5の抗体変異体)を添加し、これをまず15分間最大未満の結合シグナル(50〜70%)により測定した。次にプレートをPBT緩衝液(PBS及び0.05%(v/v)Tween20)で5回洗浄した。結合したビオチン化h7H5.v1 hIgG1をPBST緩衝液中1:2500希釈したストレプトアビジンセイヨウワサビパーオキシダーゼ結合体(Pierce)で検出し、3,3’,5,5’−テトラメチルベンジジン(TMB,Kirkegaard & Perry Labs,Gaithersburg,MD)基質で約5分間発色させ、1.0MのH3PO4でクエンチングし、そして450nmにおいて分光光度的に読み取った。曲線を4パラメーター非線形回帰曲線フィッティングプログラム(Kaleidagraph,Synergy Software)によりフィットさせた。
Claims (60)
- ヒトアルファ5ベータ1に結合し、そしてヒトアルファ5ベータ1への抗アルファ5ベータ1抗体の結合を競合的に抑制することができる抗体であって、該抗アルファ5ベータ1抗体が2006年3月7日にATCCにおいてアルファ5/ベータ1 7H5.4.2.8(ATCC No.PTA−7421)として寄託されたハイブリドーマ及びアルファ5/ベータ17H12.5.1.4(ATCC No.PTA−7420)として寄託されたハイブリドーマからなる群より選択されるハイブリドーマにより生産される、抗体。
- 請求項1記載の抗体であって、該抗体が2006年3月7日にATCCにおいてアルファ5/ベータ1 7H5.4.2.8(ATCC No.PTA−7421)として寄託されたハイブリドーマ及びアルファ5/ベータ17H12.5.1.4(ATCC No.PTA−7420)として寄託されたハイブリドーマからなる群より選択されるハイブリドーマにより生産される、抗体。
- 請求項1記載の抗体であって、該抗体が2006年3月7日にATCCにおいてアルファ5/ベータ1 7H5.4.2.8(ATCC No.PTA−7421)として寄託されたハイブリドーマにより生産される抗体の可変重鎖(VH)及び可変軽鎖(VL)ドメイン配列を含む、抗体。
- 請求項1記載の抗体であって、該抗体が2006年3月7日にATCCにおいてアルファ5/ベータ17H12.5.1.4(ATCC No.PTA−7420)として寄託されたハイブリドーマにより生産される抗体の可変重鎖(VH)及び可変軽鎖(VL)ドメイン配列を含む、抗体。
- 請求項1記載の抗体であって、該抗体が2006年3月7日にATCCにおいてアルファ5/ベータ1 7H5.4.2.8(ATCC No.PTA−7421)として寄託されたハイブリドーマ及びアルファ5/ベータ17H12.5.1.4(ATCC No.PTA−7420)として寄託されたハイブリドーマからなる群より選択されるハイブリドーマにより生産される抗アルファ5ベータ1抗体のヒト化抗体又はキメラ抗体である、抗体。
- 前記抗体が500nM〜1pMのKdでアルファ5への結合の間のKdでヒトアルファ5ベータ1に結合する請求項1〜5の何れか1項に記載の抗体。
- 前記抗体がアルファVベータ3にもアルファVベータ5にもアルファVベータ1にも結合しない請求項1記載の抗体。
- 前記抗体がヒトIgGのFc配列を含む請求項1及び3〜5の何れか1項に記載の抗体。
- 前記抗体がヒトIgG1又はヒトIgG4のFc配列を含む請求項1及び3〜5の何れか1項に記載の抗体。
- 前記抗体が抗体依存性細胞性細胞毒性(ADCC)エフェクター機能を欠いたFc配列を含む請求項8記載の抗体。
- 抗体がFab、Fab’、F(ab’)2、単鎖Fv(scFv)及びFvフラグメント;ダイアボディー及び線状抗体からなる群より選択される請求項1及び3〜5の何れか1項に記載の抗体。
- 前記抗体が多重特異性抗体である請求項1及び3〜5の何れか1項に記載の抗体。
- 治療薬に結合体化された請求項1及び3〜5の何れか1項に記載の抗体。
- 前記治療薬が細胞毒性剤、放射性同位体及び化学療法剤からなる群より選択される請求項13記載の抗体。
- 標識に結合体化された請求項1及び3〜5の何れか1項に記載の抗体。
- 前記標識が放射性同位体、蛍光染料及び酵素からなる群より選択される請求項15記載の抗体。
- 請求項1〜5に記載の抗体の何れか1つの可変重鎖ドメイン(VH)又は可変軽鎖ドメイン(VL)又はVH及びVLドメインの両方をコードする単離された核酸分子。
- 請求項17記載の核酸分子をコードする発現ベクター。
- 請求項17記載の核酸分子を含む細胞。
- 前記細胞が2006年3月7日にATCCにおいてアルファ5/ベータ1 7H5.4.2.8(ATCC No.PTA−7421)として寄託されたハイブリドーマ又はアルファ5/ベータ17H12.5.1.4(ATCC No.PTA−7420)として寄託されたハイブリドーマである請求項19記載の細胞。
- 請求項19又は請求項20記載の細胞を培養すること、及び、細胞培養物から抗体を回収することを含む抗体の製造方法。
- 請求項1及び3〜5の何れか1項に記載の抗体および製薬上許容しうる担体を含む組成物。
- 患者に由来する試料に請求項1〜5の何れか1項に記載の抗体を接触させること、及び該アルファ5ベータ1蛋白に結合した該抗アルファ5ベータ1抗体を検出することによる、該試料中の該アルファ5ベータ1蛋白を検出する方法。
- 前記抗体が免疫組織化学アッセイ(IHC)又はELISAアッセイにおいて使用される請求項23記載の方法。
- 対象における血管新生及び/又は血管透過性を抑制するための医薬の製造における請求項1及び3〜5の何れか1項に記載の抗体の使用。
- 対象における疾患を治療するための医薬の製造における請求項1及び3〜5の何れか1項に記載の抗体の使用であって、該疾患が異常な血管新生又は血管透過性である、使用。
- VEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストを投与することを含む疾患に罹患した対象における血管新生及び/又は血管透過性を抑制するための方法。
- VEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストを投与することを含むVEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストを含む対象における癌を治療するための方法。
- VEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストを投与することを含む対象における眼疾患を治療するための方法。
- VEGFアンタゴニスト及びアルファ5ベータ1アンタゴニストを投与することを含む対象における自己免疫疾患を治療するための方法。
- 前記対象が前記VEGFアンタゴニストを投与され、その後、前記アルファ5ベータ1アンタゴニストを投与される、請求項27〜30の何れか1項に記載の方法。
- 前記対象が前記VEGFアンタゴニスト及び前記アルファ5ベータ1アンタゴニストを同時に投与される請求項27〜30の何れか1項に記載の方法。
- 前記対象が異常な血管新生又は血管透過性を有する疾患に罹患している請求項27記載の方法。
- 前記疾患が腫瘍、免疫疾患又は眼の疾患からなる群より選択される請求項27記載の方法。
- 前記対象がVEGFアンタゴニスト治療に非応答性となるまで該対象を前記VEGFアンタゴニストで治療し、そして次に該対象をアルファ5ベータ1アンタゴニストで治療する請求項27〜30の何れか1項に記載の方法。
- 前記癌が非侵襲性である場合には前記対象を前記VEGFアンタゴニストで治療し、前記癌が侵襲性である場合には前記アルファ5ベータ1アンタゴニストで治療する請求項28記載の方法。
- 前記対象が前記疾患に罹患していない対象由来の組織と比較して罹患組織において上昇したアルファ5ベータ1レベルを有する、請求項27記載の方法。
- 前記対象が、更に抗腫瘍剤、化学療法剤、増殖抑制剤および細胞毒性剤からなる群より選択される治療薬を投与される請求項27〜30の何れか1項に記載の方法。
- 前記抗VEGF抗体がAvastin(登録商標)抗体によりヒトVEGFへの結合を競合的に抑制され得る、請求項27〜30の何れか1項に記載の方法。
- 前記抗VEGF抗体がAvastin(登録商標)抗体である請求項42記載の方法。
- 前記アルファ5ベータ1アンタゴニストが細胞毒性剤の結合体化される請求項27〜30の何れか1項に記載の方法。
- 前記細胞毒性剤が放射性同位体、化学療法剤又は毒素である請求項41記載の方法。
- 前記VEGFアンタゴニストが抗体である請求項27〜30の何れか1項に記載の方法。
- 前記アルファ5ベータ1アンタゴニストが抗体である請求項27〜30の何れか1項に記載の方法。
- 前記抗VEGF抗体がヒト化抗体又はヒト抗体である請求項43記載の方法。
- 前記抗アルファ5ベータ1抗体がヒト化抗体又はヒト抗体である請求項44記載の方法。
- VEGFアンタゴニスト、アルファ5ベータ1アンタゴニスト、及び製薬上許容しうる阻害剤を含む組成物。
- VEGFアンタゴニストで治療された対象においてアルファ5ベータ1を検出するための説明書を含むキット。
- 疾患に罹患した対象において血管新生及び/又は血管透過性を抑制するための医薬の製造における請求項47記載の組成物の使用。
- 前記疾患が対象における癌、眼の疾患、自己免疫疾患からなる群より選択される請求項49記載の使用。
- 前記疾患が固形腫瘍、転移性腫瘍、軟組織腫瘍、眼の新生血管形成を有する疾患、異常な血管新生を有する炎症性疾患、前記対象への移植後に生じる疾患、及び線維血管組織の異常な増殖を有する疾患からなる群より選択される請求項49記載の使用。
- 前記癌が乳癌、子宮頚癌、結腸直腸癌、肺癌、非ホジキンリンパ腫(NHL)、腎細胞癌、前立腺癌、肝癌、頭部頚部癌、メラノーマ、卵巣癌、中皮腫、軟組織癌、及び多発性骨髄腫からなる群より選択される請求項50記載の使用。
- 前記疾患が網膜症、加齢誘発性黄斑変性、皮膚紅潮、乾癬、乾癬性関節炎、炎症性腎疾患、溶血性尿毒症症候群、糖尿病性腎症、関節炎、炎症性腸疾患、慢性炎症、慢性網膜剥離、慢性ブドウ膜炎、慢性硝子体炎、角膜移植片拒絶、角膜新生血管形成、角膜移植片新生血管形成、クローン病、近視、眼の血管新生性疾患、変形性関節症、パジェット病、類天疱瘡、多発性動脈炎、レーザー後の放射状角膜切開、網膜の新生血管形成、シェーグレン症候群、潰瘍性結腸炎、移植片拒絶、肺の炎症、ネフローゼ症候群、浮腫、悪性疾患に関連する腹水、卒中、血管線維腫、及び血管新生緑内障からなる群より選択される請求項49記載の使用。
- 疾患に罹患した対象を治療するための医薬の製造におけるアルファ5ベータアンタゴニストの使用であって、該対象がVEGFアンタゴニストを用いた該疾患に対する治療には応答性であったが、該VEGFアンタゴニストに対して部分的に応答するか、またはもはや応答しない、使用。
- 前記対象が前記疾患に罹患していない対象由来の組織と比較して罹患組織において上昇したアルファ5ベータ1レベルを有する、請求項54記載の使用。
- 前記対象が更に抗腫瘍剤、化学療法剤、増殖抑制剤および細胞毒性剤からなる群より選択される治療薬を投与される請求項54記載の使用。
- 疾患に罹患した対象を治療するための医薬の製造におけるVEGFアンタゴニストの使用であって、該対象がアルファ5ベータ1アンタゴニストを用いた該疾患に対する治療には応答性であったが、該アルファ5ベータ1アンタゴニストに対して部分的に応答するか、またはもはや応答しない、使用。
- VEGFアゴニスト及びアルファ5ベータ1アゴニストを含む組成物。
- 医薬の製造における請求項58記載の組成物の使用。
- 前記医薬が創傷治癒を促進する請求項59記載の使用。
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