JP4544639B2 - αVβ5仲介血管形成の阻止に有効な方法及び組成物 - Google Patents
αVβ5仲介血管形成の阻止に有効な方法及び組成物 Download PDFInfo
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- JP4544639B2 JP4544639B2 JP2007112625A JP2007112625A JP4544639B2 JP 4544639 B2 JP4544639 B2 JP 4544639B2 JP 2007112625 A JP2007112625 A JP 2007112625A JP 2007112625 A JP2007112625 A JP 2007112625A JP 4544639 B2 JP4544639 B2 JP 4544639B2
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Description
血管が以前から存在する血管から発芽する;2)血管の新規発生が前駆細胞から生じる(血管形成);又は3)存在する小血管の直径が増大する。Bloodら,Bioch.Biophys.Acta,1032:89−118(1990)。血管内皮細胞は、ビトロネクチンレセプター(αvβ3又はαvβ5)、コラーゲンI及びIV型レセプター(αvβ1)、ラミニンレセプター(α2β1)、フィブロネクチン/ラミニン/コラーゲンレセプター(α3β1)及びフィブロネクチンレセプター(α5β1)を含む少なくとも5種類のRGD依存性インテグリンを含むことが既知である。Davisら,J.Cell.Biochem.,51:206−218(1993)。平滑筋は、α5β1、αvβ3及びαvβ5を含む少なくとも6種類のRGD依存性インテグリンを含むことが既知である。
図面は、本開示の一部をなすものである。
A.定義
アミノ酸残基:ポリペプチドのペプチド結合における化学消化(加水分解)によって生成されたアミノ酸。本明細書に記載されるアミノ酸残基は、“L”異性体であることが好ましい。しかしながら、所望の機能性がポリペプチドによって保持される限りL−アミノ酸残基を“D”異性体の残基に置き換えることができる。NH2は、ポリペプチドのアミノ末端に存在する遊離アミノ基を意味する。COOHは、ポリペプチドのカルボキシ末端に存在する遊離カルボキシ基を意味する。標準ポリペプチド命名法(J.Biol.Chem.,243:3552−59(1969)に記載され、37 CFR§1.822(b)(2))で採用された)に従うに当たり、アミノ酸残基の略号を下記の対応表に示す。
本発明は、一般的には、血管形成が特定のビトロネクチンレセプターαvβ5によって仲介されかつαvβ5機能阻害が血管形成を阻止するという発見に関する。
本発明は、組織において血管形成を阻止し、血管形成に関係する組織における現象を阻止する方法を提供する。一般的には、本方法は、αvβ5拮抗体の血管形成阻止量を含む組成物を該組織に投与することを特徴とする。
本発明は、本明細書に記載される治療法を実施するのに有効な治療組成物を企図する。本発明の治療組成物は、有効成分としてその中に溶解又は分散されたαvβ5拮抗体と共に生理的に許容しうる担体を含有する。好適実施態様においては、αvβ5拮抗体治療組成物は治療のために哺乳動物又はヒト患者に投与される場合に免疫原性ではない。
αvβ5拮抗体は、組織において血管形成を阻止する本方法に用いられ、天然αvβ5リガンドとの機能上の相互作用が妨害されるような方法でαvβ5と相互作用する化合物を含むさまざまな形態をとることができる。具体的な拮抗体としては、αvβ5上のリガンド結合部位に由来するαvβ5の類縁体又は擬似体、αvβ5リガンド結合相互作用に関係する構造領域に似ている天然αvβ5リガンドの擬似体、特にαvβ5の天然リガンドのRGD含有ドメインに対応するαvβ5に特異的な天然リガンドの機能上の結合ドメインに対応する配列をもつポリペプチド、及び全てが本明細書に定義される拮抗体活性を示すαvβ5或いは天然リガンドと免疫反応する抗体が含まれる。
実施態様においては、本発明は、ポリペプチドとしてのαvβ5拮抗体を企図する。ポリペプチド(ペプチド)αvβ5拮抗体は、αvβ5リガンド相互作用に関係する領域において天然αvβ5リガンド或いはαvβ5自体の配列特徴をもちかつ本明細書に記載されるαvβ5拮抗体活性を示すものである。好ましいαvβ5拮抗体ペプチドは、RGDトリペプチドを含み、配列がRGD含有領域において天然リガンドに対応する。
実施態様においては、本発明は、αvβ5と免疫反応しかつ本明細書に記載される天然リガンドへのαvβ5結合を阻害するモノクローナル抗体としてのαvβ5拮抗体を述べるものである。本発明は、また、抗体を産生する細胞系、該細胞系の生産方法及び該モノクローナル抗体の生産方法を述べるものである。
本発明は、αvβ5機能を妨害する能力をもつポリペプチド、抗体及び“擬似体”と称する他の分子が含まれるたいていのαvβ5拮抗体が本発明に用いられることを証明する。αvβ5機能を特に妨害しかつ他のインテグリン機能を妨害しない拮抗体が特に好ましい。
本発明は、また、本方法に従って使用するための候補αvβ5拮抗体を同定する分析法を述べるものである。これらの分析法においては、候補分子について天然リガンドへのαvβ5結合を阻害する点での効力を評価し、組織において血管形成を阻止する点での効力を評価する。
Waynerら,J.Cell Biol.,113:919−929(1991)に記載されるようにA549肺がん腫細胞をRBF/DnJマウスに免疫することにより標準ハイブリドーマ法を用いてモノクローナル抗体、P1F6及びP5H9を生産した。この文献の記載は本願明細書に含まれるものとする。脾臓を免疫マウスから切除し、Ns−1/FOX−NYミエローマ細胞と融合する。がん腫細胞ビトロネクチンレセプターに対するハイブリドーマ産生抗体を、Waynerらに記載されるビトロネクチン被覆表面へのUCLA−P3接着の特異的阻害により選別し、胸腺細胞支持細胞上で限界希釈することによりクローン化した。
A.ビトロネクチンに対する特異性 実施例1で調製されたP5H9モノクローナル抗体は、UCLA−P3がん腫細胞のビトロネクチンへの結合を阻止しコラーゲン又はフィブロネクチンへの細胞結合に影響しないことがWaynerら,J.Cell Biol.,113:919−929(1991)によってわかった。その細胞は、αvβ5ビトロネクチンレセプターのみ含み、αvβ3特異性を有するものを含まず、非還元条件でα鎖(160kD)及びβ鎖(95kD)からなるヘテロ二量体を免疫沈降することもわかった。P5H9で検出されたαvβ5レセプターは、M21メラノーマ細胞及びH2981がん腫細胞のビトロネクチンへの接着を仲介することもわかった。P1F6モノクローナル抗体は、同じ免疫反応性プロファイルを有する。
創傷治癒中、血管の基底膜はフォンビルブラント因子、フィブロネクチン及びフィブリンを含む数種の接着性タンパク質を発現する。更に、接着性レセプターのインテグリンファミリーの一部は培養した平滑筋及び内皮細胞の表面上で発現する。Cheresh,Proc.Natl.Acad.Sci.,USA,84:6471(1987); Janatら,J.Cell Physiol.,151:588(1992); Chengら,J.Cell Physiol.,139:275(1989)を参照されたい。
眼の血管新生は、視力の破滅的消失を生じる多数の眼疾患に認められる最も共通の病変である。以前から存在する脈絡膜、網膜又は縁周囲血管から新しい血管の発生は、浮腫、出血又は線維血管膜形成を招き、眼の正常な解剖学的関係の破壊を生じ、付随して正常な視覚機能の消失を生じる。
本発明の方法を実施するのに用いられる環状ポリペプチドを、例えば、Merrifield,Adv.Enzymol.,32:221−296(1969)及びFields,G.B. & Noble,R.L.,Int.J.Peptide Protein Res.,35:161−214(1990)に記載される標準固相合成法を用いて合成した。
増殖因子誘導血管形成に対する抗αvβ5拮抗体の作用は、眼の角膜によって例示される天然の透明構造で観察される。新しい血管は角膜縁から増殖し、本来は血管がない角膜の中心に血液が豊富に供給される。角膜に適用されるVEGF及びTGF−αのような血管形成刺激物質は、角膜縁から新しい血管の増殖を誘導する。角膜に適用される血管形成拮抗体は、角膜縁からの新しい血管の増殖を阻止する。従って、角膜は、角膜縁から見えやすい堅いコラーゲン充填角膜組織へ内皮細胞の侵入によって血管形成を受ける。従って、ウサギ眼モデル分析は、化合物を眼の角膜へ直接接種した後の血管形成の促進及び阻止を直接観察するための生体内モデルとなる。
下記のように生体内ウサギ眼モデル分析において増殖因子による血管形成を誘導した。
増殖因子及びモノクローナル抗体(mAb)を含むハイドロンポリマーペレットをD’Amatoら,Proc.Natl.Acad.Sci.,91:4082−4085(1994)に記載されるように調製した。個々のペレットは、スクラルフェート(カラフェート)(Carafet,Marion Merrell Dow Corporation,オハイオ州シンシナテイ)に結合した750ngの増殖因子(サイトカインとも言われる)、特にbFGF或いはVEGFを含有しサイトカンを安定化すると共に周囲組織への緩慢な放出を行わせた。更に、PBS中40μgのmAb P1F6(抗αvβ5)又は制御抗体、LM609(抗αvβ3)を含有するハイドロンペレットを調製した。
A.未処理CAMの確認
1)CAMの調製
血管形成は、正常胚血管形成が成熟血管の形成をもたらした後にニワトリ絨毛尿膜(CAM)に誘導される。血管形成は、Leibovichら,Nature,329:630(1987)及びAusprunkら,Am.J.Pathol.,79:597(1975)に記載されるように特定のサイトカイン又は腫瘍断片に応答して誘導されることがわかった。ニワトリ胚から後続の血管形成誘導及び本発明のαvβ5拮抗体による下記の実施例6に記載されるその阻止のためのCAMを調製した。
ニワトリ胚CAMの顕微鏡的構造を分析するために、凍結塊から免疫蛍光分析用クリオスタットミクロトームで6ミクロン(μm)厚切片を切り取った。
血管形成は、ウサギ眼モデルにおいてサイトカン又は実施例4Aに記載される増殖因子によって誘導されることがわかった。ここに記載される実験においては、実施例4に記載されるウサギ角膜標品での血管形成をここに記載されるCAM血管に局所適用される増殖因子によって同様に誘導した。
腫瘍誘導血管形成におけるαvβ5の役割を調べるために、Brooksら,J.Cell Biol.,122:1351(1993)及びここに記載される卵生17日のニワトリ胚のCAMから以前に増殖及び単離した種々のαvβ5陰性ヒトミエローマ及びがん腫断片をCAM分析に用いる。
A.インヒビターの静脈内適用による増殖因子誘導血管形成の阻止
CAM標品に静脈内注入したモノクローナル抗体による増殖因子誘導血管形成に対する作用を、本発明の生体内モデル系として使用するために評価した。
αvβ5が血管形成において活発な役割を果たすかを求めるために、上記の増殖因子で飽和したフィルターディスクをCAM上に置き、血管形成を誘導した後にP1F6或いはLM609を適用する。
1)モノクローナル抗体による処理
抗αvβ5抗体及びペプチド拮抗体の作用を評価した上記の血管形成分析のほかに、腫瘍誘導血管形成におけるαvβ5の役割を調べる。誘導物質として、卵生17日のニワトリ胚のCAMから以前に増殖及び単離したαvβ5陰性ヒト組織を用いる。断片を実施例5Cに記載されたように調製する。
1)モノクローナル抗体による処理
上で調製した腫瘍誘導血管を、静注で投与したmAbで処理した。CS−1メラノーマ腫瘍を実施例5Cに記載されたようにCAM上に置き、窓をテープで閉じ、24時間後に100〜300μgの精製mAbを上記のニワトリ胚血管の静脈内に1回接種した。次に、ニワトリ胚を7日間インキュベートした。次に、血管形成の程度を上記のように観察した。この後、腫瘍を切除し、その重量で分析して腫瘍増殖又は抑制に対する抗体曝露の影響を求めた。
CAM分析系において腫瘍誘導血管系に対するペプチド又は有機分子の影響を評価する。mAbの静注の代わりに実施例3及び10に各々記載されるように調製した合成ペプチド及び有機分子鎖を可視血管に別個に静注する。
実施例1及び3で各々調製したαvβ5免疫反応性抗体及び合成ペプチドを、精製リガンド−レセプター結合分析においてαvβ5、αvβ3及びαIIbβ3レセプター結合活性を拮抗する能力を測定することにより選別する。これらの結合実験の方法は、Barbasら,Proc.Natl.Acad.Sci.,USA,90:10003−10007(1993),Smithら,J.Biol.Chem.,265:11008−11013(1990)及びPfaffら,J.Biol.Chem.,269:20233−20238(1994)に記載されており、これらの文献の記載は本願明細書に含まれるものとする。
SCIDマウスからの皮膚の一部をヒト新生児包皮に置き換えることにより生体内キメラマウス:ヒトモデルをつくった。生体内キメラマウス:ヒトモデルを実質的にYanら,J.Clin.Invest.,91:986−996(1993)に記載されるように調製した。概要としては、2cm2の正方形の皮膚面をSCIDマウス(6〜8週齢)から外科的に切除し、ヒト包皮に置き換えた。マウスに麻酔をかけ、腹部側方部の各側の5cm2領域を剃髪した。皮膚の下の筋膜まで十分な厚さを除去することにより2cm2の2枚の円形移植片床を調製した。ヒト新生児包皮に由来する同じサイズの十分な厚さのヒト皮膚移植片を創傷床に入れ、適所を縫合した。移植片にバンドエイドを被覆し、皮膚を縫合した。創傷を被覆するためにミクロポア布テープも用いた。
網膜血管新生組織でのαvβ3及びαvβ5発現の実施例2Cの観察に基づき、新規なマウスモデルを用いて網膜血管形成に対する両インテグリンの全身系に投与し環状ペプチド拮抗体の作用を実験した。新生仔マウスは、生後最初の2週間で網膜血管を発生し、表在性網膜血管系が視神経頭から始まり末梢に放射状に伸びる血管の多くの高度に分枝した網目を形成して他の哺乳動物及びヒトに観察されるのと同じ方法で網膜表面を被覆する(Jiangら,Glia,15:1−10(1995)。
αvβ5拮抗体有機化合物7、9、10、12、14、15、16、17及び18の合成を、下記及び簡単な説明の付いた図面に示す。次に、本発明の有機模擬体と呼ばれる得られた有機分子をαvβ5仲介血管形成を阻止する方法に用いる。
ジメチルホルムアミド(DMF;5ml)中化合物600(200mg;0.5ミリモル)、3.5−ジメチルピラゾル−1−カルボキサミジン硝酸塩(DPFN)(170mg;0.8ミリモル;Aldrich Chemical Co.)及びトリエチルアミン(0.15ml、1.0ミリモル)を60℃で12時間加熱した。冷却後、溶媒を減圧下で蒸発し、残留物をHPLC(Lichrocart RP−18、勾配アセトニトリル/水+0.3%TFA99:1〜1:99)で精製して凍結乾燥後に50mg(25%)の化合物10を白色無定形粉末として得た。FAB−MS: 415(M+H+)、m.p.:70℃。
塩化メチレン(0.10M)中p−アミノベンゾニトリル(1.0当量;Aldrich)を2,3−エポキシプロパノール(1.0当量;Aldrich)と25℃で12時間攪拌した。次に、溶媒を減圧下で除去し、粗4−(2,3−ジヒドロキシプロピルアミノ)ベンゾニトリルを下記の通り次の工程へ続けた。
1.9gの2−N−BOC−アミノ−3−(4−ヒドロキシフェニル)プロピオネート(上記)、20mlのジメチルホルムアミド(DMF)及びNaH(1.0当量)の混合液を室温で30分間攪拌した。攪拌後、10mlのジメチルホルムアミド(DMF)中1.8gの3−p−N−BOC−アミジノフェニル−5−メタンスルホニルオキシメチル−2−オキサゾリジノン(上記)を加え、室温で15分間攪拌した。次に、反応混合液を酢酸エチル(0.10M)で希釈し、水で2×、食塩水で1×洗浄し、硫酸マグネシウムで乾燥した。次に、溶媒を減圧下で除去し、粗生成物をシリカゲルカラムクロマトグラフィーで精製して保護形態の化合物15、3−(4−BOC−アミジノフェニル)−5−(4−(2−メトキシカルボニル−2N−BOC−アミノエチル)フェニルオキシメチル−2−オキサゾリジノンを得、次の工程へ続けた。
保護形態の化合物15、3−(4−BOC−アミジノフェニル)−5−(4−(2−メトキシカルボニル−2N−BOC−アミノエチル)フェニオキシルメチル−2−オキサゾリジノン(1.0当量;上記のように合成)を4mlの2NNaOHで室温において4時間処理した。次に、ジオキサン中40mlの2NHCl溶液を滴下して0〜25℃で3時間混合した。次に、反応混合液を重炭酸ナトリウム(5当量)で急冷し、酢酸エチル(0.10M)で希釈し、水で2×、食塩水で1×洗浄し、硫酸マグネシウムで乾燥した。次に、溶媒を減圧下で除去し、粗生成物をシリカゲルカラムクロマトグラフィーで精製して化合物15:3−(4−アミジノフェニル)−5−(4−(2−カルボキシ−2−アミノエチル)フェノキシ)メチル−2−オキサゾリジノン、二塩酸塩;m.p.165℃(d)を得た。
1)化合物16の出発物質2−N−ブチルスルホニルアミノ−3−(4−ヒドロキシフェニル(プロピオネート)の合成
塩化メチレン(0.10M)中p−アミノベンゾニトリル(1.0当量;Aldrich)を2,3−エポキシプロパノール(1.0当量;Aldrich)と25℃で12時間攪拌した。次に、溶媒を減圧下で除去し、粗4−(2,3−ジヒドロキシプロピルアミノ)ベンゾニトリルを下記のように次の工程へ続けた。
1.9gの2−N−ブチルスルホニルアミノ−3−(4−ヒドロキシフェニル)プロピオネート(上記)、20mlのジメチルホルムアミド(DMF)及びNaH(1.0当量)の混合液を室温で30分間攪拌した。攪拌後、10mlのジメチルホルムアミド(DMF)中1.8gの3−p−N−BOC−アミジノフェニル−5−メタンスルホニルオキシメチル−2−オキサゾリジノン(上記)を加え、室温で15分間攪拌した。次に、反応混合液を酢酸エチル(0.10M)で希釈し、水で2×、食塩水で1×洗浄し、硫酸マグネシウムで乾燥した。次に、溶媒を減圧下で除去し、粗生成物をシリカゲルカラムクロマトグラフィーで精製して保護形態の化合物16、3−(4−BOC−アミジノフェニル)−5−(4−(2−メトキシカルボニル−2−N−ブチルスルホニルアミノエチル)フェニオキシルメチル−2−オキサゾリジノンを得、次の工程へ続けた。
保護形態の化合物16、3−(4−BOC−アミジノフェニル)−5−(4−(2−メトキシカルボニル−2−N−ブチルスルホニルアミノエチル)フェニオキシルメチル−2−オキサゾリジノン(1.0当量;上記のように合成)を4mlの2N NaOHで室温において4時間処理した。次に、ジオキサン中40mlの2N HCl溶液を滴下して0〜25℃で3時間混合した。次に、反応混合液を重炭酸ナトリウム(5当量)で急冷し、酢酸エチル(0.10M)で急冷し、水で2×、食塩水で1×洗浄し、硫酸マグネシウムで乾燥した。次に、溶媒を減圧下で除去し、粗生成物をシリカゲルカラムクロマトグラフィーで精製して化合物16:3−(4−アミジノフェニル)−5−(4−(2−カルボキシ−2−N−ブチルスルホニルアミノエチル)フェノキシ)メチル−2−オキサゾリジノン;m.p.236−237℃を得た。
1)化合物17の出発物質2−N−プロピルスルホニルアミノ−3−(4−ヒドロキシフェニル(プロピオネート)の合成
塩化メチレン(0.10M)中p−アミノベンゾニトリル(1.0当量;Aldrich)を2,3−エポキシプロパノール(1.0当量;Aldrich)と25℃で12時間攪拌した。次に、溶媒を減圧下で除去し、粗4−(2,3−ジヒドロキシプロピルアミノ)ベンゾニトリルを下記のように次の工程へ続けた。
1.9gの2−N−プロピルスルホニルアミノ−3−(4−ヒドロキシフェニル)プロピオネート(上記)、20mlのジメチルホルムアミド(DMF)及びNaH(1.0当量)の混合液を室温で30分間攪拌した。攪拌後、10mlのジメチルホルムアミド(DMF)中1.8gの3−p−N−BOC−アミジノフェニル−5−メタンスルホニルオキシメチル−2−オキサゾリジノン(上記)を加え、室温で15分間攪拌した。次に、反応混合液を酢酸エチル(0.10M)で希釈し、水で2×、食塩水で1×洗浄し、硫酸マグネシウムで乾燥した。次に、溶媒を減圧下で除去し、粗生成物をシリカゲルカラムクロマトグラフィーで精製して保護形態の化合物17、3−(4−BOC−アミジノフェニル)−5−(4−(2−メトキシカルボニル−2−N−プロピルスルホニルアミノエチル)フェニルオキシメチル−2−オキサゾリジノンを得、次の工程へ続けた。
保護形態の化合物17、3−(4−BOC−アミジノフェニル)−5−(4−(2−メトキシカルボニル−2−N−プロピルスルホニルアミノエチル)フェニオキシルメチル−2−オキサゾリジノン(1.0当量;上記のように合成)を4mlの2N NaOHで室温において4時間処理した。次に、ジオキサン中40mlの2N HCl溶液を滴下して0〜25℃で3時間混合した。次に、反応混合液を重炭酸ナトリウム(5当量)で急冷し、酢酸エチル(0.10M)で急冷し、水で2×、食塩水で1×洗浄し、硫酸マグネシウムで乾燥した。次に、減圧下で溶媒を除去し、粗生成物をシリカゲルカラムクロマトグラフィーで精製して化合物17:3−(4−アミジノフェニル)−5−(4−(2−カルボキシ−2−N−プロピルスルホニルアミノエチル)フェノキシ)メチル−2−オキサゾリジノン;m.p.200℃(d)を得た。
1)化合物18の出発物質2−N−エチルスルホニルアミノ−3−(4−ヒドロキシフェニル(プロピオネート)の合成
塩化メチレン(0.10M)中p−アミノベンゾニトリル(1.0当量;Aldrich)を2,3−エポキシプロパノール(1.0当量;Aldrich)と25℃で12時間攪拌した。次に、溶媒を減圧下で除去し、粗4−(2,3−ジヒドロキシプロピルアミノ)ベンゾニトリルを下記のように次の工程へ続けた。
1.9gの2−N−ブチルスルホニルアミノ−3−(4−ヒドロキシフェニル)プロピオネート(上記)、20mlのジメチルホルムアミド(DMF)及びNaH(1.0当量)の混合液を室温で30分間攪拌した。攪拌後、10mlのジメチルホルムアミド(DMF)中1.8gの3−p−N−BOC−アミジノフェニル−5−メタンスルホニルオキシメチル−2−オキサゾリジノン(上記)を加え、室温で15分間攪拌した。次に、反応混合液を酢酸エチル(0.10M)で希釈し、水で2×、食塩水で1×洗浄し、硫酸マグネシウムで乾燥した。次に、溶媒を減圧下で除去し、粗生成物をシリカゲルカラムクロマトグラフィーで精製して保護形態の化合物18、3−(4−BOC−アミジノフェニル)−5−(4−(2−メトキシカルボニル−2−N−ブチルスルホニルアミノエチル)フェニオキシルメチル−2−オキサゾリジノンを得、次の工程へ続けた。
保護形態の化合物18、3−(4−BOC−アミジノフェニル)−5−(4−(2−メトキシカルボニル−2−N−エチルスルホニルアミノエチル)フェニオキシルメチル−2−オキサゾリジノン(1.0当量;上記のように合成)を4mlの2N NaOHで室温において4時間処理した。次に、ジオキサン中40mlの2N HCl溶液を滴下して0〜25℃で3時間混合した。次に、反応混合液を重炭酸ナトリウム(5当量)で急冷し、酢酸エチル(0.10M)で急冷し、水で2×、食塩水で1×洗浄し、硫酸マグネシウムで乾燥した。次に、溶媒を減圧下で除去し、粗生成物をシリカゲルカラムクロマトグラフィーで精製して化合物18:3−(4−アミジノフェニル)−5−(4−(2−カルボキシ−2−N−エチルスルホニルアミノエチル)フェノキシ)メチル−2−オキサゾリジノン;m.p.212℃(d)を得た。
Claims (12)
- αvβ5含有組織において血管形成を阻止するための医薬組成物であって、該医薬組成物はαvβ5拮抗体の血管形成阻止量を含み、該αvβ5拮抗体がαvβ5に免疫特異的であるがαvβ1、αvβ3又はαIIbβ3に免疫特異的でないモノクローナル抗体である、前記医薬組成物。
- 前記モノクローナル抗体が、P1F6と称するモノクローナル抗体である請求項1記載の医薬組成物。
- 前記組織が炎症組織であり、前記血管形成が炎症組織血管形成である請求項1記載の医薬組成物。
- 前記組織が関節炎組織である請求項3記載の医薬組成物。
- 前記関節炎組織が、リウマチ様関節炎に罹った哺乳動物に存在する請求項4記載の医薬組成物。
- 前記血管形成が、糖尿病性網膜症、老人性黄斑変性症、推定眼ヒストプラズマ症、未熟児網膜症及び血管新生緑内障からなる眼疾患群より選ばれた眼疾患における血管形成である、請求項1記載の医薬組成物。
- 前記組織が血管腫である請求項1記載の医薬組成物。
- 前記組織が充実性腫瘍又は充実性腫瘍転移であり、前記血管形成が腫瘍血管形成である請求項1記載の医薬組成物。
- 前記血管形成がサイトカインによって誘導される請求項1記載の医薬組成物。
- 前記サイトカインが、血管内皮細胞増殖因子、トランスフォーミング増殖因子−α及び表皮増殖因子からなる群より選ばれる請求項9記載の医薬組成物。
- 前記サイトカインが血管内皮細胞増殖因子であり、前記血管形成が網膜血管形成、腫瘍血管形成及び炎症組織血管形成からなる群より選ばれる請求項10記載の医薬組成物。
- 前記血管形成阻止量が2μM〜5mMである請求項1記載の医薬組成物。
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EP0844874B1 (en) | 2005-11-09 |
CN1198667A (zh) | 1998-11-11 |
MX9801228A (es) | 1998-05-31 |
DE69635417T2 (de) | 2006-07-13 |
NO319264B1 (no) | 2005-07-11 |
CZ40998A3 (cs) | 1998-09-16 |
KR19990036426A (ko) | 1999-05-25 |
AU726793B2 (en) | 2000-11-23 |
ATE308981T1 (de) | 2005-11-15 |
WO1997006791A1 (en) | 1997-02-27 |
CA2754102C (en) | 2012-12-18 |
UA84665C2 (ru) | 2008-11-25 |
CA2227265A1 (en) | 1997-02-27 |
HUP9802675A3 (en) | 2000-09-28 |
JP4903921B2 (ja) | 2012-03-28 |
SK18898A3 (en) | 1998-07-08 |
NO980622D0 (no) | 1998-02-13 |
EP0844874A1 (en) | 1998-06-03 |
DK0844874T3 (da) | 2006-01-16 |
HUP9802675A2 (hu) | 1999-03-29 |
NO980622L (no) | 1998-04-07 |
JPH11511171A (ja) | 1999-09-28 |
CA2227265C (en) | 2012-01-03 |
JP2007262073A (ja) | 2007-10-11 |
CN101053561A (zh) | 2007-10-17 |
CA2754102A1 (en) | 1997-02-27 |
EP0844874A4 (en) | 2001-02-14 |
RU2214268C2 (ru) | 2003-10-20 |
ES2250996T3 (es) | 2006-04-16 |
AU6846696A (en) | 1997-03-12 |
CN1313146C (zh) | 2007-05-02 |
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ZA966886B (en) | 1997-04-24 |
DE69635417D1 (de) | 2005-12-15 |
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