JP2009521412A - 癌を治療するためのアンジオポエチン−2アンタゴニストとVEGF−A、KDR、及び/又はFlt1アンタゴニストの組合せ - Google Patents
癌を治療するためのアンジオポエチン−2アンタゴニストとVEGF−A、KDR、及び/又はFlt1アンタゴニストの組合せ Download PDFInfo
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Abstract
Description
i)受容体チロシンキナーゼ活性を阻害する化合物、
ii)受容体へのリガンド結合を阻害する化合物、
iii)受容体の細胞内経路の活性化を阻害する化合物、
iv)VEGF又はTie受容体系のリガンド又は受容体の発現を阻害するか又は活性化する化合物、
v)VEGF/VEGF受容体又はアンジオポエチン/Tie受容体系の認識を介して細胞傷害剤又は凝固誘導剤を内皮へ標的指向させる、抗体、リガンド、高アフィニティー結合オリゴヌクレオチド又はオリゴペプチド、又はリポソームのような送達系、あるいは、
vi)内皮へ標的指向されて、壊死又はアポトーシスを誘導する、抗体、リガンド、高アフィニティー結合オリゴヌクレオチド又はオリゴペプチド、又はリポソームのような送達系。
A.VEGF受容体チロシンキナーゼ阻害剤:(4−クロロフェニル)[4−(4−ピリジルメチル)−フタラジン−1−イル]アンモニウム ハイドロジェン スクシネート(Wood et al., Cancer Res. 60 2178-2189, 2000)、又は
B.抗VEGF抗体;VEGF−A−中和モノクローナル抗体、4301−42−35(Schlaeppi et al., J. Cancer Res. Clin. Oncol. 125, 336-342, 1999)、又はヒトVEGF−A/VEGF受容体I複合体を特異的に認識する単鎖抗体(scFv)(WO9919361)のいずれか1つ、
であり得る。
i.VEGF−A、及び/又は
ii.KDR、及び/又は
iii.Flt1
の生物学的活性のアンタゴニストの組合せが提供される。
別の態様では、アンジオポエチン−2の生物学的活性のアンタゴニストがsTie−2ではない、上記に記載の組合せが提供される。
本発明の別の側面により、疾患関連性の血管新生の治療用のための医薬品の製造のための上記に記載の組み合わせの使用が提供される。
抗体を含んでなる本発明の態様では、組合せを患者へ投与した後に、清浄剤を投与してもよい。好ましくは、清浄剤は、過剰な循環抗体を血液より取り除くことができる。
本発明のさらなる側面により、アンジオポエチン−2の生物学的活性のアンタゴニストとVEGF−A、及び/又はKDR、及び/又はFlt1の生物学的活性のアンタゴニストの組合せを含んでなるキットが提供される。
a)第一の単位剤形中のアンジオポエチン−2の生物学的活性のアンタゴニスト;
b)第二の単位剤形中のVEGF−A、及び/又はKDR、及び/又はFlt1の生物学的活性のアンタゴニスト;および
c)前記第一及び第二の剤形を含有するための容器手段
を含んでなるキットが提供される。
a)第一の単位剤形中の、医薬的に許容される賦形剤又は担体を伴うアンジオポエチン−2の生物学的活性のアンタゴニスト;
b)第二の単位剤形中の、医薬的に許容される賦形剤又は担体を伴うVEGF−A、及び/又はKDR、及び/又はFlt1の生物学的活性のアンタゴニスト;および
c)前記第一及び第二の剤形を含有するための容器手段
を含んでなるキットが提供される。
アンタゴニストは、ポリペプチド、核酸、炭水化物、脂質、低分子量化合物、オリゴヌクレオチド、オリゴペプチド、RNA干渉(RNAi)、アンチセンス、組換えタンパク質、抗体、又はそのコンジュゲート若しくはそれらの融合タンパク質であってよい。RNAiの概説については、Milhavet O, Gary DS, Mattson MP.(Pharmacol Rev. 2003 Dec; 55(4):629-48. Review.) を アンチセンスの概説については、Opalinska JB, Gewirtz AM. (Sci STKE. 2003 Oct 28;2003(206):pe47.) を参照のこと。
疾患関連性の血管新生は、どの異常な、望まれないか又は病理学的な血管新生であってもよく、例えば、腫瘍関連性の血管新生である。血管新生関連性の疾患には、限定されないが、白血病、多発性骨髄腫、血液の悪性腫瘍、又はリンパ腫のような非固形腫瘍と、黒色腫、非小細胞肺癌、神経膠腫、肝細胞(肝臓)癌、膠芽腫、甲状腺、胆管、骨、胃、脳/CNS、頭頸部、肝臓、胃、前立腺、乳房、腎、精巣、卵巣、皮膚、頸部、肺、筋肉、神経細胞、食道、膀胱、肺、子宮、外陰、子宮内膜、腎臓、結直腸、膵臓、胸膜/腹膜、唾液腺の癌腫と類表皮腫瘍のような固形腫瘍とその転移が含まれる。
用語「抗体」は、抗原の抗原決定基の特性に相補的な内部の表面形状及び荷電分布を有する三次元の結合空間を有するポリペプチド鎖のフォールディングより形成される少なくとも1つの結合ドメインからなる、ポリペプチド又はポリペプチドの群を意味する。抗体は、典型的には、ポリペプチド鎖の2つの同一対を含んでなる四量体の形態を有し、各対は、1つの「軽」鎖と1つの「重」鎖を有する。各軽鎖/重鎖対の可変領域は、抗体結合部位を形成する。抗体は、オリゴクローナル、ポリクローナル抗体、モノクローナル抗体、キメラ抗体、CDR移植抗体、多重特異性抗体、二重特異性抗体、触媒抗体、キメラ抗体、ヒト化抗体、完全ヒト抗体、抗イディオタイプ抗体、及び、可溶型又は結合型で標識し得る抗体、並びにそれらの断片、変異体、又は誘導体であってよく、単独であっても、既知の技術により提供される他のアミノ酸配列との組合せであってもよい。抗体は、どの種に由来してもよい。用語「抗体」には、本発明の抗体の結合断片も含まれ、例示の断片には、Fv、Fab、Fab’、一本鎖抗体(svFC)、二量体の可変領域(ダイアボディ)と、ジスルフィド安定化可変領域(dsFv)が含まれる。
アンジオポエチン−1又はアンジオポエチン−2ポリペプチドに関して、「活性な」又は「活性」は、ネイティブなポリペプチドそのものとして生物学的又は免疫学的な活性を有するポリペプチドの部分を意味する。「生物学的」は、本明細書において使用するとき、ネイティブポリペプチドの活性により生じる生物学的機能を意味する。例えば、好ましいアンジオポエチン−2生物学的活性には、アンジオポエチン−2誘導性の血管新生が含まれる。
酵素、パパインでの抗体の消化は、「Fab」断片としても知られる2つの同一の抗原結合断片と、抗原結合活性を有さないが、結晶化する能力は有する「Fc」断片をもたらす。酵素、ペプシンでの抗体の消化は、抗体分子の2つのアームが連結したままであり、2つの抗原結合部位を含むF(ab’)2断片をもたらす。F(ab’)2断片は、抗原を架橋連結する能力を有する。
「Fab」は、本明細書に使用するとき、軽鎖の定常ドメインと重鎖のCH1ドメインを含む抗体の断片を意味する。
「リポソーム」は、本明細書に使用するとき、本発明のアンジオポエチン−2ポリペプチド、又はそのようなアンジオポエチン−2ポリペプチドに対する抗体が含まれ得る薬物の哺乳動物への送達に有用であり得る小さな小胞を意味する。
これから本発明を以下の非限定的な実施例により例示するが、これらは、例示目的のためにのみ提供されて、本明細書の教示を限定するものと解釈してはならない。
免疫化
R&D Systems社(ミネソタ州ミネアポリス、カタログ番号623−AM/CF)より入手した組換えヒトアンジオポエチン−2を抗原として使用した。アンジオポエチン−2に対するモノクローナル抗体は、XenoMouse(登録商標)マウス(XenoMouse系XMG2及びXMG4(3C−1系)、Abgenix社、カリフォルニア州フレモント)を連続的に免疫化することによって発生させた。すべての注射でフットパッド経路によりXenoMouse動物を免疫化した。各注射の全容量は、マウスあたり50μl、フットパッドあたり25μlであった。初回の注射は、マウスあたり、発熱物質フリーのダルベッコPBS(DPBS)中に10μg CpG(15μlのImmunEasy Mouse Adjuvant,カタログ番号303101;ロット番号11553042;キアジェン)と1:1(v/v)混合した2.35μg組換えヒトアンジオポエチン−2(rhアンジオポエチン−2,カタログ番号623−AM/CF;ロット番号BN023202A)で行った。次の6回の追加免疫は、マウスあたり、25μgのAdju−Phos(リン酸アルミニウムゲル、カタログ番号1452−250,バッチ番号8937,HCI Biosector)と10μg CpGと混合した、発熱物質フリーのDPBS中2.35μgのrhアンジオポエチン−2で行って、その後、アジュバントを含まない発熱物質フリーのDPBS中2.35μgのrhアンジオポエチン−2による最後の追加免疫を行った。XenoMouseマウスは、このプロトコールの0、3、6、10、13、17、20、及び24日目に免疫化して、融合を29日目に実施した。
免疫化XenoMouseマウスからの血清中の抗アンジオポエチン−2抗体力価をELISAにより測定した。簡潔に言えば、抗原コーティング緩衝液(0.1M炭酸塩緩衝液、pH9.6,NaHCO3 8.4g/L)中、4℃で一晩、組換えアンジオポエチン−2(1μg/ml)を Costar Labcoat Universal Binding Polystyrene 96ウェルプレート(コーニング、マサチューセッツ州アクトン)上へコートした。翌日、Biotekプレート洗浄器を使用して、プレートを洗浄緩衝液(1×PBS中0.05% Tween20)で3回洗浄した。次いで、プレートを200μl/ウェルのブロッキング緩衝液(1×PBS中0.5% BSA,0.1% Tween20,0.01%チメロサール)でブロックして、室温で1時間インキュベートした。1時間のブロッキングの後で、Biotekプレート洗浄器を使用して、プレートを洗浄緩衝液で3回洗浄した。アンジオポエチン−2免疫化XenoMouseマウス又は未処置XenoMouse動物のいずれか由来の血清を0.5% BSA/PBS緩衝液中で、1:100開始希釈液からデュプリケートで1:3希釈で滴定した。最後のウェルは、ブランクのままとした。これらのプレートを室温で2時間インキュベートしてから、Biotekプレート洗浄器を使用して、プレートを洗浄緩衝液で3回洗浄した。ヤギ抗ヒトIgG Fc特異的西洋ワサビペルオキシダーゼ(HRP,ピアス、イリノイ州ロックフォード)コンジュゲート抗体を1μg/mlの最終濃度で加えて、室温で1時間インキュベートした。次いで、Biotekプレート洗浄器を使用して、プレートを洗浄緩衝液で3回洗浄した。
免疫化マウスを頸部脱臼により犠牲にし、各コホートより漏出するリンパ節を採取して、プールした。リンパ様細胞をDMEM中で粉砕することにより解離させて細胞を組織より遊離させて、その細胞をDMEMに懸濁させた。この細胞を計数し、1億個のリンパ球あたり0.9ml DMEMを細胞ペレットへ加えて、細胞を穏やかに、しかし完全に再懸濁させた。1億個の細胞につき100μlのCD90+磁気ビーズを使用して、細胞を磁気ビーズとともに4℃で15分間インキュベートすることによって、細胞を標識した。108個までの陽性細胞(又は、2×109個までの全細胞)を含有する磁気的に標識した細胞懸濁液をLS+カラム上へロードして、このカラムをDMEMで洗浄した。全ての溶出液をCD90陰性画分(これらの細胞のほとんどがB細胞であると予測された)として採取した。
膜破壊電圧:3000V,時間:30μ秒。
融合後の保持時間:3秒。
ECFの後で、細胞上清を無菌条件下に融合チャンバより慎重に取り出して、L−グルタミン、ペニシリン/ストレプトマイシン、OPI(オキサロ酢酸塩、ピルビン酸塩、ウシインスリン)(いずれもシグマより)とIL−6(ベーリンガーマンハイム)を補充した、同容量のハイブリドーマ培養メディウム(DMEM,JRH Biosciences)、15% FBS(Hyclone)を含有する滅菌管へ移した。この細胞を37℃で15〜30分間インキュベートしてから、400×g(1000rpm)で5分間遠心分離した。この細胞を少量のハイブリドーマ選択培メディウム(0.5×HA(シグマ、カタログ番号A9666)を補充したハイブリドーマ培養メディウム)に穏やかに再懸濁させて、96ウェルプレートあたり全部で5×106個のB細胞とウェルにつき200μlの最終プレーティングに基づいて、追加のハイブリドーマ選択培メディウムで適宜容量を調整した。この細胞を穏やかに混合してピペットで96ウェルプレートへ移し、そのまま増殖させた。7又は10日目にメディウムの半分を除去し、細胞にハイブリドーマ選択メディウムを再供給した。
14日間の培養後、ハイブリドーマ上清をアンジオポエチン−2特異的モノクローナル抗体のスクリーニングにかけた。ELISAプレート(Fisher,カタログ番号12−565−136)をコーティング緩衝液(0.1M炭酸緩衝液、pH9.6,NaHCO3 8.4g/L)中50μl/ウェルのヒトアンジオポエチン−2(2μg/ml)でコートしてから、4℃で一晩インキュベートした。インキュベーション後、プレートを洗浄緩衝液(PBS中0.05% Tween20)で3回洗浄した。200μl/ウェルのブロッキング緩衝液(1×PBS中0.5% BSA,0.1% Tween20,0.01%チメロサール)を加えて、プレートを室温で1時間インキュベートした。インキュベーション後、プレートを洗浄緩衝液で3回洗浄した。50μl/ウェルのハイブリドーマ上清と陽性及び陰性の対照を加えて、プレートを室温で2時間インキュベートした。全体を通して使用する陽性対照は、アンジオポエチン−2免疫化XenoMouseマウス、XMG2アンジオポエチン−2 1群、フットパッド(fp)N160−7由来の血清であり、陰性対照は、KLH免疫化XenoMouseマウス、XMG2 KLH 1群、フットパッド(fp)L627−6由来の血清であった。
以下の表1は、抗アンジオポエチン−2抗体の同定番号を対応する重鎖及び軽鎖の遺伝子の配列番号とともに報告する。
上記に考察したように、アンジオポエチン−2は、Tie−2受容体へ結合することによってその生物学的効果を発揮する。改変ELISAを使用する競合結合アッセイによって、アンジオポエチン−2/Tie−2結合を阻害したモノクローナル抗体を同定した。使用するmAbは、アンジオポエチン−2に特異的であったハイブリドーマプール(上記参照)の50mlの消耗上清からのミクロ精製の産物であった。4℃で一晩インキュベートすることによって、96ウェルNunc ImmplatesTMを100μlの組換えヒトTie−2/Fc融合タンパク質(R&DSystems社、カタログ番号313−TI−100)、4μg/mlでコートした。SkanTMWasher 300ステーション(SKATRON)を使用して、リン酸緩衝化生理食塩水(PBS)でこのプレートを4回洗浄した。ウェルを、100μlのABXブロッキング緩衝液(PBS中0.5% BSA,0.1% Tween,0.01%チメロサール)で1時間ブロックした。
Biacore分析を使用する抗アンジオポエチン−1抗体アフィニティーの定量
mAbのアンジオポエチン−1に対するアフィニティーを測定することによって、この抗体のアンジオポエチン−1への交差反応性をさらに検討した。ELISAベースのカウンター結合で記載のように、アンジオポエチン−1を固定する代わりに、mAbをCM5 Biacoreチップへ固定して、溶液中のアンジオポエチン−1をオン速度及びオフ速度の測定用に注入した。6種のmAb;3.3.2、3.31.2、5.16.3、5.86.1、5.88.3、及び3.19.3について試験した。
ラベルフリーの表面プラズモン共鳴(SPR)、又はBiacore2000装置を利用して、抗体のアンジオポエチン−1へのアフィニティーを測定した。この目的のために、定型的なアミンカップリングを使用して、CM5 Biacoreチップ上に高密度ヤギα−ヒト抗体表面を調製した。発色実験用に、精製mAb(クローン3.3.2、3.31.2、5.16.3、5.86.1、5.88.3、及び3.19.3)を、100μg/ml BSAを含有するHBS−Pランニング緩衝液中ほぼ2.5〜3.5μg/mlへ希釈した。各mAbの捕捉レベルは、ほぼ150RUであった。mAbベースラインを安定化させるために、各捕捉サイクルに5分の洗浄を続けた。
低分子VEGFチロシンキナーゼ阻害剤と組み合わせたmAb3.19.3の活性について評価した。
A431及びColo205細胞系をそれぞれ使用するヒト皮膚類表皮癌の異種移植片モデル(試験A)と結直腸癌のモデル(試験B)において、VTKI:4−(4−フルオロ−2−メチルインドール−5−イルオキシ)−6−メトキシ−7−(3−ピペリジノプロポキシ)キナゾリンと組み合わせたモノクローナル抗体3.19.3の抗腫瘍活性について評価した。
A431組合せ異種移植片有効性試験の結果を図1aに示す。これは、この組合せがそれぞれの単剤単独より有意に高い活性を生じることを例示する。達成された腫瘍増殖阻害(%)は、以下の通りである:
3.19.3(10mg/kg 2×週)=46%;(p<0.01)
4−(4−フルオロ−2−メチルインドール−5−イルオキシ)−6−メトキシ−7−(3−ピペリジノプロポキシ)キナゾリン(3mg/kg/日)=69%;(p<0.001)
組合せ:3.19.3 + 4−(4−フルオロ−2−メチルインドール−5−イルオキシ)−6−メトキシ−7−(3−ピペリジノプロポキシ)キナゾリン=89%阻害(組合せ対単剤について、p<0.001)。
Colo205組合せ異種移植片有効性試験の結果を図2aに示す。これは、この組合せがそれぞれの単剤単独より有意に高い活性を生じることを例示する。達成された阻害(%)は、以下の通りである:
3.19.3(10mg/kg 2×週)=35%;(p<0.05)
4−(4−フルオロ−2−メチルインドール−5−イルオキシ)−6−メトキシ−7−(3−ピペリジノプロポキシ)キナゾリン(6mg/kg/日)=57%;(p<0.001)
組合せ:3.19.3 + 4−(4−フルオロ−2−メチルインドール−5−イルオキシ)−6−メトキシ−7−(3−ピペリジノプロポキシ)キナゾリン=87%阻害(組合せ対単剤について、p<0.001)。
結腸直腸癌のLovo異種移植片モデルにおいて、モノクローナル抗体、3.19.3の抗腫瘍活性を評価した。簡潔に言えば、Lovo細胞を、細胞がサブコンフルエントに達するまで、定常通りにフラスコで培養した。免疫不全である8週齢の雄性NCrヌードマウスを使用した。3×106個の細胞を含有する細胞懸濁液をマウスの右脇腹へ皮下注射し、腫瘍体積が200mm3に達したとき、マウスを数群に無作為にグループ分けして、処置を開始した。生理食塩水中のmAb3.19.3 10mg/kgを週2回、2週間、腹腔内注射した。ZactimaTMを、1% Tween80を含有する水中25〜50mg/kgの用量で連日経口処置した。それぞれの腫瘍の寸法を週2回測定した。腫瘍の体積は:体積=長さ×(幅)2×0.5(cm3)として計算した。図4aに例示されるように、mAb3.19.3とZactimaTMは、単剤として、Lovo腫瘍の増殖を有意に遅らせた。しかしながら、mAb3.19.3とZD6474の組合せは、以下の腫瘍阻害の数値により例示されるように、単剤単独より有意に大きな効果を及ぼした:
3.19.3(10mg/kg 2×週)=48%;(p<0.001)
ZactimaTM(50mg/kg/日)=46%;(p<0.001)
組合せ:3.19.3+ZactimaTM=83%阻害(組合せ対単剤について、p<0.001)。
SW620結腸直腸癌異種移植片モデルにおいて、VEGFR−2/KDRに対して向けられるモノクローナル抗体、DC101と組み合わせたmAb3.19.3の抗腫瘍活性を評価した。簡潔に言えば、SW620細胞を、細胞がサブコンフルエントに達するまで、フラスコにおいて定常の組織培養条件下で培養した。免疫不全である8〜10週齢のNCrヌードマウスを使用して、ほぼ1×106個の細胞を含有する細胞懸濁液をマウスの右脇腹へ皮下注射した。腫瘍体積が100mm3に達した後で、マウスを無作為に群に分け、処置を開始した。生理食塩水中のmAb3.19.3 10mg/kgを週2回、3週間、腹腔内注射した。生理食塩水中のmAb DC101 15mg/kgも、週2回、3週間の同じスケジュールに従って、腹腔内注射した。それぞれの腫瘍の寸法を週2回測定した。腫瘍の体積は:体積=長さ×(幅)2×0.5(cm3)として計算した。図5aに例示されるように、mAb3.19.3とDC101の組合せは、どちらかの単剤単独よりも有意に高い活性を示す。このことは、以下の腫瘍阻害の数値によっても例示される:
3.19.3(10mg/kg 2×週)=48%;(p<0.03)
DC101(15mg/kg 2×週)=66%;(p<0.01)
組合せ:3.19.3+DC101=93%阻害(組合せ対単剤について、p<0.001)。
ヒト腫瘍の異種移植片モデルにおいて、AVASTINTMと組み合わせたモノクローナル抗体3.19.3の抗腫瘍活性を評価することができる。A431、Colo205、LoVo、又は他の細胞を、細胞がサブコンフルエントに達するまで、定常通りにフラスコで培養することができる。免疫不全である7〜10週齢の雄性又は雌性NCRヌードマウスをモデル開発に利用することができる。細胞は採取し、Matrigelに懸濁させ、各マウスへ皮下注射することができる。次いで、このマウスを、無作為に8〜10匹のマウスを含有するコホートへ分けることができる。AVASTINTMとmAb3.19.3は、腹腔内又は静脈内の注射により投与することができる。それぞれの腫瘍の寸法は、週2回測定することができる。腫瘍の体積は:体積=長さ×(幅)2×0.5(cm3)として、又は両側ノギス測定、長さを腫瘍を横切る最長直径であり、幅を対応する垂線であるとし、式:(π/6)×(長さ×幅)×√(長さ×幅)を使用して計算することができる。処置の開始からの増殖阻害について、対照群と処置群間の腫瘍体積の差の比較により測定することができる。
ヒト腫瘍の異種移植片モデルにおいて、Sutent又はSorafinibと組み合わせたモノクローナル抗体3.19.3の抗腫瘍活性を評価することができる。HT29、A431、Colo205、LoVo、又は他のヒト腫瘍細胞を、細胞がサブコンフルエントに達するまで、定常通りにフラスコで培養することができる。免疫不全である7〜10週齢の雄性又は雌性NCRヌードマウスをモデル開発に利用することができる。細胞は採取し、Matrigelに懸濁させてから、各マウスへ皮下注射することができる。次いで、このマウスを、無作為に8〜10匹のマウスを含有するコホートへ分けることができる。SutentとmAb3.19.3は、以下の表に従って、腹腔内又は静脈内の注射により投与することができる。
抗Ang−2モノクローナル抗体3.3.2
重鎖可変領域のヌクレオチド配列:
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGTCTCTGGATTCACCTTTAGTAGCTATTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGCAAGATGGAAGTGAGAAATACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATCAAGGTATAGCAGTGGCTGGGCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCC(配列番号1)
重鎖可変領域のアミノ酸配列:
EVQLVESGGGLVQPGGSLRLSCAVSGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDQGIAVAGPFDYWGQGTLVTVSSA(配列番号2)
軽鎖可変領域のヌクレオチド配列:
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGACTGTTAGCAGCGACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGAGCATCCATTAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTCCTGTCAGCAGTATTATAACTGGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAA(配列番号3)
軽鎖可変領域のアミノ酸配列:
EIVMTQSPATLSVSPGERATLSCRASQTVSSDLAWYQQKPGQAPRLLIYGASIRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYSCQQYYNWWTFGQGTKVEIKR(配列番号4)
抗アンジオポエチン−2モノクローナル抗体3.19.3
重鎖可変領域のヌクレオチド配列:
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCACTAACTATGGCATGCACTGGGGCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCACATGATGGAAATAATAAGTATTATGTAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAGAGGGAATCGATTTTTGGAGTGGCCTCAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCC(配列番号:5)
重鎖可変領域のアミノ酸配列:
QVQLVESGGGVVQPGRSLRLSCAASGFTFTNYGMHWGRQAPGKGLEWVAVISHDGNNKYYVDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGIDFWSGLNWFDPWGQGTLVTVSSA(配列番号6)
軽鎖可変領域のヌクレオチド配列:
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACTCTCTCCTGCAGGGCCAGTCAGAGTATTACCGGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGACTCCTCATCTGTGGTGCATCCAGCTGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGTAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTATAGTAGTTCACCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGA(配列番号7)
軽鎖可変領域のアミノ酸配列:
EIVLTQSPGTLSLSPGERATLSCRASQSITGSYLAWYQQKPGQAPRLLICGASSWATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYSSSPITFGQGTRLEIKR(配列番号8)
抗Ang−2モノクローナル抗体3.31.2
重鎖可変領域のヌクレオチド配列:
GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGTAGCTATTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGCAAGATGGAAGTGACAAATACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCGAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTTTTACTGTGCGAGAGATATGGGCAGTGGCTGGTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCC(配列番号9)
重鎖可変領域のアミノ酸配列:
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGSDKYYVDSVKGRFTISRDNAKNSLYLRMNSLRAEDTAVFYCARDMGSGWFDYWGQGTLVTVSSA(配列番号10)
軽鎖可変領域のヌクレオチド配列:
GAAGTAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTGGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTGCTGTCAGCAGTATAATCACTGGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGA(配列番号11)
軽鎖可変領域のアミノ酸配列:
EVVMTQSPATLSVSPGERATLSCRASQSVGSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYCCQQYNHWWTFGQGTKVEIKR(配列番号12)
抗Ang−2モノクローナル抗体5.16.3
重鎖可変領域のヌクレオチド配列:
CAGGTACAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTTCTATATGTACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTAACAGTAGTGGCACAAACCATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCAGGATATAGCAACAGCTGGTCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGC(配列番号13)
重鎖可変領域のアミノ酸配列:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGFYMYWVRQAPGQGLEWMGWINPNSSGTNHAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDQDIATAGPFDYWGQGTLVTVSS(配列番号14)
軽鎖可変領域のヌクレオチド配列:
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTTTGGTGCATCCACCCGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAACTGGTGGACGTTCGGCCGAGGGACCAAGGTGGAAATCAAACGAA(配列番号15)
軽鎖可変領域のアミノ酸配列:
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIFGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWWTFGRGTKVEIKR(配列番号16)
抗Ang−2モノクローナル抗体5.28.1
重鎖可変領域のヌクレオチド配列:
GAAGTGCAGCTGGTGGAGTCTGGGGGAATCGTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATACCATGCACTGGGTCCGTCAAACTCCGGGGAAGGGTCTGGAGTGGGTCTCTCTTATTAGTTGGGATGGTGGTAGCACATACTATGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACAGCAAAAACTCCCTGTATCTGCAAATGAACAGTCTGAGAACTGAGGACACCGCCTTGTATTACTGTGCAAAAGATATAGATATAGCAGTGGCTGGTACAGGATTTGACCACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCT(配列番号17)
重鎖可変領域のアミノ酸配列:
EVQLVESGGIVVQPGGSLRLSCAASGFTFDDYTMHWVRQTPGKGLEWVSLISWDGGSTYYADSVKGRFTISRDNSKNSLYLQMNSLRTEDTALYYCAKDIDIAVAGTGFDHWGQGTLVTVSSA(配列番号18)
軽鎖可変領域のヌクレオチド配列:
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTACCAGCAACCTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATTAATTAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAATATAATAACTGGCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGA(配列番号19)
軽鎖可変領域のアミノ酸配列:
EIVMTQSPATLSVSPGERATLSCRASQSVTSNLAWYQQKPGQAPRLLIYGALIRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPFTFGPGTKVDIKR(配列番号20)
抗Ang−2モノクローナル抗体5.78.3
重鎖可変領域のヌクレオチド配列:
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATAGGGGCTGGAACTACGCAGACTACTACTACTACGGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCT(配列番号21)
重鎖可変領域のアミノ酸配列:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDRGWNYADYYYYGMDVWGQGTTVTVSSA(配列番号22)
軽鎖可変領域のヌクレオチド配列:
GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGTTCCAACAATCAGAACTTCTTAGCTTGGTATCAGCAGAAACCAGGACAGCCTCCTAAACTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCACCAATATTATAGTACTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGA(配列番号23)
軽鎖可変領域のアミノ酸配列:
DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNQNFLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCHQYYSTPITFGQGTRLEIKR(配列番号24)
抗Ang−2モノクローナル抗体5.86.1
重鎖可変領域のヌクレオチド配列:
CAGGTGCAGCTGGTGCAGTCCGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACCATATGTACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGCTGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGTGAGAGATCAGGGTATAGCAGCAGCTGGTCCCTTTGACTACTGGTGCCAGGGAACCCTGGTCACCGTCTCCTCAGCT(配列番号25)
重鎖可変領域のアミノ酸配列:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMYWVRQAPGQGLEWLGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCVRDQGIAAAGPFDYWCQGTLVTVSSA(配列番号26)
軽鎖可変領域のヌクレオチド配列:
GACATCCGGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTTGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGCGCATTAGCACCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGTTCCTGATCTATGCTGCATCTAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGAGTTACACTACCCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGA(配列番号27)
軽鎖可変領域のアミノ酸配列:
DIRMTQSPSSLSASVGDRVTITCRASQRISTYLNWYQQKPGKAPKFLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYTTPFTFGPGTKVDIKR(配列番号28)
抗Ang−2モノクローナル抗体5.88.3
重鎖可変領域のヌクレオチド配列:
GAGGTGCAGATGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCGGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTAAGAAGCTACTGGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGGAAGACGGAAGTGAGAAATACCATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCGAGAACTCACTGTTTCTGCAAATGAGCAGCCTGCGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGATATGGAAGCATCAGCTGGCCTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCT(配列番号29)
重鎖可変領域のアミノ酸配列:
EVQMVESGGGLVQPGGSLRLSCAASGFTLRSYWMSWVRQAPGKGLEWVANIKEDGSEKYHVDSVKGRFTISRDNAENSLFLQMSSLRAEDTAVYYCARDMEASAGLFDYWGQGTLVTVSSA(配列番号30)
軽鎖可変領域のヌクレオチド配列:
GAAATAGTGATGACGCAGTCCCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCATCCTCTCCTGCAGGGCCAGTCAGAGTATTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATTACTGGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGA(配列番号31)
軽鎖可変領域のアミノ酸配列:
EIVMTQSPATLSVSPGERAILSCRASQSISSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNYWWTFGQGTKVEIKR(配列番号32)
抗Ang−2モノクローナル抗体5.101.1
重鎖可変領域のヌクレオチド配列:
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATATGCACTGGGTGCCACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCTTACATGGAGCTGAGGAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATGGGGGTAGTATACCAGTGTCTGGTCACTTTGACTACTGGGGGCAGGGAACCCTGGTCACCGTCTCCTCAGCT(配列番号33)
重鎖可変領域のアミノ酸配列:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMHWVPQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELRRLRSDDTAVYYCARDGGSIPVSGHFDYWGQGTLVTVSSA(配列番号34)
軽鎖可変領域のヌクレオチド配列:
GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTCTTATCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTTTGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCATCAGTATAATAACTGGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGA(配列番号35)
軽鎖可変領域のアミノ酸配列:
EIVMTQSPATLSVSPGERATLSCRASQSLISNLAWYQQKPGQAPRLLIFGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCHQYNNWWTFGQGTKVEIKR(配列番号36)
抗Ang−2モノクローナル抗体5.103.1
重鎖可変領域のヌクレオチド配列:
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAAAAGCCTGGGGCCTCAGTCAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCACCGGCTACTATTTGTACTGGGTGCCACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAGCCCTAACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATCAGGTCATAGCAGTAGCTGGTCCCTTTGACTACTGGGCCCAAGGAACCCTGGTCACCGTCTCCTCAGCT(配列番号37)
重鎖可変領域のアミノ酸配列:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYLYWVPQAPGQGLEWMGWISPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDQVIAVAGPFDYWAQGTLVTVSSA(配列番号38)
軽鎖可変領域のヌクレオチド配列:
GAAACAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGTCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTATCAGCAGCTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTATAATAATTGGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGA(配列番号39)
軽鎖可変領域のアミノ酸配列:
ETVMTQSPATLSVSPGERVTLSCRASQSVISSLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWWTFGQGTKVEIKR(配列番号40)
特許、特許出願、論文、教科書、等が含まれる、本明細書に引用するすべての参考文献と、そこに引用された参考文献は、それらがまだ引用されていない限りにおいて、その全体が参照により本明細書に組み込まれる。
Claims (18)
- アンジオポエチン−2の生物学的活性のアンタゴニストと、
i.VEGF−A、及び/又は
ii.KDR、及び/又は
iii.Flt1
の生物学的活性のアンタゴニストの組合せ。 - アンジオポエチン−2のアンタゴニストが抗体である、請求項1に記載の組合せ。
- アンジオポエチン−2のアンタゴニストが完全ヒトモノクローナル抗体である、請求項2に記載の組合せ。
- 抗体が、完全ヒトモノクローナル抗体;
i.3.31.2、又は
ii.5.16.3、又は
iii.5.86.1、又は
iv.5.88.3、又は
v.3.3.2、又は
vi.5.103.1、又は
vii.5.101.1、又は
viii.3.19.3、又は
ix.5.28.1、又は
x.5.78.3
のいずれか1つと同じエピトープへ結合する、請求項2又は3のいずれか1項に記載の組合せ。 - 抗体が、
i.3.31.2、又は
ii.5.16.3、又は
iii.5.86.1、又は
iv.5.88.3、又は
v.3.3.2、又は
vi.5.103.1、又は
vii.5.101.1、又は
viii.3.19.3、又は
ix.5.28.1、又は
x.5.78.3
のいずれか1つより選択される完全ヒトモノクローナル抗体である、請求項4に記載の組合せ。 - KDR又はFlt1の生物学的活性のアンタゴニストが抗体である、請求項1に記載の組合せ。
- VEGF−Aの生物学的活性のアンタゴニストが抗体である、請求項1に記載の組合せ。
- VEGF−Aの生物学的活性のアンタゴニストがAvastin又はDC101である、請求項7に記載の組合せ。
- KDR又はFlt1の生物学的活性のアンタゴニストが化合物である、請求項1に記載の組合せ。
- KDR又はFlt1の生物学的活性のアンタゴニストがチロシンキナーゼ阻害剤である、請求項9に記載の組合せ。
- KDR又はFlt1の生物学的活性のアンタゴニストが、
ZactimaTM、AZD2171、SU11248、SU14813、Vatalanib、BAY43−9006、XL−647、XL−999、AG−013736、AMG706、BIBF1120、TSU68、GW786034、AEE788、CP−547632、KRN951、CHIR258、CEP−7055、OSI−930、ABT−869、E7080、ZK−304709、BAY57−9352、L−21649、BMS582664、XL−880、XL−184、又はXL−820
より選択される、請求項10に記載の組合せ。 - KDR又はFlt1の生物学的活性のアンタゴニストが、
ZactimaTM、AZD2171、SU11248、又はBAY43−9006
より選択される、請求項11に記載の組合せ。 - KDR又はFlt1の生物学的活性のアンタゴニストがZactimaTMである、請求項11に記載の組合せ。
- KDR又はFlt1の生物学的活性のアンタゴニストがAZD2171である、請求項11に記載の組合せ。
- 請求項1〜14のいずれか1項の組合せを含んでなる医薬組成物。
- 請求項1〜15のいずれか1項に記載の組合せを投与することを含んでなる、アンジオポエチン−2と
i.VEGF−A、及び/又は
ii.KDR、及び/又は
iii.Flt1
のいずれか1つの生物学的活性を拮抗させる方法。 - 請求項1〜15のいずれか1項の組合せの治療的に有効な量を投与することを含んでなる、哺乳動物において疾患関連性の血管新生を処置する方法。
- 請求項1〜15のいずれか1項の組合せの治療的に有効な量を含んでなる、哺乳動物において癌を処置する方法。
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- 2006-12-12 WO PCT/GB2006/004611 patent/WO2007068895A1/en active Application Filing
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KR101907572B1 (ko) | 2011-04-01 | 2018-10-15 | 베링거 인겔하임 인터내셔날 게엠베하 | VEGF와 Ang2에 결합하는 이중특이성 결합분자 |
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