JP6446560B2 - VEGFA/Ang2化合物 - Google Patents
VEGFA/Ang2化合物 Download PDFInfo
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- JP6446560B2 JP6446560B2 JP2017539538A JP2017539538A JP6446560B2 JP 6446560 B2 JP6446560 B2 JP 6446560B2 JP 2017539538 A JP2017539538 A JP 2017539538A JP 2017539538 A JP2017539538 A JP 2017539538A JP 6446560 B2 JP6446560 B2 JP 6446560B2
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Description
a)かかる抗体は、同一重鎖(HC)2本および同一軽鎖(LC)2本を含み、ここで、各重鎖は、アミノ酸配列が配列番号1に示される重鎖可変領域(HCVR)を含み、各軽鎖は、アミノ酸配列が配列番号4に示される軽鎖可変領域(LCVR)を含み、
b)2つのscFvポリペプチドは同一であり、それぞれが、LCVRに機能的に結合したHCVRを含み、ここで、各HCVRは、配列番号7に示されるアミノ酸配列を有し、各LCVRは、配列番号8に示されるアミノ酸配列を有し、かつ
c)2つのリンカーはグリシンに富む同一リンカーであり、それぞれが、抗体の1本のHCのカルボキシ末端と、scFvポリペプチドの一方のアミノ末端とを機能的に結合している。
a)かかる抗体は、同一重鎖(HC)2本および同一軽鎖(LC)2本を含み、ここで、各重鎖は、アミノ酸配列が配列番号1に示される重鎖可変領域(HCVR)を含み、各軽鎖は、アミノ酸配列が配列番号4に示される軽鎖可変領域(LVCR)を含み、
b)2つのscFvポリペプチドは同一であり、それぞれが、LCVRに機能的に結合したHCVRを含み、ここで、各HCVRは、配列番号7に示されるアミノ酸配列を有し、各LCVRは、配列番号8に示されるアミノ酸配列を有し、かつ
c)2つのリンカーはグリシンに富む同一リンカーであり、それぞれが、抗体の1本のHCのカルボキシ末端と、scFvポリペプチドの一方のアミノ末端とを機能的に結合している。
表1に示す実施例1(化合物A)では、2つの第1のポリペプチド(化合物Aの「抗体HC−リンカー−scFv」)は配列番号3のアミノ酸配列を有し、2つの第2のポリペプチド(化合物Aの抗体のLC)は配列番号5のアミノ酸配列を有する。
結合動態、親和性、および選択性
本発明の化合物について、ヒトAng2およびヒトVEGFAに対する結合動態、親和性、および選択性を、Biacore(登録商標)2000、Biacore(登録商標)3000、もしくはBiacore(登録商標)T100(GE HealthCare)などの表面プラズモン共鳴(SPR)バイオセンサーを使用するか、または代替として、Kinexa3000もしくはKinexa3200と連携した結合平衡除外アッセイ(Sapidyne Instruments)により、当技術分野で公知の方法にしたがって決定する。
本発明の化合物について、可溶性完全長のヒトAng2およびヒトVEGFAに対する動態および平衡解離定数(KD)を、25℃にて、またはBiacore表面プラズモン共鳴アッセイ法を使用して決定する。ヒトAng2はR&D Systems(#623-AN-01M/CF)製であり、ヒトVEGFA165はR&D systems(#293-VE-001MG/CF)製、Peprotech(#00-20)製、または組換え発現法によって調製する。抗体捕捉用のタンパク質A表面を以下の方法を用いて準備する。可溶性タンパク質A(Calbiochem #539202)をCM4(GE Healthcare #BR-1005-34)またはCM5(GE Healthcare #BR-1000-99)上に固定化する準備を、EDC/NHSアミンカップリング方法(GE Healthcare #BR-1000-50)を使用して行う。手短に言えば、EDC/NHSの1:1混合物を10μL/分で7分間注入して、全4フローセルの表面を活性化させる。その後、可溶性タンパク質AをpH4.5の10mM酢酸緩衝液で50〜100μg/mLまで希釈し、フローセル(Fc)2、3または4上に流速10μL/分で7分間固定化する。エタノールアミンを10μL/分にて7分注入し、チップ表面に残っている未反応部位をブロッキングする。ランニング緩衝液は、100mM NaCl添加、HBS-EP+(GE Healthcare #BR-1006-69)である。化合物試料は、ランニング緩衝液に希釈して1μg/mLに調製する。2倍段階希釈を使用してランニング緩衝液に50nM〜1.56nMの範囲のヒトAng2またはヒトVEGFA165を調製する。各分析サイクルは5部に分かれ、すなわち、(1)別々のフローセル(Fc2、Fc3、およびFc4)上に化合物を捕捉させる、(2)個々の濃度のヒトAng2またはヒトVEGFA165の250μL(表面接触時間300秒)を全Fcに50μL/分で注入する(kinject使用)、(3)緩衝液流に20分間戻し、解離相を監視する、(4)pH1.5、10mMグリシンを10μL(接触時間30秒)注入してチップ表面の再生を行う、(5)HBS-EP+ランニング緩衝液15μL(接触時間45秒)を注入してチップ表面の平衡化を行う、という一連のステップで構成される。得られたデータを標準の二重参照を用いて処理し、Biacore 2000 Evaluationソフトウェア(バージョン4.1)を使用して1:1結合モデルに当てはめ、会合速度(kon、M−1s−1単位)、解離速度(koff、s−1単位)を決定する。平衡解離定数(KD)を、関係KD=koff/konから計算し、モル単位で表す。
KinExA 3200装置を使用してヒトVEGFA165に対する結合動態を測定する。手短に言えば、NHS活性化させたsepharoseビーズ(GE Healthcare #17-0906-01)にヒトVEGFA165を共有結合で結合させ、複合体化したビーズに対する遊離Mabの結合をKinExA 3200で検出する。KDを測定するため、固定濃度(典型的に1〜5pM)の化合物を含有する個々のチューブを、段階希釈で徐々に濃度を低くしながらヒトVEGFA165と混合し、Casein Blocking Buffer(ThermoFisher #37528)中で25℃または37℃にて(分析温度に応じて)、24時間以上プレインキュベートする。プレインキュベーションで定常的な平衡状態に達した後、各試料を、以下の5ステップからなる分析サイクル、すなわち、1)小カラムのVEGFA165結合ビーズをキャピラリの所定の高さまで充填し、2)個々のヒトVEGFA165/化合物混合物のそれぞれの定義された容量を定義された時間カラムに注入し、3)適切な蛍光標識抗体(すなわち、CY5標識した抗ヒトFcガンマ特異的抗体:Jackson Immunoresearch #309-175-008)の定義された容量をカラムに注入し、4)カラムを1×PBSで洗浄して過剰の検出抗体および非特異的に結合した物質を除去し、5)特異的に結合した物質の検出を、結合二次抗体に励起し、その後の発信を監視して測定する、というサイクルに供する。これらのステップの発生シグナルの相対強度は、各被験溶液中に存在する遊離/未結合化合物の程度に比例する。混成セットとして得られた蛍光強度を、各個別試料に存在するヒトVEGFA165濃度の関数としてプロットし、N曲線分析ソフトウェア(KinExA)を使用して標準的2状態結合モデル(two state binding model)に当てはめ、所与のMOIに対するKDを決定する。統計的信頼性は、95%信頼区間の算出によりレポートされる。
本発明の化合物による、ヒトAng2とその受容体のヒトTie2との結合遮断を固相インビトロELISA法で測定する。細胞を用いるインビトロアッセイを使用して、本発明の化合物と、かかる化合物のscFvポリペプチド部分と同一のHCDR配列およびLCDR配列を有するAng2抗体との間の比較可能な遮断活性を確立した。
細胞を用いるインビトロでの本発明化合物によるヒトAng2の阻害を、Ang1およびAng2が結合してヒトTie2リン酸化が用量依存的に誘導される細胞系アッセイで測定する。細胞を用いるインビトロアッセイを使用して、本発明の化合物が、用量依存的にAng1介在性ではなくAng2介在性のTie−2受容体のリン酸化を選択的に無効化する能力を評価する。Ang2抗体、Ang2/Ang1抗体、および対照ヒトIgG4 PAAアイソタイプ抗体をそれぞれ、陽性対照および陰性対照として含めた。
VEGFR2発現細胞株上でVEGFA165がVEGFR2に結合すると、VEGFR2のリン酸化が用量依存的に誘導される細胞系アッセイにおいて、細胞を用いたインビトロでのヒトVEGFA阻害を測定する。アッセイを使用して、本発明の化合物が、用量依存的にVEGFR2受容体のVEGFA介在性リン酸化を選択的に無効化する能力を評価する。VEGFA抗体と、無関係の抗体であるヒトIgG4 PAAアイソタイプとをそれぞれ、陽性対照および陰性対照として含めた。
本発明の化合物による、細胞を用いたインビトロでのヒトVEGFA阻害を、VEGFA165が用量依存的に増殖を誘導する細胞系アッセイで測定した。本発明の化合物がヒトVEGFA165誘導による増殖を無効化する能力を、ヒトECFC(内皮コロニー形成細胞、臍帯血内皮前駆細胞由来)で測定した。VEGFA抗体と、無関係のヒトIgG4 PAA抗体とを、陽性対照および陰性対照として含めた。
インビボにおけるVEGFA−Ang2二重特異性分子、例えば化合物Aによる病理学的血管新生の抑制を、マウス網膜の酸素誘発性網膜症モデルで測定する。アッセイを使用して、本発明の化合物が、マウス網膜の病理学的血管新生を抑制する能力を試験する。
インビトロにおけるVEGFA誘導性の索状形成の阻害をインビトロ共培養系で測定する。アッセイを使用して、本発明の化合物によるVEGFA誘導性の索状形成の阻害を測定する。
本発明の化合物の有効性をインビボ異種移植モデルにより測定する。親VEGFA抗体、化合物A、およびその併用の抗腫瘍効果を、トリプルネガティブ患者由来の乳癌皮下移植モデル(EL1997)および卵巣異種移植皮下モデル(SKOV3x.1)で評価する。腫瘍担持マウスを、PBSで希釈した化合物を週2回腹腔内注射して処置する。処置期間中、週2回、腫瘍容量の三次元カリパス測定を行って腫瘍増殖を決定する。
アミノ酸およびヌクレオチド配列
配列番号1(抗体のHCVR−化合物A)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPSDSSSWYFAFDIWGQGTTVTVSS
配列番号2(抗体のHC−化合物A)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPSDSSSWYFAFDIWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
配列番号3(抗体のHC/リンカー/scFvポリペプチド−化合物A)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDPSDSSSWYFAFDIWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYSFTDYNMVWVRQAPGQCLEWMGYIDPYNGGTGYNQKFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARTRDRYDVWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCKASQDVYIAVAWYQQKPGKAPKLLIYWASTRDTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYSSYPPTFGCGTKVEIK
配列番号4(抗体のLCVR−化合物A)
DIVMTQSPATLSVSPGQRATLSCRASQNIRNNLAWYQQKRGQAPRLLIYGASTRATGIPDRFSGSGSGADFTLTISKLEPEDFAVYYCQQYGSSPRTFGQGTKVDIK
配列番号5(抗体のLC−化合物A)
DIVMTQSPATLSVSPGQRATLSCRASQNIRNNLAWYQQKRGQAPRLLIYGASTRATGIPDRFSGSGSGADFTLTISKLEPEDFAVYYCQQYGSSPRTFGQGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号6(scFvポリペプチド−化合物A)
QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYNMVWVRQAPGQCLEWMGYIDPYNGGTGYNQKFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARTRDRYDVWYFDVWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSVSASVGDRVTITCKASQDVYIAVAWYQQKPGKAPKLLIYWASTRDTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYSSYPPTFGCGTKVEIK
配列番号7(scFvポリペプチドのHCVR−化合物A)
QVQLVQSGAEVKKPGASVKVSCKASGYSFTDYNMVWVRQAPGQCLEWMGYIDPYNGGTGYNQKFEGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARTRDRYDVWYFDVWGQGTLVTVSS
配列番号8(scFvポリペプチドのLCVR−化合物A)
DIQMTQSPSSVSASVGDRVTITCKASQDVYIAVAWYQQKPGKAPKLLIYWASTRDTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQYSSYPPTFGCGTKVEIK
配列番号9(抗体重鎖/リンカー/scFvポリペプチド−化合物AのDNA)
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGGTAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCAAGAGATCCCTCGGATAGCAGCAGCTGGTACTTTGCTTTTGATATCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCCTCTACCAAGGGCCCATCGGTCTTCCCGCTAGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGGCCGCCGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAAAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTGGCGGAGGCTCCGGGGGAGGGGGTAGCGGAGGAGGGGGATCCCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGTTACTCATTCACTGACTACAACATGGTGTGGGTGCGACAGGCCCCTGGACAATGCCTTGAGTGGATGGGATATATTGATCCTTACAATGGTGGTACTGGCTACAACCAGAAGTTCGAGGGCAGAGTCACCATGACCACAGACACATCCACGAGCACAGCCTACATGGAGCTGAGGAGCCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAACGAGGGATAGGTACGACGTCTGGTACTTCGATGTCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGAGGCGGAGGTTCCGGGGGAGGGGGCAGCGGAGGAGGCGGATCGGGCGGAGGAGGAAGTGGAGGCGGAGGATCTGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTAAGGCCAGTCAGGATGTGTATATTGCTGTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTGGGCATCCACCCGGGACACTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTACTATTGTCACCAATATAGCAGCTATCCTCCTACGTTCGGCTGCGGGACCAAGGTGGAGATCAAA
配列番号10(抗体軽鎖−化合物AのDNA)
GATATTGTGATGACTCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGCAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAAAATATTAGGAATAACTTAGCCTGGTACCAGCAGAAACGTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCGTCCACTCGGGCCACAGGTATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGGCGGACTTCACTCTCACCATCAGCAAACTGGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAATATGGTAGCTCACCTCGGACGTTCGGCCAAGGGACCAAAGTGGATATCAAAAGAACTGTGGCGGCGCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCCGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC
配列番号11(ヒトVEGFA165)
APMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNKCECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR
配列番号12(ヒトAng2)
YNNFRKSMDSIGKKQYQVQHGSCSYTFLLPEMDNCRSSSSPYVSNAVQRDAPLEYDDSVQRLQVLENIMENNTQWLMKLENYIQDNMKKEMVEIQQNAVQNQTAVMIEIGTNLLNQTAEQTRKLTDVEAQVLNQTTRLELQLLEHSLSTNKLEKQILDQTSEINKLQDKNSFLEKKVLAMEDKHIIQLQSIKEEKDQLQVLVSKQNSIIEELEKKIVTATVNNSVLQKQQHDLMETVNNLLTMMSTSNSAKDPTVAKEEQISFRDCAEVFKSGHTTNGIYTLTFPNSTEEIKAYCDMEAGGGGWTIIQRREDGSVDFQRTWKEYKVGFGNPSGEYWLGNEFVSQLTNQQRYVLKIHLKDWEGNEAYSLYEHFYLSSEELNYRIHLKGLTGTAGKISSISQPGNDFSTKDGDNDKCICKCSQMLTGGWWFDACGPSNLNGMYYPQRQNTNKFNGIKWYYWKGSGYSLKATTMMIRPADF
配列番号13
GGGGSGGGGS
配列番号14
GGGGSGGGGSGGGGS
配列番号15
GGGGSGGGGSGGGGSGGGGS
配列番号16
GGGGSGGGGSGGGGSGGGGSGGGGS
配列番号17
GGGSGGGGSGGGGS
本発明は、以下の態様を含む。
[1]
2つの単鎖可変領域(scFv)ポリペプチドに対し2つのリンカーにより融合している抗体を含む化合物であって、
a)前記抗体は、同一重鎖(HC)2本および同一軽鎖(LC)2本を含み、ここで、各重鎖は、アミノ酸配列が配列番号1に示される重鎖可変領域(HCVR)を含み、各軽鎖は、アミノ酸配列が配列番号4に示される軽鎖可変領域(LCVR)を含み、
b)前記2つのscFvポリペプチドは同一であり、それぞれが、LCVRに機能的に結合したHCVRを含み、ここで、各HCVRは、配列番号7に示されるアミノ酸配列を有し、各LCVRは、配列番号8に示されるアミノ酸配列を有し、かつ
c)前記2つのリンカーは、グリシンに富む同一リンカーであり、それぞれが、前記抗体の1本のHCのカルボキシ末端と、前記scFvポリペプチドの一方のアミノ末端とを機能的に結合する、前記化合物。
[2]
前記2つのscFvポリペプチドは、それぞれが、1つのscFvポリペプチドのLCVRのアミノ末端に機能的に結合した1つのscFvポリペプチドのHCVRのカルボキシ末端を含む、[1]に記載の化合物。
[3]
前記抗体は、重鎖(HC)を2本および軽鎖(LC)を2本含み、各HCは配列番号2のうちの1つに示されるアミノ酸配列を有し、各LCは配列番号5のうちの1つに示されるアミノ酸配列を有する、[1]または[2]に記載の化合物。
[4]
各scFvポリペプチドは、配列番号6に示される同一アミノ酸配列を有する、[1]〜[3]のいずれか一項に記載の化合物。
[5]
2つの第1のポリペプチドおよび2つの第2のポリペプチドを含む化合物であって、前記第1のポリペプチドの各々は配列番号3のアミノ酸配列を有し、前記第2のポリペプチドの各々は配列番号5のアミノ酸配列を有する、前記化合物。
[6]
前記第1のポリペプチドの各々は前記第2のポリペプチドの各々と鎖間ジスルフィド結合を形成し、前記第1のポリペプチドは、もう一方の第1のポリペプチドと2つの鎖間ジスルフィド結合を形成し、かつ前記第1のポリペプチドの各々は7つの鎖内ジスルフィド結合を形成する、[5]に記載の化合物。
[7]
配列番号3に示される第1のポリペプチドをコードするポリヌクレオチド配列と、配列番号5に示される第2のポリペプチドをコードするポリヌクレオチド配列とを含むDNA分子を含む哺乳類の細胞であって、前記第1のポリペプチドと前記第2のポリペプチドとを含む化合物を発現する能力がある、前記哺乳類細胞。
[8]
配列番号3に示される2つの第1のポリペプチドおよび配列番号5に示される2つの第2のポリペプチドを含む化合物を作製するプロセスであって、前記化合物が発現するような条件下で[7]に記載の哺乳類細胞を培養すること、および前記発現した化合物を回収することを含む、前記プロセス。
[9]
[8]に記載のプロセスによって得ることができる、化合物。
[10]
[1]〜[6]のいずれか一項に記載の化合物、および許容される担体、希釈剤、または賦形剤を含む、医薬組成物。
[11]
[1]〜[6]のいずれか一項に記載の化合物の有効量を、それを必要とする患者に投与することを含む、癌を治療する方法。
[12]
前記癌は、乳癌、肺癌、卵巣癌、胃癌、大腸癌、または肝細胞癌である、[11]に記載の方法。
[13]
[1]〜[6]のいずれか一項に記載の化合物の有効量を、それを必要とする患者に投与することを含む、増殖性網膜症を治療する方法。
[14]
前記増殖性網膜症は、糖尿病網膜症、または未熟児網膜症である、[13]に記載の方法。
[15]
[1]〜[6]のいずれか一項に記載の化合物の有効量を、それを必要とする患者に投与することを含む、眼内血管新生性疾患を治療する方法。
[16]
前記眼内血管新生性疾患は、血管新生緑内障、加齢黄斑変性症、糖尿病黄斑浮腫、角膜血管新生、角膜移植片血管新生、角膜移植片拒絶、網膜/脈絡膜血管新生、隅角の血管新生(ルベオーシス)、眼内血管新生性疾患、血管再狭窄、または動静脈奇形(AVM)である、[15]に記載の方法。
[17]
治療で使用するための、[1]〜[6]のいずれか一項に記載の化合物。
[18]
癌の治療で使用するための、[1]〜[6]のいずれか一項に記載の化合物。
[19]
前記癌は、乳癌、肺癌、卵巣癌、胃癌、大腸癌、または肝細胞癌である、[18]の使用のための化合物。
[20]
増殖性網膜症の治療で使用するための、[1]〜[6]のいずれか一項に記載の化合物。
[21]
前記増殖性網膜症は、糖尿病網膜症、または未熟児網膜症である、[20]の使用のための化合物。
[22]
眼内血管新生性疾患の治療で使用するための、[1]〜[6]のいずれか一項に記載の化合物。
[23]
前記眼内血管新生性疾患は、血管新生緑内障、加齢黄斑変性症、糖尿病黄斑浮腫、角膜血管新生、角膜移植片血管新生、角膜移植片拒絶、網膜/脈絡膜血管新生、隅角の血管新生(ルベオーシス)、眼内血管新生性疾患、血管再狭窄、または動静脈奇形(AVM)である、[22]の使用のための化合物。
Claims (10)
- 2つの第1のポリペプチドおよび2つの第2のポリペプチドを含む化合物であって、前記第1のポリペプチドの各々は配列番号3のアミノ酸配列を有し、前記第2のポリペプチドの各々は配列番号5のアミノ酸配列を有し、前記第1のポリペプチドの各々は前記第2のポリペプチドの各々とHC領域において鎖間ジスルフィド結合を形成し、前記第1のポリペプチドは、もう一方の第1のポリペプチドと2つの鎖間ジスルフィド結合を形成する、前記化合物。
- 前記第1のポリペプチドの各々は7つの鎖内ジスルフィド結合を形成する、請求項1に記載の化合物。
- 請求項1〜2のいずれか一項に記載の化合物、および許容される担体、希釈剤、または賦形剤を含む、医薬組成物。
- 医薬品の製造で使用するための、請求項1〜2のいずれか一項に記載の化合物。
- 癌治療用医薬品の製造で使用するための、請求項1〜2のいずれか一項に記載の化合物。
- 前記癌は、乳癌、肺癌、卵巣癌、胃癌、大腸癌、または肝細胞癌である、請求項5の使用のための化合物。
- 増殖性網膜症の治療用医薬品の製造で使用するための、請求項1〜2のいずれか一項に記載の化合物。
- 前記増殖性網膜症は、糖尿病網膜症、または未熟児網膜症である、請求項7の使用のための化合物。
- 眼内血管新生性疾患の治療用医薬品の製造で使用するための、請求項1〜2のいずれか一項に記載の化合物。
- 前記眼内血管新生性疾患は、血管新生緑内障、加齢黄斑変性症、糖尿病黄斑浮腫、角膜血管新生、角膜移植片血管新生、角膜移植片拒絶、網膜/脈絡膜血管新生、隅角の血管新生(ルベオーシス)、眼内血管新生性疾患、血管再狭窄、または動静脈奇形(AVM)である、請求項9の使用のための化合物。
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CN109863171B (zh) | 2016-08-23 | 2023-08-04 | 免疫医疗有限公司 | 抗vegf-a和抗ang2抗体及其用途 |
JP7005772B2 (ja) * | 2018-02-06 | 2022-02-10 | エフ.ホフマン-ラ ロシュ アーゲー | 眼科疾患の処置 |
EP3775267A4 (en) * | 2018-04-10 | 2022-05-18 | Askgene Pharma, Inc. | NEW DUAL ANTAGONISTS OF VEGF AND ANGIOPOIETIN 2 |
CN109053895B (zh) * | 2018-08-30 | 2020-06-09 | 中山康方生物医药有限公司 | 抗pd-1-抗vegfa的双功能抗体、其药物组合物及其用途 |
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JP5179373B2 (ja) | 2005-12-15 | 2013-04-10 | アストラゼネカ アクチボラグ | 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 |
US8268314B2 (en) * | 2008-10-08 | 2012-09-18 | Hoffmann-La Roche Inc. | Bispecific anti-VEGF/anti-ANG-2 antibodies |
US8703132B2 (en) * | 2009-06-18 | 2014-04-22 | Hoffmann-La Roche, Inc. | Bispecific, tetravalent antigen binding proteins |
TWI426920B (zh) * | 2010-03-26 | 2014-02-21 | Hoffmann La Roche | 雙專一性、雙價抗-vegf/抗-ang-2抗體 |
TW201138821A (en) | 2010-03-26 | 2011-11-16 | Roche Glycart Ag | Bispecific antibodies |
US20120100166A1 (en) | 2010-07-15 | 2012-04-26 | Zyngenia, Inc. | Ang-2 Binding Complexes and Uses Thereof |
US9527925B2 (en) | 2011-04-01 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Bispecific binding molecules binding to VEGF and ANG2 |
EA032192B1 (ru) * | 2012-07-13 | 2019-04-30 | Роше Гликарт Аг | Биспецифическое антитело к vegf/ang-2, нуклеиновая кислота, кодирующая это антитело, вектор, содержащий нуклеиновую кислоту, клетка-хозяин, способ получения биспецифического антитела и содержащая его фармацевтическая композиция |
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WO2016016299A1 (en) * | 2014-07-29 | 2016-02-04 | F. Hoffmann-La Roche Ag | Multispecific antibodies |
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EP3250597A1 (en) | 2017-12-06 |
MA41424A (fr) | 2017-12-05 |
WO2016122996A1 (en) | 2016-08-04 |
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