JP2022521529A - Cd44標的化マルチアームコンジュゲート - Google Patents
Cd44標的化マルチアームコンジュゲート Download PDFInfo
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- JP2022521529A JP2022521529A JP2021549200A JP2021549200A JP2022521529A JP 2022521529 A JP2022521529 A JP 2022521529A JP 2021549200 A JP2021549200 A JP 2021549200A JP 2021549200 A JP2021549200 A JP 2021549200A JP 2022521529 A JP2022521529 A JP 2022521529A
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
Abstract
Description
によって表され得る。
構造式(I)において、「R」は、1~100個の原子を有する有機コア基である。好ましくは、Rは、3~50個の原子を含有し、より好ましくは、Rは、約3~30個の原子を含有する。Rは、全ての原子が炭素原子であるコア基であり得るか、又は使用される具体的な中心分子に応じて、O、S、N及びPなど、1個以上のヘテロ原子を選択的に含有し得る。Rは、直鎖、分枝又は環状コア基であり得、少なくとも3つの独立したポリマー分岐鎖を有する。構造式(I)において、「q」は、「R」のポリマー分岐鎖の数に対応する数である。
構造式(I)において、「POLY」は、ポリマー、好ましくは水溶性ポリマーであり、本発明のコンジュゲートの形成には、任意の水溶性ポリマーを使用することができる。本発明のポリマーは、任意の幾何学的形状又は形態であり得る。代表的なポリマーとしては、限定はされないが、ポリエチレングリコール、ポリプロピレングリコール、ポリ(ビニルピロリドン)、ポリ(メタクリル酸ヒドロキシアルキルアミン)、ポリ(メタクリル酸ヒドロキシアルキル)、ポリ(サッカライド)、ポリ(α-ヒドロキシ酸)、ポリ(アクリル酸)、ポリ(酢酸ビニル)、ポリホスファジン、ポリオキサゾリン及びポリ(N-アクリロイルモルホリン)が挙げられる。
Ac-KPSSPPEE-NH2;Ac-NASAPPEE-NH2;QETWFQNGWQGKNP;KEKWFENEWQGKNP;KEQWFGNRWHEGYR;及びQIRQQPRDPPTETLELEVSPDPAS。
を含む。
である。
活性薬剤Dを多価リンカーLに連結してD-L部分を得ること;
D-L部分をマルチアームポリマー
を含む。
250ml三つ口フラスコに18.20gの化合物BP103a05及び100mlのEAを加え;この化合物を撹拌しながら溶解させて、次に混合物を0℃に冷却し;150mlのHCl/EA(3.5M)を加え、温度を0℃に維持し;TLCにより反応が完了したことが検出された後、反応液を濃縮乾固し、メチルtert-ブチルエーテルを加えることによりスラリー化してろ過し;及びろ過ケーキをTBMEで洗浄し、真空乾燥させて、10.40gのBP103aを白色固体として得た。
100mLフラスコに3.00gのBP103a(1.0当量)、4.02g(1.0当量)のBP102c07、40mlのDCM及び4.0mlのDIEA(2.0当量)を加え、この混合物を室温で撹拌し;TLCにより反応が完了したことが検出された後、有機溶媒を蒸発除去し;及び残渣をカラムクロマトグラフィーに供して6.4gのBP103a07を油として得た。
200ml三つ口フラスコに9.00gのBP103a07(1.0当量)、3.96gのHOSU(1.53当量)、90mlのDCM及び6.60gのEDC・HCl(1.53当量)を加え、室温で2時間反応させ;及びTLCにより反応が完了したことが検出された後、混合物をDCMで希釈し、次に50mmol/Lのリン酸二水素カリウム水溶液で2回洗浄し、飽和ブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、濃縮して、5.93gのBP103a08を無色の油として得た。
200mLフラスコに2.93gの化合物NH2-Lys(Boc)-OH・HCl(1.0当量)、60mlの水及び2.00gのNaHCO3(2.0当量)を加え;60mlのDME中5.91gのBP103a08(1.0当量)の溶液を撹拌しながら滴下して加え;60mlのTHFを補足し;この混合物を一晩撹拌し;TLCにより反応が完了したことが検出された後、有機溶媒を蒸発除去し;及び残渣を希塩酸でpH≒3に調整し、EAで抽出し、無水硫酸ナトリウムで乾燥させ、濃縮して、4.50gのBP103a30を無色の油として得た。
100ml三つ口フラスコに5.00gのBP103a30(1.0当量)、1.40gのHOSU(1.53当量)、50mlのDCM及び2.33gのEDC・HCl(1.53当量)を加え、室温で2時間反応させ;及びTLCにより反応が完了したことが検出された後、混合物をDCMで希釈し、次に50mmol/Lのリン酸二水素カリウム水溶液で2回洗浄し、飽和ブラインで洗浄し、無水硫酸ナトリウムで乾燥させ、濃縮して、4.89gのBP103a31を無色の油として得た。
250mL丸底フラスコに3.50gの塩酸イリノテカン三水和物(1.0当量)及び52.5mlのDMFを加え、60℃に加熱してそれを溶解させ;5~10分後、DMFを減圧下で蒸発除去し;300mlのn-ヘプタンを加え、混合物を減圧下で3回蒸留し、ロータリーエバポレーターにかけ;次に、105mlのDCM、1.08gのBoc-Gly-OH(1.2当量)及び63mgのDMAP(0.1当量)を加え;10mlのDCM中1.59gのDCC(1.5当量)の溶液を滴下して加え、混合物を20℃で4時間反応させ;TLCにより反応が完了したことが検出された後、混合物をろ過し、元の容積の25%に濃縮し、120mlのIPAを加え;溶媒の75%を蒸発除去し;及び150mlのn-ヘプタンを加え、混合物を室温で1時間撹拌し、ろ過し、n-ヘプタンで2回洗浄し、乾燥させて、4.02gのBP143b02を淡黄色固体として得た。
100ml三つ口フラスコに4.02gのBP143b02及び50mlのDCMを加え、この化合物を撹拌しながら溶解させ;次に11.6mlのTFAを滴下して加え、混合物を室温で2時間反応させ;TLCにより反応が完了したことが検出された後、150mlのアセトニトリルを加え;120mlの溶媒を減圧下で留去し、残渣を320mlのTBME溶液に注入し;この混合物を30分間撹拌し、ろ過し;及びろ過ケーキをTBMEで洗浄して、4.00gのBP143b03を淡黄色固体として得た。
200ml三つ口フラスコに3.69gのBP143b03、100mlのDCM、3.21g(1.05当量)のBP103a30、2.7mlのDIEA(3.0当量)及び1.2mlのDEPC(1.5当量)を加え、室温で1時間反応させ;TLCにより反応が完了したことが検出された後、混合物をDCMで希釈し、次に水で2回洗浄し、飽和ブラインで1回洗浄し、乾燥させて、濃縮し、HPLCにより精製し、次に凍結乾燥して、1.85gのBP143b04を淡黄色固体として得た。
50mL丸底フラスコに1.20gのBP143b04及び10mlの10%TFA/DCMを加え、室温で反応させ;TLCにより反応が完了したことが検出された後、得られた生成物をTBMEに注入し、この混合物を遠心し、乾燥させて、210mgの化合物BP143b05を淡黄色固体として得た。
10mL丸底フラスコに51mgのBP143b05(4.0当量)、2mlのDCM、11ulのTEA(8.0当量)及び201mgの4アームPEG20K-SCM(1.0当量)を加え、室温で一晩反応させて濃縮し;得られた生成物をTBMEに加え、混合物を遠心し、分取HPLCにより精製し、凍結乾燥して、85mgの化合物BP143b06を黄色がかった緑色の固体として得た。
100ml三つ口フラスコに10.00gの化合物SN38(1.0当量)及び110mlのDMSOを加え;化合物が溶解して澄明な溶液が生じた後、5.56gの(Boc)2O(1.0当量)及び9.82gのDIEA(3.0当量)を加え、混合物を2時間反応させ;TLCにより反応が完了したことが検出された後、反応液を精製水に注入し、この混合物を酢酸エチルで3回抽出し;有機相を合わせ、精製水及び飽和ブラインで洗浄し、無水硫酸ナトリウムで乾燥させると、オフホワイトの固体が得られ、これを、メチルtert-ブチルエーテルを加えることによりスラリー化し、ろ過し、乾燥させて、7.95gの化合物BP149a01をオフホワイトの固体として得た。
250mL丸底フラスコに7.95gの化合物BP149a01(1.0当量)、2.83gのBoc-Gly-OH(1.0当量)、80mlのジクロロメタン及び390mgのDMAP(0.2当量)を加え;20mlのDCM中5.00gのDCC(1.5当量)の溶液を滴下して加え、混合物を室温で1時間反応させ;TLCにより反応が完了したことが検出された後、混合物をろ過し、液体が全て蒸発するまで濃縮し;30mlのIPAを加えて溶解させることにより澄明な溶液を生じさせ、次に200mlのn-ヘプタンを加え;及びこの混合物を30分間撹拌してスラリー化し、ろ過し、n-ヘプタンで2回洗浄し、乾燥させて、8.73gの化合物BP149a02を淡黄色固体として得た。
100ml三つ口フラスコに8.73gの化合物BP149a02及び40mlのDCMを加え;この化合物を撹拌しながら溶解させて、次に混合物を0℃に冷却し;40mlのTFAを滴下して加え、混合物を室温で2時間反応させ;TLCにより反応が完了したことが検出された後、反応液を800mlのTBME溶液に注入し、この混合物を30分間撹拌し、ろ過し;及びろ過ケーキをTBMEで洗浄し、真空乾燥させて、4.95gのBP149a03を淡黄色固体として得た。
200ml三つ口フラスコに2.3gの化合物BP149a03、45mlのDCM、3.196gの化合物BP103a31(1.05当量)及び1.75mlのTEA(3.0当量)を加え、室温で4時間反応させ;TLCにより反応が完了したことが検出された後、混合物をDCMで希釈し、希塩酸で1回洗浄し、水で2回洗浄し、飽和ブラインで1回洗浄し、無水硫酸ナトリウムで乾燥させて濃縮すると、粗製生成物が得られ、これを分取HPLCにより精製し、DCMで抽出し、無水硫酸ナトリウムで乾燥させて、濃縮し、乾燥させて、2.20gのBP149b01を淡黄色固体として得た。
200ml三つ口フラスコに2.0gの化合物BP149b01及び40mlの10%TFA/DCMを加え、室温で反応させ;TLCにより反応が完了したことが検出された後、得られた生成物をTBMEに注入し、この混合物を遠心し、乾燥させて、1.75gのBP149b02を淡黄色固体として得た。
200ml三つ口フラスコに4.08gの化合物BP149b02(5.0当量)、100mlのDMF、1.96gのDIEA(20当量)及び16.05gの4アームPEG20K-SCM(1.0当量)を加え、室温で2時間反応させて、得られた生成物を1Lのメチルtert-ブチルエーテルに注入し;この混合物を30分間撹拌し、次にろ過し、乾燥させると、20.50gの粗製生成物がオフホワイトの固体として得られ、これを分取HPLCにより精製し、凍結乾燥して、12.36gの純粋なBP149b03を得た。
1.材料及び方法
1.1 本発明の化合物のビオチン標識コンジュゲート
化合物a-ビオチンコンジュゲート、化合物b-ビオチンコンジュゲート、化合物c-ビオチンコンジュゲート及び化合物d-ビオチンコンジュゲートは、実験ではそれぞれコンジュゲートa、コンジュゲートb、コンジュゲートc及びコンジュゲートdと称され、その構造及びその調製方法は、実施例10~15に示されるとおりである。
SKOV3細胞をMcCoy 5A培養液で培養した。細胞培養液に10%のFBS、1000U/mLのペニシリン、100μg/mLのストレプトマイシン及び4mmol/L L-グルタミンを補足した。
コンジュゲートa、コンジュゲートb、コンジュゲートc及びコンジュゲートd(それぞれ100μmol/Lの濃度が実現するように氷冷PBSに溶解させた)に5mmol/Lのスベリン酸ビス(スルホスクシンイミド)を加えて、コンジュゲートをSKOV3細胞に結合させた。Triton X-100溶解緩衝液を加え;細胞を溶解させて、次に遠心し;及び上清をポリフッ化ビニリデン(PVDF)膜に転写し、ウエスタンブロット分析に供した。PVDF膜を西洋ワサビペルオキシダーゼコンジュゲートストレプトアビジン(HRP-SA)と共にインキュベートし、コンジュゲートと架橋したタンパク質を検出した。抗CD44モノクローナル抗体DF1485及びペルオキシダーゼ標識ロバ抗マウス免疫グロブリンを使用したウエスタンブロットによりCD44を検出した。検出には、配合したての化学発光試薬及びHypermax ECLフィルム露光を用いた。
コンジュゲートと架橋したSKOV3細胞をTriton X-100によって溶解し、プロテインAセファロースと共に室温で2時間インキュベートし、予洗し;100μgの洗浄後の溶解緩衝液を、2μgのDF1485(抗CD44抗体)又はマウスIgG1を補足した20μLのプロテインAセファロースと共に室温で一晩インキュベートした。溶解緩衝液で5回洗浄した後、混合物をSDS-PAGE負荷緩衝液中で煮沸し、免疫沈降したタンパク質をプロテインAセファロースから溶出させた。溶出した材料及び5μgの初期材料をSDS-PAGEに加え、PVDF膜に転写し、次にHRP-SAで染色した。
SKOV3細胞は、コンジュゲートに結合する。この細胞から調製したライセートをDF1485で免疫沈降させた。溶出したタンパク質及び初期ライセートをPAGE/ブロッティングに供し、ここで、それぞれHRP-SA染色を用いてビオチン標識を検出し、DF1485染色を用いてCD44を検出した。
を参照することができ、ここで、%T/C≦40%及び統計的分析によるP<0.05は、有効であることの指標である。相対腫瘍増殖速度が低いほど、抗腫瘍効果が高い。
試験試料:化合物M、化合物a、化合物b、化合物c及び化合物d。
試験試料:化合物M、化合物a、化合物b、化合物c及び化合物d。
試験試料:化合物M、化合物a、化合物b、化合物c及び化合物d。
試験試料:化合物M、化合物a、化合物b、化合物c及び化合物d。
試験試料:イリノテカン、nktr-102、化合物a、化合物b、化合物c及び化合物d。
Claims (17)
- 構造式(I):
によって表されるカンプトテシン系薬物であり;及び
Tは、CD44標的化ポリペプチドである)
の多分岐薬物コンジュゲート又はその薬学的に許容可能な塩。 - 請求項1に記載の多分岐薬物コンジュゲート又はその薬学的に許容可能な塩
によって表されるカンプトテシン系薬物であり;及び
Tは、CD44標的化ポリペプチドである)。 - POLYは、ポリエチレングリコール、ポリプロピレングリコール、ポリ(ビニルピロリドン)、ポリ(メタクリル酸ヒドロキシアルキルアミン)、ポリ(メタクリル酸ヒドロキシアルキル)、ポリ(サッカライド)、ポリ(α-ヒドロキシ酸)、ポリ(アクリル酸)、ポリ(酢酸ビニル)、ポリホスファジン、ポリオキサゾリン又はポリ(N-アクリロイルモルホリン)である、請求項1又は2に記載の多分岐薬物コンジュゲート又はその薬学的に許容可能な塩。
- Dは、イリノテカン又はSN38である、請求項6に記載の多分岐薬物コンジュゲート又はその薬学的に許容可能な塩。
- Tは、Ac-KPSSPPEE-NH2、Ac-NASAPPEE-NH2、ヒアルロン酸(HA)、オステオポンチン(OPN)、セルグリシン、コラーゲン、フィブロネクチン、ラミニン、コンドロイチン硫酸C(CSC)、ヘパラン硫酸(HS)、アンキリン、ガレクチン-3、L-セレクチン、P-セレクチン、C型レクチン又はアドレシンである、請求項1~7のいずれか一項に記載の多分岐薬物コンジュゲート又はその薬学的に許容可能な塩。
- Tは、Ac-KPSSPPEE-NH2又はAc-NASAPPEE-NH2並びにその置換変異体、付加変異体及び化学修飾誘導体である、請求項1~7のいずれか一項に記載の多分岐薬物コンジュゲート又はその薬学的に許容可能な塩。
- 化合物a、化合物b、化合物c及び化合物dの塩酸塩であって、各分岐鎖は、それぞれ塩酸の1つ又は2つの分子に結合されている、塩酸塩;又は化合物a、化合物b、化合物c及び化合物dの酢酸塩であって、各分岐鎖は、それぞれ酢酸の1つ又は2つの分子に結合されている、酢酸塩である、請求項11に記載の多分岐薬物コンジュゲート又はその薬学的に許容可能な塩。
- CD44の高発現を有する腫瘍を治療するための薬物の調製における、請求項1~12のいずれか一項に記載の多分岐薬物コンジュゲートの使用。
- 前記CD44の高発現を有する腫瘍は、胃癌、膵癌、小細胞肺癌、結腸癌、乳癌、肺腺癌、肝癌、上咽頭癌、悪性神経膠腫、リンパ腫、腎癌、卵巣癌、頭頸部癌及び扁平上皮癌から選択される、請求項13に記載の使用。
- 請求項1~12のいずれか一項に記載の多分岐薬物コンジュゲート又は薬学的に許容可能な塩と、薬学的に許容可能な賦形剤とを含む医薬組成物。
- CD44の高発現を有する腫瘍を治療するための薬物の調製における、請求項15に記載の組成物の使用。
- 前記CD44の高発現を有する腫瘍は、胃癌、膵癌、小細胞肺癌、結腸癌、乳癌、肺腺癌、肝癌、上咽頭癌、悪性神経膠腫、リンパ腫、腎癌、卵巣癌、頭頸部癌及び扁平上皮癌から選択される、請求項16に記載の使用。
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JP2014514330A (ja) * | 2011-04-29 | 2014-06-19 | ケーシーアイ ライセンシング インク | 創傷環境における治療因子の結合のためのアプタマー変性高分子材料 |
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AU2020226475B2 (en) | 2023-02-16 |
KR20210107083A (ko) | 2021-08-31 |
JP7353378B2 (ja) | 2023-09-29 |
CA3126574A1 (en) | 2020-08-27 |
AU2020226475A1 (en) | 2021-08-05 |
TW202031296A (zh) | 2020-09-01 |
WO2020169004A1 (zh) | 2020-08-27 |
EP3928797A1 (en) | 2021-12-29 |
TW202142263A (zh) | 2021-11-16 |
CN111603567A (zh) | 2020-09-01 |
EP3928797A4 (en) | 2022-04-13 |
TWI792468B (zh) | 2023-02-11 |
TWI771652B (zh) | 2022-07-21 |
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