JP6484607B2 - アフィニティー樹脂を使用するadcの合成方法 - Google Patents
アフィニティー樹脂を使用するadcの合成方法 Download PDFInfo
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- JP6484607B2 JP6484607B2 JP2016509554A JP2016509554A JP6484607B2 JP 6484607 B2 JP6484607 B2 JP 6484607B2 JP 2016509554 A JP2016509554 A JP 2016509554A JP 2016509554 A JP2016509554 A JP 2016509554A JP 6484607 B2 JP6484607 B2 JP 6484607B2
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- biomolecule
- antibody
- drug
- resin
- capture
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Classifications
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Description
[1]生体分子薬物複合体を合成する方法であって、
(i)生体分子と捕捉樹脂とを、生体分子を固定化するために適切な条件下で接触させ、それによって、固定化生体分子を提供し、該生体分子が抗体、改変抗体又は抗体断片であり、該捕捉樹脂が、(1)アミノ酸系、プロテインA、プロテインG又はプロテインL模倣体を含む非ペプチド系、(2)ペプチド系のプロテインA、プロテインG又はプロテインL模倣体、(3)ヌクレオチド結合部位捕捉部分及び(4)糖タンパク質捕捉部分、からなる群から選択される生体分子捕捉部分を含む工程、
(ii)場合により、固定化生体分子と化学的改変剤又は活性化剤とを接触させて、化学的に改変された、又は活性化された固定化生体分子を提供する工程、
(iii)固定化生体分子又は化学的に改変された、若しくは活性化された固定化生体分子と、薬物成分とを接触させて、生体分子薬物複合体を形成する工程、
(iv)生体分子薬物複合体を捕捉樹脂から放出する工程
を含む方法。
[2]工程(i)が、生体分子と捕捉樹脂とをインキュベートする工程を含む、上記[1]に記載の方法。
[3]インキュベーションが、約10から約40℃、場合により約15から約37℃の温度において実施される、上記[2]に記載の方法。
[4]インキュベーションが、約10分から約18時間の期間実施される、上記[2]又は上記[3]に記載の方法。
[5]インキュベーションが、バッファー溶液、場合によりリン酸緩衝生理食塩水(PBS)中で実施される、上記[2]から[4]のいずれかに記載の方法。
[6]インキュベーションが、約5から約8のpHにおいて実施される、上記[2]から[5]のいずれかに記載の方法。
[7]工程(i)の後で、固定化生体分子が洗浄され、捕捉樹脂に固定化されなかったすべての生体分子が除去される、上記[1]から[6]のいずれかに記載の方法。
[8]工程(ii)が、生体分子を還元する工程を伴う、上記[1]から[7]のいずれかに記載の方法。
[9]生体分子が、生体分子と還元剤、例えば、トリス(2−カルボキシエチル)ホスフィン(TCEP)、ジチオスレイトール(DTT)、メルカプトエチルアミン(merceptoethylamine)又は他の適切な還元剤とを接触させる工程により還元される、上記[8]に記載の方法。
[10]工程(ii)が、生体分子と架橋剤部分とを反応させる工程を伴い、場合により、上記架橋剤部分がスクシンイミジル4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)である、上記[1]から[7]のいずれかに記載の方法。
[11]工程(ii)が、バッファー溶液、例えばリン酸緩衝生理食塩水(PBS)中で実施される、上記[8]から[10]のいずれかに記載の方法。
[12]工程(ii)が、約7から約8のpHにおいて実施される、上記[8]から[11]のいずれかに記載の方法。
[13]工程(ii)が、キレート剤、例えばEDTAの存在下で実施される、上記[8]から[12]のいずれかに記載の方法。
[14]工程(ii)が、生体分子と還元剤とを、約6時間から約18時間の期間インキュベートする工程を伴う、上記[8]から[13]のいずれかに記載の方法。
[15]工程(ii)の後で、活性化された固定化生体分子が洗浄され、すべての改変剤/活性化剤が除去される、上記[1]から[14]のいずれかに記載の方法。
[16]工程(iii)が、化学的に改変された、又は活性化された固定化生体分子と薬物成分とを、バッファー溶液中で接触させる工程を伴う、上記[1]から[15]のいずれかに記載の方法。
[17]工程(iii)が、化学的に改変された、又は活性化された固定化生体分子と薬物成分とを、約7から約8、好ましくは約7.4のpHにおいて接触させる工程を伴う、上記[1]から[16]のいずれかに記載の方法。
[18]工程(iii)が、キレート剤、例えばEDTAの存在下で実施される、上記[1]から[17]のいずれかに記載の方法。
[19]工程(iii)が、化学的に改変された、又は活性化された固定化生体分子と薬物成分とを、約6時間から約18時間の期間インキュベートする工程を伴う、上記[1]から[18]のいずれかに記載の方法。
[20]工程(iii)の後で、固定化生体分子薬物複合体が洗浄され、すべての未反応の薬物成分が除去される、上記[1]から[19]のいずれかに記載の方法。
[21]工程(iv)が、pHを変更して、支持体−生体分子の結合を破壊する工程を伴う、上記[1]から[20]のいずれかに記載の方法。
[22]pHが、約pH5未満、場合により約pH3に低下される、上記[21]に記載の方法。
[23]溶出された生体分子薬物複合体が、捕捉樹脂から複合体を放出する工程の後で中和され、場合により、上記複合体が、2%v/vの1M トリス(ヒドロキシメチル)アミノエタン(TRIS)中に捕捉される、上記[21]又は[22]に記載の方法。
[24](i)(1)非ペプチド系プロテインA、プロテインG又はプロテインL模倣体、(2)ペプチド系プロテインA、プロテインG又はプロテインL模倣体、(3)ヌクレオチド結合部位捕捉部分、並びに(4)糖タンパク質捕捉部分からなる群から選択される、抗体、改変抗体又は抗体断片捕捉部分を含む、捕捉樹脂、並びに
(ii)化学的改変剤又は活性化剤
を含む混合物。
[25]捕捉樹脂が、固定化された抗体、改変抗体又は抗体断片をこれらの表面に含む、上記[24]に記載の混合物。
[26](1)非ペプチド系プロテインA、プロテインG又はプロテインL模倣体、(2)ペプチド系プロテインA、プロテインG又はプロテインL模倣体、(3)ヌクレオチド結合部位捕捉部分及び(4)糖タンパク質捕捉部分からなる群から選択される抗体、改変抗体又は抗体断片捕捉部分を含む捕捉樹脂の、生体分子薬物複合体の合成における使用。
[27]捕捉樹脂が非タンパク質性捕捉樹脂である、上記[1]から[26]のいずれかに記載の方法、混合物又は使用。
[28]捕捉樹脂の生体分子捕捉部分が、約1000Da以下の分子量を有する、上記[1]から[27]のいずれかに記載の方法、混合物又は使用。
[29]捕捉樹脂のリガンドが、構造:
を有する、上記[1]から[28]のいずれかに記載の方法、混合物又は使用。
[30]生体分子が抗体であり、場合により、上記抗体が、モノクローナル抗体である、及び/又は上記抗体がトラスツズマブである、上記[1]から[29]のいずれかに記載の方法、混合物又は使用。
[31]薬物が、チューブリン阻害剤又はDNA相互作用剤であり、場合により上記チューブリン阻害剤が、(a)オーリスタチン及び(b)メイタンシン誘導体からなる群から選択され、場合により、上記DNA相互作用剤が、(a)カリケアマイシン、(b)デュオカルマイシン及び(c)ピロロベンゾジアゼピン(PBD)からなる群から選択される、上記[1]から[30]のいずれかに記載の方法、混合物又は使用。
生体分子薬物複合体の合成方法:
(i)生体分子と捕捉樹脂とを、生体分子を固定化するために適切な条件下で接触させ、それによって、固定化生体分子を提供し、該生体分子が抗体、改変抗体又は抗体断片であり、該捕捉樹脂が、(1)アミノ酸系、プロテインA、プロテインG又はプロテインL模倣体を含む非ペプチド系、(2)ペプチド系のプロテインA、プロテインG又はプロテインL模倣体、(3)ヌクレオチド結合部位捕捉部分及び(4)糖タンパク質捕捉部分、からなる群から選択される生体分子捕捉部分を含む工程、
(ii)場合により、固定化生体分子と化学的改変剤又は活性化剤とを接触させて、化学的に改変された、又は活性化された固定化生体分子を提供する工程、
(iii)固定化生体分子又は化学的に改変された、若しくは活性化された固定化生体分子と、薬物成分とを接触させて、生体分子薬物複合体を形成する工程、
(iv)生体分子薬物複合体を捕捉樹脂から放出する工程、
を含む。
(i)生体分子と捕捉樹脂とを、生体分子を固定化するために適切な条件下で接触させ、それによって、固定化生体分子を提供し、該生体分子が抗体、改変抗体又は抗体断片であり、該捕捉樹脂が、(1)アミノ酸系、プロテインA、プロテインG又はプロテインL模倣体を含む非ペプチド系、(2)ペプチド系のプロテインA、プロテインG又はプロテインL模倣体、(3)ヌクレオチド結合部位捕捉部分及び(4)糖タンパク質捕捉部分、からなる群から選択される生体分子捕捉部分を含む工程、並びに
(ii)固定化生体分子と化学的改変剤又は活性化剤とを接触させて、化学的に改変された、又は活性化された固定化生体分子を提供する工程、
を含む。
1.媒体に添加された非天然アミノ酸
2.直交アミノアシル−tRNAシンセターゼ(aaRS)
3.直交tRNA
を発現系に包含することによって、非天然アミノ酸を異種タンパク質に組み込むプラットホームである。
a)支持体−生体分子化合物を放出剤に曝露する工程、及び/又は
b)pHを変更して、支持体−生体分子の結合を破壊する工程、
を伴う。
(i)(1)非ペプチド系プロテインA、プロテインG又はプロテインL模倣体、(2)ペプチド系プロテインA、プロテインG又はプロテインL模倣体、(3)ヌクレオチド結合部位捕捉部分及び(4)糖タンパク質捕捉部分、からなる群から選択される抗体、改変抗体又は抗体断片捕捉部分を含む捕捉樹脂、並びに
(ii)化学的改変剤又は活性化剤
を含む混合物が提供される。
1.高度な初期精製を可能にする、抗体に対する高い選択性
2.有用な動的結合能
3.抗体完全性の保持と適合性の溶出条件
4.複数の溶出/クリーニングサイクルの間の支持体の安定性
5.プロテインA、G又はL系支持体と比較して低コスト
であった。
固相抗体薬物複合体のスクリーニング
バッチモードの固相部分的TCEP還元
カラムにおける固相部分的TCEP還元
リジン側鎖のSMCC活性化を介した、バッチモードにおけるDM1との固相ハーセプチン複合体化
Claims (35)
- 生体分子薬物複合体を合成する方法であって、
(i)生体分子と、FAbsorbent F1P HF(商品名)樹脂、MAbsorbent A1P(商品名)樹脂、またはMAbsorbent A2P(商品名)樹脂、または前記生体分子のための捕捉部分を含む捕捉樹脂とを、前記生体分子を固定化するために適切な条件下で接触させ、それによって、固定化生体分子を提供する工程であって、前記捕捉部分が、
下記式の分枝型リガンド足場:
下記式の分枝型トリアジル足場:
(ii)場合により、前記固定化生体分子と化学的改変剤又は活性化剤とを接触させて、化学的に改変された、又は活性化された固定化生体分子を提供する工程、
(iii)前記固定化生体分子又は前記化学的に改変された、若しくは活性化された固定化生体分子と、薬物成分とを接触させて、固定化生体分子薬物複合体を形成する工程、
(iv)前記生体分子薬物複合体を前記捕捉樹脂から放出する工程を含む方法。 - 工程(i)が、前記生体分子と前記捕捉樹脂とをインキュベートする工程を含む、請求項1に記載の方法。
- 前記インキュベーションが、約10から約40℃、場合により約15から約37℃の温度において実施される、請求項2に記載の方法。
- 前記インキュベーションが、約10分から約18時間の期間実施される、請求項2又は請求項3に記載の方法。
- 前記インキュベーションが、バッファー溶液、場合によりリン酸緩衝生理食塩水(PBS)中で実施される、請求項2から4のいずれかに記載の方法。
- 前記インキュベーションが、約5から約8のpHにおいて実施される、請求項2から5のいずれかに記載の方法。
- 工程(i)の後で、前記固定化生体分子が洗浄され、前記捕捉樹脂に固定化されなかったすべての生体分子が除去される、請求項1から6のいずれかに記載の方法。
- 工程(ii)が、前記生体分子を還元する工程を伴う、請求項1から7のいずれかに記載の方法。
- 前記生体分子が、生体分子と還元剤、例えば、トリス(2−カルボキシエチル)ホスフィン(TCEP)、ジチオスレイトール(DTT)、メルカプトエチルアミン(merceptoethylamine)又は他の適切な還元剤とを接触させる工程により還元される、請求項8に記載の方法。
- 工程(ii)が、前記生体分子と架橋剤部分とを反応させる工程を伴い、場合により、前記架橋剤部分がスクシンイミジル4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)である、請求項1から7のいずれかに記載の方法。
- 工程(ii)が、バッファー溶液、例えばリン酸緩衝生理食塩水(PBS)中で実施される、請求項8から10のいずれかに記載の方法。
- 工程(ii)が、約7から約8のpHにおいて実施される、請求項8から11のいずれかに記載の方法。
- 工程(ii)が、キレート剤、例えばEDTAの存在下で実施される、請求項8から12のいずれかに記載の方法。
- 工程(ii)が、前記生体分子と前記還元剤とを、約6時間から約18時間の期間インキュベートする工程を伴う、請求項8から13のいずれかに記載の方法。
- 工程(ii)の後で、前記活性化された固定化生体分子が洗浄され、すべての改変剤/活性化剤が除去される、請求項1から14のいずれかに記載の方法。
- 工程(iii)が、前記化学的に改変された、又は活性化された固定化生体分子と薬物成分とを、バッファー溶液中で接触させる工程を伴う、請求項1から15のいずれかに記載の方法。
- 工程(iii)が、前記化学的に改変された、又は活性化された固定化生体分子と薬物成分とを、約7から約8、好ましくは約7.4のpHにおいて接触させる工程を伴う、請求項1から16のいずれかに記載の方法。
- 工程(iii)が、キレート剤、例えばEDTAの存在下で実施される、請求項1から17のいずれかに記載の方法。
- 工程(iii)が、前記化学的に改変された、又は活性化された固定化生体分子と薬物成分とを、約6時間から約18時間の期間インキュベートする工程を伴う、請求項1から18のいずれかに記載の方法。
- 工程(iii)の後で、前記固定化生体分子薬物複合体が洗浄され、すべての未反応の薬物成分が除去される、請求項1から19のいずれかに記載の方法。
- 工程(iv)が、pHを変更して、支持体−生体分子の結合を破壊する工程を伴う、請求項1から20のいずれかに記載の方法。
- pHが、約pH5未満、場合により約pH3に低下される、請求項21に記載の方法。
- 前記溶出された生体分子薬物複合体が、前記捕捉樹脂から前記複合体を放出する工程の後で中和され、場合により、前記複合体が、2%v/vの1M トリス(ヒドロキシメチル)アミノエタン(TRIS)中に捕捉される、請求項21又は22に記載の方法。
- (i)抗体、改変抗体、又は抗体断片が固定化された捕捉樹脂であって、前記捕捉樹脂がFAbsorbent F1P HF(商品名)樹脂、MAbsorbent A1P(商品名)樹脂、またはMAbsorbent A2P(商品名)樹脂、または前記生体分子のための捕捉部分を含む捕捉樹脂であり、前記捕捉部分が、
下記式の分枝型リガンド足場:
下記式の分枝型トリアジル足場:
- 前記還元剤が、トリス(2−カルボキシエチル)ホスフィン(TCEP)、ジチオスレイトール(DTT)、およびメルカプトエチルアミン(merceptoethylamine)からなる群から選択され、前記架橋剤部分が、スクシンイミジル4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)である、請求項24に記載の混合物。
- 前記捕捉樹脂が、その表面に固定化された、抗体、改変抗体、又は抗体断片を含む、請求項24または25に記載の混合物。
- 生体分子薬物複合体の合成における捕捉樹脂の使用であって、前記捕捉樹脂が、FAbsorbent F1P HF(商品名)樹脂、MAbsorbent A1P(商品名)樹脂、またはMAbsorbent A2P(商品名)樹脂、または前記生体分子のための捕捉部分を含む捕捉樹脂であり、前記捕捉部分が、
下記式の分枝型リガンド足場:
下記式の分枝型トリアジル足場:
- 前記捕捉樹脂の前記リガンドが、下記の構造:
- 前記生体分子が抗体であり、場合により、前記抗体が、モノクローナル抗体であり、および/または前記抗体がトラスツズマブである、請求項1〜23および請求項28のいずれか一項に記載の方法。
- 前記薬物が、チューブリン阻害剤またはDNA相互作用剤であり、場合により、前記チューブリン阻害剤が、(a)オーリスタチン、および(b)メイタンシン誘導体からなる群から選択され、場合により、前記DNA相互作用剤が、(a)カリケアマイシン、(b)デュオカルマイシン及び(c)ピロロベンゾジアゼピン(PBD)からなる群から選択される、請求項1〜23および請求項28〜29のいずれか一項に記載の方法。
- 前記捕捉樹脂の前記リガンドが、下記の構造:
- 前記生体分子が抗体であり、場合により、前記抗体が、モノクローナル抗体であり、および/または前記抗体がトラスツズマブである、請求項24〜26および請求項31のいずれか一項に記載の混合物。
- 前記捕捉樹脂の前記リガンドが、下記の構造:
- 前記生体分子が抗体であり、場合により、前記抗体が、モノクローナル抗体であり、および/または前記抗体がトラスツズマブである、請求項27または33に記載の使用。
- 前記薬物が、チューブリン阻害剤またはDNA相互作用剤であり、場合により、前記チューブリン阻害剤が、(a)オーリスタチン、および(b)メイタンシン誘導体からなる群から選択され、場合により、前記DNA相互作用剤が、(a)カリケアマイシン、(b)デュオカルマイシン及び(c)ピロロベンゾジアゼピン(PBD)からなる群から選択される、請求項27、33、および34のいずれか一項に記載の使用。
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PCT/GB2014/051304 WO2014174316A1 (en) | 2013-04-26 | 2014-04-25 | Method of synthesising adcs using affinity resins |
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GB201419184D0 (en) * | 2014-10-28 | 2014-12-10 | Adc Biotechnology Ltd | Method of synthesising biomolecule-effector/reporter-conjugates using affinity resins |
TW202408592A (zh) | 2016-03-02 | 2024-03-01 | 日商衛材R&D企管股份有限公司 | 基於艾日布林之抗體-藥物結合物及使用方法 |
EP3603663A4 (en) * | 2017-03-30 | 2020-04-08 | Jiangsu Hengrui Medicine Co., Ltd. | METHOD FOR PRODUCING ANTIBODY-ACTIVE SUBSTANCE CONJUGATES |
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US4978744A (en) | 1989-01-27 | 1990-12-18 | Arizona Board Of Regents | Synthesis of dolastatin 10 |
US5635483A (en) | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
US6117996A (en) | 1995-09-20 | 2000-09-12 | Novo Nordisk A/S | Triazine based ligands and use thereof |
GB9519197D0 (en) * | 1995-09-20 | 1995-11-22 | Affinity Chromatography Ltd | Novel affinity ligands and their use |
CA2264177C (en) | 1996-08-30 | 2015-03-17 | Upfront Chromatography A/S | Isolation of immunoglobulins |
WO2001083515A2 (en) | 2000-04-28 | 2001-11-08 | Accurate Polymers, Inc. | Simulated activity of protein a displayed by ligands attached to a cellulose bead surface |
US20020197694A1 (en) * | 2001-06-20 | 2002-12-26 | Weiping Shao | Conjugates of reduced antibodies and biomolecules |
GB0224446D0 (en) * | 2002-10-21 | 2002-11-27 | Univ Cambridge Tech | Affinity adsorbents for immunoglobulins |
WO2005039641A2 (en) * | 2003-10-15 | 2005-05-06 | The Regents Of The University Of California | Biomacromolecule polymer conjugates |
BRPI0510883B8 (pt) | 2004-06-01 | 2021-05-25 | Genentech Inc | composto conjugado de droga e anticorpo, composição farmacêutica, método de fabricação de composto conjugado de droga e anticorpo e usos de uma formulação, de um conjugado de droga e anticorpo e um agente quimioterapêutico e de uma combinação |
CN109045307A (zh) * | 2004-06-01 | 2018-12-21 | 健泰科生物技术公司 | 抗体-药物偶联物和方法 |
ITMI20071119A1 (it) | 2007-06-01 | 2008-12-02 | Tecnogen Spa | Nuovi ligandi sintetici per immunoglobuline e composizioni farmaceutiche che li comprendono |
US20090240033A1 (en) | 2008-03-11 | 2009-09-24 | Rongxiu Li | Affinity matrix library and its use |
WO2009117531A1 (en) * | 2008-03-18 | 2009-09-24 | Seattle Genetics, Inc. | Auristatin drug linker conjugates |
EP2277044B1 (en) * | 2008-05-13 | 2015-06-17 | Genentech, Inc. | Analysis of antibody drug conjugates by bead-based affinity capture and mass spectrometry |
GB0808908D0 (en) * | 2008-05-16 | 2008-06-25 | Avecia Biolog Ltd | Purification process |
WO2009141384A2 (en) | 2008-05-21 | 2009-11-26 | Novo Nordisk A/S | Process for the purification of factor vii polypeptides using affinity resins comprising specific ligands |
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US9598460B2 (en) | 2011-01-18 | 2017-03-21 | University Of Notre Dame Du Lac | Antibody purification via affinity chromatography |
GB201106173D0 (en) * | 2011-04-12 | 2011-05-25 | Adc Biotechnology Ltd | System for purifyng, producing and storing biomolecules |
LT3415531T (lt) * | 2011-05-27 | 2023-09-25 | Glaxo Group Limited | Bcma (cd269/tnfrsf17) – surišantys baltymai |
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US10201544B2 (en) | 2019-02-12 |
GB201307574D0 (en) | 2013-06-12 |
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CA2910064A1 (en) | 2014-10-30 |
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EP2988785B1 (en) | 2017-11-01 |
MX2015014935A (es) | 2016-06-02 |
ES2658420T3 (es) | 2018-03-09 |
KR20160003080A (ko) | 2016-01-08 |
EP2988785B8 (en) | 2018-04-04 |
CN105579066A (zh) | 2016-05-11 |
JP2016519116A (ja) | 2016-06-30 |
DK2988785T3 (en) | 2018-02-05 |
AU2014259160B2 (en) | 2019-03-21 |
CN105579066B (zh) | 2019-03-12 |
GB2513405A (en) | 2014-10-29 |
MX366908B (es) | 2019-07-30 |
US20190216819A1 (en) | 2019-07-18 |
CA2910064C (en) | 2019-07-23 |
AU2014259160A1 (en) | 2015-11-19 |
US20160067352A1 (en) | 2016-03-10 |
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