JP2020533565A - 抗体−薬物複合体の評価方法 - Google Patents
抗体−薬物複合体の評価方法 Download PDFInfo
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- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
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Abstract
Description
本出願は、2017年9月8日に出願した、米国仮出願第62/556,153号の優先権を主張するものであって、本明細書の一部を構成するものとして、同出願の全内容を援用する。
従来、DARは、UV−Vis分光法を使用して測定を行っていた(例えば、Chen,Methods Mol. Biol.1045:267−73(2013)を参照されたい)。この分析の基礎は、物質の吸光度と濃度との間の直接比例関係に関するランベルトの法則:
A=εcl、
であり、式中、Aは吸光度、εは吸光係数(物質の物理定数)、lは被検物質を含むセルを通る光路長、及び、cは、濃度である。
ある実施形態では、サイズ排除を使用してDARを決定する。一部の実施形態では、本明細書で開示した方法は、抗体−薬物複合体を含む試料を、サイズ排除クロマトグラフマトリックスに適用することを含む。一部の実施形態では、本明細書で開示した方法は、サイズ排除クロマトグラフマトリックスに、抗体−薬物複合体を含む試料に適用して、移動させることを含む。一部の実施形態では、ADC試料の総量を、分析のためにサイズ排除マトリックスに適用する。例えば、次のUPLCをベースとした方法論を使用して、DARを評価した。
一部の実施形態では、ADC試料での抗体及び薬物の濃度を計算してDARを決定する。例えば、勾配分光法は、様々な光路長で溶液の吸光度を決定するための公知の方法である。次いで、様々な光路長での吸光度の値を使用して、ランベルト・ベールの法則に基づいて、溶液に含まれる化合物の濃度を計算することができる。勾配分光法を使用する方法とシステムは公知であり(例えば、米国公開第20120130649号を参照されたい)、また、市販されている(例えば、SoloVPE(C Technologies,Inc.,Bridgewater,NJを参照されたい))。このような方法とシステムを、ADC製剤に含まれる抗体と薬物の濃度を測定するために適応させ、そこからDARを決定した。
本明細書で使用する用語「抗体−薬物複合体」とは、抗体を、生物学的に活性な細胞傷害性ペイロードまたは薬物に結合させて作り出すタンパク質のことを指す。抗体−薬物複合体(ADC)は、一般的には、当業者に公知の化学修飾/カップリング反応で作り出す。本明細書に記載した方法を使用して、あらゆる抗体−薬物複合体を分析することができる。
本開示の方法には様々な用途があり、例えば、原薬または製剤の製造における異なる段階での品質管理、原薬または製剤の製造の完了前、及び/または、完了後(例えば、充填/仕上げ環境、または、施設への流通の前後)、原薬または製剤の商取引に向けた出荷の前後(例えば、薬局、介護者、患者、または、その他の消費者に流通させる前)でのADC調製物の分析がある。一部の事例では、ADC製剤とは、原薬(医薬品有効成分、または、「API」)、または、製剤(ヒト患者などの対象での使用のために製剤したAPI)である。一部の事例では、ADC製剤は、介護者、または、その他の消費者に向けて流通させる前の製造または使用の段階から;シリンジ、ペン、バイアル、または、複数回投与バイアルなどの個々の剤形に包装する前から;試験証明書、Material Safety Data Sheet(MSDS)、または、分析証明書(CofA)の作成に先駆けて、バッチを商業流通させることが可能であると判断する前にある。
Claims (3)
- 抗体−薬物複合体を含む試料における薬物/抗体比(DAR)を決定する方法であって:
前記試料を、サイズ排除クロマトグラフマトリックスに適用する;
第1の光波長(λ1)で、前記試料の吸光度の検出を行い、前記第1の波長は、前記抗体の所定の吸光度最大値である;
第2の光波長(λ2)で、前記試料の吸光度の検出を行い、前記第2の波長は、前記薬物の所定の吸光度最大値である;
前記第1及び第2の波長での前記試料の全吸光度を決定する;及び、
以下の式1を使用して、DARを計算する、ことを含み:
は、前記第1の波長での前記抗体の吸光係数であり;
総面積λ1は、前記第1の波長での前記試料の総吸光度であり;及び、
総面積λ2は、前記第2の波長での前記試料の総吸光度である、前記方法。 - 抗体−薬物複合体を含む試料における薬物/抗体比(DAR)を決定する方法であって:
前記抗体−薬物複合体を含む試料の全吸光度を測定するものであって:
前記抗体−薬物複合体を含む前記試料を、サイズ排除クロマトグラフマトリックスに適用する;
第1の光波長(λ1)で、前記試料の吸光度の検出を行い、前記第1の波長は、前記抗体の所定の吸光度最大値である;
第2の光波長(λ2)で、前記試料の吸光度の検出を行い、前記第2の波長は、前記薬物の所定の吸光度最大値である;
前記第1及び第2の波長での前記試料の全吸光度を決定することで、前記全吸光度を測定する;
前記抗体を含む試料の全吸光度を測定するものであって:
前記抗体を含む前記試料を、サイズ排除クロマトグラフマトリックスに適用する;
前記第1の光波長(λ1)で、前記抗体を含む試料の吸光度を検出する;
前記第2の光波長(λ2)で、前記抗体を含む試料の吸光度を検出する;
前記第1及び第2の波長での前記抗体を含む試料の全吸光度を決定することで、前記全吸光度を測定する;及び
以下の式2を使用して、DARを計算する、ことを含み:
は、前記第2の波長での前記抗体−薬物複合体を含む前記試料の総吸光度である、前記方法。 - 抗体−薬物複合体を含む試料における薬物/抗体比(DAR)を決定する方法であって:
前記試料を容器に入れる;
プローブを前記容器に対して移動させて、前記プローブを前記容器の底部に接触させる;
前記溶液を通る事前に選択した光路長を充足する所定の増分に従って、前記プローブを前記容器に対して移動させて、前記プローブを、前記容器の底部から前記試料を通るようにして移動させる;
第1の光波長(λ1)で、前記試料の吸光度の検出を行い、前記第1の波長は、前記抗体の所定の吸光度最大値である;
前記試料に対して前記プローブを移動させ、そして、前記第1の波長で測定するステップを反復する;
前記第1の光波長と光路長での吸光度から回帰直線を生成して、前記回帰直線の勾配を得る;
前記回帰直線の勾配を、前記第1の波長での前記抗体の吸光係数で割って、前記抗体の濃度を決定する;
第2の光波長(λ2)で、前記試料の吸光度の検出を行い、前記第2の波長は、前記薬物の所定の吸光度最大値である;
前記試料に対して前記プローブを移動させ、そして、前記第2の波長で測定するステップを反復する;
前記第2の光波長と光路長での吸光度から回帰直線を生成して、前記回帰直線の勾配を得る;
前記回帰直線の勾配を、前記第2の波長での前記薬物の吸光係数で割って、前記薬物の濃度を決定する;及び
決定した薬物の濃度と、決定した抗体の濃度とを使用して、DARを算出する;
ことを含む前記方法。
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