TW201920933A - 評定抗體－藥物共軛體之方法 - Google Patents

評定抗體－藥物共軛體之方法 Download PDF

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TW201920933A
TW201920933A TW107131123A TW107131123A TW201920933A TW 201920933 A TW201920933 A TW 201920933A TW 107131123 A TW107131123 A TW 107131123A TW 107131123 A TW107131123 A TW 107131123A TW 201920933 A TW201920933 A TW 201920933A
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安卓亞 斯金納
娜塔莉 庫利巴
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美商雷傑納榮製藥公司
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Abstract

本發明提供評估抗體-藥物共軛體(ADC)產品之藥物對抗體之比例(DAR)的方法，該方法提供超越已知方法之優點。具體地，本發明之方法可用於高通量應用及/或不必在評估期間稀釋ADC樣品。

Description

評定抗體－藥物共軛體之方法
本發明關於評定抗體-藥物共軛體之方法。
抗體-藥物共軛體(ADC)為新興類別之藥物分子。其定位在特定標靶和遞送有效藥物之能力使它們成為有吸引力之用於研發基於標靶之治療性產品的選項。ADC係經由選定之化學連接子將有效之藥物分子與單株抗體化學連接來產生。與單株抗體共軛結合之藥物分子的平均數量稱為藥物對抗體之比例(“DAR”)。DAR為ADC產品之重要品質屬性，因為它會影響產品效力、安全性和/或穩定性。因此，需要以可靠且高通量之方式評估ADC產物之DAR的方法。
本發明提供具有超越已知方法之優點的評估ADC產物之DAR的方法。具體地，本發明之方法可用於高通量應用中及/或不必在評估期間稀釋ADC樣品。

UV-Vis 和比爾 - 朗伯 (Beer-Lambert) 定律
傳統方法係使用UV-Vis光譜術測量DAR(參見，例如Chen, Methods Mol. Biol. 1045:267-73 (2013))。該分析之基礎為比爾-朗伯定律，吸光度和物質濃度之間的直接比例關係：

其中A為吸光度，ε為消光係數(物質之物理常數)，為通過含有該分析物之細胞的路徑長度且為濃度。
使用UV-Vis光譜術測量ADC產品之DAR係依賴該抗體之最大吸光度(例如280nm)與該藥物之最大吸光度(例如252nm)的差異。例如平均DAR可使用該共軛結合之物質在280nm和252nm處測量之吸光度的差異計算。儘管UV-Vis方法被廣泛用於工業中，但其缺乏配製篩選研究所需之通量。該UV-Vis方法亦必須稀釋樣品才能使用，這導致與樣品稀釋有關之誤差。
因此，本發明至少部分基於使用尺寸排阻色層分析法(例如UPLC)和斜率光譜術來測量DAR之替代方法。就再現性、精確度和靈敏度來表徵這些方法並與UV-Vis光譜術相比較。產生之數據支持使用基於UPLC之DAR方法來克服傳統UV-Vis方法之通量限制。此外，可使用基於斜率光譜術之方法來分析ADC樣品而無需稀釋樣品。
基於 UPLC 之方法
於一實施態樣中，使用尺寸排除法來測定DAR。於一些實施態樣中，本文所揭示之方法包含將包含抗體-藥物共軛體之樣品施加在尺寸排阻色層分析法基質。於一些實施態樣中，本文揭示之方法包含將包含抗體-藥物共軛體之樣品施加至尺寸排阻色層分析基質並令該樣品運行通過尺寸排阻色層分析基質。於一些實施態樣中，將ADC樣品之總量施加至尺寸排阻基質以用於分析。例如，使用下列基於UPLC之方法學來評估DAR。

使用Empower之Apex Track積分法(Empower apex track integration method)和肩峰檢測整合在280nm處收集之數據。該滯留時間積分範圍係取決於分子，但通常在3至9分鐘內。具有最大高度和面積之峰被分類為“天然”、“主要”或“單體”峰。早於該“天然”峰洗提出之任何峰被分類為“HMW”峰。晚於該“天然峰”洗提出之任何峰被分類為“LMW”峰。
從個別峰之面積對所有峰之總面積的比例計算出各物種之相對百分比。以下報告之相對百分比面積為純度之指標：%總HMW，%天然(或主要或單體)及%總LMW。加總所有峰之面積的總和並用於隨後之DAR計算。然而，於一些實施態樣中，僅使用該天然峰之面積。
使用Empower之Apex Track積分法和肩峰檢測以將在252nm處收集之數據整合。該滯留時間積分範圍係取決於分子，但通常在3至9分鐘內。加總所有峰之總面積並用於隨後之DAR計算。然而，於一些實施態樣中，僅使用該天然峰之面積。
從280nm處之峰總面積(ADC之Amax )和252nm處之峰總面積(藥物之Amax )測定DAR。雖然252nm為用於ADC之藥物共軛體的常見Amax ，但可，例如使用已知之方法選擇用於特定之共軛體的合適波長。若適用時，使用裸出之抗體作為參考標準，藉由該二個波長處之峰總面積的差異來測定與該抗體結合之藥物的量。
以下二個公式(其源自比爾-朗伯定律)得到驗證且證明一致性。


公式1：
公式1不需要使用裸出之抗體參考標準。然而，需要系統性測定該抗體及藥物在252nm處之消光係數(ε)。藉由使用具有已知濃度之抗體或藥物的溶液並在指定之波長處測量吸光度可輕易地從比爾-朗伯定律計算出在指定波長處之消光係數。
公式2：
公式2不需要測定抗體在252nm處之消光係數，但其確實需要收集裸出之抗體參考標準的UPLC數據。
雖然已示例UPLC，本文所描述之方法可使用其他尺寸排阻色層分析技術。尺寸排阻色層分析法通常係指按大小分離分子，其中該色層分析洗提時間為特定分子之特徵。其他方法包括，例如SEC-HPLC、逆相(RP)HPLC、RP-UPLC。
於一些實施態樣中，在藉由尺寸排阻色層分析法(例如HPLC或UPLC)分析之前不稀釋ADC樣品。於一些實施態樣中，在藉由尺寸排阻色層分析法分析之前不需要稀釋ADC樣品，因為將全部量之ADC樣品施加於尺寸排阻色層分析法基質。於一些實施態樣中，分析含有約1μg/μL至約500μg/μL之ADC的樣品。

基於斜率光譜術之方法
於一些實施態樣中，藉由計算ADC樣品中抗體和藥物之濃度來測定DAR。例如，斜率光譜術為已知用於測定溶液在各種路徑長度下之吸光度的方法。然後可使用各種路徑長度之吸光度值，基於比爾-朗伯定律計算溶液中之化合物的濃度。採用斜率光譜術之方法和系統為已知(參見，例如美國刊物第20120130649號)且可商購獲得(參見，例如SoloVPE(C Technologies公司，紐澤西州Bridgewater))。該等方法和系統可適用於測量ADC製劑中之抗體和藥物之濃度，從該抗體和藥物之濃度可測定DAR。
例如，可將ADC樣品置於容器中；可相對於容器移動該探針，從而使該探針與該容器之底部接觸；可相對於該容器移動該探針，從而使該探針從該容器之底部以預定之增量通過該樣品，從而獲得通過該溶液之預先選擇的路徑長度；可在最大吸光處採取該抗體之吸光度讀數；可相對於該樣品重複移動該探針並可進行測量；可從該吸光度和路徑長度產生回歸線，從而獲得該回歸線之斜率；該抗體之濃度可藉由將該回歸線之斜率除以該抗體之消光係數測定。然後，可使用藥物之最大吸光度重複這些步驟以測定該藥物之濃度。從測定之藥物濃度和抗體濃度可計算出DAR。
於一些實施態樣中，在藉由斜率光譜術分析之前不稀釋ADC樣品。於一些實施態樣中，分析含有約0.1μg/μL至約500μg/μL之ADC的樣品。

抗體 - 藥物 共軛體
如本文所使用之術語“抗體-藥物共軛體”係指經由將抗體與生物活性之細胞毒性有效載荷或藥物連接來創建之蛋白質。抗體-藥物共軛體(ADC)通常係透過本技藝之技術熟習人士已知之化學修飾/偶聯反應產生。可使用本文所描述之方法分析任何抗體-藥物共軛體。
於一些實施態樣中，抗體-藥物共軛體包括抗腫瘤抗體(參見，例如Adler et al., Hematol. Oncol. Clin. North Am. 26:447-81 (2012)；Li et al., Drug Discov. Ther. 7:178-84 (2013)；Scott et al., Cancer Immun. 12:14 (2012)；及Sliwkowski et al., Science 341:1192-1198 (2013))。表1呈現某些可被已知之可取用的抗體試劑靶向之人多肽抗原的非全面性列表且註明已建議使用該抗體試劑的某些癌症適應症。表1中之任何抗體可被包含在使用本方法評估之抗體-藥物共軛體中。



表1：
於一些實施態樣中，抗體-藥物共軛體包括為下列一或多者之藥物：促凋亡劑、細胞抑制劑及/或細胞毒性劑，例如，具體而言，包括用於及/或推薦用於治療一或多種與不良細胞增殖相關之疾病、病症或病況的藥劑。於許多實施態樣中，藥物為可用於治療癌症之化學治療劑。於一些實施態樣中，化療劑可為或包含下列群組：一或多種烷化劑、一或多種蒽環類抗生素、一或多種細胞骨架破壞劑(例如微管靶向劑，諸如紫杉烷、美登素(maytansine)及其類似物)、一或多種埃坡黴素(epothilone)、一或多種組蛋白脫乙醯酶抑制劑(HDAC)、一或多種拓撲異構酶抑制劑(例如拓撲異構酶I及/或拓撲異構酶II之抑制劑)、一或多種激酶抑制劑、一或多種核苷酸類似物或核苷酸前體類似物、一或多種肽抗生素、一或多種以鉑為基底之試劑、一或多種類視色素、一或多種長春花生物鹼及/或下列群組之一或多者的一或多種類似物(即，共有相關之抗增殖活性)。於一些特定之實施態樣中，化療劑可為或包含下列之一或多者：放線菌素(actinomycin)、全反式A酸、澳瑞他汀(Auiristatin)、阿扎胞苷(Azacitidine)、硫唑嘌呤(Azathioprine)、博來黴素(Bleomycin)、硼替佐米(Bortezomib)、卡鉑、卡培他濱(Capecitabine)、順鉑、瘤克寧(Chlorambucil)、環磷醯胺、薑黃素(Curcumin)、阿糖胞苷(Cytarabine)、柔紅黴素(Daunorubicin)、多西紫杉醇(Docetaxel)、去氧氟尿苷(Doxifluridine)、多柔比星(Doxorubicin)、表柔比星(Epirubicin)、埃博黴素、依托泊苷(Etoposide)、氟尿嘧啶、吉西他濱(Gemcitabine)、羥基脲、伊達比星(Idarubicin)、伊馬替尼(Imatinib)、伊立替康 (Irinotecan)、美登素及/或其類似物(例如DM1)、二氯甲基二乙胺(Mechlorethamine)、巰嘌呤(Mercaptopurine)、甲胺蝶呤(Methotrexate)、米托蒽醌(Mitoxantrone)、美登木素(Maytansinoid)、奧沙利鉑(Oxaliplatin)、太平洋紫杉醇、培美曲塞(Pemetrexed)、替尼泊苷(Teniposide)、硫鳥嘌呤(Tioguanine)、托泊替康(Topotecan)、戊柔比星(Valrubicin)、長春鹼、長春新鹼、長春地辛、長春瑞濱及彼等之組合。
於一些實施態樣中，使用本發明方法評估之抗體-藥物共軛體為hLL1-多柔比星、hRS7-SN-38、hMN-14-SN-38、hLL2-SN-38、hA20-SN-38、hPAM4-SN-38、hLL1-SN-38、hRS7-Pro-2-P-Dox、hMN-14-Pro-2-P-Dox、hLL2-Pro-2-P-Dox、hA20-Pro-2-P-Dox、hPAM4-Pro-2-P-Dox、hLL1-Pro-2-P-Dox、P4/D10-多柔比星、吉妥珠單抗奧佐米星(gemtuzumab ozogamicin)、維布妥昔單抗(brentuximab vedotin)、曲妥珠單抗美坦新(trastuzumab emtansine)、英妥珠單抗奧佐米星(inotuzumab ozogamicin)、格巴妥單抗維多汀 (glembatumomab vedotin)、SAR3419、SAR566658、BIIB015、BT062、CMC-544、SAR3419、CDX-011、SGN-75、SGN-CD19A、AMG-172、AMG-595、BAY-94-9343、ASG-5ME、ASG-22ME、ASG-16M8F、MDX-1203、MLN-0264、抗PSMA ADC、RG-7450、RG-7458、RG-7593、RG-7596、RG-7598、RG-7599、RG-7600、RG-7636、ABT-414、IMGN-853、IMGN-529、IMGN-901、伏司妥珠單抗-馬佛多汀(vorsetuzumab mafodotin)或洛伐單抗美登素(lorvotuzumab mertansine)(參見，例如Sassoon et al., Methods Mol. Biol. 1045:1-27 (2013)；Bouchard et al., Bioorganic Med. Chem. Lett. 24: 5357-5363 (2014))。

應用
本發明方法具有多種應用且包括，例如在製造原料藥或藥物產品之不同階段的品質控制、在原料藥或藥物產品製造完成之前及/或之後的ADC製劑分析(例如在分配到填充/完成環境或設施之前或之後)、在原料藥或藥物產品釋入商購之前或之後(例如在分配給藥房、護理人員、患者或其他終端用戶之前)。在某些情況下，ADC製劑為原料藥(活性製藥成分或“API”)或藥物產品(經配製以用於個體，例如人類患者之API)。在某些情況下，ADC製劑係來自釋出給護理人員或其他終端用戶之前的製造或使用階段；在包裝成個別劑型(例如注射器、筆、小瓶或多劑量小瓶)之前；在決定該批次可釋出販售之前；在產生測試證書、材料安全數據表(MSDS)或分析證書(CofA)之前。
來自本文所描述之方法的評估可用於指導、控制或執行製造、分配和監控過程中的許多活動或步驟並提供ADC製劑之安全和有效用途。因此，於一實施態樣中，例如對評估之反應為，例如根據是否符合標準(例如特定之DAR、平均DAR及/或DAR範圍)，採取決定或步驟。本文描述之方法可包括決定：(a)關於ADC製劑是否可配製成原料藥或藥物產品；(b)關於ADC製劑是否可再加工(例如該製劑可重複先前之加工步驟)及/或(c) 該ADC製劑不適合配製成原料藥或藥物產品。在某些情況下，方法包含：依步驟(a)中所述配製、依步驟(b)中所述再加工、或依步驟(c)中所述使該製劑不能用於商購，例如藉由標記或破壞它。

Claims (3)

  1. 一種測定在包含抗體-藥物共軛體之樣品中藥物對抗體之比例(DAR)的方法，其包含： 將樣品施加於尺寸排阻色層分析基質； 測定該樣品在第一光波長(λ1)處之吸光度，其中該第一波長為該抗體之預定最大吸光度； 測定該樣品在第二光波長(λ2)處之吸光度，其中該第二波長為該藥物之預定最大吸光度； 測定該樣品在該第一和第二波長處之總吸光度；及 使用下列公式1計算DAR： 其中為該抗體在該第一波長處之消光係數；為該抗體在該第二波長處之消光係數；為該藥物在該第一波長處之消光係數；為該藥物在該第二波長處之消光係數；為該樣品在該第一波長處之總吸光度；且為該樣品在該第二波長處之總吸光度。
  2. 一種測定包含抗體-藥物共軛體之樣品中藥物對抗體之比例(DAR)的方法，其包含： 藉由下述步驟測量包含該抗體-藥物共軛體之樣品的總吸光度： 將包含該抗體-藥物共軛體之樣品施加於尺寸排阻色層分析基質； 測定該樣品在第一光波長(λ1)處之吸光度，其中該第一波長為該抗體之預定最大吸光度； 測定該樣品在第二光波長(λ2)處之吸光度，其中該第二波長為該藥物之預定最大吸光度；及 測定該樣品在該第一和第二波長處之總吸光度； 藉由下述步驟測量包含該抗體之樣品的總吸光度： 將包含該抗體之樣品施加於尺寸排阻色層分析基質； 測定包含該抗體之樣品在第一光波長(λ1)處之吸光度； 測定包含該抗體之樣品在第二光波長(λ2)處之吸光度；及 測定包含該抗體之樣品在該第一和第二波長處之總吸光度；及 使用下列公式2計算DAR： D 其中為該抗體在該第一波長處之消光係數；為該藥物在該第一波長處之消光係數；為該藥物在該第二波長處之消光係數；為包含該抗體之樣品在該第一波長處之總吸光度；為包含該抗體之樣品在該第二波長處之總吸光度；為包含該抗體-藥物共軛體之樣品在該第一波長處之總吸光度；且為包含該抗體-藥物共軛體之樣品在該第二波長處之總吸光度。
  3. 一種測定包含抗體-藥物共軛體之樣品中藥物對抗體之比例(DAR)的方法，其包含： 將樣品置於容器中； 相對於該容器移動探針，從而使該探針與該容器之底部接觸； 相對於該容器移動該探針，從而使該探針從該容器之底部以預定之增量移動通過該樣品，從而取得通過該溶液之預先選定的路徑長度； 測定該樣品在第一光波長(λ1)處之吸光度，其中該第一波長為該抗體之預定最大吸光度； 重複相對於該樣品移動該探針之步驟並在該第一波長處進行測量； 從該第一波長處之吸光度和路徑長度產生回歸線，從而取得該回歸線之斜率； 藉由將該回歸線之斜率除以該抗體在該第一波長處之消光係數以測定該抗體之濃度； 測定該樣品在第二光波長(λ2)處之吸光度，其中該第二波長為該藥物之預定最大吸光度； 重複相對於該樣品移動該探針之步驟並在該第二波長處進行測量； 從該第二波長處之吸光度和路徑長度產生回歸線，從而取得該回歸線之斜率； 藉由將該回歸線之斜率除以該藥物在該第二波長處之消光係數以測定該藥物之濃度；及 使用測定之藥物濃度和測定之抗體濃度以計算DAR。
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