TW201519904A - 抗體藥物結合物(adc)之純化 - Google Patents
抗體藥物結合物(adc)之純化 Download PDFInfo
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- TW201519904A TW201519904A TW103109819A TW103109819A TW201519904A TW 201519904 A TW201519904 A TW 201519904A TW 103109819 A TW103109819 A TW 103109819A TW 103109819 A TW103109819 A TW 103109819A TW 201519904 A TW201519904 A TW 201519904A
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Abstract
本發明提供獲得具有規定藥物對抗體比(DAR)之抗體藥物結合物(ADC)之組合物之方法。在本發明內包括純化具有6或更大之藥物負載物質之ADC之ADC混合物的方法,其係藉由使該混合物與疏水性樹脂接觸以獲得包含小於15%之該6或更大之藥物負載物質的組合物來實施。本發明亦提供組合物,其中70%或更高之存在之該等ADC具有4或更小之藥物負載物質,其中該ADC包含抗EGFR抗體及奧裡斯他汀(auristatin)。
Description
本申請案主張於2013年3月15日申請之美國臨時申請案第61/792,834號之權益。上述優先權文件之全部內容在此以引用方式併入。
抗體藥物結合物(ADC)係一類新興有效抗癌劑,最近已證明其具有顯著臨床益處。ADC包含經由穩定連接體附著至抗體之細胞毒性劑。據推定,藉由一系列事件,包括於細胞表面之抗原結合、胞吞作用、運輸至溶酶體、ADC降解、有效負載之釋放、細胞加工(例如有絲分裂)之中斷及細胞凋亡,ADC可破壞具有細胞表面蛋白質過表現之癌細胞。ADC組合抗原驅動之單株抗體之靶向性質與細胞毒性劑之有效抗腫瘤效應。例如,在2011年,ADCETRIS®(抗CD30抗體-MMAE ADC)獲得規章性批準用於治療頑固性霍奇金(Hodgkin)淋巴瘤及全身性退行性變化性淋巴瘤。
研究已證明高藥物負載ADC之有害效應(Liu等人(2010)Analy.Chem.82:5219)。較高量之結合之該等有害效應包括形成聚焦物之傾向性增加(King等人(2002)J Med.Chem.45:4336;Hollander等人(2008)Bioconjugate Chem 19:358;Burke等人(2009)Bioconjugate Chem 20:1242;及Zhao等人(2011)J Med.Chem.54:3606)。
已使用各種方法來嘗試控制ADC之藥物負載,包括:(i)限制藥物-連接體中間體或連接體試劑相對於抗體之莫爾過量,(ii)限制結合反應時間或溫度,及(iii)用於半胱胺酸巰基修飾之部分或限制性還原條件。儘管已使用限制抗體上附著位點之數量之還原方法來達成每抗體具有較少藥物之ADC(Alley等人(2004)Proc Amer Assoc Cancer Res 45:Abst 627),但仍需要可提供最佳藥物負載物質之方法及組合物。
本發明提供分離具有不同藥物負載之抗體藥物結合物(ADC)之有效方法以及使用此等方法獲得之組合物。本發明亦提供其中去除ADC之較高藥物負載物質之組合物。
在一個實施例中,本發明之特徵在於獲得包含抗體藥物結合物(ADC)之組合物之方法,該方法包含使包含4或更小之藥物負載物質及6或更大之藥物負載物質之ADC混合物與疏水性樹脂接觸,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許該4或更小之藥物負載物質之顯著結合;及自該ADC混合物去除該疏水性樹脂,以獲得該包含ADC之組合物,其中該組合物包含小於15%之該6或更大之藥物負載物質,且其中該ADC包含抗體與奧裡斯他汀(auristatin)之結合物。在一個實施例中,該組合物包含小於10%之6或更大之藥物負載物質。在另一實施例中,該組合物包含5%或更小之6或更大之藥物負載物質。
在一個實施例中,本發明方法包括為ADC混合物中6或更大之藥物負載物質之重量3至12倍之疏水性樹脂重量的用途。在一個實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的4至8倍。在又一實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的5至10倍。
在再一實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的6至12倍,且其中ADC混合物包含在0至1N之間之NaCl或其等效離子強度。在又一實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的3至6倍,且其中ADC混合物包含在1N至2N之間之NaCl或其等效離子強度。在再一實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的3至7倍,且其中奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)。在又一實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的5至10倍,且其中奧裡斯他汀係單甲基奧裡斯他汀F(MMAF)。在又一實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的3至7倍,且其中奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)。
本發明進一步提供產生包含平均藥物對抗體比(DAR)為4.5或更小之ADC且包含小於15%之不期望ADC之組合物的方法,該方法包含使ADC混合物與疏水性樹脂接觸,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該等不期望ADC之結合;及自該ADC混合物去除該疏水性樹脂,以產生具有4.5或更小之平均DAR且包含小於15%之不期望ADC之組合物,其中該ADC包含抗體與奧裡斯他汀之結合物。在一個實施例中,具有4或更小之平均DAR之組合物包含小於10%之不期望ADC。在一個實施例中,不期望ADC係6及8藥物負載物質。在又一實施例中,不期望ADC係8藥物負載物質。
在一個實施例中,添加至ADC混合物中之疏水性樹脂之量係為ADC混合物中不期望ADC之重量3至12倍的樹脂重量。
在又一實施例中,添加至ADC混合物中之疏水性樹脂之量係為ADC混合物中6或更大之藥物負載物質之重量4至8倍的樹脂重量。在再一實施例中,添加至ADC混合物中之疏水性樹脂之量係為ADC混合
物中6或更大之藥物負載物質之重量5至7倍的樹脂重量。在又一實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的6至12倍,且其中ADC混合物包含在0至1N之間之NaCl或其等效離子強度。在一個實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的3至6倍且ADC混合物包含在1N至2N之間之NaCl或其等效離子強度。在另一實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的3至7倍,且其中奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)。在又一實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的5至10倍,且其中奧裡斯他汀係單甲基奧裡斯他汀F(MMAF)。在再一實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的3至7倍,且其中奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)。在一個實施例中,疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的5至10倍,且其中奧裡斯他汀係單甲基奧裡斯他汀F(MMAF)。
在一個實施例中,使用本發明方法來獲得包含具有4.5或更小之平均DAR之ADC之組合物。在一個實施例中,使用本發明方法來獲得包含具有4或更小之平均DAR之ADC之組合物。在一個實施例中,使用本發明方法來獲得包含具有3.5或更小之平均DAR之ADC之組合物。在一個實施例中,使用本發明方法來獲得包含具有3或更小之平均DAR之ADC之組合物。在一個實施例中,該組合物具有2.5或更小之平均DAR。
在一個實施例中,本發明方法之特徵在於將疏水性樹脂添加至ADC混合物中以形成樹脂混合物,其中該樹脂混合物之離子強度等於或高於ADC混合物。
在本發明之又一實施例中,依照超濾/透析過濾製程獲得ADC混合物。
在本發明之一個實施例中,用於本發明方法中之疏水性樹脂係丁基疏水性樹脂。
在本發明之一個實施例中,本發明方法係分批製程,或或者,循環製程或流過式製程(flow through process)。
在一個實施例中,本發明之特徵在於使用本文所述方法獲得之組合物。
本發明之特徵進一步在於包含ADC之組合物,其中70%之ADC具有4或更小之藥物負載物質,其中該ADC包含抗EGFR抗體(例如,抗體1)及奧裡斯他汀(例如,MMAE或MMAF)。在本發明之一個實施例中,該組合物包含75%具有4或更小之藥物負載物質之存在之ADC。在本發明之另一實施例中,該組合物包含80%具有4或更小之藥物負載物質之存在之ADC。在本發明之一個實施例中,該組合物包含85%之具有4或更小之藥物負載物質之存在的ADC。在本發明之又一實施例中,該組合物包含90%具有4或更小之藥物負載物質之ADC。在一個實施例中,本發明組合物包含95%具有4或更小之藥物負載物質之存在之ADC。在另一實施例中,本發明組合物包含其中70%或更高之ADC具有負載4至1種、3至1種或或者2至1種藥物之物質的ADC。
本發明之特徵進一步在於包含具有4.5或更小之平均DAR之ADC之組合物,其中該ADC包含抗EGFR抗體(例如,抗體1)及奧裡斯他汀(例如,MMAE或MMAF)。在本發明之一個實施例中,該組合物包含具有4或更小之平均DAR之ADC。在本發明之另一實施例中,該組合物包含具有4或更小之平均DAR之ADC。在本發明之再一實施例中,該組合物包含具有3.5或更小之平均DAR之ADC。在本發明之一個實施例中,該組合物包含具有3或更小之平均DAR之ADC。在本發明之再一實施例中,該組合物包含具有2.5或更小之平均DAR之ADC。在另一實施例中,本發明組合物包含具有4.5至0.001、4至0.001、3.5至
0.001、3至0.001或或者2.5至0.001之平均DAR之抗EGFR ADC(例如,抗體1與MMAE或MMAF之結合物)。
在一個實施例中,本發明之方法及組合物包括包含抗表皮生長因子受體(EGFR)抗體之ADC。在本發明之一個實施例中,抗EGFR抗體包含含有互補決定區1(CDR1)、CDR2及CDR3結構域之輕鏈可變區,該等結構域包含分別如SEQ ID NO:7、SEQ ID NO:8及SEQ ID NO:9中所述之胺基酸序列;且包含含有CDR1、CDR2及CDR3結構域之重鏈可變區,該等結構域包含如SEQ ID NO:2、SEQ ID NO:3及SEQ ID NO:4中所述之胺基酸序列。在本發明之另一實施例中,抗EGFR抗體包含含有SEQ ID NO:6中所述之胺基酸序列之輕鏈可變區及包含SEQ ID NO:1中所述之胺基酸序列之重鏈可變區。
在本發明之另一實施例中,抗EGFR ADC包含胺基酸序列SEQ ID NO:6中所述之輕鏈可變區中所述之CDR(即,輕鏈CDR1、CDR2及CDR3)及胺基酸序列SEQ ID NO:1中所述之CDR(即,重鏈CDR1、CDR2及CDR3)。
在又一實施例中,本發明之方法及組合物之特徵在於為單甲基奧裡斯他汀E(MMAE)或單甲基奧裡斯他汀F(MMAF)之奧裡斯他汀。
在一個實施例中,MMAE經由纈胺酸-瓜胺酸(vc)連接體結合抗體(vc-MMAE)。在另一實施例中,MMAF經由馬來醯亞胺基己醯基連接體結合抗體(mc-MMAF)。
在一個實施例中,本發明組合物係醫藥組合物。
在本發明中亦包括治療個體之癌症之方法,其包含向該個體投與本文所述組合物,以治療癌症。在一個實施例中,癌症係選自由以下組成之群:鱗狀瘤(包括肺、頭頸、子宮頸等之鱗狀瘤)、神經膠母細胞瘤、神經膠質瘤、非小細胞肺癌、肺癌、結腸癌、頭頸癌、乳癌、鱗狀細胞瘤、肛門癌、皮膚癌及陰門癌。
在一個實施例中,本發明組合物用於治療多形性神經膠母細胞瘤。
在一個實施例中,本發明組合物用於治療具有EGFR過表現之實體瘤。在一個實施例中,本發明組合物用於治療患有可能過表現EGFR之晚期實體瘤之個體。
在一個實施例中,經靜脈內投與本發明組合物。
圖1提供實例中所述製程之概況,包括抗體1之還原、抗體1與vcMMAE之結合及使用具有HIC樹脂之分批純化對ADC之純化。
圖2圖解繪示在HIC樹脂分批純化之前及之後對抗體1 ADC溶液之HIC HPLC分析。
圖3提供實例6中所述純化具有2.7、4及5.5之平均DAR之ADC混合物之製程的概況。
為更容易地理解本發明,首先定義某些術語。另外,應注意,無論何時列舉參數之值或值之範圍,皆意欲所列舉值之中間值及範圍亦意欲為本發明之一部分。
術語「抗體-藥物-結合物」或「ADC」係指化學連接至一或多種可視情況為治療劑或細胞毒性劑之化學藥物(在本文中亦稱作藥劑)之結合蛋白質,例如抗體或其抗原結合片段。在較佳實施例中,ADC包括抗體、細胞毒性或治療性藥物及使該藥物能夠與該抗體附著或結合之連接體。ADC通常具有1至8之任何種結合抗體之藥物,包括負載2種、4種、6種或8種藥物之物質。可包括在ADC中之藥物之非限制性實例係有絲分裂抑制劑、抗瘤抗生素、免疫調節劑、用於基因療法之載體、烷基化劑、抗血管生成劑、抗代謝物、含硼藥劑、化學保護
劑、激素、抗激素劑、皮質類固醇、光敏治療劑、寡核苷酸、放射性核種劑、拓樸異構酶抑制劑、酪胺酸激酶抑制劑及放射敏化劑。
在本文中可互換使用之術語「抗表皮生長因子抗體藥物結合物」、「抗EGFR抗體藥物結合物」或「抗EGFR ADC」係指包含特異性結合EGFR之抗體之ADC,其中該抗體結合一或多種化學劑。在一個實施例中,抗EGFR抗體藥物結合物係抗體1與奧裡斯他汀(例如,MMAE或MMAF)之結合物。對應於抗體1之輕鏈及重鏈之胺基酸序列提供於SEQ ID NO:1-10中。
如本文所使用之術語「奧裡斯他汀」係指抗有絲分裂劑家族。在術語「奧裡斯他汀」之定義內亦包括奧裡斯他汀衍生物。奧裡斯他汀之實例包括但不限於奧裡斯他汀E(AE)、單甲基奧裡斯他汀E(MMAE)、單甲基奧裡斯他汀F(MMAF)及多拉司他汀(dolastatin)之合成類似物。
術語「藥物對抗體比」或「DAR」係指附著至ADC之抗體之藥物(例如,奧裡斯他汀)之數量。ADC之DAR可在1至8之範圍內,但更高負載,例如,10,亦可能,此取決於抗體上連接位點之數量。術語DAR可參考負載至個別抗體上之藥物數量使用,或或者可參考ADC群之平均DAR使用。
如本文所使用之術語「不期望ADC物質」係指欲與具有不同藥物負載之ADC物質分離之任何藥物負載物質。在一個實施例中,術語不期望ADC物質可係指6或更大之藥物負載物質,即,具有6或更大之DAR(包括DAR6、DAR7、DAR8及DAR大於8)之ADC(即,6、7、8或大於8之藥物負載物質)。在單獨實施例中,術語不期望ADC物質可係指8或更大之藥物負載物質,即,具有8或更大之DAR(包括DAR8及DAR大於8)之ADC(即,8或大於8之藥物負載物質)。
如本文所使用之術語「ADC混合物」係指含有不均勻DAR分佈
之ADC之組合物。在一個實施例中,ADC混合物含有具有1至8(例如,2、4、6及8)之DAR分佈之ADC(即,2、4、6及8之藥物負載物質)。值得注意地,降解產物可使得在混合物中亦可包括1、3、5及7之DAR。此外,混合物內之ADC亦可具有大於8之DAR。ADC混合物源於鏈間二硫化物還原、之後結合。在一個實施例中,ADC混合物包含具有4或更小之DAR之ADC(即,4或更小之藥物負載物質)與具有6或更大之DAR之ADC(即,6或更大之藥物負載物質)兩者。
本文所用術語「疏水性樹脂」或「疏水性交互作用樹脂」係指用於純化分子混合物之目的之由疏水性配體組成之介質,其中該混合物內之分子上存在疏水性表面部分促進與該介質之交互作用,使得交互作用分子至少短暫地結合該介質。在一個實施例中,疏水性樹脂係包含烷基部分之樹脂,例如,C4-C8烷基疏水性樹脂,其係包含4至8員直鏈或支鏈碳烷烴基團(例如丁基、戊基、己基、庚基或辛基)偶合至固體載體(例如,瓊脂糖、二氧化矽等)之樹脂。疏水性烷基樹脂之實例包括疏水性丁基樹脂或疏水性己基樹脂。在一個實施例中,疏水性樹脂係包含芳基部分之樹脂,例如,疏水性苯基樹脂。在一個實施例中,疏水性樹脂包含烯基部分。在一個實施例中,疏水性樹脂包含醚部分。在再一實施例中,疏水性樹脂包含苯基部分。疏水性部分(例如,烷基、芳基等)可連接至惰性物質(例如,二氧化矽、瓊脂糖及/或其他多糖聚合物)。在一個實施例中,樹脂係甲基丙烯酸酯樹脂。
術語「離子強度」廣泛地係指溶液中之離子濃度(即,溶液之傳導性)之量度。可用於調節溶液之離子強度之實例性鹽包括但不限於溴化鈉、氯化鈉、檸檬酸鈉、碘化鈉、磷酸鈉、硫酸鈉、溴化鉀、氯化鉀、檸檬酸鉀、碘化鉀、磷酸鉀、硫酸鉀、氯化銫、氯化鋰或氨之其他鹽(例如,NH4Cl、(NH4)2SO4)、碳酸鹽(NaHCO3)、檸檬酸(NaH2(C3H5O(COO)3)、Na2H(C3H5O(COO)3)、Na3H(C3H5O(COO)3))、
磷酸(例如,KH2PO4、K2HPO4、K3PO4)、硝酸鹽(KNO3)或該等組份之任一混合物。熟習此項技術者瞭解,陰離子與陽離子兩者皆可如熟習此項技術者所已知變化,只要提供足夠離子強度而無沈澱或其他不期望之副效應。
術語「抗EGFR抗體」意指特異性結合EGFR之抗體。「結合」所關注抗原(即,EGFR)之抗體係能夠以足夠親和力結合該抗原從而使得可用於靶向表現該抗原之細胞之抗體。抗體1係抗EGFR抗體之一實例。
術語「抗體」廣泛地係指一般包含四條多肽鏈(兩條重(H)鏈及兩條輕(L)鏈)之免疫球蛋白(Ig)分子或其保留Ig分子之基本靶結合特徵之任何功能片段、突變體、變體或衍生物。
在全長抗體中,每一重鏈包含重鏈可變區(本文縮寫為HCVR或VH)及重鏈恆定區。重鏈恆定區包含三個結構域:CH1、CH2及CH3。每一輕鏈包含輕鏈可變區(本文縮寫為LCVR或VL)及輕鏈恆定區。輕鏈恆定區包含一個結構域(CL)。可將VH及VL區進一步細分成高度可變區(稱為互補決定區(CDR))及較為保守之區(稱為框架區(FR)),二者間雜佈置。每一VH及VL由三個CDR及四個FR構成,其自胺基端至羧基端按下列順序佈置:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。免疫球蛋白分子可為任何類型(例如IgG、IgE、IgM、IgD、IgA及IgY)及類別(例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)或亞類。
如本文所用之術語抗體之「抗原結合部分」(或簡稱為「抗體部分」)係指一或多個保留特異性結合抗原(例如,hIL-13)之能力的抗體片段。已顯示,抗體之抗原結合功能可由全長抗體之片段來實施。此等抗體實施例亦可具有雙特異性、雙重特異性或多特異性模式;特異性結合兩種或更多種不同抗原。術語抗體之「抗原結合部分」內所涵
蓋結合片段之實例包括(i)Fab片段,即由VL、VH、CL及CH1結構域組成之單價片段;(ii)F(ab')2片段,即包含兩個由鉸鏈區之二硫橋鍵所連接Fab片段的二價片段;(iii)由VH及CH1結構域組成之Fd片段;(iv)由抗體單臂之VL及VH結構域組成之Fv片段;(v)dAb片段(Ward等人,(1989)Nature 341:544-546;Winter等人,PCT公開案WO 90/05144 A1,其以引用方式併入本文中),其包含單可變結構域;及(vi)經分離互補決定區(CDR)。此外,儘管Fv片段之兩個結構域(VL及VH)係由單獨基因編碼,但可使用重組方法藉由合成連接體將該兩個結構域接合在一起,該合成連接體使其能夠以其中VL及VH區配對形成單價分子之單一蛋白鏈(稱作單鏈Fv(scFv))產生;例如,參見Bird等人,(1988)Science 242:423-426;及Huston等人(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。此等單鏈抗體亦意欲涵蓋於術語抗體之「抗原結合部分」內。亦涵蓋單鏈抗體之其他形式,例如雙鏈抗體。雙鏈抗體係二價雙特異性抗體,其中VH及VL結構域在多肽單鏈上表現,但所用連接體太短以致不允許相同鏈上之兩個結構域之間配對,從而迫使該等結構域與另一鏈之互補結構域配對並形成兩個抗原結合位點(參見,例如,Holliger,P.等人(1993)Proc.Natl.Acad.Sci.USA 90:6444-6448;Poljak,R.J.等人(1994)Structure 2:1121-1123)。該等抗體結合部分為業內已知(Kontermann及Dubel編輯,Antibody Engineering(2001)Springer-Verlag.New York.第790頁(ISBN 3-540-41354-5)。
如本文所用之「經分離抗體」係指實質上不含具有不同抗原特異性之其他抗體的抗體(例如,特異性結合EGFR之經分離抗體實質上不含特異性結合除EGFR以外之抗原的抗體)。然而,特異性結合EGFR之經分離抗體可與其他抗原(例如來自其他物種之EGFR分子)具有交叉反應性。此外,經分離抗體可實質上不含其他細胞材料及/或
化學品。
術語「人類化抗體」係指包含來自非人類物種(例如小鼠)之重鏈及輕鏈可變區序列但其中VH及/或VL序列之至少一部分已變得更「人類樣(human-like),即更類似於人類種系可變序列的抗體。在特定實施例中,術語「人類化抗體」係特異性結合所關注抗原之抗體或其變體、衍生物或片段,且包含實質上具有人類抗體之胺基酸序列的框架(FR)區,且包含實質上具有非人類抗體之胺基酸序列的CDR。如本文所用之術語「實質上」在CDR背景下係指胺基酸序列與非人類抗體CDR之胺基酸序列至少80%、較佳至少85%、至少90%、至少95%、至少98%或至少99%一致之CDR。在一個實施例中,一種類型之人類化抗體係CDR-移植抗體,其中將人類CDR序列引入非人類VH及VL序列中以替代相應之非人類CDR序列。
如本文所用之術語「CDR」係指抗體可變序列內之互補決定區。對於可變區之每一者而言,在重鏈及輕鏈可變區之每一者中存在三個CDR,其命名為CDR1、CDR2及CDR3。如本文所用之術語「CDR組」係指存在於能夠結合抗原之單一可變區中之三個CDR群。已根據不同系統不同地界定該等CDR之準確邊界。由Kabat闡述之系統(Kabat等人,Sequences of Proteins of Immunological Interest(National Institutes of Health,Bethesda,Md.(1987)及(1991))不僅提供適用於抗體之任一可變區之明確殘基編號系統,且亦提供界定該三個CDR之精確殘基邊界。該等CDR可稱作Kabat CDR。Chothia及coworkers(Chothia及Lesk,J.Mol.Biol.196:901-917(1987)及Chothia等人,Nature 342:877-883(1989))發現Kabat CDR內之某些次部分採取接近相同之肽主鏈構象,但在胺基酸序列之層面上具有巨大多樣性。將該等次部分命名為L1、L2及L3或H1、H2及H3,其中「L」及「H」分別命名輕鏈及重鏈區。該等區可稱作Chothia CDR,其具有與Kabat
CDR重疊之邊界。界定與Kabat CDR重疊之CDR之其他邊界已由Padlan(FASEB J.9:133-139(1995))及MacCallum(J Mol Biol 262(5):732-45(1996))闡述。其他CDR邊界定義可不嚴格地遵循上述系統中之一者,但將與Kabat CDR重疊,儘管其可根據特定殘基或殘基群或甚至整個CDR不顯著地影響抗原結合之預測或實驗發現來縮短或延長。本文所用方法可利用根據該等系統中之任一者界定之CDR,但較佳實施例使用Kabat或Chothia界定之CDR。
術語「病症」係指將受益於用本發明調配物治療之任何病況,例如需要用調配物中之抗EGFR抗體治療之病症。此術語包括慢性及急性病症或疾病,包括彼等使哺乳動物易患所述病症之病理學病況。
術語「癌症」意指或闡述哺乳動物中特徵通常在於細胞生長失調之生理學病況。癌症之實例包括但不限於癌瘤、淋巴瘤、母細胞瘤、肉瘤及白血病或淋巴樣惡性腫瘤。此等癌症之更特定實例包括神經膠母細胞瘤、非小細胞肺癌、肺癌、結腸癌、頭頸癌、乳癌、鱗狀細胞瘤、肛門癌、皮膚癌及陰門癌。在一個實施例中,向患有含有EGFR基因擴增之腫瘤之患者投與本發明組合物,其中該腫瘤表現EGFR de2-7之截短形式。在一個實施例中,可向個體投與包含ADC-1之本發明調配物用於治療結腸直腸癌、頭頸癌(包括但不限於咽下癌、口咽癌、食道癌、喉癌及口腔癌)、非小細胞肺癌、胰腺癌、胃癌及乳癌。此等癌症之更特定實例包括鱗狀瘤(包括肺、頭頸、子宮頸等之鱗狀瘤)、神經膠母細胞瘤、神經膠質瘤、非小細胞肺癌、肺癌、結腸癌、頭頸癌、乳癌、鱗狀細胞瘤、肛門癌、皮膚癌及陰門癌。在本發明之一個實施例中,使用該組合物來治療患有實體瘤(例如,可能過表現表皮生長因子受體(EGFR)之實體瘤)或多形性神經膠母細胞瘤之個體。
如本文所用之術語「投與」意指遞送物質(例如,抗EGFR抗體藥
物結合物)以達成治療目標(例如,治療EGFR相關病症)。投與模式可係非經腸、腸及局部。非經腸投與通常藉由注射,且包括但不限於靜脈內、肌內、動脈內、鞘內、囊內、眶內、心內、真皮內、腹膜內、經氣管、皮下、角皮下、關節內、囊下、蛛膜下、脊椎內及胸骨內注射及輸注。
如本文所用之術語抗體之「治療有效量」或「有效量」係指有效預防或治療或緩和可經該抗體有效治療之病症之症狀的量。
術語「治療」係指治療性治療與預防性(prophylactic或preventative)措施兩者。彼等需要治療者包括彼等已患有病症者以及彼等欲預防病症者。
本發明之各種態樣進一步詳細地闡述於以下子部分中。
本發明提供純化抗體藥物結合物(ADC)之方法,且提供用於自ADC混合物去除不期望ADC物質(例如,6或更大之藥物負載物質)之有效手段。儘管本發明方法可用於分離任何藥物負載物質,但在較佳實施例中,本文所述方法用於分離高藥物負載ADC與具有最佳藥物對抗體比(DAR)(例如4或更小之DAR)之ADC。在某些實施例中,本發明方法可相對於傳統管柱層析提供多個優點,包括改良之回收率,此乃因可無需分餾及餾分之隨後彙集。應理解,本發明通篇所述之方法及組合物可用於純化抗EGFR抗體-奧裡斯他汀ADC,尤其在某一實施例中,包含抗體1之抗EGFR ADC經由馬來醯亞胺基己醯基連接體偶合至MMAF(mc-MMAF)或經由馬來醯亞胺基己醯基纈胺酸-瓜胺酸連接體偶合至MMAE(vc-MMAE)。
本發明方法通常包括將疏水性樹脂添加至ADC混合物中,使得不期望ADC(即,較高藥物負載ADC)結合該樹脂且可自該混合物選擇性地去除。在某些實施例中,ADC之分離可藉由使ADC混合物(例
如,包含4或更小之ADC藥物負載物質與6或更大之ADC藥物負載物質之混合物)與疏水性樹脂接觸來達成,其中樹脂之量足以允許欲自ADC混合物去除之藥物負載物質之結合。將樹脂及ADC混合物混合在一起,使得欲去除之ADC物質(例如,6或更大之藥物負載物質)結合樹脂且可與ADC混合物中之其他ADC物質分離。用於該方法中之樹脂之量係基於欲去除之物質與樹脂之間之重量比,其中所用樹脂之量不允許所期望藥物負載物質之顯著結合。因此,本發明提供將ADC混合物之平均DAR自例如5.5降低至小於4之方法。此外,本文所述純化方法可用於分離具有任何期望範圍之藥物負載物質(例如,4或更小之藥物負載物質、3或更小之藥物負載物質、2或更小之藥物負載物質、1或更小之藥物負載物質)之ADC。
本發明提供其中某一分子物質基於該物質與疏水性樹脂之間之疏水性交互作用結合表面之純化方法。在一個實施例中,本發明方法係指依賴於疏水性樹脂與ADC混合物之互混之純化製程,其中添加至該混合物中之樹脂之量確定將結合之物質(例如,具有6或更大之DAR之ADC)。
在自表面系統(例如,哺乳動物表現系統)產生並純化抗體後,將該抗體還原並經由結合反應使其偶合至藥物。所得ADC混合物經常含有具有一定範圍之DAR(例如,1至8)之ADC。在一個實施例中,ADC混合物包含4或更小之藥物負載物質及6或更大之藥物負載物質。根據本發明方法,可使用諸如但不限於分批製程等製程來純化ADC混合物,以選擇具有4或更小之藥物負載物質之ADC並將其與具有較高藥物負載之ADC(例如,具有6或更大之藥物負載物質之ADC)分離。值得注意地,本文所述純化方法可用於分離具有任何期望範圍之DAR(例如,4或更小之DAR、3或更小之DAR、2或更小之DAR)之ADC。
因此,在一個實施例中,本發明方法包含使包含4或更小之藥物
負載物質及6或更大之藥物負載物質之ADC混合物與疏水性樹脂接觸以形成樹脂混合物,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許該4或更小之藥物負載物質之顯著結合;及自該ADC混合物去除該疏水性樹脂,以獲得該包含ADC之組合物,其中該組合物包含小於15%之該6或更大之藥物負載物質,且其中該ADC包含抗體與奧裡斯他汀之結合物。在單獨實施例中,本發明方法包含使包含4或更小之藥物負載物質及6或更大之藥物負載物質之ADC混合物與疏水性樹脂接觸以形成樹脂混合物,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許該4或更小之藥物負載物質之顯著結合;及自該ADC混合物去除該疏水性樹脂,以獲得該包含ADC之組合物,其中該組合物包含小於15%之該6或更大之藥物負載物質,且其中該ADC包含抗體與奧裡斯他汀之結合物,其中疏水性樹脂重量係該ADC混合物中之該6或更大之藥物負載物質之重量的3至12倍。
本發明方法提供分離低及高DAR ADC之有效方法。在一個實施例中,該方法可使用分批純化方法實施。分批純化製程通常包括將ADC混合物添加至容器中之疏水性樹脂中,混合並隨後自上清液分離該樹脂。例如,在分批純化之背景下,在期望平衡緩衝液中製備疏水性樹脂或將該疏水性樹脂平衡至該緩衝液中。因此可獲得疏水性樹脂漿液。然後可使該ADC混合物與該漿液接觸以吸附欲藉由疏水性樹脂分離之特定ADC物質。然後可例如藉由過濾或藉由允許漿液沉降並去除上清液來自漿液分離出包含不結合疏水性樹脂材料之期望ADC之溶液。所得漿液可經受一或多個洗滌步驟。為了溶析經結合ADC,可降低鹽濃度。在一個實施例中,用於本發明中之製程包括不超過50g之疏水性樹脂。
因此,在本發明之一個實施例中,分批製程可用於使包含4或更小之藥物負載物質及6或更大之藥物負載物質之ADC混合物與疏水性樹脂接觸以形成樹脂混合物,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許該4或更小之藥物負載物質之顯著結合;及自該ADC混合物去除該疏水性樹脂,以獲得該包含ADC之組合物,其中該組合物包含小於15%之該6或更大之藥物負載物質,且其中該ADC包含抗體與奧裡斯他汀之結合物。在單獨實施例中,分批製程用於使包含4或更小之藥物負載物質及6或更大之藥物負載物質之ADC混合物與疏水性樹脂接觸以形成樹脂混合物,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許該4或更小之藥物負載物質之顯著結合;及自該ADC混合物去除該疏水性樹脂,以獲得該包含ADC之組合物,其中該組合物包含小於15%之該6或更大之藥物負載物質,且其中該ADC包含抗體與奧裡斯他汀之結合物,其中疏水性樹脂重量係該ADC混合物中之該6或更大之藥物負載物質之重量的3至12倍。
或者,在單獨實施例中,可使用循環製程實施本發明,其中將樹脂填充於容器中並使ADC混合物經過疏水性樹脂床直至已去除欲分離之特定ADC物質。然後自容器抽送上清液(含有期望ADC物質)且樹脂床可經受洗滌步驟。
循環製程可用於使包含4或更小之藥物負載物質及6或更大之藥物負載物質之ADC混合物與疏水性樹脂接觸以形成樹脂混合物,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許該4或更小之藥物負載物質之顯著結合;及自該ADC混合物去除該疏水性樹脂,以獲得該包含ADC之組合物,其中該組合物包含小於15%之該6或更大之藥物負載物質,且其
中該ADC包含抗體與奧裡斯他汀之結合物。在單獨實施例中,循環製程用於使包含4或更小之藥物負載物質及6或更大之藥物負載物質之ADC混合物與疏水性樹脂接觸以形成樹脂混合物,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許該4或更小之藥物負載物質之顯著結合;及自該ADC混合物去除該疏水性樹脂,以獲得該包含ADC之組合物,其中該組合物包含小於15%之該6或更大之藥物負載物質,且其中該ADC包含抗體與奧裡斯他汀之結合物,其中疏水性樹脂重量係該ADC混合物中之該6或更大之藥物負載物質之重量的3至12倍。
或者,在本發明之單獨實施例中,可使用流過式製程實施純化方法,其中將樹脂填充於容器(例如,管柱)中,且使ADC混合物經過經填充樹脂,使得期望ADC物質實質上不結合樹脂並流過樹脂,且不期望ADC物質結合樹脂。流過式製程可以單通模式(其中由於單次通過容器之樹脂而獲得所關注ADC物質)或以多通模式(其中由於多次通過容器之樹脂而獲得所關注ADC物質)實施。實施流過式製程,使得所選重量之樹脂結合不期望ADC群體,且期望ADC(例如,DAR 2-4)流過樹脂並在一或多次通過後收集於流過物中。
在本發明之一個實施例中,流過式製程可用於使包含4或更小之藥物負載物質及6或更大之藥物負載物質之ADC混合物與疏水性樹脂接觸,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許該4或更小之藥物負載物質之顯著結合,其中該4或更小之藥物負載物質穿過該樹脂且隨後在一或多次通過後經收集,以獲得包含期望ADC(例如DAR 2-4)之組合物,其中該組合物包含小於15%之該6或更大之藥物負載物質,且其中該ADC包含抗體與奧裡斯他汀之結合物。在單獨實施例中,流過式製程用於藉由使包含4或更小之藥物負載物質及6或更大之藥物負載物
質之ADC混合物穿過疏水性樹脂使該ADC混合物與該樹脂接觸,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許該4或更小之藥物負載物質之顯著結合,其中該4或更小之藥物負載物質穿過該樹脂且隨後經收集,以獲得該包含ADC之組合物,其中該組合物包含小於15%之該6或更大之藥物負載物質,且其中該ADC包含抗體與奧裡斯他汀之結合物,其中疏水性樹脂重量之量係ADC混合物中6或更大之藥物負載物質之重量的3至12倍。
在本發明之一個實施例中,在流過式製程之後利用一或多次洗滌來洗滌樹脂,以進一步回收具有期望DAR範圍之ADC(在洗滌流中發現)。例如,具有降低傳導性之複數次洗滌可用於進一步回收具有DAR所關注之ADC。自樹脂之洗滌獲得之溶析材料隨後可與源於流過式製程之濾液組合用於改進具有所關注DAR之ADC之回收。
本發明純化方法係基於使用疏水性樹脂來分離ADC之高對低藥物負載物質。疏水性樹脂包含與ADC之疏水性性質交互作用之疏水性基團。ADC上之疏水性基團與疏水性樹脂內之疏水性基團交互作用。蛋白質之疏水性愈高,其與疏水性樹脂交互作用將愈強。
疏水性樹脂通常包含疏水性配體(例如,烷基或芳基)所偶合之基底基質(例如,交聯瓊脂糖或合成共聚物材料)。許多疏水性樹脂可自市面購得。實例包括但不限於具有低或高取代之Phenyl SepharoseTM 6 Fast Flow(Pharmacia LKB Biotechnology,AB,Sweden);Phenyl SepharoseTM High Performance(Pharmacia LKB Biotechnology,AB,Sweden);Octyl SepharoseTM High Performance(Pharmacia LKB Biotechnology,AB,Sweden);FractogelTM EMD Propyl或FractogelTM EMD Phenyl管柱(E.Merck,Germany);Macro-PrepTM Methyl或Macro-PrepTM.t-Butyl Supports(Bio-Rad,California);WP HI-Propyl(C3)TM
(J.T.Baker,New Jersey);和ToyopearlTM醚、己基、苯基或丁基(TosoHaas,PA)。在一個實施例中,疏水性樹脂係丁基疏水性樹脂。在另一實施例中,疏水性樹脂係苯基疏水性樹脂。在另一實施例中,疏水性樹脂係己基疏水性樹脂、辛基疏水性樹脂或癸基疏水性樹脂。在一個實施例中,疏水性樹脂係具有正丁基配體之甲基丙烯酸聚合物(例如TOYOPEARL® Butyl-600M)。
本發明方法係至少部分地基於以下發現:疏水性樹脂可以某些量使用以選擇性地結合具有某些DAR之ADC。樹脂與具有給定DAR之ADC之間之結合取決於樹脂相對於欲自ADC混合物去除之ADC之重量之重量。通過相對於ADC混合物中之特定藥物負載物質重量改變與ADC混合物接觸之樹脂負載量(基於乾重計算),樹脂將選擇性地結合具有例如8或更大之DAR之ADC、具有6-8之DAR之ADC、具有5-8之DAR之ADC等。因此,疏水性樹脂之選擇性取決於樹脂與欲藉由樹脂去除之ADC物質之重量之重量比。在一個實施例中,與ADC混合物接觸之疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的3至12倍。在一個實施例中,與ADC混合物接觸之疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的4至8倍。在一個實施例中,與ADC混合物接觸之疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的5至10倍。在另一實施例中,與ADC混合物接觸之疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的5至7倍。在另一實施例中,與ADC混合物接觸之疏水性樹脂重量係ADC混合物中6或更大之藥物負載物質之重量的5至6倍。例如,如下文實例之表5中所述,採用約5-10樹脂重量(乾)來減少6及8負載藥物物質(3.2mg樹脂/0.54mg 6/8負載物質=約6),從而產生經富集組合物(富集具有小於6之DAR之ADC)。在如下文表7中所述之另一實例中,證明為6及8藥物負載物質約8至12倍之樹脂重量對於減少彼等來
自ADC混合物之物質有效。在如下文表7中所述之又一實例中,證明為6及8藥物負載物質約4倍之樹脂重量對於顯著減少彼等來自ADC混合物之物質有效。
樹脂對於ADC之選擇性可受到樹脂混合物之離子強度與本文鑑別為提供適當負載樹脂:ADC重量比之比率的組合影響,該等重量比導致具有某一期望DAR分佈(例如,6-8之DAR分佈)之ADC之選擇性結合。通常,藉由降低樹脂混合物之離子強度,疏水性樹脂將具有更低吸附性,而增加樹脂混合物之離子強度將提供吸附性更高之樹脂。高鹽濃度有助於ADC吸附至疏水性樹脂,但實際濃度可在寬範圍內變化,此取決於所選ADC之性質及特定疏水性樹脂。一般而言,Na、K或NH4之硫酸鹽有效地促進疏水樹脂中之配體-蛋白質交互作用。所調配之鹽可如由以下關係所給出影響交互作用之強度:(NH4)2SO4>Na2SO4>NaCl>NH4Cl>NaBr>NaSCN。一般而言,可使用以下鹽濃度:在約0.75M與約2M之間之硫酸銨或在約1M與4M之間之NaCl。在一個實施例中,樹脂混合物具有0-2N NaCl之離子強度。可在添加疏水性樹脂之前、同時或之後調節ADC混合物之離子強度。
在一個實施例中,本發明方法使用為ADC混合物中6或更大之藥物負載物質之重量6至12倍之疏水性樹脂重量,其中該ADC混合物具有0至1N NaCl之離子強度或其等效離子強度。在單獨實施例中,使用為ADC混合物中6或更大之藥物負載物質之重量3至6倍之疏水性樹脂重量來實施本發明分離方法,且其中該ADC混合物包含在1N至2N之間之NaCl或其等效離子強度。該方法亦可使用為ADC混合物中6或更大之藥物負載物質之重量3至7倍之疏水性樹脂重量來實施,且其中奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)。分離6或更大之藥物負載物質之另一方法包括使ADC混合物與為6或更大之藥物負載物質之重量5至10倍之疏水性樹脂重量接觸,其中奧裡斯他汀係單甲基奧裡斯
他汀F(MMAF)。
另一純化或加工步驟可在本文所述方法之前或之後實施。例如,在一個實施例中,在超濾/透析過濾製程之後獲得ADC混合物。在另一實施例中,使ADC之經純化組合物經受超濾/透析過濾。
在一個實施例中,本發明方法包括使ADC混合物與疏水性樹脂接觸,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許4或更小之藥物負載物質之顯著結合及自ADC混合物去除疏水性樹脂。疏水性樹脂結合較高藥物負載物質,例如,6或更大之藥物負載物質,而較低藥物負載物質(例如,4或更小之藥物負載物質)主要保留在上清液中。與ADC混合物接觸且不允許4或更小之藥物負載物質之顯著結合之疏水性樹脂的量係在一個實施例中結合35%或更小之4或更小之藥物負載物質之樹脂的量。在某些實施例中,將4或更小之藥物負載物質之顯著結合定義為30%或更小、25%或更小、20%或更小、15%或更小、10%或更小或5%或更小。在其他實施例中,將藥物負載物質之顯著結合定義為30%至1%、25%至1%、20%至1%、15%至1%、10%至1%或5%至1%。
在一個實施例中,本發明方法可用於獲得具有低不期望ADC物質(例如,6或更大之藥物負載物質)含量之組合物。在一個實施例中,本發明組合物具有15%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組合物具有14%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組合物具有13%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組合物具有12%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組合物具有11%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組合物具有10%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組
合物具有9%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組合物具有8%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組合物具有7%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組合物具有6%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組合物具有5%或更小之6或更大之藥物負載物質。在一個實施例中,本發明組合物具有4%或更小之6或更大之藥物負載物質。在其他實施例中,該組合物具有15%至1%之6或更大之藥物負載物質、10%至1%之6或更大之藥物負載物質、5%至1%之6或更大之藥物負載物質、10%至0.5%之6或更大之藥物負載物質或5%至0.5%之6或更大之藥物負載物質。
在一個實施例中,本發明方法可用於產生包含具有4之平均DAR之ADC之組合物。此一組合物可藉由以下方式來獲得:在物質吸收製程中使ADC混合物與一定量之疏水性樹脂接觸以形成樹脂混合物,其中該ADC混合物包含4或更小之藥物負載物質及6或更大之藥物負載物質,且其中疏水性樹脂之量係ADC混合物中6或更大之藥物負載物質之重量的5至10倍;及自該樹脂混合物獲得上清液,以產生包含具有4或更小之平均DAR之ADC之組合物。在一個實施例中,本發明組合物包含具有3.5或更小之平均DAR之ADC。在本發明之一個實施例中,該組合物包含具有3或更小之平均DAR之ADC。在一個實施例中,本發明組合物包含具有2-4之平均DAR之ADC。在本發明之一個實施例中,該組合物包含具有2.4-3.6之平均DAR之ADC。在一個實施例中,該組合物包含ADC且具有4或更小之平均DAR,或或者,3.5或更小之平均DAR、3或更小之平均DAR或2.5或更小之平均DAR。
在一個實施例中,本發明方法可用於產生包含平均藥物對抗體比(DAR)為4或更小之ADC且包含小於15%之不期望ADC的組合物。該方法包括使ADC混合物與疏水性樹脂接觸,其中與該ADC混合物接觸
之疏水性樹脂之量足以允許該等不期望ADC之結合;及自該ADC混合物去除該疏水性樹脂,以產生具有4或更小之平均DAR且包含小於15%之不期望ADC之組合物。在一個實施例中,不期望ADC係6及8藥物負載物質。在一個實施例中,添加至ADC混合物中之疏水性樹脂之量係為ADC混合物中不期望ADC之重量5至10倍的樹脂重量。在另一實施例中,添加至ADC混合物中之疏水性樹脂之量係為ADC混合物中不期望ADC之重量5至7倍的樹脂重量。在一個實施例中,添加至ADC混合物中之疏水性樹脂之量係為ADC混合物中不期望ADC之重量3至12倍的樹脂重量。
ADC之DAR可根據業內之常見方法量測,該等方法包括但不限於ADC之UV/VIS光譜分析及分析型HIC及HPLC,例如,HPLC-MS。
本文所述組合物及方法係至少部分地基於包含特異性結合與奧裡斯他汀結合之EGFR之抗EGFR抗體或其抗原結合部分之抗體藥物結合物(ADC)。
特定而言,本發明係關於方法及包含抗EGFR抗體藥物結合物之組合物,該抗EGFR抗體藥物結合物包含識別在致腫瘤性細胞、過度增殖性細胞或異常細胞中發現之EGFR表位之抗體或其抗原結合部分,其中該表位在正常或野生型細胞中檢測不到。較佳地,在過表現不存在下且在正常EGFR轉譯後修飾存在下,抗體或其抗原結合部分不結合或識別含有正常或野生型EGFR表位之正常或野生型細胞。
適用於本發明組合物及方法之抗EGFR抗體通常為單株且可包括例如嵌合抗體(例如,具有人類恆定區及小鼠可變區)、人類化抗體或人類抗體;單鏈抗體;或諸如此類。免疫球蛋白分子可為任何類型(例如IgG、IgE、IgM、IgD、IgA及IgY)、類別(例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)或亞類之免疫球蛋白分子。例如,用於本
發明之抗EGFR抗體藥物結合物中之抗EGFR抗體可為抗體1。抗體1之序列及特性闡述於下文中(亦參見WO 2011/041319及US20110076232(例如,參見圖55之抗體序列),其全文以引用方式併入本文中)。抗體1靶向存在於50%之所有上皮來源之癌症中之過表現形式之表皮生長因子受體(EGFR)。
在本發明之特定實施例中,用於本發明之抗EGFR抗體藥物結合物中之抗EGFR抗體識別經擴增野生型EGFR及de2-7 EGFR。本發明之抗EGFR抗體顯示可用特異性,原因於其識別de2-7 EGFR及經擴增EGFR,但不識別正常、野生型EGFR或de2-7 EGFR所特有之獨有接合肽。抗體1之序列提供於下文中。
如上文所述,抗體1係人類化抗EGFR抗體。抗體1之重鏈可變(VH)及恆定(CH)區分別以SEQ ID NO:1及5示於下文中。VH區CDR1、CDR2及CDR3(分別為SEQ ID NO:2、3及4)係以下劃線表示。
重鏈可變區胺基酸序列(SEQ ID NO:1)(CDR帶下劃線):
QVQLQESGPGLVKPSQTLSLTCTVSGYSISSDFAWNWIRQPPGKGLEWMGYISYSGN TR
CDR1(SEQ ID NO:2) CDR2(SEQ ID NO:
3)
YQPSLKSRITISRDTS KNQFFLKLNSVTAADTATYYCVTAGRGFPYWGQGTLVTVSSCDR3(SEQ ID NO:4)
重鏈恆定區胺基酸序列(SEQ ID NO:5):
抗體1之輕鏈可變(VL)及恆定(CL)區分別以SEQ ID NO:6及10示於下文中。VL區CDR1、CDR2及CDR3(分別為SEQ ID NO:7、8及9)係以下劃線表示。
輕鏈可變區胺基酸序列(SEQ ID NO:6)(CDR帶下劃線):DIQMTQSPSSMSVSVGDRVTITCHSSQDINSNIGWLQQKPGKSFKGLIYHGTNLDDGV PS CDR1(SEQ ID NO:7) CDR2(SEQ ID NO:8)
RFSGSGSGTDYTLTISSLQPEDFATYYCVQYAQFPWTFGGGTKLEIKR CDR3(SEQ ID NO:9)
輕鏈恆定區胺基酸序列(SEQ ID NO:10):TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
因此,在一個實施例中,抗EGFR抗體(用於本文所述ADC中)包含含有互補決定區1(CDR1)、CDR2及CDR3結構域之輕鏈可變區,該等結構域包含分別如SEQ ID NO:7、SEQ ID NO:8及SEQ ID NO:9中所述之胺基酸序列;且包含含有CDR1、CDR2及CDR3結構域之重鏈可變區,該等結構域包含如SEQ ID NO:2、SEQ ID NO:3及SEQ ID NO:4中所述之胺基酸序列。
在一個實施例中,本發明提供包含含有抗EGFR抗體(結合奧裡斯他汀)之ADC的調配物,該抗EGFR抗體具有包含如胺基酸序列SEQ ID NO:6中所述之CDR之輕鏈可變區、包含如胺基酸序列SEQ ID NO:1中所述之CDR之重鏈可變區。
在一個實施例中,抗EGFR抗體(用於本文所述ADC中)包含含有SEQ ID NO:6中所述之胺基酸序列之輕鏈可變區及包含SEQ ID NO:1中所述之胺基酸序列之重鏈可變區。
在較佳實施例中,用於本發明之方法及組合物中之ADC包含抗EGFR抗體(例如,抗體1)及奧裡斯他汀。在一個實施例中,奧裡斯他汀係單甲基奧裡斯他汀E(MMAE),例如,vc-MMAE。在一個實施例中,奧裡斯他汀係或單甲基奧裡斯他汀F(MMAF),例如,mc-MMAF。
或者,可根據本發明方法製備其他基於奧裡斯他汀之ADC,可用於製備奧裡斯他汀-ADC之抗體之實例包括嵌合抗體、人類抗體及人類化抗體。
可藉由業內已知之任何適宜方法來產生可用於製備ADC(包括抗EGFR抗體藥物結合物)之抗體(包括抗EGFR抗體)。例如,可使用眾多種技術(包括例如使用融合瘤、重組及噬菌體顯示技術或其組合)來製備單株抗體。融合瘤技術通常論述於例如Harlow等人,Antibodies:A Laboratory Manual,(Cold Spring Harbor Laboratory Press,第2版,1988)及Hammerling等人,Monoclonal Antibodies and T-Cell Hybridomas,第563-681頁(Elsevier,N.Y.,1981)中。可用於製備抗CD70抗體之噬菌體顯示方法之實例包括例如彼等揭示於以下文獻中者:Brinkman等人,1995,J Immunol Methods 182:41-50;Ames等人,1995,J Immunol Methods 184:177-186;Kettleborough等人,1994,Eur J Immunol 24:952-958;Persic等人,1997,Gene 187:9-18;Burton等人,1994,Advances in Immunology 57:191-280;PCT申請案第PCT/GB91/01 134號;PCT公開案WO 90/02809、WO 91/10737、WO 92/01047、WO 92/18619、WO 93/11236、WO 95/15982、WO 95/20401及美國專利第5,698,426號、第5,223,409號、第5,403,484號、第5,580,717號、第5,427,908號、第5,750,753號、第5,821,047號、第5,571,698號、第5,427,908號、第5,516,637號、第5,780,225號、第5,658,727號、第5,733,743號及第5,969,108號(其揭示內容以引用方式
併入本文中)。
用於表現本發明重組抗體之哺乳動物宿主細胞包括中國倉鼠卵巢細胞(CHO細胞)(包括dhfr-CHO細胞,其闡述於Urlaub及Chasin,(1980)Proc.Natl.Acad.Sci.USA 77:4216-4220中,其與DHFR可選標記物(例如,如Kaufman及Sharp(1982)J.Mol.Biol.159:601-621中所述)連用)及DG44或DUXB11細胞(Urlaub等人(1986)Som.Cell Molec.Genet.12:555;Haynes等人(1983)Nuc.Acid.Res.11:687-706;Lau等人(1984)Mol.Cell.Biol.4:1469-1475)、NS0骨髓瘤細胞、猴腎細胞系(例如,CVI及COS,例如COS 7細胞)、SP2細胞、人類胚腎(HEK)細胞(例如HEK-293細胞)、中國倉鼠纖維母細胞(例如,R1610)、人類子宮頸癌(例如,HELA)、鼠類纖維母細胞(例如,BALBc/3T3)、鼠類骨髓瘤(P3x63-Ag3.653;NS0;SP2/O)、倉鼠腎細胞系(例如,HAK)、鼠類L細胞(例如,L-929)、人類淋巴球(例如,RAJI)、人腎(例如,293及293T)。宿主細胞系通常可自市面購得(例如,來自BD Biosciences,Lexington,Ky.;Promega,Madison,Wis.;Life Technologies,Gaithersburg,Md.)或來自美國典型培養物保藏中心(American Type Culture Collection,ATCC,Manassas,Va.)。
當將編碼抗體之重組表現載體引入哺乳動物宿主細胞中時,藉由將宿主細胞培養一段時間來產生抗體,該段時間足以使宿主細胞中表現抗體或使抗體分泌至生長宿主細胞之培養基中。可使用標準蛋白質純化方法自培養基回收抗體。
在用於重組表現抗體之實例性系統中,藉由磷酸鈣介導之轉染將編碼抗體重鏈與抗體輕鏈兩者之重組表現載體引入dhfr-CHO細胞中。在重組表現載體內,抗體重鏈及輕鏈cDNA各自可操作地連接至CMV增強子/AdMLP啟動子調控元件以驅動cDNA之高程度轉錄。重組表現載體亦攜帶編碼DHFR之cDNA,從而使得可對已利用胺甲蝶呤
選擇/擴增經載體轉染之CHO細胞進行選擇。對所選轉化體宿主細胞進行培養以允許表現抗體重鏈及輕鏈並自培養基回收完整抗體。使用標凖分子生物學技術來製備重組表現載體,對宿主細胞實施轉染,選擇轉化體,培養宿主細胞並自培養基回收抗體。此外,本發明提供藉由在適宜培養基中培養本發明宿主細胞直至合成抗體來合成該抗體之方法。該方法可進一步包含自培養基分離抗體。
在較佳實施例中,抗EGFR抗體或其抗原結合部分結合奧裡斯他汀(一或多種)。已顯示奧裡斯他汀干擾微管動力學、GTP水解及/或細胞核及細胞分裂且具有抗癌及/或抗真菌活性。奧裡斯他汀代表一群多拉司他汀類似物,其通常藉由干擾微管動力學及GTP水解由此抑制細胞分裂而顯示具有抗癌活性。例如,奧裡斯他汀E(美國專利第5,635,483號,以引用方式併入本文中)係海洋天然產物多拉司他汀10之合成類似物,多拉司他汀10係藉由結合微管蛋白上與抗癌藥物長春新鹼相同之位點來抑制微管蛋白聚合之化合物(G.R.Pettit,Prog.Chem.Org.Nat.Prod,70:1-79(1997))。多拉司他汀10、奧裡斯他汀PE及奧裡斯他汀E係具有4個胺基酸、其中3個係多拉司他汀類別化合物所獨有之線性肽。奧裡斯他汀亞類有絲分裂抑制劑之實例性實施例包括但不限於單甲基奧裡斯他汀D(MMAD或奧裡斯他汀D衍生物)、單甲基奧裡斯他汀E(MMAE或奧裡斯他汀E衍生物)、單甲基奧裡斯他汀F(MMAF或MMAF衍生物)、奧裡斯他汀F苯二胺(AFP)、奧裡斯他汀EB(AEB)、奧裡斯他汀EFP(AEFP)及5-苯甲醯基戊酸-AE酯(AEVB)。奧裡斯他汀衍生物之合成及結構闡述於以下文獻中:美國專利申請公開案第2003-0083263號、第2005-0238649號及第2005-0009751號;國際專利公開案第WO 04/010957號;國際專利公開案第WO 02/088172號及美國專利第6,323,315號、第6,239,104號、第6,034,065號、第5,780,588號、第5,665,860號、第5,663,149號、第
5,635,483號、第5,599,902號、第5,554,725號、第5,530,097號、第5,521,284號、第5,504,191號、第5,410,024號、第5,138,036號、第5,076,973號、第4,986,988號、第4,978,744號、第4,879,278號、第4,816,444號及第4,486,414號,其每一者以引用方式併入本文中。
在一個實施例中,本發明之抗EGFR抗體結合至少一種MMAF(單甲基奧裡斯他汀F)。單甲基奧裡斯他汀F(MMAF)藉由阻斷微管蛋白之聚合來抑制細胞分裂。其具有帶電C末端苯基丙胺酸殘基,該殘基相較於其不帶電之對應體MMAE衰減其細胞毒性活性。由於其超級毒性,因此其本身不能用作藥物,但可連接至將其引導至癌細胞之單株抗體(mAb)。在一個實施例中,連接至抗EGFR抗體之連接體在細胞外液中係穩定的,但在結合物進入腫瘤細胞後由組織蛋白酶解離,由此活化抗有絲分裂機制。在一個實施例中,使用不可解離之馬來醯亞胺基己醯基(mc)連接物使抗體1結合MMAF。MMAF之結構提供於圖1中。
在一個實施例中,本發明之抗EGFR抗體結合至少一種MMAE(單甲基奧裡斯他汀E)。單甲基奧裡斯他汀E(MMAE,維多汀(vedotin))藉由阻斷微管蛋白之聚合來抑制細胞分裂。由於其超級毒性,因此其本身亦不能用作藥物。在最近之癌症療法研發中,將其連接至識別癌細胞中表現之特異性標記物且將MMAE引導至癌細胞之單株抗體(mAb)。在一個實施例中,將MMAE連接至抗EGFR抗體之連接體在細胞外液(即,細胞外部之介質或環境)中係穩定的,但在ADC已結合特異性癌細胞抗原並進入癌細胞後由組織蛋白酶解離,由此釋放毒性MMAE並活化有效抗有絲分裂機制。MMAE之結構提供於圖1中。
用於將治療劑結合至蛋白質且特定而言結合至抗體之技術係眾所周知的。(例如,參見Arnon等人,「Monoclonal Antibodies For
Immunotargeting Of Drugs In Cancer Therapy」,Monoclonal Antibodies And Cancer Therapy(Reisfeld等人編輯,Alan R.Liss公司,1985);Hellstrom等人,「Antibodies For Drug Delivery」,Controlled Drug Delivery(Robinson等人編輯,Marcel Dekker公司,第2版,1987);Thorpe,「Antibody Carriers Of Cytotoxic Agents In Cancer Therapy:A Review」,Monoclonal Antibodies '84:Biological And Clinical Applications(Pinchera等人編輯,1985);「Analysis,Results,and Future Prospective of the Therapeutic Use of Radiolabeled Antibody In Cancer Therapy」,Monoclonal Antibodies For Cancer Detection And Therapy(Baldwin等人編輯,Academic Press,1985);及Thorpe等人,1982,Immunol.Rev.62:119-58。亦例如參見PCT公開案WO 89/12624)。
在一個實施例中,抗EGFR-ADC包含在細胞毒性藥物與抗體之間之連接體區。例如,此等連接體、間隔體及/或拉伸體(stretcher)化合物包括但不限於以下:胺基苯甲酸間隔體(例如且不受限制,參見美國專利第7,091,186號及第7,553,816號,該等專利中每一者之全文皆在此以引用方式併入);馬來醯亞胺基己醯基;對胺基苄基胺基甲醯基(PAB);溶酶體醇可解離連接體(例如且不受限制,參見美國專利第6,214,345號,其全文在此引用方式併入);馬來醯亞胺基己醯基-聚乙二醇20(MC(PEG)6-OH);N-甲基-纈胺酸瓜胺酸;4-(N-馬來醯亞胺基甲基)環己烷-1-甲酸N-琥珀醯亞胺基酯(SMCC)(例如且不受限制,參見Yoshitake等人(1979)Eur.J.Biochem.,101,395-399,其全文在此以引用方式併入);4-(2-吡啶基二硫基)丁酸N-琥珀醯亞胺基酯(SPDB)(例如且不受限制,參見美國專利第4,563,304號,其全文在此以引用方式併入);4-(2-吡啶基硫基)戊酸N-琥珀醯亞胺基酯(SPP);纈胺酸-瓜胺酸(vc);及其他連接體、間隔體及/或拉伸體化合物(例如且不受
限制,參見美國專利第7,090,843號、第7,223,837號及第7,659,241號及美國專利公開案第2004/0018194號、第2004/0121940號、第2006/0116422號、第2007/0258987號、第2008/0213289號、第2008/0241128號、第2008/0311136號、第2008/0317747號及第2009/0010945號,其每一者之全文在此以引用方式併入)。一般而言,用於將上文所述之藥劑以及其他藥劑附著及/或結合至本發明之特異性結合成員、尤其抗體及其片段之技術為業內已知。例如且不受限制,參見Amon等人,「Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy」,Monoclonal Antibodies And Cancer Therapy,Reisfeld等人(編輯),第243至56頁(Alan R.Liss公司1985);Hellstrom等人,「Antibodies For Drug Delivery」,Controlled Drug Delivery(第2版);Robinson等人(編輯),第623-53頁(Marcel Dekker公司1987);Thorpe,「Antibody Carriers Of Cytotoxic Agents In Cancer Therapy:A Review」,Monoclonal Antibodies '84:Biological And Clinical Applications,Pinchera等人(編輯),第475-506頁(1985);「Analysis,Results,And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy」,Monoclonal Antibodies For Cancer Detection And Therapy;Baldwin等人(編輯),第303-16頁(Academic Press 1985)及Thorpe等人,「The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates」,Immunol.Rev.,62:119-58(1982),其每一者之全文在此以引用方式併入。
多個不同反應可用於將藥物共價附著至抗體。此經常係藉由抗體分子之胺基酸殘基(包括離胺酸之胺基、麩胺酸及天冬胺酸之游離羧酸基、半胱胺酸之巰基及芳香族胺基酸之各部分)之反應來達成。最常用之非特異性共價附著方法之一係碳二亞胺反應以將化合物之羧基(或胺基)連接至抗體之胺基(或羧基)。另外,已使用諸如二醛或醯
亞胺酯等二官能劑來將化合物之胺基連接至抗體分子之胺基。希夫鹼(Schiff base)反應亦可用於將藥物附著至抗體。此方法涉及含有二醇基或羥基之藥物之過碘酸氧化,由此形成醛,其然後與抗體分子反應。附著經由與抗體分子之胺基形成希夫鹼進行。亦可使用異硫氰酸酯作為用於將藥物共價附著至抗體之偶合劑。其他技術為熟習此項技術者已知且在本發明範圍內。此等技術之非限制性實例闡述於例如美國專利第5,665,358號、第5,643,573號及第5,556,623號中,該等專利之全文以引用方式併入本文中。
在某些實施例中,使為連接體之前體之中間體在適當條件下與藥物反應。在某些實施例中,在藥物及/或中間體上使用反應性基團。隨後使藥物與中間體之間之反應產物或衍生化藥物與抗EGFR抗體在適當條件下反應。
結合方法之其他實例闡述於美國專利第7,837,980號(Seattle Genetics)、Carter及Senter(2008)Cancer J,14(3):154以及美國已公開申請案第2004-0157782 A1號及第2005-0238649號及國際專利申請案第PCT/US04/038392號中。
在本發明之一個實施例中,抗EGFR抗體或其抗原結合部分結合為MMAF之奧裡斯他汀。在一個實施例中,抗EGFR ADC係抗體1-mc-MMAF。抗體1-mc-MMAF包含共價連接至一或多個單甲基奧裡斯他汀F(MMAF)分子(結構參見圖1)之抗體1(上文及SEQ ID NO:1至10中所述)。為了產生抗體1-me-MMAF,將抗體1之鏈間二硫鍵還原成巰基。然後MMAF經由該等巰基偶合至抗體。抗體1-mc-MMAF係使用不可解離之連接體(即,如圖1中所示之不可解離之馬來醯亞胺基己醯基(mc)連接物)來產生。
在本發明之一個實施例中,抗EGFR抗體或其抗原結合部分結合為MMAE之奧裡斯他汀。在一個實施例中,抗EGFR ADC包含抗體1-
vc-MMAE。抗體1-vc-MMAF包含共價連接至一或多個單甲基奧裡斯他汀E(MMAE)分子(結構參見圖1)之抗體1(上文及SEQ ID NO:1至10中所述)。為了產生抗體1-vc-MMAE,將抗體1之鏈間二硫鍵還原成巰基。然後vcMMAE經由該等巰基偶合至抗體。抗體1-vc-MMAE係使用如圖1中所示之纈胺酸瓜胺酸連接體(vc)來產生,由此形成抗體1-vc-MMAE。
根據本發明方法,向患有需要用抗EGFR抗體治療之病症(或具有此風險)之個體投與包含具有期望平均DAR之抗EGFR ADC之組合物。包含抗EGFR ADC之調配物可單獨或與其他組合物組合投與用以預防或治療需要用抗EGFR抗體治療之病症。
如本文所用之術語「EGFR有害之病症」意欲包括疾病及其他病症,其中已顯示EGFR在罹患該病症之個體中之存在係或懷疑係造成該病症病理生理學的原因或導致該病症惡化之因素。因此,EGFR活性有害之病症係其中預計抑制EGFR活性可緩和病症之症狀及/或進展的病症。此等病症可例如藉由存在於來自罹患該病症之個體之生物試樣中之EGFR活性的增加或EGFR之量的增加(例如,個體之組織試樣、血清、血漿、滑液等中之EGFR濃度之增加)來證明,該增加可例如使用抗EGFR抗體檢測。
因此,具有例如2-4之平均DAR之本發明之ADC組合物可用於治療癌症。可治療之癌症之實例包括但不限於神經膠母細胞瘤、非小細胞肺癌、鱗狀非小細胞肺癌(NSCLC)、肺癌、結腸癌、頭頸癌、乳癌、鱗狀細胞瘤、肛門癌、皮膚癌及陰門癌。具有期望平均DAR之ADC組合物亦可用於治療患有可能過表現表皮生長因子受體(EGFR)之實體瘤或多形性神經膠母細胞瘤之個體。
在一個實施例中,具有例如2-4之平均DAR之本發明之經純化
ADC組合物用於治療結腸直腸癌、頭頸癌(包括但不限於咽下癌、口咽癌、食道癌、喉癌及口腔癌)、非小細胞肺癌、鱗狀非小細胞肺癌(NSCLC)、胰腺癌、胃癌、實體瘤、可能過表現表皮生長因子受體(EGFR)之實體瘤、多形性神經膠母細胞瘤及乳癌。此等癌症之更特定實例包括鱗狀瘤(包括、肺、頭頸、子宮頸等之鱗狀瘤)、神經膠母細胞瘤、神經膠質瘤、肺癌、結腸癌、頭頸癌、乳癌、鱗狀細胞瘤、肛門癌、皮膚癌及陰門癌。
包含抗EGFR ADC之組合物之獨有特異性提供用以鑑別、表徵、靶向及治療、降低或消除多個致腫瘤性細胞類型及腫瘤類型之診斷及治療用途,該等致腫瘤性細胞類型及腫瘤類型例如但不限於神經膠母細胞瘤、非小細胞肺癌、肺癌、結腸癌、頭頸癌、乳癌、鱗狀細胞瘤、肛門癌、皮膚癌、可能過表現表皮生長因子受體(EGFR)之實體瘤、多形性神經膠母細胞瘤及陰門癌,而沒有可利用先前已知之EGFR抗體見到之與正常組織攝取相關之問題。因此,可利用本發明之抗體或其片段來識別、分離、表徵、靶向及治療或消除過表現EGFR(例如藉由突變或變體EGFR之擴增或表現)之細胞及(在特定實施例中)彼等表現異常轉譯後修飾者。本發明組合物可用於治療EGFR陽性腫瘤。檢測腫瘤中之EGFR表現之方法為業內已知,例如,EGFR pharmDxTM Kit(Dako)。相反,將「EGFR陰性腫瘤」定義為如藉由免疫組織化學技術所測定腫瘤試樣中不存在高於背景之EGFR膜染色之腫瘤。
在本發明之一個態樣中,提供治療個體之方法,其包含投與治療有效量之如本文所述任一組合物中之抗EGFR ADC,其中該個體患有需要用組合物中之抗EGFR抗體治療之病症(例如腫瘤、癌性病況、癌前期病況及與過度增殖性細胞生長有關或源於其之任何病況)。
因此包含抗EGFR ADC之組合物可藉由染色或以其他方式識別彼
等其中存在EGFR過表現、尤其擴增及/或EGFR突變、尤其de2-7EGFR之腫瘤或細胞來特異性地分類EGFR腫瘤或致腫瘤性細胞之性質。
因此,在本發明之又一態樣中,提供治療腫瘤、癌性病況、癌前期病況及與過度增殖性細胞生長有關或源於其之任何病況之方法,其包含投與包含含有抗體1之抗EGFR ADC之本發明組合物。
各種遞送系統係已知的且可用於投與本發明之抗EGFR ADC組合物。引入方法包括但不限於真皮內、肌內、腹膜內、靜脈內、皮下、鼻內、硬膜外及經口途徑。ADC可例如藉由輸注或推注、藉由經由上皮或黏膜皮膚襯裡(例如,口腔黏膜、直腸及腸黏膜及諸如此類)吸收投與且可與諸如化學治療劑等其他生物活性劑一起投與。投與可為全身性或局部。在一個實施例中,將本發明調配物經靜脈內遞送至個體。在另一實施例中,將本發明調配物經皮下遞送至個體。在一個實施例中,個體自身投與調配物(自投與)。
有效治療或預防需要用調配物中之抗EGFR抗體治療之病症(例如癌症)之ADC的量可藉由標準臨床技術測定。另外,可視情況採用活體外分析來幫助確定最佳劑量範圍。調配物中所用確切劑量亦將取決於投與途徑及免疫病症或表現EGFR之癌症之階段,且應根據從業醫師之判斷及每一患者之情況來決定。在一個實施例中,投與治療有效量之調配物。如本文所用之術語抗體之「治療有效量」或「有效量」係指有效預防或治療或緩和可經該抗體有效治療之病症之症狀的量。調配物之治療有效量之實例係足以抑制有害EGFR活性或治療EGFR活性有害之病症之量。
抗EGFR ADC之劑量可例如每天一次、每週一次(once per week、weekly)、每週兩次、每週三次、每週四次、每週五次、每兩週一次、每三週一次、每月一次、每四周一次、服用兩週/停用一週或視需要以其他方式投與。
因此,除了活性成份(ADC)外,根據本發明及用於本發明之醫藥組合物亦可包含醫藥上可接受之賦形劑、載劑、緩衝液、穩定劑或熟習此項技術者熟知之其他材料。此等材料應無毒且應不干擾活性成份之功效。載劑或另一材料之確切性質可取決於投與途徑,其可為經口或藉由注射,例如靜脈內。在一個實施例中,醫藥組合物包含ADC(例如,抗EGFR抗體,例如結合MMAE或MMAF之抗體1)及醫藥上可接受之載劑。如本文所用之「醫藥上可接受之載劑」包括任何及所有溶劑、分散介質、塗料、抗細菌及抗真菌劑、等滲劑及吸收延遲劑及生理上相容之類似試劑。醫藥上可接受之載劑之實例包括以下中之一或多者以及其組合:水、鹽水、磷酸鹽緩衝鹽水、右旋糖、甘油、乙醇及諸如此類。在許多情況下,較佳可將等滲劑,例如,糖、多元醇(例如,甘露醇、山梨醇)或氯化鈉納入組合物中。
在某些實施例中,可向個體共投與抗EGFR ADC與一或多種其他治療劑以治療癌症。術語「共投與」意指藉由相同醫藥組合物之組合或單獨醫藥組合物向個體投與兩種或更多種不同醫藥劑或治療(例如,放射治療)。因此共投與涉及同時投與包含兩種或更多種醫藥劑之單一醫藥組合物或同時或於不同時間向同一個體投與兩種或更多種不同組合物。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,其中該等藥劑之實例包括例如放射、烷基化劑、血管生成抑制劑、抗體、抗代謝物、抗有絲分裂物、抗增生物、抗病毒劑、極光激酶抑制劑(aurora kinase inhibitor)、細胞凋亡促進劑(例如Bcl-xL、Bcl-w及Bfl-1)抑制劑、死亡受體途徑活化劑、Bcr-Abl激酶抑制劑、BiTE(雙特異性T細胞銜接體(Engager))抗體、抗體藥物結合物、生物反應調節劑、週期蛋白依賴性激酶抑制劑、細胞週期抑制劑、環氧合酶-2抑制劑、DVD(雙重可變結構域抗體)、白血病病毒致癌基因同系物
(ErbB2)受體抑制劑、生長因子抑制劑、熱休克蛋白(HSP)-90抑制劑、組蛋白去乙醯酶(HDAC)抑制劑、激素治療劑、免疫劑、細胞凋亡蛋白抑制劑(IAP)、嵌入抗生素、激酶抑制劑、致動蛋白抑制劑、Jak2抑制劑、哺乳動物雷帕黴素(rapamycin)靶標抑制劑、微小RNA之促分裂原活化之細胞外信號調節激酶抑制劑、多價結合蛋白、非類固醇抗炎藥(NSAID)、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制劑、鉑化學治療劑、polo樣激酶(Plk)抑制劑、磷酸肌醇-3激酶(布羅莫結構域(bromodomain))抑制劑、蛋白體抑制劑、嘌呤類似物、嘧啶類似物、受體酪胺酸激酶抑制劑、類視色素/類維生素D(deltoid)植物生物鹼、小抑制核糖核酸(siRNA)、拓撲異構酶抑制劑、替莫唑胺(temozolomide)、泛素連接酶抑制劑及諸如此類及一或多種該等試劑之組合。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括BiTE抗體,其係藉由同時結合兩種細胞來引導T-細胞以攻擊癌細胞之雙特異性抗體。隨後T細胞攻擊靶標癌細胞。BiTE抗體之實例包括阿德木單抗(adecatumumab)(Micromet MT201)、不來木單抗(blinatumomab)(Micromet MT103)及諸如此類。不受限於理論,T細胞誘發靶標癌細胞凋亡之一種機制係藉由細胞溶解顆粒組份(其包括穿孔蛋白及顆粒酶B)之胞吐作用。就此而言,Bcl-2已顯示可減弱穿孔蛋白及顆粒酶B兩者對於細胞凋亡之誘導。該等數據表明抑制Bcl-2可增強T細胞在靶向癌細胞時誘發之細胞毒性效應(V.R.Sutton,D.L.Vaux及J.A.Trapani,J.of Immunology 1997,158(12),5783)。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括siRNA)共投與。SiRNA係具有內源性RNA鹼基或化學改質核苷酸之分子。改質不會消除細胞活性,而是賦予增大之穩定性及/或增
大之細胞效能。化學改質之實例包括硫代磷酸酯基團、2’-去氧核苷酸、含有2’-OCH3之核糖核苷酸、2’-F-核糖核苷酸、2’-甲氧基乙基核糖核苷酸、其組合及諸如此類。siRNA可具有不同長度(例如,10-200bp)及結構(例如,髮夾形、單鏈/雙鏈、凸起、凹痕/空隙、失配)且可在細胞中處理以提供活性基因沉默。雙鏈siRNA(dsRNA)可在各鏈(鈍端)或不對稱端(突出端)上具有相同數量之核苷酸。1至2個核苷酸之突出端可存在於有義鏈及/或反義鏈上,亦可存在於給定鏈之5’-及/或3’-末端。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括DVD及其他多價結合蛋白質)共投與。多價結合蛋白係包含兩個或更多個抗原結合位點之結合蛋白。將多價結合蛋白改造為具有三個或更多個抗原結合位點且通常為不天然存在之抗體。術語「多特異性結合蛋白」意指能夠結合兩個或更多個相關或不相關靶標之結合蛋白。雙重可變結構域(DVD)結合蛋白係結合包含兩個或更多個抗原結合位點之蛋白的四價或多價結合蛋白。此等DVD可具有單特異性(即,能夠結合一種抗原)或多特異性(即,能夠結合兩種或更多種抗原)。包含兩條重鏈DVD多肽及兩條輕鏈DVD多肽之DVD結合蛋白稱作DVD Ig。DVD Ig之每一半部均包含重鏈DVD多肽、輕鏈DVD多肽及兩個抗原結合位點。各結合位點包含重鏈可變結構域及輕鏈可變結構域,每個抗原結合位點具有總共6個參與抗原結合之CDR。多特異性DVD包括結合DLL4及VEGF、或C-met及EFGR或ErbB3及EGFR之DVD結合蛋白。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括烷基化劑)共投與。烷基化劑包括六甲嘧胺、AMD-473、AP-5280、阿帕齊醌(apaziquone)、苯達莫司汀(bendamustine)、伯斯坦尼辛(brostallicin)、白消安(busulfan)、卡波醌(carboquone)、卡莫司汀
(carmustine)(BCNU)、苯丁酸氮芥(chlorambucil)、CLORETAZINE®(拉羅司汀(laromustine),VNP 40101M)、環磷醯胺、達卡巴嗪(decarbazine)、雌莫司汀(estramustine)、福莫司汀(fotemustine)、麥磺醯胺(glufosfamide)、異環磷醯胺(ifosfamide)、KW-2170、洛莫司汀(lomustine)(CCNU)、馬磷醯胺(mafosfamide)、黴法蘭(melphalan)、二溴甘露醇(mitobronitol)、二溴衛矛醇(mitolactol)、尼莫司汀(nimustine)、氮芥N-氧化物、雷莫司汀(ranimustine)、替莫唑胺、噻替哌(thiotepa)、TREANDA®(苯達莫司汀)、曲奧舒凡(treosulfan)、曲磷胺(rofosfamide)及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括血管生成抑制劑)共投與。血管生成抑制劑包括內皮特異性受體酪胺酸激酶(Tie-2)抑制劑、表皮生長因子受體(EGFR)抑制劑、胰島素生長因子-2受體(IGFR-2)抑制劑、基質金屬蛋白酶-2(MMP-2)抑制劑、基質金屬蛋白酶-9(MMP-9)抑制劑、血小板源生長因子受體(PDGFR)抑制劑、凝血酶敏感蛋白類似物、血管內皮生長因子受體酪胺酸激酶(VEGFR)抑制劑及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括抗代謝物)共投與。抗代謝物包括ALIMTA®(美曲塞二鈉(pemetrexed disodium)、LY231514、MTA)、5-阿紮胞苷(5-azacitidine)、XELODA®(卡培他濱(capecitabine))、卡莫氟(carmofur)、LEUSTAT®(克拉屈濱(cladribine))、氯法拉濱(clofarabine)、阿糖胞苷(cytarabine)、阿糖胞苷十八烷基磷酸酯(cytarabine ocfosfate)、胞嘧啶阿拉伯糖苷、地西他濱(decitabine)、去鐵胺、去氧氟尿苷、依氟鳥胺酸(eflornithine)、EICAR(5-乙炔基-1-β-D-核糖呋喃基咪唑-4-甲醯胺)、依諾他濱(enocitabine)、乙炔基胞苷、氟達拉濱(fludarabine)、單獨5-氟尿嘧啶或與甲醯四氫葉酸
(leucovorin)組合、GEMZAR®(吉西他濱(gemcitabine))、羥基脲、ALKERAN®(黴法蘭)、巰基嘌呤、6-巰基嘌呤核苷、胺甲蝶呤、黴酚酸(mycophenolic acid)、耐拉濱(nelarabine)、諾拉曲塞(nolatrexed)、十八烷基磷酸酯(ocfosfate)、培裡克松(pelitrexol)、噴司他丁(pentostatin)、雷替曲塞(raltitrexed)、利巴韋林(Ribavirin)、特那平(triapine)、曲美沙特(trimetrexate)、S-1、噻唑呋林(tiazofurin)、替加氟(tegafur)、TS-1、阿糖腺苷(vidarabine)、UFT及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括抗病毒劑)共投與。抗病毒劑包括利托那韋(ritonavir)、羥氯喹及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括極光激酶抑制劑)共投與。極光激酶抑制劑包括ABT-348、AZD-1152、MLN-8054、VX-680、極光A特異性激酶抑制劑、極光B特異性激酶抑制劑、pan-極光激酶抑制劑及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括Bcl-2蛋白質抑制劑)共投與。Bcl-2蛋白抑制劑包括AT-101((-)棉酚(gossypol))、GENASENSE®(G3139或奧利默森(oblimersen)(Bcl-2-靶向反義寡核苷酸))、IPI-194、IPI-565、N-(4-(4-((4'-氯(1,1'-聯苯)-2-基)甲基)六氫吡嗪-1-基)苯甲醯基)-4-(((1R)-3-(二甲基胺基)-1-((苯基硫烷基)甲基)丙基)胺基)-3-硝基苯磺醯胺)(ABT-737)、N-(4-(4-((2-(4-氯苯基)-5,5-二甲基-1-環己-1-烯-1-基)甲基)六氫吡嗪-1-基)苯甲醯基)-4-(((1R)-3-(嗎啉-4-基)-1-((苯基硫烷基)甲基)丙基)胺基)-3-((三氟甲基)磺醯基)苯磺醯胺(ABT-263)、GX-070(奧巴克拉(obatoclax))、ABT-199及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括Bcr-Abl激酶抑制劑,例如DASATINIB®(BMS-
354825)、GLEEVEC®(伊馬替尼(imatinib))及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括CDK抑制劑)共投與。CDK抑制劑包括AZD-5438、BMI-1040、BMS-032、BMS-387、CVT-2584、夫拉平度(flavopyridol)、GPC-286199、MCS5A、PD0332991、PHA-690509、斯利西克(seliciclib)(CYC-202或R-羅克韋汀(R-roscovitine))、ZK-304709及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括COX-2抑制劑)共投與。COX-2抑制劑包括ABT-963、ARCOXIA®(依託考昔(etoricoxib))、BEXTRA®(伐地考昔(valdecoxib))、BMS347070、CELEBREX®(塞來考昔(celecoxib))、COX-189(魯米考昔(lumiracoxib))、CT-3、DERAMAXX®(地拉考昔(deracoxib))、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-胺磺醯基苯基-1H-吡咯)、MK-663(依託考昔)、NS-398、帕瑞考昔(parecoxib)、RS-57067、SC-58125、SD-8381、SVT-2016、S-2474、T-614、VIOXX®(羅非考昔(rofecoxib))及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括其他EGFR抑制劑)共投與。EGFR抑制劑包括EGFR抗體、ABX-EGF、抗-EGFR免疫脂質體、EGF-疫苗、EMD-7200、ERBITUX®(西土西單抗(cetuximab))、HR3、IgA抗體、IRESSA®(吉非替尼(gefitinib))、TARCEVA®(埃羅替尼(erlotinib)或OSI-774)、TP-38、EGFR融合蛋白、TYKERB®(拉帕替尼(lapatinib))及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括HER2抑制劑)共投與。ErbB2受體抑制劑包括CP-724-714、CI-1033(卡納替尼(canertinib))、HERCEPTIN®(曲司佐單抗(trastuzumab))、TYKERB®(拉帕替尼)、OMNITARG®(2C4、佩佐單
抗(petuzumab))、TAK-165、GW-572016(洛那法尼(ionafarnib))、GW-282974、EKB-569、PI-166、dHER2(HER2疫苗)、APC-8024(HER-2疫苗)、抗-HER/2neu雙特異性抗體、B7.her2IgG3、AS HER2三功能雙特異性抗體、mAB AR-209、mAB 2B-1及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括組蛋白去乙醯酶抑制劑,例如縮酚酸肽、LAQ-824、MS-275、曲坡欣(trapoxin)、辛二醯醯替苯胺羥胺酸(SAHA)、TSA、丙戊酸及諸如此類。
抗EGFR ADC與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括HSP-90抑制劑,包括17-AAG-nab、17-AAG、CNF-101、CNF-1010、CNF-2024、17-DMAG、格爾德黴素(geldanamycin)、IPI-504、KOS-953、MYCOGRAB®(連接至HSP-90之人類重組抗體)、NCS-683664、PU24FCl、PU-3、根赤殼菌素(radicicol)、SNX-2112、STA-9090 VER49009及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括細胞凋亡蛋白質抑制劑,例如HGS1029、GDC-0145、GDC-0152、LCL-161、LBW-242及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括其他ADC,例如抗CD22-MC-MMAF、抗CD22-MC-MMAE、抗CD22-MCC-DM1、CR-011-vcMMAE、PSMA-ADC、MEDI-547、SGN-19Am SGN-35、SGN-75及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括死亡受體途徑活化劑,例如TRAIL,靶向TRAIL或死亡受體(例如,DR4及DR5)之抗體或其他藥劑,例如阿普單抗(Apomab)、可那木單抗(conatumumab)、ETR2-ST01、GDC0145(來沙木單抗(lexatumumab))、HGS-1029、LBY-135、PRO-1762及曲司佐單
抗。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括致動蛋白抑制劑,例如Eg5抑制劑,例如AZD4877、ARRY-520;CENPE抑制劑,例如GSK923295A及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括JAK-2抑制劑,例如CEP-701(來他替尼(lesaurtinib))、XL019及INCB018424及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括MEK抑制劑,例如ARRY-142886、ARRY-438162PD-325901、PD-98059及諸如此類。
抗EGFR ADC(或包含抗EGFR ADC之調配物)可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括mTOR抑制劑,例如AP-23573、CCI-779、依維莫司(everolimus)、RAD-001、雷帕黴素、替西羅莫司(temsirolimus)、ATP-競爭性TORC1/TORC2抑制劑,包括PI-103、PP242、PP30、托瑞1(Torin)1及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括非類固醇抗炎藥(NSAID),例如AMIGESIC®(雙水楊酯)、DOLOBID®(雙氟尼酸(diflunisal))、MOTRIN®(布洛芬(ibuprofen))、ORUDIS®(酮洛芬(ketoprofen))、RELAFEN®(萘丁美酮(nabumetone))、FELDENE®(吡羅昔康(piroxicam))、布洛芬乳霜、ALEVE®(萘普生(naproxen))及NAPROSYN®(萘普生)、VOLTAREN®(雙氯芬酸(diclofenac))、INDOCIN®(吲哚美辛(indomethacin))、CLINORIL®(舒林酸(sulindac))、TOLECTIN®(托美汀(tolmetin))、LODINE®(依託度酸(etodolac))、TORADOL®(酮咯酸(ketorolac))、DAYPRO®(奧沙普秦(oxaprozin))及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括PDGFR抑制劑,例如C-451、CP-673、CP-868596及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括鉑化學治療劑,例如順鉑、ELOXATIN®(奧沙利鉑(oxaliplatin))、依他鉑(eptaplatin)、洛鉑(lobaplatin)、奈達鉑(nedaplatin)、PARAPLATIN®(卡鉑)、沙鉑、皮卡鉑(picoplatin)及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括polo樣激酶抑制劑,例如,BI-2536及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括磷酸肌醇-3激酶(PI3K)抑制劑,例如渥曼青黴素(wortmannin)、LY294002、XL-147、CAL-120、ONC-21、AEZS-127、ETP-45658、PX-866、GDC-0941、BGT226、BEZ235、XL765及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括凝血酶敏感蛋白類似物,例如ABT-510(凝血酶敏感蛋白模擬物)、ABT-567、ABT-898(凝血酶敏感蛋白-1模擬肽)、TSP-1及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括VEGFR抑制劑,例如AVASTIN®(貝伐單抗(bevacizumab))、ABT-869、AEE-788、ANGIOZYMETM(抑制血管生成之核酶(Ribozyme Pharmaceuticals(Boulder公司)及Chiron,(Emeryville,CA))、阿昔替尼(axitinib)(AG-13736)、AZD-2171、CP-547,632、IM-862、MACUGEN(培加尼布(pegaptamib))、NEXAVAR®
(索拉非尼(sorafenib)、BAY43-9006)、帕唑帕尼(pazopanib)(GW-786034)、伐他拉尼(vatalanib)(PTK-787、ZK-222584)、SUTENT®(舒尼替尼(sunitinib)、SU-11248)、VEGF特拉普(VEGF trap)、ZACTIMATM(凡德他尼(vandetanib)、ZD-6474)、GA101、歐法單抗(ofatumumab)、ABT-806(mAb-806)、ErbB3特異性抗體、BSG2特異性抗體、DLL4特異性抗體及C-met特異性抗體及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括抗生素,例如嵌入抗生素阿克拉黴素(aclarubicin)、放線菌素D(actinomycin D)、胺柔比辛(amrubicin)、脂質體蒽環黴素(annamycin)、阿德力黴素(adriamycin)、BLENOXANE®(博來黴素(bleomycin))、道諾黴素(daunorubicin)、CAELYX®或MYOCET®(脂質體阿黴素(liposomal doxorubicin))、依沙蘆星(elsamitrucin)、泛艾黴素(epirbucin)、加柔比辛(glarbuicin)、ZAVEDOS®(艾達魯比辛(idarubicin))、絲裂黴素C(mitomycin C)、奈莫柔比辛(nemorubicin)、新抑癌素(neocarzinostatin)、培洛黴素(peplomycin)、畢拉魯比辛(pirarubicin)、蝴蝶黴素(rebeccamycin)、左旋咪唑(stimalamer)、鏈尿佐菌素(streptozocin)、VALSTAR®(戊柔比辛(valrubicin))、淨司他丁(zinostatin)及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括拓撲異構酶抑制劑,例如阿克拉黴素、9-胺基喜樹鹼、胺萘非特(amonafide)、安吖啶(amsacrine)、貝特卡令(becatecarin)、貝洛替康(belotecan)、BN-80915、CAMPTOSAR®(鹽酸伊立替康(irinotecan hydrochloride))、喜樹鹼、CARDIOXANE®(右雷佐生(dexrazoxine))、雙氟莫替康(diflomotecan)、印都特卡瑞(edotecarin)、ELLENCE®或PHARMORUBICIN®(泛艾黴素)、依託泊苷(etoposide)、依克沙替康(exatecan)、10-羥基喜樹鹼、吉馬替康
(gimatecan)、勒托替康(lurtotecan)、邁杜蔥酮(mitoxantrone)、奧拉塞辛(orathecin)、畢拉魯比辛(pirarubicin)、匹杉瓊(pixantrone)、魯比替康(rubitecan)、索布佐生(sobuzoxane)、SN-38、他氟泊苷(tafluposide)、托泊替康(topotecan)及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括治療抗體,例如AVASTIN®(貝伐單抗)、CD40特異性抗體、chTNT-1/B、地諾單抗(denosumab)、ERBITUX®(西土西單抗)、HUMAX-CD4®(紮木單抗(zanolimumab))、IGF1R特異性抗體、林妥珠單抗(lintuzumab)、PANOREX®(依決洛單抗(edrecolomab))、RENCAREX®(WX G250)、RITUXAN®(利妥昔單抗(rituximab))、替西木單抗(ticilimumab)、曲妥珠單抗(trastuzimab)、CD20抗體I型及II型及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括激素治療劑,例如ARIMIDEX®(阿那曲唑(anastrozole))、AROMASIN®(依西美坦(exemestane))、阿佐昔芬(arzoxifene)、CASODEX®(比卡魯胺(bicalutamide))、CETROTIDE®(西曲瑞克(cetrorelix))、地加瑞克(degarelix)、地洛瑞林(deslorelin)、DESOPAN®(曲洛司坦(trilostane))、地塞米松(dexamethasone)、DROGENIL®(氟利坦(flutamide))、EVISTA®(雷洛昔芬(raloxifene))、AFEMATM(法屈唑(fadrozole))、FARESTON®(托瑞米芬(toremifene))、FASLODEX®(氟維司群(fulvestrant))、FEMARA®(來曲唑(letrozole))、福美司坦(formestane)、糖皮質激素、HECTOROL®(度骨化醇(doxercalciferol))、RENAGEL®(碳酸司維拉姆(sevelamer carbonate))、拉索昔芬(lasofoxifene)、乙酸亮丙瑞林(leuprolide acetate)、MEGACE®(甲地孕酮(megesterol))、MIFEPREX®(米非司酮(mifepristone))、NILANDRONTM(尼魯米特nilutamide)、NOLVADEX®
(檸檬酸他莫昔芬(tamoxifen citrate))、PLENAXISTM(阿巴瑞克(abarelix))、普賴蘇(prednisone)、PROPECIA®(菲斯坦(finasteride))、瑞樂司坦(rilostane)、SUPREFACT®(布舍瑞林(buserelin))、TRELSTAR®(黃體生成激素釋放激素(LHRH))、VANTAS®(組胺瑞林(Histrelin)植入物)、VETORYL®(曲洛司坦或莫卓司坦(modrastane))、ZOLADEX®(福斯瑞林(fosrelin)、戈舍瑞林(goserelin))及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括類維生素D及類視色素,例如西奧骨化醇(seocalcitol)(EB1089、CB1093)、來沙骨化醇(lexacalcitrol)(KH1060)、芬維A胺(fenretinide)、PANRETIN®(阿利維A酸(aliretinoin))、ATRAGEN®(維A酸脂質體(liposomal tretinoin))、TARGRETIN®(貝沙羅汀(bexarotene))、LGD-1550及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括PARP抑制劑,例如ABT-888(veliparib)、奧拉帕尼(olaparib)、KU-59436、AZD-2281、AG-014699、BSI-201、BGP-15、INO-1001、ONO-2231及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括植物生物鹼,例如但不限於長春新鹼、長春鹼、長春地辛(vindesine)、長春瑞濱(vinorelbine)及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括蛋白酶體抑制劑,例如VELCADE®(硼替佐米(bortezomib))、MG132、NPI-0052、PR-171及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑(包括免疫劑)共投與。免疫劑之實例包括干擾素及其他免疫增強劑。干擾素包括干擾素α、干擾素α-2a、干擾素α-2b、干擾素β、干擾素γ-1a、ACTIMMUNE®(干擾素γ-1b)或干擾素γ-n1、其組合及諸如此類。
其他藥劑包括ALFAFERONE®(IFN-α)、BAM-002(氧化麩胱甘肽)、BEROMUN®(他索那明(tasonermin))、BEXXAR®(托西莫單抗(tositumomab))、CAMPATH®(阿來組單抗(alemtuzumab))、CTLA4(細胞毒性淋巴球抗原4)、達卡巴嗪、地尼介白素(denileukin)、依帕珠單抗(epratuzumab)、GRANOCYTE®(來格司亭(lenograstim))、蘑菇多糖(lentinan)、白血球α干擾素、咪喹莫特(imiquimod)、MDX-010(抗CTLA-4)、黑素瘤疫苗、米妥莫單抗(mitumomab)、莫拉司亭(molgramostim)、MYLOTARGTM(吉妥珠單抗奧佐米星(gemtuzumab ozogamicin))、NEUPOGEN®(非格司亭(filgrastim))、OncoVAC-CL、OVAREX®(奧戈伏單抗(oregovomab))、培圖莫單抗(pemtumomab)(Y-muHMFG1)、PROVENGE®(西普魯塞T(sipuleucel-T))、沙格司亭(sargaramostim)、西佐喃(sizofilan)、替西介白素(teceleukin)、THERACYS®(卡介苗(Bacillus Calmette-Guerin))、烏苯美司(ubenimex)、VIRULIZIN®(免疫治療劑,Lorus Pharmaceuticals)、Z-100(Maruyama之特定物質(SSM))、WF-10(四氯十氧化物(TCDO))、PROLEUKIN®(阿地介白素(aldesleukin))、ZADAXIN®(胸腺法新(thymalfasin))、ZENAPAX®(達克珠單抗(daclizumab))、ZEVALIN®(90Y-替伊莫單抗(90Y-Ibritumomab tiuxetan))及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括生物反應調節劑,例如調節活生物體防禦機制或生物反應(例如組織細胞之存活、生長或分化)以引導其具有抗腫瘤活性之藥劑且包括雲芝胞內多糖、蘑菇多糖、西佐喃、畢西巴尼(picibanil)PF-3512676(CpG-8954)、烏苯美司及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括嘧啶類似物,例如阿糖胞苷(ara C或阿拉伯糖苷C)、胞嘧啶阿拉伯糖苷、去氧氟尿苷、FLUDARA®(氟達拉濱)、5-
FU(5-氟尿嘧啶)、氟尿苷、GEMZAR®(吉西他濱)、TOMUDEX®(雷替曲塞(ratitrexed))、TROXATYLTM(三乙醯基膽鹼曲沙他濱(triacetyluridine troxacitabine))及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括嘌呤類似物,例如LANVIS®(硫鳥嘌呤)及PURI-NETHOL®(巰嘌呤)。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括抗有絲分裂劑,例如巴他布林(batabulin)、埃坡黴素D(epothilone D)(KOS-862)、N-(2-((4-羥基苯基)胺基)吡啶-3-基)-4-甲氧基苯磺醯胺、伊沙匹隆(ixabepilone)(BMS 247550)、太平洋紫杉醇(paclitaxel)、TAXOTERE®(多西他賽(docetaxel))、PNU100940(109881)、帕妥匹隆(patupilone)、XRP-9881(拉羅他塞(larotaxel))、長春氟寧(vinflunine)、ZK-EPO(合成埃坡黴素)及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括泛素連接酶抑制劑,例如MDM2抑制劑(例如努特林(nutlin))、NEDD8抑制劑(例如MLN4924)及諸如此類。
本發明化合物亦可用作增強放射療法功效之放射敏化劑。放射療法之實例包括外部光束放射療法、遠隔療法、近程放射療法及密封、未密封源放射療法及諸如此類。
抗EGFR ADC可與治療有效量之一或多種用以治療癌症之藥劑共投與,該等藥劑包括化學治療劑,例如ABRAXANETM(ABI-007)、ABT-100(法尼基轉移酶抑制劑)、ADVEXIN®(Ad5CMV-p53疫苗)、ALTOCOR®或MEVACOR®(洛維汀(lovastatin))、AMPLIGEN®(聚I:聚C12U,一種合成RNA)、APTOSYN®(依昔舒林(exisulind))、AREDIA®(帕米膦酸(pamidronic acid))、阿格拉賓(arglabin)、L-天冬
醯胺酶、阿他美坦(atamestane)(1-甲基-3,17-二酮-雄固-1,4-二烯)、AVAGE®(他紮羅汀(tazarotene))、AVE-8062(考布他汀(combreastatin)衍生物)、BEC2(米托莫單抗)、惡病質素(cachectin)或卡車辛(cachexin)(腫瘤壞死因子)、康伐辛(canvaxin)(疫苗)、CEAVAC®(癌症疫苗)、CELEUK®(西莫介白素(celmoleukin))、CEPLENE®(組胺二鹽酸鹽)、CERVARIX®(人類乳突狀瘤病毒疫苗)、CHOP®(C:CYTOXAN®(環磷醯胺);H:ADRIAMYCIN®(羥基阿黴素);O:長春新鹼(ONCOVIN®);P:(普賴蘇)、CYPATTM(乙酸環丙孕酮(acetate cyproterone))、康普瑞汀(combrestatin)A4P、DAB(389)EGF(經由His-Ala連接體融合至人類表皮生長因子之白喉毒素的催化及轉運結構域)或TransMID-107RTM(白喉毒素)、達卡巴嗪、放線菌素、5,6-二甲基酮-4-乙酸(DMXAA)、恩尿嘧啶(eniluracil)、EVIZONTM(乳酸角鯊胺(squalamine lactate))、DIMERICINE®(T4N5脂質體洗劑)、盤形德莫利得(discodermolide)、DX-8951f(甲磺酸依克沙替康(exatecan mesylate))、恩紮妥林(enzastaurin)、EPO906(埃坡黴素B)、GARDASIL®(四價人類乳突狀瘤病毒(6、11、16、18型)重組疫苗)、GASTRIMMUNE®、GENASENSE®、GMK(神經節苷脂結合物疫苗)、GVAX®(前列腺癌疫苗)、鹵夫酮(halofuginone)、組胺瑞林(histerelin)、羥基脲、伊班膦酸(ibandronic acid)、IGN-101、IL-13-PE38、IL-13-PE38QQR(貝辛介白素(cintredekin besudotox))、IL-13-假單胞菌外毒素、干擾素-α、干擾素-γ、JUNOVANTM或MEPACTTM(米法莫肽(mifamurtide))、洛那法尼、5,10-亞甲基四氫葉酸酯、米替福新(miltefosine)(十六烷基磷膽鹼)、NEOVASTAT®(AE-941)、NEUTREXIN®(曲美沙特葡萄糖醛酸酯)、NIPENT®(噴托他丁)、ONCONASE®(一種核糖合核酸酶)、ONCOPHAGE®(黑色素瘤疫苗治療)、ONCOVAX®(IL-2疫苗)、ORATHECINTM(魯比替康)、OSIDEM®
(基於抗體之細胞藥物)、OVAREX® MAb(鼠類單株抗體)、太平洋紫杉醇、PANDIMEXTM(來自包含20(S)原人參二醇(aPPD)及20(S)原人參三醇(aPPT)之人參的苷配基皂苷)、帕木單抗(panitumumab)、PANVAC®-VF(調查研究用癌症疫苗)、培門冬酶(pegaspargase)、PEG干擾素A、苯妥帝爾(phenoxodiol)、丙卡巴肼(procarbazine)、瑞馬司他(rebimastat)、REMOVAB®(卡妥索單抗(catumaxomab))、REVLIMID®(來那度胺(lenalidomide))、RSR13(乙法昔羅(efaproxiral))、SOMATULINE® LA(蘭瑞肽(lanreotide))、SORIATANE®(阿維A)、星狀孢子素(staurosporine)(鏈黴菌星狀孢子(Streptomyces staurospores))、他波司他(talabostat)(PT100)、TARGRETIN®(貝沙羅汀)、TAXOPREXIN®(DHA-太平洋紫杉醇)、TELCYTA®(坎磷醯胺(canfosfamide)、TLK286)、特米利芬(temilifene)、TEMODAR®(替莫唑胺)、替米利芬(tesmilifene)、沙立度胺(thalidomide)、THERATOPE®(STn-KLH)、塞米他(thymitaq)(2-胺基-3,4-二氫-6-甲基-4-側氧基-5-(4-吡啶巰基)喹唑啉二鹽酸鹽)、TNFERADETM(腺病毒載體:含有腫瘤壞死因子-α之基因的DNA載體)、TRACLEER®或ZAVESCA®(骨化三醇(bosentan))、維A酸(tretinoin、Retin-A)、粉防己鹼(tetrandrine)、TRISENOX®(三氧化二砷)、VIRULIZIN®、烏克蘭(ukrain)(來自白屈菜(greater celandine)植物之生物鹼的衍生物)、維他辛(vitaxin)(抗αvβ3抗體)、XCYTRIN®(莫特沙芬釓(motexafin gadolinium))、XINLAYTM(阿曲生坦(atrasentan))、XYOTAXTM(聚麩胺酸太平洋紫杉醇(paclitaxel poliglumex))、YONDELIS®(曲貝替定(trabectedin))、ZD-6126、ZINECARD®(右雷佐生)、ZOMETA®(唑來膦酸(zolendronic acid))、佐柔比辛(zorubicin)及諸如此類。
在一個實施例中,向患有神經膠母細胞瘤之個體經靜脈內投與
包含抗EGFR-ADC之調配物與放射及/或TEMODAR®(替莫唑胺)之組合。
此外,在一個實施例中,本發明組合物可作為醫藥套組提供,該醫藥套組包含(a)含有凍乾形式之抗EGFR ADC之容器及(b)含有醫藥上可接受之注射用稀釋劑(例如,無菌水)之第二容器。醫藥上可接受之稀釋劑可用於重構或稀釋經凍乾ADC。視情況,此(等)容器可附帶有監管醫藥物或生物產品之製造、使用或銷售之政府機構所規定形式之公告,該公告顯示政府機構已批準用於人類投與之製造、使用或銷售。
本發明進一步闡述於以下實例中,該等實例不欲限制本發明之範圍。
以下實例闡述抗體與奧裡斯他汀結合以形成抗體藥物結合物(ADC),具體而言MMAE與抗EGFR抗體1之結合。每抗體具有減少之vc-MMAE分子藥物負載之抗體1 ADC之產生涉及mAb之部分還原、之後與Val-Cit-MMAE(vcMMAE)反應以完成結合,如下文所詳細闡述。
抗體1之還原係使用TCEP(三羧基乙膦)來達成。重組單株抗體1係藉由經轉染中國倉鼠卵巢(CHO)細胞系產生並於Abbott Bioresearch Center(Worcester,MA)純化。在抗體純化後,將抗體溶液(148mg/mL,6mL)裝入50mL聚丙烯離心管中。然後藉由添加PBSE緩衝液(360mL;125mM K2HPO4,150mM NaCl;6.3mM EDTA,pH 7.7)將抗體溶液稀釋至41mL之總體積。蛋白質含量為21.6mg/ml,如藉由A280所測定。將19ml抗體溶液裝入反應器中,總共為410.6mg。將抗體
溶液升溫至37℃。然後藉由將TCEP(Sigma Aldrich Fine Chemical(St.Louis,MO))添加至抗體溶液中將抗體1(20mg/mL)部分地還原。具體而言,將9.67mM TCEP溶液(0.592mL,2.05當量)添加至抗體溶液(TCEP:mAb之莫耳當量為2.05)中。在添加TCEP後,將抗體溶液在37℃下培育1小時。然後將還原反應物冷卻至20℃。此過程導致抗體1之二硫鍵之還原。
以下闡述在還原抗體後使MMAE結合實例性抗體1之製程。
結合抗體1之巰基、Val-Cit-MMAE(vc-MMAE)。將Val-Cit(對胺基苄基胺基甲酸酯-單甲基奧裡斯他汀E;Sigma Aldrich Fine Chemical(St.Louis,MO))添加至抗體溶液中以達成1.15之最終vc-MMAE:經還原半胱胺酸(Cys)莫耳比。在10% v/v DMSO(二甲亞碸;Sigma Aldrich Fine Chemical(St.Louis,MO))存在下實施結合反應,且在20℃下進行45分鐘。
在結合反應後,添加過量游離N(乙醯基)-半胱胺酸(Sigma Aldrich Fine Chemical(St.Louis,MO)(2.3當量對vcMMAE載荷)以使未反應之vc-MMAE驟冷以產生N(乙醯基)-Cys-vc-MMAE。使N(乙醯基)-Cys驟冷反應在20℃下進行約30分鐘。然後將驟冷反應混合物(亦稱作粗製溶液)純化,如下文於實例2中所述。
或者,較小規模之反應亦使用以下方案。藉由裝載10mM vcMMAE DMSO溶液(1.32mL,4.72當量)實施結合。裝載DMSO(0.86mL)。然後在環境溫度下將反應混合物攪拌1小時。藉由添加50mM N-(乙醯基)半胱胺酸(0.53mL)使過量藥物連接體驟冷。然後將混合物攪拌約15分鐘。然後將反應混合物儲存於冷藏器中。
實施反應混合物之分析型分析。藉由疏水性交互作用層析-高效
液相層析(HIC-HPLC)使用TSKgel Butyl-NPR管柱(4.6mm ID×3.5cm,2.5um;Tosoh Bioscience LLC,Japan))達成上清液試樣之分析。
蛋白質含量之UV分析顯示386.4mg蛋白質。HIC痕量分析顯示抗體1-vcMMAE之平均藥物對抗體比(DAR)為3.85,如下文於表1中所述。平均DAR係藉由對2、4、6及8 ADC之PA%(PA%係如藉由A280下之峰下量測之面積測定峰面積百分比)乘以必需藥物負載之乘積求和並除以100來測定,例如,[(6.3 PA%×0)+(24.8 PA%×2)+(34.8×4)+(20.9×6)+(8.8×8)]/100=3.85。
如表1中所述,結合反應產生具有一定範圍之藥物負載(即,2至8之DAR)之ADC物質之混合物。較小百分比之ADC不具有藥物負載,如表1中所述。
以下實例闡述ADC(抗體1-vc-MMAE)之分批純化,其中所得純化組合物具有2.8之平均DAR。以下純化製程選擇性地去除較高負載之ADC,即,6及8藥物負載物質,產生包含較低級藥物負載物質之經純化分佈,即,2-4之DAR。該純化製程利用了少量疏水性樹脂,可將其滴定至粗製抗體溶液(或混合物)中以選擇性地去除不同結合程度之ADC。
該純化製程提供實際、可縮放之製程來選擇性地調節奧裡斯他汀E結合物及奧裡斯他汀F結合物兩者之分佈,該等結合物源於部分鏈間二硫化物還原及隨後利用vc-MMAE或mc-MMAF之烷基化。已以毫克至多克規模以分批模式或以循環模式證明下文所述純化方法提供86%產率之經純化分佈。抗體還原、結合及純化製程之概況闡述於圖1中。
本文所述緩衝液製備如下:藉由裝載K2HPO4(0.87g)(K2HPO4;Fisher Scientific)及NaCl(11.7g)(NaCl;EMD)、用WIFI稀釋至約90mL來製備緩衝液A(50mM K2HPO4緩衝液pH 7緩衝液/2M NaCl)。用1.0N HCl將所得溶液處理至7.0之最終pH並進一步稀釋至100mL之總體積。
藉由將NaCl(2.92g)裝入燒瓶中、之後裝載流動相A以達成25mL之最終體積來製備緩衝液A’(50mM K2HPO4/4M NaCl)。
藉由裝載K2HPO4(0.87g)及NaCl(11.7g)、用WIFI(注射用水;Gibco)稀釋至約90mL來製備緩衝液B(50mM K2HPO4緩衝液pH 7緩衝液)。用1.0N HCl(1.0N HCl;JT Baker)將所得溶液處理至7.0之最終pH且進一步稀釋至100mL之總體積。
藉由短暫地混合ToyoPearl Butyl-600M樹脂漿液(ToyoPearl Bu-HIC樹脂(600M);Tosoh Bioscience)之散裝容器、將(1克)倒入粗聚丙烯過濾器中來製備預處理之Butyl-HIC(Bu-HIC)樹脂。將漿液過濾並用緩衝液A(3×2mL)沖洗。藉由使經過濾氮穿過濕餅達10分鐘或直至在粗漏斗之底部不再觀察到小滴將該濕餅乾燥。藉由減去存在於濕餅上之水量來計算乾重。水分量係藉由卡耳費雪(Karl Fisher)分析來量測(通常含有55%水)。
實施固相滴定研究以測定用於去除具有6-8之DAR之ADC之條件。藉由疏水性交互作用層析-高效液相層析(HIC-HPLC)使用TSKgel Butyl-NPR管柱(4.6mm ID×3.5cm,2.5um;Tosoh Bioscience LLC,Japan))來達成上清液試樣之分析。該方法係由12分鐘內之100%緩衝液A[25mM磷酸鈉,1.5M(NH4)2SO4,pH 7.0]至100%緩衝液B[75% v/v 25mmol/L磷酸鈉(pH 7.0),25% v/v異丙醇]之線性梯度組成。將流速設定為0.8mL/min,注射30uL,將溫度設定為30℃,且在280nm進行檢測。
藉由經由5um注射器過濾器濾出反應混合物漿液來製備試樣。用緩衝液A(30uL/注射)將濾液稀釋5倍。
在每種情況下利用不同量之樹脂測試8種條件(分析-Bu-0、Bu-1、Bu-2、Bu-4、Bu-8、Bu-16、Bu-32及按比例放大)。藉由將100uL粗製抗體1-vcMMAE反應溶液(實例1)(18mg/mL)裝入小瓶中來實施分析-Bu-0。添加緩衝液A’(100uL),之後添加100uL緩衝液B。然後以最低設定(軌道式混合器)振盪該溶液。於20分鐘時取上清液試樣。對上清液取樣並根據HIC-HPLC進行量測。具體而言,藉由移出30uL上清液、用120uL緩衝液A將其稀釋並藉由HIC-HPLC量測含量來進行試樣製備。關於分佈之匯總,參見表5。
分析-Bu-1至Bu-32係分析-Bu-0之所有變體,該分析-Bu-0不含有任何疏水性交互作用樹脂且為對照。分析-Bu-1與分析-Bu-0相同,只是在添加緩衝液B之前將0.8mg預處理之n-Bu HIC 600M樹脂添加至溶液中。分析-Bu-2與分析-Bu-0相同,只是在添加緩衝液B之前添加1.6mg預處理之n-Bu HIC 600M樹脂。分析-Bu-4與分析-Bu-0相同,只是在添加緩衝液B之前添加3.2mg預處理之n-Bu HIC 600M樹脂。分析-Bu-8與分析-Bu-0相同,只是在添加緩衝液B之前添加6.4mg預
處理之n-Bu HIC 600M樹脂。分析-Bu-16與分析-Bu-0相同,只是在添加緩衝液B之前添加12.8mg預處理之n-Bu HIC 600M樹脂。分析-Bu-32與分析-Bu-0相同,只是在添加緩衝液B之前添加25.6mg預處理之n-Bu HIC 600M樹脂。對於該等實驗中之每一者而言,最終NaCl濃度皆為1.3M NaCl。來自8種條件之結果匯總於下文表2-5中。
表2提供各種ADC物質之分佈(例如,單獨/未結合之抗體(mAb%)、具有2之DAR之ADC(2負載%)、具有4之DAR之ADC(4負載%)等)之匯總。表2中所述之負載對蛋白質比代表樹脂之乾重對計算之抗體蛋白質重量。ADC重量係藉由如藉由280nm下之UV吸收量測之總蛋白質含量乘以藥物負載物質之峰面積%來計算。如表2中所述,樹脂負載:蛋白質比影響具有某些DAR之ADC之%。例如,1.8之樹脂負載對總蛋白質(或5.9重量之樹脂對6-8負載;參見表2之「分析-Bu-4」列)產生94%純度之2或4藥物負載物質(各為47%)及不可檢測含量之具有6或8之DAR之ADC,如藉由HIC-HPLC所測定。表3闡述針對表2中所述之每一實驗所添加Bu-HIC樹脂之量,而表4闡述存在於篩選中之藥物負載物質之淨重之計算。
上述分析型HIC結果證明減少某些藥物負載物質(例如,具有6-8之DAR之ADC)之存在之足夠選擇性。來自表2及5之數據表明,在約1.3M NaCl濃度之最終離子強度或其等效離子強度存在下,可主要藉由利用0.5(具體而言為0.44% wt)wt樹脂載荷來減少8-負載物質;可經由將約兩重量之疏水性樹脂添加至粗製結合反應混合物中來減少6/8負載物質。可主要藉由使用約3.5重量之樹脂(相對總蛋白質)(參見表5之「分析-Bu-8」列)來去除4-8藥物負載物質且可藉由利用約7重量之樹脂(相對總蛋白質)(參見表5之「分析-Bu-16」列)來去除2-8負載物質。該等數據亦表明,以乾重計之4重量負載或2重量負載(相對總蛋白質)對於去除高藥物負載具有選擇性,其中2或4藥物負載物質損失最少。
計算樹脂負載對欲減少之物質之重量比且將其匯總於表5中。
分析型HIC研究結果之匯總提供於表5中。
總之,用緩衝液A’(4N NaCl,0.05M pH 7 K2HPO4磷酸鹽緩衝液,1mL/mL結合反應混合物)稀釋自實例1獲得之反應混合物。用計算量之預處理Bu-HIC樹脂處理經稀釋反應混合物,經由粗聚丙烯過濾器過濾,且用緩衝液B(0.05M pH 7 K2HPO4磷酸鹽緩衝液,1mL/mL結合反應混合物)進一步稀釋。如表5中所示之計算量之樹脂取決於欲自粗製混合物去除之藥物負載物質。例如,為6及8藥物負載物質約5至10倍之樹脂重量證明對於自粗製混合物去除該等物質有效。將樹脂/稀釋反應混合物攪拌適當時間,且藉由分析型疏水性交互作用層析監測規定藥物結合物產物之減少。
將用於去除自滴定篩選鑑別之高DAR ADC之最佳條件按比例放
大以用於更大規模純化。
為了首先還原抗體,將含有抗體1之溶液(151mg/mL,50mL,7.52g)添加至500mL燒瓶中。藉由添加藉由混合pH 6,15mM組胺酸緩衝液(30mL)與PBSE緩衝液(360mL;125mM K2HPO4,150mM NaCl;6.3mM EDTA,pH 7.7)製備之溶液將該溶液稀釋至395mL之總體積。將所得抗體溶液升溫至37℃。然後將10.98mM TCEP溶液(12.1mL,2.05當量)添加該溶液中,將其攪拌30分鐘。然後經20分鐘將抗體溶液冷卻至環境溫度。
在還原後,藉由將10mM vcMMAE DMSO溶液(28.8mL,4.72當量)添加至抗體溶液中使抗體1結合vcMMAE。接下來添加DMSO(21.2mL),此後在環境溫度下將溶液攪拌45分鐘。藉由添加50mM N-乙醯基半胱胺酸(9.7mL)將過量藥物連接體驟冷。將溶液攪拌約15分鐘。在抗體1結合vcMMAE後,將UV蛋白質濃度測定為7.4g蛋白質,且HIC分析顯示4.1之DAR(約25 PA%(或1.85g)組合之6-8藥物負載物質)。
然後用等體積之4N NaCl/0.05M pH 7 K2HPO4緩衝液稀釋粗製反應混合物。然後添加30.7g預洗滌之Bu HIC濕樹脂(KF=56wt%水;淨17.2g樹脂,以乾重計;2.3重量樹脂對總蛋白質;9.3重量樹脂對6-8負載物質),之後添加50mM KH2PO4 pH7緩衝液(460mL)。在室溫下將抗體樹脂溶液輕輕地攪拌3小時。或者,將溶液在冷藏器中儲存12小時,且隨後再攪拌2.5小時。
然後經由粗聚丙烯過濾器濾出樹脂。將澄清濾液傾倒入新容器中。測定重量為1469g(密度=1.06g/mL)。經純化ADC溶液之分析型分析顯示,該溶液具有3.7mg/ml之UV蛋白質含量或5.07g之總蛋白質(67%總產率)。HIC痕量分析顯示2.8之DAR。
顯示抗體溶液在純化之前及純化之後之HIC-HPLC重疊圖的圖形提供於圖2中。圖2中之兩個晚期溶析峰代表具有6-8之DAR之ADC(滯
留時間:分別為8.6分鐘及9.6分鐘)。該等峰在純化後消失,證明0、2及4 DAR ADC物質不受影響且此純化製程具有選擇性,原因在於其僅去除高(例如,6-8)DAR ADC物質。
在純化後,使經純化ADC溶液經受超濾/透析過濾(UF/DF)及最終緩衝液交換。將濾液添加至UF/DF儲液中,在Pall Centramate Omega 30K LV1(部件OS030C12P1,序列號31061058R)上在約25psi之跨膜壓力及80-100mL/分鐘之蠕動幫浦速度下將溶液濃縮至約50mg/mL並去除1400g(濃縮約1小時)。在濃縮至約50mg/mL後,運行10 DV 15mM pH 6.0組胺酸緩衝液。排乾UF/DF系統且隨後用15mM pH 6.0組胺酸緩衝液(2×20mL)沖洗。將濃度量測為(127g溶液)40.1mg/mL。用15mM組胺酸pH6.0緩衝液稀釋至35.1mg/mL(141g BDS)之濃度。經由0.45微米注射器過濾器過濾BDS,之後進行0.2微米無菌過濾。將濾液裝入12個小瓶(各100mg)及Falcon管(3×35mL)中。
上述UF/DF製程可在分批純化過程之前或之後使用。
在單獨實驗中,以2克預處理之Toyopearl Butyl-600M HIC樹脂(Tosoh Bioscience,Japan)/1克mAb且用0.05M pH 7 K2HPO4磷酸鹽緩衝液進一步稀釋並在環境溫度下攪拌6小時。將漿液經由粗聚丙烯過濾器過濾且用緩衝液A(2個濕餅床體積)洗滌。將所得濾液及沖洗物合併且藉由透析過濾將緩衝液交換成0.015M pH 6組胺酸緩衝液,提供稱作抗體1-vcMMAEp之經純化抗體1-Val-Cit-MMAE。在此實例中,總產率為67%抗體1-vcMMAEp。基於粗製反應混合物中0-4藥物負載物質之量,純化產率為87%。
以下實例闡述抗EGFR抗體1mc-MMAF ADC之製備。
在抗體純化後,將抗體溶液(151mg/mL,86mL)裝入1L燒瓶中。然後藉由添加PBSE緩衝液(600mL;125mM K2HPO4,150mM NaCl;6.3mM EDTA,pH 7.7)及15mM組胺酸緩衝液(43mL,pH 6)將抗體溶液稀釋至729mL之總體積。蛋白質含量為20.0mg/ml,如藉由UV光譜法(A280)所測定。將含有抗體1之溶液加熱至37℃。然後在攪拌30分鐘下將9.67mM TCEP溶液(0.592mL,2.05當量)添加至抗體1之溶液中。隨後經20分鐘將反應冷卻至環境溫度。
隨後使抗EGFR抗體1結合馬來醯亞胺基己醯基-MMAF(抗體1-mcMMAF)。裝載10mM mcMMAF/DMSO(38mL,4.72當量)。裝載DMSO(18.6mL)。在環境溫度下攪拌1小時。藉由添加100mM N-乙醯基半胱胺酸(7.6mL)將過量mc-MMAF驟冷並攪拌15分鐘。將驟冷反應物置於冷藏器中。
分析反應混合物以測定蛋白質濃度。UV光譜法(A280)顯示17.7mg/mL之蛋白質濃度。所得HIC痕量之分析顯示3.93之DAR(表6)。平均DAR係藉由對2、4、6及8 ADC之PA%乘以必需藥物負載之乘積求和並除以100來測定,例如,[(5.72 PA%×0)+(27.27 PA%×2)+(41.08×4)+(16.79×6)+(9.13×8)]/100=3.93。
如表6中所述,結合反應產生具有一定範圍之藥物負載(即,2至8之DAR)之ADC的物質混合物。較小百分比之ADC不具有如表6中所述之藥物負載。
使經純化ADC溶液經受超濾/透析過濾(UF/DF)及最終緩衝液交換。在Millipore Biomax Pellicon 3的88cm2膜上實施切向流過濾。在20psi(TMP)及40mL/min下交叉流將試樣濃縮至100mg/mL。隨後藉由在約20psi(TMP)下以40mL/min之速率實施10 DVs用15mM組胺酸緩衝液(pH 6)將蛋白質稀釋至60mg/mL之濃度。經由0.45μm Millipak 20過濾器(Millipore)將所得溶液過濾。經由UV光譜法(A 280 )將蛋白質濃度測定為59.7mg/mL。隨後用15mM組胺酸緩衝液(pH 6.0)將UF/DF純化之本體mc-MMAF抗體1溶液之58.6mL試樣稀釋至100mL之最終體積。藉由UV光譜法測定之濃度為35.7mg/mL。然後經由0.2μm Millipak 20過濾器(Millipore)將蛋白質溶液過濾至無菌125ml PETG瓶中。將經純化mc-MMAF抗體1溶液冷凍並儲存於-80℃深低溫冷藏器(cryofreezer)中。
使來自實例4之經純化抗體1-mc-MMAF經受樹脂處理純化篩選。藉由改變總樹脂載荷(0.5wt、1wt、2wt及3wt;經純化抗體1-mc-MMAF自9.5mg/mL至34mg/mL變化)、NaCl濃度(0N、0.65N、1.3N)及滯留時間(0.5小時、4小時及20小時)實施篩選。表7提供各種ADC物質隨樹脂載荷、NaCl濃度及滯留時間而變化之分佈之匯總。藉由如上文所述之HIC痕量分析來測定DAR值。藉由UV光譜法測定計算產率且將其匯總於表8中。
表7之粗體字指示去除<3 PA%(峰面積%)之6-負載物質之條件;8-負載物質在該等實驗條件下不可檢測。「T0」係指0分鐘之滯留時間(即不具有樹脂之對照實驗);「M30」係指0.5小時之滯留時間;「H4」係指4小時之滯留時間;「H20」係指20小時之滯留時間。
總之,實施表7及8中所述之樹脂滴定篩選以測定樹脂負載、NaCl濃度及滯留時間對自實例4之UF/DF純化之抗體1-mc-MMAF ADC獲得之純化製程(DAR、蛋白質濃度)的影響。如表7中所示之樹脂之計算量取決於欲自粗分佈去除之藥物負載物質。如下文所述(表7及8中所提及)測試使用來自實例4之抗體1-mcMMAF之一系列反應條件。緩衝液A含有以下物質:4.35g K2HPO4;58.5g NaCl;495mL水(WFI);用5mL 1N HCl將pH調節至7.0。
反應1:0N NaCl:無樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0mg Bu-HIC樹脂
3)振盪
4)於0.5小時、4小時及20小時吸取(Pull)上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
5)分析UV蛋白質濃度並實施HIC分析。
反應2:0N NaCl;0.5wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載17.5mg Bu-HIC樹脂
3)振盪
4)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
5)分析UV蛋白質濃度並實施HIC分析。
反應3:0N NaCl;1wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載350mg Bu-HIC樹脂
3)振盪
4)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
5)分析UV蛋白質濃度並實施HIC分析。
反應4:0N NaCl;2wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載70mg Bu-HIC樹脂
3)振盪
4)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
5)分析UV蛋白質濃度並實施HIC分析。
反應5:0N NaCl;3wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載105mg Bu-HIC樹脂
3)振盪
4)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
5)分析UV蛋白質濃度並實施HIC分析。
反應6:0.65N NaCl:無樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0.195mL 4N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A')。
3)裝載0mg Bu-HIC樹脂
4)振盪
5)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
6)分析UV蛋白質濃度並實施HIC分析。
反應7:0.65N NaCl;0.5wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0.195mL 4N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液 A')。
3)裝載17.5mg Bu-HIC樹脂
4)振盪
5)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
6)分析UV蛋白質濃度並實施HIC分析。
反應8:0.65N NaCl;1wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0.195mL 4N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A')。
3)裝載35mg Bu-HIC樹脂
4)振盪
5)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
6)分析UV蛋白質濃度並實施HIC分析。
反應9:0.65N NaCl;2wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0.195mL 4N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A')。
3)裝載70mg Bu-HIC樹脂
4)振盪
5)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
6)分析UV蛋白質濃度並實施HIC分析。
反應10:0.65N NaCl;3wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0.195mL 4N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A')。
3)裝載105mg Bu-HIC樹脂
4)振盪
5)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
6)分析UV蛋白質濃度並實施HIC分析。
反應11:1.3N NaCl:無樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0.48mL 4N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A')。
3)裝載0mg Bu-HIC樹脂
4)振盪
5)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
6)分析UV蛋白質濃度並實施HIC分析。
反應12:1.3N NaCl;0.5wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0.48mL 4N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A')。
3)裝載17.5mg Bu-HIC樹脂
4)振盪
5)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
6)分析UV蛋白質濃度並實施HIC分析。
反應13:1.3N NaCl;1wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0.48mL 4N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A')。
3)裝載35mg Bu-HIC樹脂
4)振盪
5)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
6)分析UV蛋白質濃度並實施HIC分析。
反應14:1.3N NaCl;2wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0.48mL 4N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A')。
3)裝載70mg Bu-HIC樹脂
4)振盪
5)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
6)分析UV蛋白質濃度並實施HIC分析。
反應15:1.3N NaCl;3wt樹脂:
1)將抗體1-mcMMAF(1.00mL,35mg)裝入4mL小瓶中
2)裝載0.48mL 4N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A')。
3)裝載105mg Bu-HIC樹脂
4)振盪
5)於0.5小時、4小時及20小時吸取上清液試樣(經由注射器過濾器移出50μL,用2N NaCl/0.05M K2HPO4 pH 7緩衝液(緩衝液A)稀釋20μL此上清液試樣,提供1/50×)。
6)分析UV蛋白質濃度並實施HIC分析。
樹脂製備及計算:樹脂之卡耳費雪(KF)滴定:Butyl=72wt%水(28%效能)。注意所有樹脂載荷皆以乾重計。
乾重樹脂載荷之試樣計算:35mg樹脂載荷/0.28乾重效能=125mg濕樹脂載荷。
通常,樹脂之效能藉由100%-來自卡耳費雪分析之w/w%水來計算。
以下實例闡述若干不同ADC混合物之分批純化,該等混合物包含具有2.7之平均DAR或5.5之更重負載之平均DAR之抗體1-vc-MMAE或抗體1-mc-MMAF。另外,亦闡述包含具有4之平均DAR之抗體1-vcMMAE之ADC混合物。更具體而言,實施篩選以測定樹脂重量、NaCl濃度對兩種不同負載之ADC(抗體1-vc-MMAE及抗體1-mc-MMAF)之純化製程(DAR、蛋白質濃度)之影響,該兩種不同負載之ADC具有不同量之6及8負載物質作為純化製程中之輸入物。如下文所述測試一系列反應條件。
如下文所述製備用於實例6中之5種粗製ADC混合物(1-5)。根據
實例1及圖1中所述之方法製備4種粗製ADC混合物(1)抗體1-vcMMAE DAR 2.7(平均值)、(2)抗體1-mcMMAF DAR 2.7(平均值)、(3)抗體1-vcMMAE DAR 5.5(平均值)及(4)抗體1-mcMMAF DAR 5.5(平均值),其中抗體1之還原係使用TCEP(1.3或2.65莫耳當量)來達成且結合係使用mc-MMAF或vcMMAE(3或6當量)中之任一者來達成,從而製備抗體-1-vcMMAE DAR 2.7(平均值)與5.5(平均值)ADC之混合物以及抗體-1-mcMMAF DAR 2.7(平均值)與5.5(平均值)ADC之混合物。另外,根據實例1製備第五種粗製ADC混合物(5)抗體1-vcMMAE DAR 4(平均值)。
根據以下方案實施篩選程序。首先,將相應量之濕Bu-HIC樹脂(如材料及方法部分中之實例2所述代表性地製備)稱量至4mL小瓶中。樹脂量係基於數次計算。首先,所需乾樹脂之量係基於6及8負載物質之質量量。質量量係基於粗製ADC起始材料溶液計算如下:
欲去除之物質之質量量:Σ(6負載+8負載),mg=20mg粗製ADC(1-5)×(Σ(6負載pa%+8負載pa%))/100
例如對於小瓶13:Σ(6負載+8負載),mg=20mg mAb×(10.7/100)=2.14mg Σ(6負載+8負載)
接下來,將6負載及8負載之總質量量乘以樹脂之目標重量。例如對於小瓶13:5重量樹脂=5×2.14mg Σ(6負載+8負載)=10.7mg乾樹脂
7.5重量樹脂=7.5×2.14mg Σ(6負載+8負載)=16.1mg乾樹脂
10重量樹脂=10×2.14mg Σ(6負載+8負載)=21.4mg乾樹脂
最後,針對水、氯化鈉及K2HPO4含量校正樹脂。進行無機鹽校正,此乃因樹脂先前藉由過濾分離並用1.95M NaCl/0.05M K2HPO4溶
液洗滌。(將Bu-HIC樹脂過濾並用1.95M NaCl/0.05M K2HPO4溶液洗滌多次。藉由KF(卡耳費雪水分滴定)分析將樹脂之水分含量測定為59.0w/w%。然後使用洗滌組份(10.6w/w% NaCl、0.8w/w% K2HPO4、88.6%水)之w/w%濃度來估計濕樹脂中之NaCl及K2HPO4之質量(51.8g濕樹脂、30.6g水、3.6g NaCl及0.3g K2HPO4),然後將其減去以計算乾樹脂量(17.3g)。
例如對於5重量乾樹脂下之小瓶13:10.7mg乾樹脂/(0.334mg乾樹脂/mg濕樹脂)=32.0mg濕樹脂
在添加Bu-HIC樹脂後,將粗製ADC混合物(1-5)(1.1-1.2mL,20mg)裝入4mL小瓶中。針對20mg總蛋白質目標調節粗製ADC溶液之體積。
接下來,製備一系列氯化鈉溶液。0.55-0.6mL(ADC溶液體積之約½)之相應莫耳濃度之氯化鈉溶液/50mM K2PO4/pH 7裝入不同小瓶中。在50mM K2HPO4(pH 7)之恆定濃度下,NaCl溶液之初始濃度係0M、1.95M、3.9M及5.85M。在添加至ADC溶液中後,NaCl濃度基於稀釋降低至0M、0.65M、1.3M及1.95M NaCl。然後將小瓶內含物(不同濃度之DAR 2.5或5.5之ADC+鹽溶液)振盪過夜(約20hr)。
在攪拌過夜(>20小時)後,取上清液試樣(經由注射器過濾器移出0.6mL,用924μL 1.95N NaCl/0.05M K2HPO4 pH 7緩衝液稀釋75μL此上清液試樣)。實施後續HPLC-HIC分析以測定每一負載物質之PA%,以及蛋白質回收率。研究結果示於下表9及10中。
表10:如藉由mc-MMAF之HIC-HPLC量測之分佈之匯總
2
總之,實施實例6、表9及10中所述之樹脂滴定篩選以測定樹脂負載及NaCl濃度對自具有2.7至5.5之DAR(平均值)範圍之粗製抗體-1-mcMMAF及抗體-1-vcMMAE ADC混合物(1)-(5)獲得之純化製程(DAR、蛋白質濃度)的影響。如表9及10中所示之樹脂之計算量取決於欲自粗分佈去除之藥物負載物質。例如,為6及8藥物負載物質約5至10倍之樹脂重量證明對於自粗製反應混合物去除該等物質有效。
根據實例1中所述之方法實施ADC(即抗體1-vc-MMAE)之粗分佈之產生。
然後用Bu-HIC樹脂處理反應混合物,該Bu-HIC樹脂預先用50mM磷酸鉀、2M NaCl及緩衝液(pH 6.8)洗滌。隨後攪拌樹脂/反應混合物,並藉由分析型疏水性交互作用層析監測藥物結合物產物之去除(根據先前實例中所述之方法)。此闡述抗體1-vc-MMAE之分批純化之額外實驗之結果闡述於表11中。表11中所提及之滯留時間係自分析型HPLC分析溶析出化合物所耗用之時間。
如表11中所述,抗體-1-vc-MMAE之分批純化產生相對於初始反應混合物更低之平均DAR。
或者,可使用流過純化模式來實施抗體1-vc-MMAE之純化。
通常根據以下方法實施流過純化:製備Tosoh Bioscience Butyl 600M樹脂之兩升批料。將樹脂過濾至2L燒結漏斗(注意漏斗已預先用IPA洗滌並乾燥)中。用2×2L 50mM磷酸鉀、2M NaCl磷酸鹽緩衝液(pH 6.8)洗滌經過濾樹脂。藉由卡耳費雪水分分析將樹脂效能測定為27%(分析顯示存在73w/w%水;注意在此實例中,無機殘餘物(NaCl及K2HPO4)之適度量不用於計算樹脂之效能)。
使用實例1中所述之還原/結合方法,以134.9g抗體1開始。相對
於實例1中所述之方案之一個變化係使用2.15當量TCEP(其產生略高之平均DAR)。該製程產生為33.8pa%之6-8負載物質。因此,在粗製反應混合物中存在45.6g 6-8負載物質。
使用5×負載之疏水性樹脂,需要228.5g乾重疏水性樹脂(即45.6g 6-8負載物質乘以5=228.5g效能調節樹脂)。在27%之樹脂效能(注意:樹脂之效能係藉由100%-來自卡耳費雪分析之w/w%水來計算)下,將等效於228.5克效能調節樹脂之856g濕重量樹脂(即計算:228.5克效能調節樹脂/(27克乾重樹脂/100克濕樹脂))=856g所需濕樹脂)加載至為4英吋×7英吋之不銹鋼管柱中。然後經由壓力石油器及蠕動幫浦使用35大小Pharmed管將粗製反應混合物自20L無菌罈抽送經過樹脂床並以185ml/min抽送至第二20L無菌罈中。然後將所收集濾液再次抽送穿過樹脂床,收集在最終濾液中含有較低DAR物質之期望ADC混合物。所用流過式製程係雙通製程(double pass process)。
然後將樹脂床洗滌多次以去除殘餘之未結合之較低DAR物質,同時留下結合樹脂之高DAR物質(藥物負載6-8)。具體而言,首先,用藉由用WFI將600ml 50mM磷酸鉀、2M NaCl稀釋至1200ml製備之1200mL 1N NaCl(95mS)洗滌樹脂床。然後用藉由用WFI將450ml 50mM磷酸鉀、2M NaCl稀釋至1200mL製備之1200ml 0.75N NaCl(71mS)洗滌樹脂床。使用藉由用900ml WFI稀釋300ml 50mM磷酸鉀、2M NaCl製備之1200mL 0.5N NaCl(50mS)實施第三次洗滌。使用藉由用WFI將150ml 50mM磷酸鉀、2M NaCl稀釋至1200ml製備之1200mL 0.25N NaCl(26mS)實施第四次洗滌。主要收集來自樹脂洗滌物之濾液並將其與來自上述流過式製程之最終濾液合併,提供本體材料(即,最終濾液+洗滌物)。
值得注意地,樹脂床之洗滌係可選的,此乃因具有2-4之DAR之經純化ADC係在來自上述初始多通程序之最終濾液中獲得的。第一次
洗滌提供來自洗滌之約10%回收率,而隨後洗滌產生約1-2%回收率。
藉由切向流過濾(TFF)將本體材料濃縮成約1200g經濃縮ADC溶液且然後與10滲濾體積(diavolume)之15mM組胺酸緩衝液(pH 6)交換,獲得抗體1-vc-MMAE之期望DAR 0-4物質以35mg/mL之最終蛋白質濃度(分離81克,66%產率,91%回收率,對DAR 0-4)。因此,流過純化方法成功地將6-8之DAR物質(即,高負載物質)與較低DAR物質分開(下文於表12中更詳細闡述)。
實施分批純化模式與流過純化模式之比較(表12)。在兩種情況下,樹脂之負載對蛋白質係5重量樹脂對抗體1-vc-MMAE之高負載DAR 6-8物質之質量。儘管個別物質之相對量存在輕微變化(由於用於流過實驗實例中之略高當量之TCEP),但去除兩種方法之較高DAR物質之有效性係相當的。表12中之「流過式製程」一欄中所提及之材料包括來自流過式製程之合併濾液及來自洗滌之材料(統稱為「本體材料」)。
總之,使用分批純化方法與流過純化方法兩者來富集具有2-4之DAR之ADC。兩種純化製程皆依賴於蛋白質(ADC)重量(與高藥物負載物質之分數偶合)對所用樹脂之負載之比率,其中為ADC混合物中
6-8(6或更大)之藥物負載物質之重量5至6倍的疏水性樹脂重量產生含量實質上降低之具有6-8之DAR之ADC。如表12中所述,兩種方法皆產生包含至少95%具有4或更小之DAR之ADC的組合物或包含具有小於4%之6或更大之藥物負載物質之ADC的組合物。
應瞭解,本文所述實例及實施例僅為舉例說明之目的,且基於其之各種修改或變化應為熟習此項技術者所瞭解且欲包括在隨附申請專利範圍之精神及範圍內。出於各種目的,本文所引用之所有出版物、專利及專利申請案之全部內容皆在此以引用方式併入。
<110> 美商艾伯維有限公司
<120> 抗體藥物結合物(ADC)之純化
<130> 117813-07020
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Claims (50)
- 一種獲得包含抗體藥物結合物(ADC)之組合物之方法,該方法包含使包含4或更小之藥物負載物質及6或更大之藥物負載物質之ADC混合物與疏水性樹脂接觸,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該6或更大之藥物負載物質與該樹脂結合,但不允許該4或更小之藥物負載物質之顯著結合;及自該ADC混合物去除該疏水性樹脂,以獲得該包含ADC之組合物,其中該組合物包含小於15%之該6或更大之藥物負載物質,且其中該ADC包含抗體與奧裡斯他汀(auristatin)之結合物。
- 如請求項1之方法,其中該組合物包含小於10%之該6或更大之藥物負載物質。
- 如請求項1之方法,其中該組合物包含5%或更小之該6或更大之藥物負載物質。
- 如請求項1至3中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的3至12倍。
- 如請求項1至3中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的4至8倍。
- 如請求項1至3中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的5至10倍。
- 如請求項1至3中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的6至12倍,且其中該ADC混合物包含在0至1N之間之NaCl或其等效離子強度。
- 如請求項4之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的3至6倍,且其中該ADC混合物包含在1N至2N之間之NaCl或其等效離子強度。
- 如請求項1至3中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的3至7倍,且其中該奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)。
- 如請求項1至3中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的5至10倍,且其中該奧裡斯他汀係單甲基奧裡斯他汀F(MMAF)。
- 如請求項1至3中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的3至7倍,且其中該奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)。
- 一種產生包含具有4.5或更小之平均藥物對抗體比(DAR)之ADC且包含小於15%之不期望ADC之組合物的方法,該方法包含使ADC混合物與疏水性樹脂接觸,其中與該ADC混合物接觸之疏水性樹脂之量足以允許該等不期望ADC之結合;及自該ADC混合物去除該疏水性樹脂,以產生該具有4.5或更小之平均DAR且包含小於15%之不期望ADC之組合物,其中該ADC包含抗體與奧裡斯他汀之結合物。
- 如請求項12之方法,其中該具有4.5或更小之平均DAR之組合物包含小於10%之不期望ADC。
- 如請求項13之方法,其中該等不期望ADC係6及8藥物負載物質。
- 如請求項12至14中任一項之方法,其中添加至該ADC混合物中之疏水性樹脂之量係為該ADC混合物中該等不期望ADC之重量3至12倍的樹脂重量。
- 如請求項12至14中任一項之方法,其中添加至該ADC混合物中之疏水性樹脂之量係為該ADC混合物中該6或更大之藥物負載物質之重量4至8倍的樹脂重量。
- 如請求項12至14中任一項之方法,其中添加至該ADC混合物中之疏水性樹脂之量係為該ADC混合物中該6或更大之藥物負載物質之重量5至7倍的樹脂重量。
- 如請求項12至14中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的6至12倍,且其中該ADC混合物包含在0至1N之間之NaCl或其等效離子強度。
- 如請求項12至14中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的3至6倍,且其中該ADC混合物包含在1至2N之間之NaCl或其等效離子強度。
- 如請求項12至14中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的3至7倍,且其中該奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)。
- 如請求項12至14中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的5至10倍,且其中該奧裡斯他汀係單甲基奧裡斯他汀F(MMAF)。
- 如請求項12至14中任一項之方法,其中該疏水性樹脂之重量係該ADC混合物中該6或更大之藥物負載物質之重量的3至7倍,且其中該奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)。
- 如請求項13至23中任一項之方法,其中該組合物具有4或更小之平均DAR。
- 如請求項13至23中任一項之方法,其中該組合物具有3.5或更小 之平均DAR。
- 如請求項13至23中任一項之方法,其中該組合物具有3或更小之平均DAR。
- 如請求項13至23中任一項之方法,其中該組合物具有2.5或更小之平均DAR。
- 如請求項1至26中任一項之方法,其中該ADC混合物係在超濾/透析過濾製程之後獲得。
- 如請求項1至27中任一項之方法,其中該疏水性樹脂係丁基疏水性樹脂。
- 如請求項1至28中任一項之方法,其係分批製程、循環製程或流過式製程(flow through process)。
- 如請求項1至29中任一項之方法,其中該ADC包含抗表皮生長因子受體(EGFR)抗體。
- 如請求項30之方法,其中該抗EGFR抗體包含含有互補決定區1(CDR1)、CDR2及CDR3結構域之輕鏈可變區,該等結構域包含分別如SEQ ID NO:7、SEQ ID NO:8及SEQ ID NO:9中所述之胺基酸序列;且包含含有CDR1、CDR2及CDR3結構域之重鏈可變區,該等結構域包含如SEQ ID NO:2、SEQ ID NO:3及SEQ ID NO:4中所述之胺基酸序列。
- 如請求項30之方法,其中該抗EGFR抗體包含含有SEQ ID NO:6中所述之胺基酸序列之輕鏈可變區及包含SEQ ID NO:1中所述之胺基酸序列之重鏈可變區。
- 如請求項1至32中任一項之方法,其中該奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)或單甲基奧裡斯他汀F(MMAF)。
- 如請求項33之方法,其中該MMAE經由纈胺酸-瓜胺酸(vc)連接體結合該抗體。
- 如請求項33之方法,其中該MMAF經由馬來醯亞胺基己醯基(mc)連接體結合該抗體。
- 一種組合物,其係經由如請求項1至35之方法中之任一者獲得。
- 一種治療個體之癌症之方法,其包含向該個體投與如請求項36之組合物,以治療癌症。
- 一種包含ADC之組合物,其中70%之存在之ADC具有4或更小之藥物負載物質,且其中該ADC包含抗EGFR抗體及奧裡斯他汀。
- 如請求項38之組合物,其中75%之存在之ADC具有4或更小之藥物負載物質。
- 如請求項38之組合物,其中80%之存在之ADC具有4或更小之藥物負載物質。
- 如請求項38之組合物,其中85%之存在之ADC具有4或更小之藥物負載物質。
- 如請求項38之組合物,其中90%之存在之ADC具有4或更小之藥物負載物質。
- 如請求項38之組合物,其中95%之存在之ADC具有4或更小之藥物負載物質。
- 如請求項38至43中任一項之組合物,其中該抗EGFR抗體包含含有互補決定區1(CDR1)、CDR2及CDR3結構域之輕鏈可變區,該等結構域包含分別如SEQ ID NO:7、SEQ ID NO:8及SEQ ID NO:9中所述之胺基酸序列;且包含含有CDR1、CDR2及CDR3結構域之重鏈可變區,該等結構域包含如SEQ ID NO:2、SEQ ID NO:3及SEQ ID NO:4中所述之胺基酸序列。
- 如請求項38至43中任一項之組合物,其中該抗EGFR抗體包含含有SEQ ID NO:6中所述之胺基酸序列之輕鏈可變區及包含SEQ ID NO:1中所述之胺基酸序列之重鏈可變區。
- 如請求項38至45中任一項之組合物,其中該奧裡斯他汀係單甲基奧裡斯他汀E(MMAE)或單甲基奧裡斯他汀F(MMAF)。
- 如請求項46之組合物,其中該MMAE經由纈胺酸-瓜胺酸(vc)連接體結合該抗體。
- 如請求項46之組合物,其中該MMAF經由馬來醯亞胺基己醯基(mc)連接體結合該抗體。
- 一種醫藥組合物,其包含如請求項38至48中任一項之組合物及醫藥上可接受之載劑。
- 一種治療個體之癌症之方法,其包含向該個體投與如請求項49之醫藥組合物,以治療癌症。
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EP (2) | EP2968589A1 (zh) |
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- 2014-03-14 CN CN201480025357.3A patent/CN105209076A/zh active Pending
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- 2014-03-14 EP EP22179414.2A patent/EP4137160A1/en not_active Withdrawn
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US20140286968A1 (en) | 2014-09-25 |
EP2968589A1 (en) | 2016-01-20 |
MX2015012562A (es) | 2016-06-21 |
KR20150132864A (ko) | 2015-11-26 |
US20190262417A1 (en) | 2019-08-29 |
JP2016519070A (ja) | 2016-06-30 |
RU2015144186A3 (zh) | 2018-03-19 |
WO2014152199A1 (en) | 2014-09-25 |
BR112015023520A2 (pt) | 2017-10-24 |
CA2906022A1 (en) | 2014-09-25 |
EP4137160A1 (en) | 2023-02-22 |
IL241004A0 (en) | 2015-11-30 |
AU2014240012A1 (en) | 2015-09-24 |
NZ630888A (en) | 2017-06-30 |
HK1217643A1 (zh) | 2017-01-20 |
CN105209076A (zh) | 2015-12-30 |
HK1219056A1 (zh) | 2017-03-24 |
SG10201800313UA (en) | 2018-02-27 |
SG11201507432XA (en) | 2015-10-29 |
RU2015144186A (ru) | 2017-04-24 |
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