TWI685350B - 抗體-藥物共軛體、醫藥組成物及其用途 - Google Patents
抗體-藥物共軛體、醫藥組成物及其用途 Download PDFInfo
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- TWI685350B TWI685350B TW106144004A TW106144004A TWI685350B TW I685350 B TWI685350 B TW I685350B TW 106144004 A TW106144004 A TW 106144004A TW 106144004 A TW106144004 A TW 106144004A TW I685350 B TWI685350 B TW I685350B
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Abstract
本發明公開一種免疫共軛體、醫藥組成物及其用途,免疫共軛體包括:抗表皮生長因子受體(EGFR)抗體或其結合片段;以及激酶抑制劑。本發明的免疫共軛體相較於單獨使用抗體或抗體與激酶抑制劑組合能夠更有效地抑制癌症細胞生長。
Description
本發明係主張美國專利臨時申請案第62/434,035號(申請日:2016年12月14日)之國際優先權,該申請案之完整內容納入為本發明專利說明書的一部分以供參照。
本發明涉及一種抗體-藥物共軛體、醫藥組成物及其用途,特別是涉及一種包含抗EGFR抗體和激酶抑制劑的免疫共軛體、醫藥組成物及其用途。
標靶療法(例如抗體)已經成為與癌症奮鬥的重要的治療方法。然而,現有技術中可知許多病患對於此療法具有抗性。西妥昔單抗是一種嵌合型小鼠-人類單株抗體,其可與表皮生長因子受體(EGFR)特異性結合,因此,西妥昔單抗被批准用於治療結腸直腸癌以及頭頸癌。然而,西妥昔單抗對於某些突變的癌症沒有治療效果,如KRAS、BRAF、PIK3CA以及PTEN突變的癌症。現有技術中已知,由西妥昔單抗引起的MET和SRC活化可能是致使抗藥性的機制(參閱Song等人2014年發表於Int.J.Mol.Sci.,15第5838-5851頁的文獻內容)。
抗體-藥物共軛體(ADC)可使細胞毒性劑專一性地遞輸至特定的癌症細胞。因此,癌症治療逐步針對ADC發展。另一方面,由於ADC可攜帶有效的細胞毒性劑,人們也擔心ADC的副作用, 且臨床研究也表明ADC在某些病患中也可能是無效的。
本發明所要解決的技術問題在於,針對現有技術的不足提供一種抗體-藥物共軛體及其用途。
為了解決上述的技術問題,本發明所採用的其中一技術方案是一種免疫共軛體,其包括一抗表皮生長因子受體(EGFR)抗體或其結合片段以及激酶抑制劑。
於本發明的一具體實施例中,激酶抑制劑是SRC抑制劑。SRC激酶抑制劑是選自由1-萘基PP1、A 419259三鹽酸鹽、AGL 2263、altenusin、ansatrienin A、AP 24534、AZM 475271、Bcr-abl抑制劑II、NVP-BHG712、博舒替尼(bosutinib)、calphostin C、單寧卡(damnacanthal)、達沙替尼(dasatinib)、格爾德黴素(geldanamycin)、星形孢菌素(staurosporine)、除莠霉素A(herbimycin A)、靛玉紅-3’-(2,3-二羥基丙基)肟醚(indirubin-3'-(2,3-dihydroxypropyl)shyoximether)、KB SRC 4、KX2-391、薰草菌素A(lavendustin A)、LCB 03-0110二鹽酸鹽、木犀草素(luteolin)、MNS、奈拉替尼(neratinib)、PD 166285二鹽酸鹽、PD 180970、JNJ-10198409、培利替尼(pelitinib)、雲杉醇(piceatannol)、PKC-412、PKI 166鹽酸鹽、PP1、PP2、槲皮素(quercetin)、saracatinib、SKI-1、SU6656、TC-S 7003、TX-1123、P21d鹽酸鹽、Tilfrinib、凡德他尼(vandetanib)、舒尼替尼(sunitinib)、伊馬替尼(imatinib)、WH-4-023、tesevatinib、ENMD-2076、TPX-0005、AZD-0424、KX2-361、CCT196969以及TX-1918所組成的群組。
於本發明的一具體實施例中,抗EGFR抗體選自由西妥昔單抗(cetuximab)、帕尼單抗(panitumumab)、耐昔妥珠單抗(necitumumab)、紮魯木單抗(zalutumumab)、馬妥珠單抗 (matuzumab)、尼妥珠單抗(nimotuzumab)、曲妥珠單抗(trastuzumab)、ior-egf/r3,弗妥昔單抗(futuximab)、depatuxizumab、duligotuzumab以及tomuzotuximab所組成的群組。
本發明所公開的免疫共軛體具有結構式:Ab-(L-D)m,其中,Ab是一抗表皮生長因子受體(EGFR)抗體或其結合片段;其中,L是一連接子;其中,D是一激酶抑制劑;以及其中,m是1至20的整數,舉例而言可以是1至10、1至15、5至15、5至20、2至15或2至8的整數,如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
於本發明的一具體實施例中,免疫共軛體具有下列結構式:
其中,Z是NH或S,M是、、、、
、或,R2是 氫或,m是1至20的整數,Q是-胜肽-、-L-苯丙氨酸-L-賴氨酸或-L-纈氨酸-L-瓜氨酸-,R3是氫、鹵素或烷基,A是、 或-Ar-,B是或,R是氫或烷基,Ar是,R1是氫、鹵素或烷基;以及n是1至10的整數。
為了解決上述的技術問題,本發明所採用的另外一技術方案是,提供一種醫藥組成物,其包含治療有效量之如本發明上述的免疫共軛體以及醫藥學上可接受的載劑。
具體而言,本發明的醫藥組成物視需求可以含有一治療劑,且治療劑可為本領域中已知的任何藥劑。
為了解決上述的技術問題,本發明所採用的另外一技術方案是提供一種活體外抑制癌症細胞生長的方法,包括在活體外使癌症細胞與有效量的本發明上述的免疫共軛體接觸。
為了解決上述的技術問題,本發明所採用的另外再一技術方案是提供一種如本發明上述的免疫共軛體的用途,其是用於製造用以抑制癌症細胞生長的藥物。
於本發明的一具體實施例中,本發明的癌症細胞是對於抗EGFR抗體或EGFR酪氨酸激酶抑制劑具有抗性的癌症細胞。
於本發明的一具體實施例中,本發明的癌症細胞是KRAS、BRAF、PIK3CA、PTEN、EGFR、P53或SRC突變的癌症細胞。
於本發明的一具體實施例中,本發明的癌症是選自由結腸直腸癌、頭頸癌、胃腸癌、肺癌、乳腺癌、胰腺癌、卵巢癌、宮頸癌、前列腺癌、腎癌、腦癌、腎癌、神經膠質瘤、膀胱癌、口腔癌以及EGFR陽性癌症所組成的群組。
為了解決上述的技術問題,本發明所採用的另外再一技術方案是提供一種製備免疫共軛體的方法,包括將一抗體或其結合片段共軛接合於本發明的星形孢菌素(staurosporine)衍生物或達沙替尼(dasatinib)衍生物。於本發明的一具體實施例中,免疫共軛體的抗體是西妥昔單抗。
為使能更進一步瞭解本發明的特徵及技術內容,請參閱以下有關本發明的詳細說明與圖式,然而所提供的圖式僅用於提供參考與說明,並非用來對本發明加以限制。
圖1為本發明的星形孢菌素和西妥昔單抗合併抑制SW480結 腸細胞的Src活化。其中,C表示西妥昔單抗、S表示星形孢菌素、p-Src表示磷酸化的Src(經活化的)。*顯著差異(p<0.05)。定量值來自西方墨點法蛋白質表現的分析結果。
圖2為本發明例示性的抗體-藥物共軛體的結構。
圖3顯示西妥昔單抗(1μg/ml)、星形孢菌素(10nM)、西妥昔單抗(C)合併星形孢菌素(S)、以及Rex-1(1μg/ml)針對SW48(野生型)、HT-29(BRAF突變型)以及SW480(KRAS突變型)結腸癌症細胞株的細胞活性抑制效果。
圖4顯示了不同批次的Rex-1(Rex-1-04、Rex-1-08以及Rex-1-03)對SW48及HT-29(BRAF突變型)結腸癌症細胞株的細胞活性抑制效果。其中,C表示西妥昔單抗、S表示星形孢菌素。
以下是通過特定的具體實施例來說明本發明所公開有關“抗體-藥物共軛體及其用途”的實施方式,本領域技術人員可由本說明書所公開的內容瞭解本發明的優點與效果。本發明可通過其他不同的具體實施例加以施行或應用,本說明書中的各項細節也可基於不同觀點與應用,在不悖離本發明的構思下進行各種修改與變更。以下的實施方式將進一步詳細說明本發明的相關技術內容,但所公開的內容並非用以限制本發明的保護範圍。
出乎意料地發現,含有抗EGFR抗體和激酶抑制劑(例如SRC抑制劑)的免疫共軛體相較於單獨使用抗體或與激酶抑制劑組合更有效地治療帶有某些基因突變的癌症。因此,本發明提供了包含抗EGFR抗體和激酶抑制劑的免疫共軛體。
具體而言,激酶抑制劑是選自由抑制激酶AATK、ABL、ABL2、ALK、AXL、BLK、BMX、BTK、CSF1R、CSK、DDR1、DDR2、EGFR、EPHA1、EPHA2、EPHA3、EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHA10、EPHB1、EPHB2、EPHB3、EPHB4、EPHB6、ERBB2、ERBB3、ERBB4、FER、FES、FGFR1、FGFR2、 FGFR3、FGFR4、FGR、FLT1、FLT3、FLT4、FRK、FYN、GSG2、HCK、IGF1R、ILK、INSR、INSRR、IRAK4、ITK、JAK1、JAK2、JAK3、KDR、KIT、KSR1、LCK、LMTK2、LMTK3、LTK、LYN、MATK、MERTK、MET、MLTK、MST1R、MUSK、NPR1、NTRK1、NTRK2、NTRK3、PDGFRA、PDGFRB、PLK4、PTK2、PTK2B、PTK6、PTK7、RET、ROR1、ROR2、ROS1、RYK、SGK493、SRC、SRMS、STYK1、SYK、TEC、TEK、TEX14、TIE1、TNK1、TNK2、TNNI3K、TXK、TYK2、TYRO3、YES1、ZAP70、MAPK、ERK、PI3K、AKT、FAK、PKC以及PKA的激酶抑制劑所組成的群組。
於一具體實施例中,SRC激酶抑制劑是選自由1-萘基PP1、A 419259三鹽酸鹽、AGL 2263、altenusin、ansatrienin A、AP 24534、AZM 475271、Bcr-abl抑制劑II、NVP-BHG712、博舒替尼(bosutinib)、calphostin C、單寧卡(damnacanthal)、達沙替尼(dasatinib)、格爾德黴素(geldanamycin)、星形孢菌素(staurosporine)、除莠霉素A(herbimycin A)、靛玉紅-3’-(2,3-二羥基丙基)肟醚(indirubin-3'-(2,3-dihydroxypropyl)shyoximether)、KB SRC 4、KX2-391、薰草菌素A(lavendustin A)、LCB 03-0110二鹽酸鹽、木犀草素(luteolin)、MNS、奈拉替尼(neratinib)、PD 166285二鹽酸鹽、PD 180970、JNJ-10198409、培利替尼(pelitinib)、雲杉醇(piceatannol)、PKC-412、PKI 166鹽酸鹽、PP1、PP2、槲皮素(quercetin)、saracatinib、SKI-1、SU6656、TC-S 7003、TX-1123、P21d鹽酸鹽、Tilfrinib、凡德他尼(vandetanib)、舒尼替尼(sunitinib)、伊馬替尼(imatinib)、WH-4-023、tesevatinib、ENMD-2076、TPX-0005、AZD-0424、KX2-361、CCT196969以及TX-1918所組成的群組。舉例而言,SRC激酶抑制劑可以是星形孢菌素或達沙替尼。
本文所用的術語“抗體”具有抗原結合活性的各種抗體結構,包括但不限於單株抗體、多株抗體、全長抗體或其片段、含Fc域 抗體、Fab片段、Fab'片段、F(ab')2片段、單股(單鏈)抗體、scFV多聚體、單價抗體,多價抗體、人源化抗體和嵌合抗體。
各種抗EGFR抗體是本領域已知或可商購的。所述抗體也可以使用本領域已知的方法產生,例如重組方法。在一些實施方案中,抗體選自由西妥昔單抗(cetuximab)、帕尼單抗(panitumumab)、耐昔妥珠單抗(necitumumab)、紮魯木單抗(zalutumumab)、馬妥珠單抗(matuzumab)、尼妥珠單抗(nimotuzumab)、曲妥珠單抗(trastuzumab)、ior-egf/r3,弗妥昔單抗(futuximab)、depatuxizumab、duligotuzumab以及tomuzotuximab。
本發明的的免疫共軛體具有結構式Ab-(L-D)m;其中,Ab是抗表皮生長因子受體(EGFR)抗體或其結合片段,L是連接子,D是激酶抑制劑,以及m是1至20的整數。
具體而言,連接子(linker)可以是可切割或不可切割的連接子,例示性的連接子包括但不限於,馬來醯亞胺己醯基連接子、馬來醯亞胺己醯基-p-氨基甲酸氨基芐酯、馬來醯亞胺己醯基-肽-氨基甲酸氨基芐酯、馬來醯亞胺己醯基-L L-苯丙氨酸-L-賴氨酸-對-氨基甲酸氨基芐酯、馬來醯亞胺己醯基-L-纈氨酸-L-瓜氨酸-對氨基甲酸氨基芐酯、3-(2-吡啶基二硫代)丙酸N-琥珀醯亞胺酯、4-琥珀醯亞胺基-氧羰基-2-甲基-2-(2-吡啶基二硫代)-甲苯、3-(2-吡啶基二硫代)丙酸N-琥珀醯亞胺酯、4-(2-吡啶基二硫代)N-(4-馬來醯亞胺基水楊醯氨基)丁基]-3'-(2'-吡啶基二硫代)丙醯胺、N(N-馬來醯亞胺基乙醯氧基)琥珀醯亞胺酯、N-[b-馬來醯亞胺丙氧基]琥珀醯亞胺酯、[N-e-馬來醯亞胺丁醯基]琥珀酸亞胺酯、N-[g-馬來醯亞胺丁醯基]琥珀亞胺酯、琥珀醯亞胺基-4-[N-馬來醯亞胺基甲基]環己烷-1-羧基-[6-醯胺基己酸]、琥珀醯亞胺基-6-(3-[2-吡啶基二硫]丙醯胺基)己酸酯、間馬來醯亞胺苯甲醯-N-羥基琥珀醯亞胺酯、N-琥珀醯亞胺基[4-碘乙醯基]氨基苯甲酸酯、琥珀醯亞胺基4-[N-馬來醯亞胺基甲基]環己烷-1-羧酸酯、N-琥珀醯亞胺基3-[2-吡啶基二硫代]-丙醯胺基、[N-e-馬來醯亞胺丁醯基]磺基琥珀酸亞胺酯、N-[g-馬來醯亞胺丁醯基]磺基琥珀酸亞胺酯、磺基琥珀醯亞胺基-6- 甲基-α-(2-吡啶基二硫代)甲苯醯氨基]己酸酯、磺基琥珀醯亞胺基-6-(3'-[2-吡啶基二硫代]丙醯胺基)己酸酯、間馬來醯亞胺苯甲醯基-N-羥基磺基琥珀醯亞胺酯、N-磺基琥珀醯亞胺基[4-碘乙醯基]氨基苯甲酸酯、4-[N-馬來醯亞胺基甲基]環己烷-1-羧酸磺基琥珀醯亞胺酯、4-[對馬來醯亞胺基苯基]丁酸磺基琥珀醯亞胺酯、乙二醇-雙(琥珀酸N-羥基琥珀醯亞胺酯)、酒石酸二琥珀醯亞胺酯、1,4,7,10-四氮雜環十二烷-1,4,7,10-四乙酸、二亞乙基三胺五乙酸以及硫脲連接子。
於一具體實施例中,免疫共軛體具有下列結構式:
其中,X是、或-Ar-,R是氫或烷基,Ar是,R1是氫、鹵素或烷基,n是1至10的整數,Y是或-CH2-,以及m是1至20的整數。舉例而言,可以是1至10、1至15、5至15、5至20、2至15或2至8的整數,如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。
於一具體實施例中,免疫共軛體含有達沙替尼(dasatinib)並具有下列結構式:
其中,Z是NH或S,M是、、、、
、或,R2是氫或,m是1至20的整數,Q是-胜肽-、-L-苯丙氨酸-L-賴氨酸或-L-纈氨酸-L-瓜氨酸-,R3是氫、鹵素或烷基,A是、 或-Ar-,B是或,R是氫或烷基,Ar是,R1是氫、鹵素或烷基;以及n是1至10的整數。
藉由連接子將化合物共軛結合至抗體的技術為所屬技術領域眾所周知,包括以下實施例中描述的方法。可以先合成含有連接子的化合物的衍生物,然後再與抗體共軛結合。
本發明更進一步公開達沙替尼(dasatinib)連接子衍生物(如下所示),每一衍生物皆可與抗-EGFR抗體(例如西妥昔單抗)共軛結合以製備免疫共軛體。
本發明的免疫共軛體可用於治療受試者的癌症或腫瘤,例如EGFR陽性癌症或腫瘤。具體而言,癌症或腫瘤可以是結腸直腸癌、頭頸癌、胃腸癌、肺癌、乳腺癌、胰腺癌、卵巢癌、宮頸癌、前列腺癌、腎癌、腦癌、腎癌、神經膠質瘤、膀胱癌、口腔癌。任選地,在用免疫共軛體治療受試者之前,可以使用本領域已知的方法確定受試者中的癌症或腫瘤是否表現EGFR。
於本發明的一具體實施例中,癌症或腫瘤對EGFR標靶治療具有抗性(或抗藥性),例如抗EGFR抗體或EGFR酪氨酸激酶抑制劑。抗性的機制可能是已知或未知的。
於本發明的一具體實施例中,癌症或腫瘤具有對EGFR標靶治療產生抗性有關聯的突變,例如KRAS、BRAF、PIK3CA、PTEN、EGFR、P53或SRC突變。任選地,在用免疫共軛體治療受試者之前,可以檢測受試者的癌症或腫瘤是否表現出對EGFR標靶治療的抗性或具有與抗性相關的突變。曾經有對EGFR標靶治療抗性的受試者也可以是用本發明的免疫共軛體治療的受試者。
本發明的免疫共軛體可配製成適合於各種施用途徑(例如,靜脈內、關節內、結膜、顱注注射、腹膜內、胸膜內、肌內、肌肉內、鞘內或皮下途徑)的醫藥組成物。醫藥組成物可以是水溶液或凍乾製劑。它可以含有藥學上可接受的載體,例如緩沖劑、賦形劑、穩定劑或防腐劑。醫藥組成物可以包含與免疫共軛體共同作用的其它活性成分,例如另一種治療劑。本發明的醫藥組成物可以用於治療個體的癌症或腫瘤。
本發明中術語“個體”或“受試者”意指人類或非人類的動物。本發明中術語“治療”是指將一種或多種上述化合物給予具有上述疾病、所述疾病的症狀或對所述疾病的傾向的受試者,其目的為賦予治療效果,例如治癒、緩解、改變、影響、改善或預防上述疾病、其症狀或其傾向。而術語“有效劑量”是指達到預期治療效果所需的活性劑(例如化合物或醫藥組成物)劑量,如所 屬技術領域具有通常知識者所習知的,有效劑量將根據所治療的疾病的類型、給藥途徑、賦形劑的使用以及可能同時使用其它藥物而有所差異。
在沒有更進一步的闡述下,相信由以上之敘述足以呈現本發明。因此,接下來的實施例是純粹做為解說性之實例,無論如何不受限於其餘以任何形式公開的事情。所有在此文中被引用之刊物皆已全部整合於參考文獻中。
本發明之實施例將進一步列舉以下的實例說明,本發明所屬技術領域中具通常知識者可以藉由本案說明書了解所述實例例僅用於說明本發明,各種修改和變化在不偏離本發明的範圍下為可行的,因此,下述的實施例僅作為本發明代表性的不同面向及特徵,而非用來限制本發明。
分析具有KRAS突變(如SW480)的結腸癌症細胞株,以確定SRC抑制劑與西妥昔單抗的組合是否能抑制SRC活化。請參閱圖1,相較於用星形孢菌素(S)或西妥昔單抗(C)任一者處理的細胞相比,合併星形孢菌素及西妥昔單抗(C+S)處理的細胞表現出顯著降低的SRC蛋白水平。
下列反應流程1顯示了星形孢菌素1連接子衍生物的合成流程。星形孢菌素可藉由二級胺與琥珀酸酐反應。藉由N-羥基琥珀醯亞胺(HOSu)以及1-乙基-3-(3-二甲基氨基丙基)碳化二亞胺(EDCI)處理,將星形孢菌素羧酸1轉化為N-羥基琥珀醯亞胺(NHS),然後可以將星形抱菌素1通過NHS基團與抗體共軛結合。
請參閱反應流程1,於星形孢菌素(10μmol)的二甲基亞碸(DMSO)溶液中,在避光條件下加入琥珀酸酐(15μmol)和4-二甲基氨基吡啶(DMAP)(20μmol)。攪拌30小時後,將上述混合物用0.1%三氟乙酸(TFA)水溶液沉澱,並用0.1%TFA水溶液研磨(triturate)沉澱物兩次,得到中間產物化合物1,產率84%。
1H NMR(300MHz,DMSO-d6)δ 12.06(s,1H),9.29(d,J=7.9Hz,1H),8.59(s,1H),8.05(d,J=7.7Hz,1H),7.99(d,J=8.5Hz,1H),7.67(d,J=8.2Hz,1H),7.48(t,J=7.7Hz,2H),7.35(t,J=7.5Hz,1H),7.29(t,J=7.5Hz,1H),7.03(t,J=7.5Hz,1H),5.00(s,3H),4.22(s,1H),2.81(s,3H),2.77(s,3H),2.68(d,J=5.6Hz,1H),2.60-2.56(m,2H),2.33(s,3H),2.28-2.17(m,1H)。
LCMS m/z理論值C32H30N4O6[M+H]+=567.220,實測值567.199(IT-TOF)。
將N-羥基琥珀醯亞胺(HOSu)(39mg,0.338mmol)以及1-乙基-3-(3-二甲基氨基丙基)碳化二亞胺(EDCI)(88mg,0.564mmol)加入星形孢菌素-COOH(1,160mg,0.282mmol)的四氫呋喃(THF)(3ml)溶液中。將反應混合物在室溫下攪拌16小時,然後用水終止反應。將所述溶液用二氯甲烷萃取,將有機層用飽和食鹽水洗滌、以MgSO4(s)乾燥,再減壓濃縮,得到呈淺白色固體的星形孢菌素1(153mg),產率為82%。
1H NMR(600MHz,DMSO-d 6);1H NMR(600MHz,DMSO-d 6)δ 9.3-9.3(m,1H),8.6(d,J=5.2Hz,1H),8.1(t,J=8.2Hz,1H),8.0(dd,J=11.2,8.5Hz,1H),7.7(dd,J=8.2,5.2Hz,1H),7.5-7.5(m,2H),7.4(q,J=7.7Hz,1H),7.3(ddd,J=8.0,7.0,1Hz,1H),7.0(ddd,J=8.5,6.7,3.6Hz,1H),5.0-5.0(m,3H),4.2(ddd,J=12.0,2.8,1.5Hz,1H),3.0(t,J=6.3Hz,1H),2.9-2.8(m,5H),2.8(s,1H),2.8(s,2H),2.7-2.7(m,1H),2.7-2.6(m,1H),2.6(s,2H),2.5-2.5(m,1H),2.3(d,J=8.5Hz,2H),2.2(tdd,J=12.0,8.2,6.7Hz,1H); 13C NMR(600MHz,DMSO-d 6)173.3,172.4,171.2,170.7,169.2,139.3,136.7,133.1,129.6,129.6,126.1,125.8,125.5,124.2,123.1,121.9,120.8,119.9,119.9,115.7,114.6,114.1,109.5,95.1,83.6,82.7,60.9,48.8,45.9,31.2,29.9,28.3,27.2,26.6,25.9,25.7。
ESI-MS m/z 664.67([M+1]+)。
下列反應流程2顯示了星形孢菌素2連接子衍生物的合成流程。將星形孢菌素與N-琥珀醯亞胺基-4-甲醯基苯甲醯胺和氰基硼氫化鈉反應,將氨基轉化為N-羥基琥珀醯亞胺(NHS)基團。然後可以將星形孢菌素2藉由NHS基團與抗體共軛接合。
參照反應流程2,將N-琥珀醯亞胺基-4-甲醯基苯甲醯胺(127mg,0.51mmol)、氰基硼氫化鈉(24mg,0.38mmol)以及乙酸(0.196mL)加入到星形孢菌素(80mg,0.17mmol)的二甲基 甲醯胺(DMF)(5ml)溶液中。將反應混合物在室溫下攪拌16小時。用旋轉蒸餾器除去DMF和乙酸。將殘餘物用二氯甲烷萃取,有機層用飽和食鹽水洗滌、用MgSO4(s)乾燥、減壓濃縮。通過管柱層析色譜(DCM:MeOH=9:1)純化,得到白色固體星形孢菌素2,產率35%。
下列反應流程3顯示了具有可切割的纈氨酸-瓜氨酸連接子的達沙替尼-1的合成流程。藉由Mitsunobu反應和聯氨(hydrazine)去保護將達沙替尼的羥基轉化為胺基。進一步參閱專利文獻CN106279143。Mal-C5-VC-PAB-PNP的離去基團對硝基苯酚(p-nitrophenol)被達沙替尼-NH2的胺取代。然後可以通過硫醚鍵與抗體共軛得到產物達沙替尼-1。
參閱反應流程3,在氬氣氣氛下將N,N-二異丙基乙胺(DIPEA)(22.8μL,0.131mmol)加入達沙替尼-NH2(31.9mg,0.0655mmol)、Mal-C5-VC-PAB-PNP(57.9mg,0.0786mmol)以及 HOBt(10mg,0.0655mmol)的DMF(0.5ml)溶液。將反應混合物在室溫下攪拌16小時,然後用水終止反應。所述溶液用乙酸乙酯萃取。再將有機層用飽和食鹽水洗滌,用MgSO4(s)乾燥、減壓濃縮,得到淡黃色固體狀達沙替尼-1(12.5mg),產率17.6%。
LC/MS m/z 1085.6。
下列反應流程4顯示了具有不可切割連接子的達沙替尼-2的合成反應流程。達沙替尼-NH2的胺基通過CS2和N,N'-二環己基碳化二亞胺(DCC)轉化為異硫氰酸酯基團。得到可以藉由所形成硫醚鍵與抗體結合的產物達沙替尼-2。
參閱反應流程4,在氬氣氣氛下將溶解於二氯甲烷(3ml)的N,N'-二環己基碳化二亞胺(50.3mg,0.244mmol)以及CS2(244.3uL,4.06mmol)加入達沙替尼-NH2(100mg,0.203mmol)溶液。混合物在低溫冰浴下攪拌5分鐘。除去冰浴,然後在室溫下攪拌混合物直到反應完成。將反應減壓濃縮以除去溶劑,然後通過矽膠管柱層析純化,得到白色固體的達沙替尼-2(16.9mg)。
1H NMR(400MHz,DMSO-d6):δ ppm 11.47(s,1H),9.88(s,1H),8.23(s,1H),7.40(dd,J=1.2,7.2Hz,1H),7.24-7.30(m,2H),6.07(s,1H),3.80(t,J=6.0Hz,2H),3.54(br,4H),2.66(t,J=6.0Hz,2H),2.54(br,4H),2.42(s,3H),2.24(s,3H)。
ESI-MS m/z 529.6。
下列的反應流程5顯示達沙替尼-3具有不可切割的NHS連接子衍生物的合成反應流程。達沙替尼-NH2的胺基團可以藉由用4-甲醯基苯甲酸還原胺化轉化為羧酸基團。通過N-羥基琥珀醯亞胺 (HOSu)和1-乙基-3-(3-二甲基氨基丙基)碳化二亞胺(EDCI)處理可以將酸基團轉化為N-羥基琥珀醯亞胺(NHS)基團。得到可藉由醯胺鍵形成與抗體的賴氨酸共軛結合的產物達沙替尼-3。
參閱反應流程5,於溶解於2mL的MeOH的4-甲醯基苯甲酸(46.2mg,0.308mmol)、溶解於1.5mL MeOH的達沙替尼-NH2(100mg,0.205mmol)以及NaBH3CN(28.3mg,0.451mmol)的溶液中加入乙酸(117μL,2.05mmol)。將混合物在室溫下攪拌過夜。然後減壓除去溶劑。將所得的中間產物化合物2不經純化用於下一步反應。
將NHS(9.4mg,0.0815mmol)、EDCI(26.1mg,0.136mmol)以及DMAP(1.7mg,0.0136mmol)加入溶於1mL DMF的中間產物化合物2,然後在室溫下攪拌過夜。將溶液用乙酸乙酯萃取,有機層用飽和食鹽水洗滌,用MgSO4(s)乾燥,減壓濃縮。通過管柱層析純化粗產物,得到淡黃色固體的達沙替尼-3。
1H NMR(400MHz,DMSO-d6):δ ppm 11.45(s,1H),9.88(s,1H),8.21(s,1H),8.09-8.07(d,J=8.2Hz,4H),7.70-7.68(d,J=8.2Hz,4H),7.40-7.39(d,J=7.5Hz,1H),7.29-7.24(m,2H),6.03(s,1H),3.78(s,4H),3.48(s,4H),2.89(s,8H),2.61-2.52(m,4H),2.40-2.39(m,7H),2.23(s,3H)。
ESI-MS m/z 949.4。
如圖2所示,將星形孢菌素1、星形孢菌素2、達沙替尼-1,達沙替尼-2以及達沙替尼-3各自與西妥昔單抗共軛接合。得到共軛體Rex-1,Rex-2、Rex-3、Rex-4和Rex-5。
藉由將連接子-藥物(Linker-Payload)與西妥昔單抗的賴氨酸殘基共軛接合來製備Rex-1、Rex-2、Rex-3和Rex-5。通常,在333μL西妥昔單抗(3.0mg/mL)的溶液與緩衝液(50mM磷酸鉀、50mM氯化鈉、2mM EDTA,pH6.5)中慢慢添加20當量的連接子激酶抑制劑(濃度5mM溶於DMSO中)。在37℃氬氣氣氛下將反應混合物攪拌4小時。將抗體製備物用具有30kDa NMWL於pH 7.4的PBS緩衝液的Amicon Ultra-15離心過濾裝置進行脫鹽並濃縮,得到抗體-藥物共軛體。HRMS被用來確定平均藥物-抗體比率(DAR)。共軛接合條件顯示在下表1中。
為了製備Rex-3,連接子-藥物(Linker-Payload)藉由其半胱氨酸殘基與西妥昔單抗共軛接合。在37℃下,於25mM硼酸鈉、25mM NaCl、1mM DTPA、pH8緩衝液(含20%甘油)中,用5.5μL的10mM TCEP(8莫耳當量)反應處理1mg西妥昔單抗(5mM)2小時。使用Amicon(Millipore)Ultra-15 30K離心過濾器純化過量的TCEP。然後將部分還原的西妥昔單抗冷卻至0至4℃並用10莫耳當量的達沙替尼-1反應30分鐘使其烷基化。使用33.4μL的2mM半胱氨酸來終止反應未反應過量的達沙替尼-1。使用Amicon Ultra-15離心過濾裝置於pH7.4的PBS緩衝液中的30kDa NMWL 對抗體製劑進行脫鹽和濃縮,得到Rex-3。HRMS被用以確定平均DAR。共軛接合條件顯示在下表2中。
用SDS-PAGE分析共軛體(即Rex-1-04、Rex-1-05、Rex-1-06、Rex-1-07、Rex-1-09、Rex-1-10、Rex-1-15、Rex-1-16、Rex-1-17、Rex-1-18、Rex-4-01、Rex-4-02、Rex-4-03、Rex-4-04以及Rex-4-05),例如4-12%非還原及還原SDS-PAGE凝膠,以確定其等是否保留了抗體結構的特性。如以下的方法藉由LC-MS分析所有共軛體。
為了進行完整的質量測量,在分析前,使經共軛的抗體與糖苷酶PNGase F(酶:蛋白質比例為1:100)於37℃下反應3小時以除去N-聚醣(N-glycans)。將得到的溶液乾燥並重新溶於0.2%(v/v)甲酸配製最終濃度0.1μg/μL的溶液。將9.8μL的溶液注射到Waters ACQUITY UPLC系統的配備MassPREP微量脫鹽柱(20μm,2.1x5mm Waters Corporation,Milford,MA,USA),並與Xevo TM G2S QTof儀器(Waters Corporation,Milford,MA,USA)在線連動。流動相A為0.1%FA水溶液,而流動相B為0.1%FA的CAN溶液。梯度溶析由10%B等度沖提0.5分鐘,然後在2.9分鐘內線性梯度自10%至90%B,然後在1分鐘內至10%B,最後以10% B等度沖提1分鐘。整個梯度溶析過程中流速保持在0.2mL/min。柱溫保持在60℃。質譜分析的去溶劑氣體和來源溫 度分別設定為450℃和150℃。毛細管電壓和錐形電壓分別設置在3kV和40V。m/z掃描範圍設置為1500-3800。數據由MassLynx 4.1軟體收集,藉由MaxEnt 1演算法將獲得的多重電荷圖譜進行去捲積處理(deconvoluted)。去捲積中,使用m/z範圍從2,000至3,500(完整蛋白質),質量範圍為140000-160000Da,最低強度比例(left/right minimum intensity ratio)為40%,模擬同位素模式光譜儀(simulated isotope pattern spectrometer)的模糊寬度(blur width)1.6Da,以及疊代次數20。
針對LC-MS分析,將1μL體積的所得溶液注入到Waters nanoACQUITY UPLC系統的預配置管柱(Waters,0.180mm×20mm,5μm C18),接著是奈米管柱(Waters,75μm×25cm,1.7μm C18),並將其在線串聯耦合至LTQ-Orbitrap XL質譜儀(Thermo Fisher Scientific,San Jose,CA,USA)。流動相A為0.1%FA水溶液,而流動相B為0.1%FA的CAN溶液。沖提程序由5%B等度沖提5分鐘,35分鐘內從5%至40%B的線性梯度,隨後5分鐘內從40%至90%B的另一線性梯度沖提,最後在90%B下進行等度沖提5分鐘。流速保持在0.3μL/min。
LTQ-Orbitrap XL質譜儀的操作如下:Orbitrap可於60,000質量解晰度(m/z 400)下取得全掃瞄MS光譜(m/z 300-2000)(離子目標值5×105個離子)。將5個最具強度且電荷狀態≧2的離子被選擇用於在具有35%校正碰撞能量、激發q=0.25、激發時間30ms以及一個微掃描的離子阱中進行測序和碎裂。目標值為1×104,離子選擇閾值為5000,最大允許離子累積時間為500ms,全掃描為30ms,CID為30ms。
分別用西妥昔單抗、星形孢菌素、合併的西妥昔單抗及星形孢菌素以及Rex-1處理SW48結腸癌症細胞(帶有野生型BRAF和KRAS)、HT-29結腸癌症細胞(BRAF突變型)和SW480結腸 癌症細胞(KRAS突變型)。如圖3所示,相較於HT-29細胞或SW480細胞,SW48細胞對西妥昔單抗敏感。與西妥昔單抗相比,Rex-1將SW48細胞的存活力降低了兩倍。值得注意的是,Rex-1顯示對HT-29細胞和SW480細胞的功效,導致兩種細胞約50%活性。且在所有三種細胞系中,Rex-1比西妥昔單抗和星形孢菌素組合顯著更有效。
此外,更分析了不同批次的Rex-1(如上表1所示的批次)。針對HT-29細胞或SW480細胞顯示出不同的效力,且對於SW48細胞而言,都比西妥昔單抗和星形孢菌素的組合顯著更有效,實驗結果請進一步參見圖4及表3。
所有揭示於此說明書中之特徵可以任何方式組合。各個揭示於此說明書中之特徵可以另一提供相同、相當、或類似目的之替代手段取代。因此,除非另有明示,各經揭示之特徵僅係一總括系列之相當或類似特徵中之一例。
由上文之敘述,熟習技藝者可輕易確認本發明之必要特徵,且在不偏離本發明精神及範圍之情形下,熟習技藝者可實施本發明之各種不同變化及修飾,以使其適用於各種用途及條件。因此,其他具體實例亦涵括於申請專利範圍中。
以上所公開的內容僅為本發明的優選可行實施例,並非因此侷限本發明的申請專利範圍,所以凡是運用本發明說明書及圖式內容所做的等效技術變化,均包含於本發明的申請專利範圍內。
Claims (17)
- 一種免疫共軛體,其包括:一抗表皮生長因子受體(EGFR)抗體或其結合片段;以及一SRC激酶抑制劑;其中所述免疫共軛體具有結構式Ab-(L-D)m,Ab是所述抗表皮生長因子受體(EGFR)抗體或其結合片段,L是一連接子,D是所述激酶SRC抑制劑,以及m是1至20的整數,且所述抗表皮生長因子受體(EGFR)抗體是西妥昔單抗(cetuximab)或帕尼單抗(panitumumab)。
- 如請求項1所述的免疫共軛體,其中,所述SRC激酶抑制劑是選自由1-萘基PP1、A 419259三鹽酸鹽、AGL 2263、altenusin、ansatrienin A、AP 24534、AZM 475271、Bcr-abl抑制劑II、NVP-BHG712、calphostin C、單寧卡(damnacanthal)、格爾德黴素(geldanamycin)、星形孢菌素(staurosporine)、除莠霉素A(herbimycin A)、靛玉紅-3’-(2,3-二羥基丙基)肟醚(indirubin-3'-(2,3-dihydroxypropyl)shyoximether)、KB SRC 4、KX2-391、薰草菌素A(lavendustin A)、LCB 03-0110二鹽酸鹽、木犀草素(luteolin)、MNS、奈拉替尼(neratinib)、PD 166285二鹽酸鹽、PD 180970、JNJ-10198409、培利替尼(pelitinib)、雲杉醇(piceatannol)、PKC-412、PKI 166鹽酸鹽、PP1、PP2、槲皮素(quercetin)、saracatinib、SKI-1、SU6656、TC-S 7003、TX-1123、P21d鹽酸鹽、Tilfrinib、WH-4-023、tesevatinib、ENMD-2076、TPX-0005、AZD-0424、KX2-361、CCT196969以及TX-1918所組成的群組。
- 如請求項1所述的免疫共軛體,其中,所述連接子是選自由馬來醯亞胺己醯基連接子、馬來醯亞胺己醯基-p-氨基甲酸氨基芐酯、馬來醯亞胺己醯基-肽-氨基甲酸氨基芐酯、馬來醯亞胺己醯基-L L-苯丙氨酸-L-賴氨酸-對-氨基甲酸氨基芐酯、馬來 醯亞胺己醯基-L-纈氨酸-L-瓜氨酸-對氨基甲酸氨基芐酯、3-(2-吡啶基二硫代)丙酸N-琥珀醯亞胺酯、4-琥珀醯亞胺基-氧羰基-2-甲基-2-(2-吡啶基二硫代)-甲苯、3-(2-吡啶基二硫代)丙酸N-琥珀醯亞胺酯、4-(2-吡啶基二硫代)N-(4-馬來醯亞胺基水楊醯氨基)丁基]-3'-(2'-吡啶基二硫代)丙醯胺、N(N-馬來醯亞胺基乙醯氧基)琥珀醯亞胺酯、N-[b-馬來醯亞胺丙氧基]琥珀醯亞胺酯、[N-e-馬來醯亞胺丁醯基]琥珀酸亞胺酯、N-[g-馬來醯亞胺丁醯基]琥珀亞胺酯、琥珀醯亞胺基-4-[N-馬來醯亞胺基甲基]環己烷-1-羧基-[6-醯胺基己酸]、琥珀醯亞胺基-6-(3-[2-吡啶基二硫]丙醯胺基)己酸酯、間馬來醯亞胺苯甲醯-N-羥基琥珀醯亞胺酯、N-琥珀醯亞胺基[4-碘乙醯基]氨基苯甲酸酯、琥珀醯亞胺基4-[N-馬來醯亞胺基甲基]環己烷-1-羧酸酯、N-琥珀醯亞胺基3-[2-吡啶基二硫代]-丙醯胺基、[N-e-馬來醯亞胺丁醯基]磺基琥珀酸亞胺酯、N-[g-馬來醯亞胺丁醯基]磺基琥珀酸亞胺酯、磺基琥珀醯亞胺基-6-甲基-α-(2-吡啶基二硫代)甲苯醯氨基]己酸酯、磺基琥珀醯亞胺基-6-(3'-[2-吡啶基二硫代]丙醯胺基)己酸酯、間馬來醯亞胺苯甲醯基-N-羥基磺基琥珀醯亞胺酯、N-磺基琥珀醯亞胺基[4-碘乙醯基]氨基苯甲酸酯、4-[N-馬來醯亞胺基甲基]環己烷-1-羧酸磺基琥珀醯亞胺酯、4-[對馬來醯亞胺基苯基]丁酸磺基琥珀醯亞胺酯、乙二醇-雙(琥珀酸N-羥基琥珀醯亞胺酯)、酒石酸二琥珀醯亞胺酯、1,4,7,10-四氮雜環十二烷-1,4,7,10-四乙酸、二亞乙基三胺五乙酸以及硫脲連接子所組成的群組。
- 如請求項5所述的免疫共軛體,其中,所述Ab是西妥昔單抗(cetuximab)。
- 如請求項4至6中任一項所述的免疫共軛體,其中,m是2至8。
- 一種醫藥組成物,其包含治療有效量的如請求項1至7中任一項所述的免疫共軛體以及醫藥學上可接受的載劑。
- 如請求項8所述的醫藥組成物,還進一步包括一治療劑。
- 一種活體外抑制癌症細胞生長的方法,包括在活體外使癌症細胞與有效量的如請求項1至7中任一項所述的免疫共軛體接觸。
- 如請求項10所述的方法,其中所述癌症細胞是對於抗EGFR抗體或EGFR酪氨酸激酶抑制劑具有抗性的癌症細胞。
- 如請求項11所述的方法,其中,所述癌症細胞是KRAS、BRAF、PIK3CA、PTEN、EGFR、P53或SRC突變的癌症細胞。
- 如請求項10至12中任一項所述的方法,其中,所述癌症是選自由結腸直腸癌、頭頸癌、胃腸癌、肺癌、乳腺癌、胰腺癌、卵巢癌、宮頸癌、前列腺癌、腎癌、腦癌、腎癌、神經膠質瘤、膀胱癌、口腔癌以及EGFR陽性癌症所組成的群組。
- 一種如請求項1至7中任一項所述的免疫共軛體的用途,其是用於製造治療癌症的藥物。
- 如請求項14所述的免疫共軛體的用途,其中,所述癌症是對於抗EGFR抗體或EGFR酪氨酸激酶抑制劑具有抗性的癌症。
- 如請求項15所述的免疫共軛體的用途,其中,所述癌症是KRAS、BRAF、PIK3CA、PTEN、EGFR、P53或SRC突變的癌症。
- 如請求項14至16中任一項所述的免疫共軛體的用途,其中,所述癌症是選自由結腸直腸癌、頭頸癌、胃腸癌、肺癌、乳腺癌、胰腺癌、卵巢癌、宮頸癌、前列腺癌、腎癌、腦癌、腎癌、神經膠質瘤、膀胱癌、口腔癌以及EGFR陽性癌症所組成的群組。
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