TW202313091A - 烏苯美司與免疫檢查點抑制劑的併用 - Google Patents
烏苯美司與免疫檢查點抑制劑的併用 Download PDFInfo
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Abstract
本發明之課題係在利用腫瘤免疫機制之癌症治療中提供更有效的治療方法。又,本發明之課題係針對更有效的腫瘤免疫療法而提供一種使抗腫瘤性、炎症性及抗炎症性細胞激素的產生亢進之藥劑。或是,本發明之課題係針對更有效的腫瘤免疫療法而提供一種使腫瘤浸潤性淋巴球增加之藥劑。
本發明之抗腫瘤劑係以烏苯美司作為有效成分,其係用以與屬於免疫檢查點抑制劑(ICI)之抗PD-1抗體、抗PD-L1抗體及/或抗CTLA-4抗體組合投予。烏苯美司與ICI之併用療法係相較於此等單獨使用時而使腫瘤免疫功能提昇且對惡性腫瘤之治療帶來許多益處。
Description
本發明係有關用以進行惡性腫瘤之治療之醫藥,該惡性腫瘤之治療係包含將烏苯美司與屬於免疫檢查點抑制劑(ICI)之抗PD-1抗體、抗PD-L1抗體及/或抗CTLA-4抗體組合投予。
近年來已揭曉癌症的惡化與炎症細胞、免疫細胞之間的關連性。以此見解為基礎,正在開發以腫瘤免疫機制為基礎之治療劑。
烏苯美司(Ubenimex,亦即(2S)-2-[(2S,3R)-3-胺基-2-羥基-4-苯基丁醯基胺基]-4-甲基戊酸,亦稱為貝司他汀(Bestatin)(註冊商標)),係藉由將巨噬細胞、T細胞、NK細胞等予以非特異性地活化及/或經由胺肽酶類而結合於負責免疫之細胞表面並使抗腫瘤免疫能予以活化而表現抗腫瘤作用之藥劑,於臨床上被利用於「藉由與對於成人急性非淋巴性白血病之完全緩解誘導後之維持強化化療劑併用,而延長生存期間」(非專利文獻1)。
另一方面,已知於癌細胞中存在有各種免疫檢查點分子,該等免疫檢查點分子會妨礙對於癌症之免疫反應,因此,現正積極研究能解除此免疫抑制機制且獲得抗腫瘤效果之治療劑。就免疫檢查點分子而言,已知有程序性細胞
死亡1(PD-1)及程序性細胞死亡配位基1(PD-L1)、或細胞傷害性T淋巴球抗原4(CTLA-4)等,現正開發以此等作為標的之ICI。PD-1係於活化T細胞上表現,在與PD-L1或PD-L2結合時,使T細胞的活性被抑制而導致其功能失調,從而抑制抗腫瘤免疫反應。於癌細胞等表現之PD-L1係與活化T細胞上之PD-1結合而控制T細胞之活性,從而抑制抗腫瘤免疫反應。CTLA-4係於控制性T細胞(Treg)或活化T細胞等中表現,藉由阻礙抗原呈遞細胞上之CD80/CD86與T細胞上之CD28之結合,而抑制T細胞之活性,從而抑制抗腫瘤免疫反應。如此,免疫檢查點分子之主要作用為將T細胞之活性控制為抑制性,ICI之標的雖分別與PD-1、PD-L1、CTLA-4不同,惟其作用本質係在於解除T細胞之活性抑制。因此,PD-1/PD-L1及CTLA-4之信號傳達路徑為腫瘤免疫反應之重要調節因子,關於將其予以阻斷之PD-1抑制劑、PD-L1抑制劑及CTLA-4抑制劑,係開發了抗PD-1抗體、抗PD-L1抗體及抗CTLA-4抗體並於複數種惡性腫瘤中達成顯著之抗腫瘤效果。於臨床上係提供了下述者:作為抗PD-1抗體之納武單抗(Nivolumab)(保疾伏(Opdivo)(註冊商標))及帕博利珠單抗(Pembrolizumab)(吉舒達(Keytruda)(註冊商標)),作為抗PD-L1抗體之阿替利珠單抗(Atezolizumab)(泰聖奇(Tecentriq)(註冊商標))、度伐利尤單抗(Durvalumab)(英飛凡(Imfinzi)(註冊商標))、阿維魯單抗(Avelumab)(巴文西歐(Bavencio)(註冊商標)),作為抗CTLA-4抗體之伊匹單抗(Ipilimumab)(益伏(Yervoy)(註冊商標))。
於惡性腫瘤之治療中,由於ICI之效果有所限定,故為了尋求更有效果的治療,嘗試將複數種抗腫瘤劑組合之併用療法,並探討包含與各種殺細胞性藥劑或分子標的藥等抗腫瘤劑之組合、其投予用量或投予時間表之併用療法。又,亦探討與腫瘤免疫相關之藥劑之併用。例如,專利文獻1記載了抗PD-
1抗體與抗CTLA-4抗體之併用療法。又,針對與腫瘤免疫相關之低分子藥劑之併用,專利文獻2及專利文獻3記載了關於將屬於細胞凋亡調節因子之類似Smac(前細胞凋亡蛋白質)之化合物(Smac模擬化合物(SMC))與ICI併用,又,專利文獻4記載了關於細胞凋亡蛋白質抑制劑(IAP)拮抗劑與抗PD-1分子之併用。
[先前技術文獻]
[非專利文獻]
[非專利文獻1]醫藥品面談表「抗惡性腫瘤劑 貝司他汀膠囊10mg 貝司他汀膠囊30mg」(日本化藥股份有限公司製造,2020年10月(修正第7版))
[專利文獻]
[專利文獻1]日本特開2012-158605號公報
[專利文獻2]日本特表2019-506438號公報
[專利文獻3]日本特表2020-515600號公報
[專利文獻4]日本特表2021-506781號公報
本發明之課題係於利用腫瘤免疫機制之癌症治療中提供更有效之治療方法。又,本發明之課題係針對更有效的腫瘤免疫療法而提供一種使抗腫瘤性細胞激素之產生亢進之藥劑。或者是,本發明之課題係針對更有效的腫瘤免疫療法而提供一種使腫瘤浸潤性淋巴球增加之藥劑。
本案發明人等發現烏苯美司與ICI之併用療法係相較於此等單獨使用時而使腫瘤免疫功能提昇,對於惡性腫瘤之治療帶來許多益處。本案係以下之發明為要旨。
[1]一種抗腫瘤劑,係以烏苯美司作為有效成分,該抗腫瘤劑係用以與屬於免疫檢查點抑制劑之抗PD-1抗體、抗PD-L1抗體及/或抗CTLA-4抗體組合投予。
[2]如[1]所述之抗腫瘤劑,其中,烏苯美司之用量係使單次投予時之血中濃度時間曲線下面積(AUC)成為3.00至50.00μg‧hr/mL之用量。
[3]如[1]或[2]所述之抗腫瘤劑,其中,烏苯美司為連日投予之用法。
[4]一種抗腫瘤劑,係以選自由抗PD-1抗體、抗PD-L1抗體及抗CTLA-4抗體所構成群組中之ICI作為有效成分,該抗腫瘤劑係用以與烏苯美司組合投予。
[5]如[4]所述之抗腫瘤劑,其中,烏苯美司之用量係使單次投予時之AUC成為3.00至50.00μg‧hr/mL之用量。
藉由烏苯美司與ICI的組合,而使有助於腫瘤免疫之活化機制之抗腫瘤性細胞激素的產生亢進。因而提供作為抗腫瘤性細胞激素產生劑之用途。
[6]一種醫藥,係以烏苯美司作為有效成分,該醫藥係藉由與屬於免疫檢查點抑制劑之抗PD-1抗體、抗PD-L1抗體及/或抗CTLA-4抗體組合投予,而用於產生抗腫瘤性細胞激素。
[7]如[6]所述之醫藥,其中,烏苯美司之用量係使單次投予時之AUC成為3.00至50.00μg‧hr/mL之用量。
烏苯美司與ICI之組合,係能獲得使屬於腫瘤免疫中之主要因子之細胞傷害性T細胞(CTL)在腫瘤中增加之效果,對有效的腫瘤免疫療法有所貢獻。因而提供作為腫瘤浸潤性淋巴球活化劑之用途。
[8]一種醫藥,係以烏苯美司作為有效成分,該醫藥係藉由與屬於免疫檢查點抑制劑之抗PD-1抗體、抗PD-L1抗體及/或抗CTLA-4抗體組合投予,而用於使腫瘤浸潤性淋巴球增加。
[9]如[8]所述之醫藥,其中,烏苯美司之用量係使單次投予時之AUC成為3.00至50.00μg‧hr/mL之用量。
烏苯美司與ICI之組合,係提供作為可適用於廣範圍之惡性腫瘤之治療的醫藥之用途。
[10]一種醫藥,係以烏苯美司作為有效成分,該醫藥係藉由與屬於免疫檢查點抑制劑之抗PD-1抗體、抗PD-L1抗體及/或抗CTLA-4抗體組合投予,而使用於選自由小細胞肺癌、非小細胞肺癌、食道癌、頭頸部癌、腦腫瘤、結腸/直腸癌、結腸腺癌、胃癌、乳癌、肝細胞癌、胰臟癌、膽管癌、腎臟癌、前列腺癌、膀胱癌、卵巢癌、子宮頸癌、甲狀腺癌及黑色素瘤所構成群組中之惡性腫瘤之治療。
[11]如[10]所述之醫藥,其中,烏苯美司之用量係使單次投予時之血中濃度時間曲線下面積(AUC)成為3.00至50.00μg‧hr/mL之用量。
[12]如[10]或[11]所述之醫藥,其中,烏苯美司為連日投予之用法。
烏苯美司與ICI之組合係相較於分別單獨使用時而使抗腫瘤效果增強。又,發揮使抗腫瘤性細胞激素或腫瘤浸潤性淋巴球增加之效果,而可提供更有效的腫瘤免疫療法。
圖1為表示在藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予而進行之對於小鼠黑色素瘤細胞B16-F0之抗腫瘤效果試驗中,各群平均腫瘤體積之推移之圖。
圖2為表示在藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予而進行之對於小鼠黑色素瘤細胞B16-F0之抗腫瘤效果試驗中,相對於「移植後15日之對照群之腫瘤體積平均值」,各群之相對腫瘤體積比率(T/C)之個別值之圖。
圖3為表示藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予所致之血漿中IFN-γ各群之個別值及平均值之圖。誤差槓(error bar)表示標準偏差。(*:P<0.05)
圖4為表示藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予所致之血漿中TNF-α各群之個別值及平均值之圖。誤差槓表示標準偏差。(*:P<0.05)
圖5為表示藉由烏苯美司及抗PD-1抗體(J43)之投予所致之從腫瘤片分散之單細胞懸濁液中每10000個生細胞之CD8陽性T細胞數之個別值及平均值之圖。誤差槓表示標準偏差。
圖6為表示藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予所致之CD8陽性T細胞數與相對腫瘤體積之關連性之圖。橫軸表示每10000個生細胞之CD8陽性T細胞數,縱軸表示相對於「對照群之腫瘤體積平均值」,每一個體之相對腫
瘤體積比率(TGI)。以虛線包圍之區域表示在顯示顯著腫瘤增殖抑制之個體群中,CD8陽性T細胞數為高值之個體。
圖7為表示藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予所致之末梢血中控制性T淋巴球(Treg)數之個別值及平均值之圖。誤差槓表示標準偏差。
圖8為表示藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予所致之末梢血中Treg數與相對腫瘤體積之關連性之圖。橫軸表示末梢血中Treg數,縱軸表示相對於「對照群之腫瘤體積平均值」,每一個體之相對腫瘤體積比率(TGI)。以虛線包圍之區域表示在顯示顯著腫瘤增殖抑制之個體群中,Treg數為低值之個體。
圖9為表示在藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予所進行之對於小鼠結腸腺癌細胞MC38之抗腫瘤效果試驗中,各群之平均腫瘤體積之推移之圖。
(*:P<0.05、**:P<0.01)
圖10為表示藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予所致之血漿中IFN-γ各群之平均值之推移之圖。(**:P<0.01)
圖11為表示藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予,血漿中TNF-α各群之平均值之推移之圖。(*:P<0.05、**:P<0.01)
圖12為表示藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予所致之血漿中IL-6各群之平均值之推移之圖。(*:P<0.05)
圖13為表示藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予所致之血漿中KC/GRO(IL-8)各群之平均值之推移之圖。
圖14為表示藉由烏苯美司及抗小鼠PD-1抗體(J43)之投予所致之血漿中IL-10各群之平均值之推移之圖。(**:P<0.01)
本發明係以將烏苯美司與ICI予以組合而成之抗腫瘤劑作為要旨。以下對此加以詳細說明。
烏苯美司為(2S)-2-[(2S,3R)-3-胺基-2-羥基-4-苯基丁醯基胺基]-4-甲基戊酸,其為具有胺肽酶阻礙活性之二肽化合物。於本發明中,烏苯美司可為鹽游離體,亦可作為鹽酸鹽、磷酸鹽等藥學上容許之鹽來使用。烏苯美司係作為「貝司他汀(註冊商標)膠囊」而於臨床上提供有10mg製劑及30mg製劑,亦可使用此等。
烏苯美司之用量係以醫藥上之有效量來使用即可。較佳是以使單次投予時之AUC成為大於3.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量來適用。又,較佳是以使最高血中濃度(Cmax)成為大於2.0μg/mL之用量來適用。更佳係使AUC成為大於5.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量,特佳係使其成為大於10.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量。
烏苯美司的用法可為經口服用,亦可使用於靜脈內投予等非經口途徑。較佳為經口投予。又,烏苯美司較佳為連日投予使用,於持續治療週期期間,較佳為經口連日投予使用。
抗PD-1抗體、抗PD-L1抗體及抗CTLA-4抗體,係與屬於用以調節腫瘤免疫之免疫檢查點分子之PD-1、PD-L1或CTLA-4結合,並阻斷PD-1/PD-L1或CTLA-4信號傳達路徑,解除對於活化T細胞之抑制機制,從而獲得抗腫瘤效果之治療劑。於本發明中,抗PD-1抗體、抗PD-L1抗體或抗CTLA-4抗體只要是能與PD-1、PD-L1或CTLA-4結合而解除腫瘤免疫抑制功能之抗體,則可無特別限制地適用。
抗PD-1抗體、抗PD-L1抗體、抗CTLA-4抗體係有多種抗腫瘤劑已上市或正在開發中,亦可應用此等。
抗PD-1抗體可列舉:納武單抗(保疾伏(註冊商標))及帕博利珠單抗(吉舒達(註冊商標))。又,亦可使用匹地珠單抗(Pidilizumab)(CT-011)、PDR-001、JS001、STI-A1110、AMP-224、AMP-514(MEDI0680)等。
抗PD-L1抗體可列舉:阿替利珠單抗(泰聖奇(註冊商標))、度伐利尤單抗(英飛凡(註冊商標))、阿維魯單抗(巴文西歐(註冊商標))。又,亦可使用BMS-936559(MDX1105)、LY3300054等。
抗CTLA-4抗體可列舉:伊匹單抗(益伏(註冊商標))。又,亦可使用曲美木單抗(Tremelimumab)(CP-675206)等。
於本發明,與烏苯美司併用之ICI較佳為抗PD-1抗體及/或抗PD-L1。更佳為烏苯美司與抗PD-1抗體之併用。
抗PD-1抗體、抗PD-L1抗體或抗CTLA-4抗體係以醫藥上之有效量來使用即可。例如,在使用屬於抗PD-1抗體之納武單抗(保疾伏(註冊商標))時,通常將每1次240mg以2週間隔並以點滴靜注來進行適用。在使用帕博利珠單抗(吉舒達(註冊商標))時,通常將每1次200mg以3週間隔並以點滴靜注來進行適用。在使用屬於抗PD-L1抗體之阿替利珠單抗(泰聖奇(註冊商標))時,通常將每1次840mg以2週間隔並以點滴靜注來進行適用,或是將每1次1200mg以3週間隔並以點滴靜注來進行適用。在使用度伐利尤單抗(英飛凡(註冊商標))時,通常將每1次10mg/kg以2週間隔並以點滴靜注來進行適用,或是將每1次1500mg以3週間隔並以點滴靜注來進行適用。在使用阿維魯單抗(巴文西歐(註冊商標))時,係將每1次10mg/kg以2週間隔並以點滴靜注來進行適用。在使用
屬於抗CTLA-4抗體之伊匹單抗(益伏(註冊商標))時,通常將每1次3mg/kg以3週間隔並以4次點滴靜注來進行適用。
本發明係關於將烏苯美司與ICI予以組合使用之併用療法。本發明之併用療法係意指將烏苯美司與ICI同時或連續地投予,係包含:在複數種藥劑的投予之治療計畫中包含烏苯美司與ICI之投予的一連串之治療方法。同時投予係包含「在實質相同之時間投予兩藥劑」。連續投予係包含「在1日或數日中投予一種藥劑後,經過任意之停藥期間,再進行另一種藥劑之投予」。於本發明中,較佳係將烏苯美司連日投予且於其投予期間將ICI以每1至3週投予之組合之用法。
本發明之烏苯美司與ICI之併用療法係提供一種對於惡性腫瘤之治療用途。惡性腫瘤可列舉:小細胞肺癌、非小細胞肺癌、食道癌、頭頸部癌、腦腫瘤、結腸/直腸癌、結腸腺癌、胃癌、乳癌、肝細胞癌、胰臟癌、膽管癌、腎臟癌、前列腺癌、膀胱癌、卵巢癌、子宮頸癌、甲狀腺癌、黑色素瘤等。例如,較佳為使用於非小細胞肺癌之處置。
烏苯美司與ICI之併用療法,係獲得比分別單獨投予時之抗腫瘤效果更優異之腫瘤增殖抑制效果。亦即,本發明係提供一種烏苯美司之與ICI組合使用之新穎用途。或者是,本發明係包含ICI之與烏苯美司組合使用之新穎用途。
烏苯美司與ICI為經由抗腫瘤性免疫而發揮腫瘤增殖抑制作用之藥劑。烏苯美司係可造成巨噬細胞、NK細胞、T細胞、骨髓細胞等之活化,藉由此等所致之直接的抗腫瘤效果,或因藉此產生之介白素1及2等各種細胞激素而將免疫系統網路予以連鎖性地活化並發揮抗腫瘤效果之藥劑。又,ICI係阻
礙PD-1/PD-L1及/或CTLA-4之結合,解除免疫抑制信號,並藉由癌抗原特異性T細胞之活化及細胞傷害性之活化而獲得抗腫瘤效果之藥劑。
本發明發現烏苯美司與ICI之組合投予係相較於各自單劑使用時而使抗腫瘤性免疫更增強,故亦包含提供作為抗腫瘤免疫增強劑之新穎用途。
就本發明之其他態樣而言,烏苯美司與ICI之組合投予係具有使干擾素(INF)-γ或TNF-α等抗腫瘤性細胞激素、IL-6或IL-8等炎症性細胞激素及IL-10等抗炎症性細胞激素之產生增強之效果。如上所述,已知烏苯美司係將免疫細胞予以活化而導致IL-1及IL-2等細胞激素之產生。然而,藉由將烏苯美司與ICI組合投予,相較於單獨投予烏苯美司時,可更明顯使抗腫瘤性及炎症性細胞激素等之產生亢進。因此,本發明提供作為以烏苯美司為有效成分之抗腫瘤性及炎症性細胞激素等之產生增強劑之用途,其係藉由與ICI組合投予所致。
在抗腫瘤性及炎症性細胞激素等之產生誘導中,烏苯美司之用量係以醫藥上之有效量來使用即可。較佳係以使單次投予時之AUC成為大於3.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量來適用。又,較佳係以使Cmax成為大於2.0μg/mL之用量來適用。更佳係使AUC成為大於5.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量,特佳係使其成為大於10.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量。
就本發明之其他態樣而言,烏苯美司與ICI之組合投予係具有使腫瘤浸潤性淋巴球之誘導提升之效果。如上所述,烏苯美司及ICI係具有CTL之誘導及活化作用。然而,藉由將烏苯美司與ICI組合投予,相較於單獨投予烏苯美司時,可帶來更多之腫瘤浸潤性淋巴球之誘導。因此,本發明提供作為以烏
苯美司為有效成分之腫瘤浸潤性淋巴球之誘導增強劑之用途,其係藉由與ICI組合投予所致。
在腫瘤浸潤性淋巴球之誘導中,烏苯美司之用量係以醫藥上之有效量來使用即可。較佳係以使單次投予時之AUC成為大於3.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量來適用。又,較佳係以使Cmax成為大於2.0μg/mL之用量來適用。更佳係使AUC成為大於5.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量,特佳係使其成為大於10.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量。
就本發明之其他態樣而言,烏苯美司與ICI之組合投予係具有將屬於抗腫瘤性免疫中之抑制因子之Treg之誘導予以抑制的效果。經由抗腫瘤免疫而進行之腫瘤增殖抑制,係有效地將直接攻擊癌細胞之CTL予以誘導/活化,並與腫瘤免疫抑制機制之解除一併發揮作用。本發明之烏苯美司與ICI之組合投予係如上述般可提供一種有效率之抗腫瘤免疫療法,其係將腫瘤浸潤性淋巴球誘導至癌細胞,並抑制Treg之誘導。
於Treg之誘導抑制中,烏苯美司之用量係以醫藥上之有效量來使用即可。較佳係以使單次投予時之AUC成為大於3.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量來適用。又,較佳係以使Cmax成為大於2.0μg/mL之用量來適用。更佳係使AUC成為大於5.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量,特佳係使其成為大於10.00μg‧hr/mL且小於50.00μg‧hr/mL之範圍之用量。
本發明之烏苯美司與ICI之併用療法,係可更進一步作成與其他抗腫瘤劑組合之併用療法。其他抗腫瘤劑係無特別限定,可使用被認可為抗腫瘤劑之醫藥品。可舉例如:環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosfamide)、
替莫唑咹(Temozolomide)等烷基化劑;阿黴素(Doxorubicin)、泛艾黴素(Epirubicin)、吡柔比星(Pirarubicin)、氨柔比星(Amrubicin)、內包阿黴素之脂質體製劑(多奇昔(Doxil)(註冊商標))等蔥環抗生素(anthracycline)系抗腫瘤劑;順鉑(Cisplatin)、卡鉑(Carboplatin)、奧沙利鉑(Oxaliplatin)等抗腫瘤性鉑錯合物;依託泊苷(Etoposide)、依託泊苷磷酸酯、替尼泊苷(Teniposide)等依託泊苷類;愛萊諾替康(Irinotecan)、諾吉替康(Nogitecan)等喜樹鹼(Camptothecin)類;紫杉醇(Paclitaxel)、歐洲紫杉醇(Docetaxel)、卡巴他賽(Cabazitaxel)、白蛋白懸濁型紫杉醇(亞伯杉(Abraxane)(註冊商標))等紫杉烷(Taxane)類;長春新鹼(Vincristine)、長春花鹼(Vinblastine)、長春地辛(Vindesine)、長春瑞濱(Vinorelbine)等長春花生物鹼類;艾日布林(Eribulin)等微管蛋白(tubulin)聚合抑制劑;5-氟尿嘧啶(5-fluorouracil)、替加氟(Tegafur)、替加氟/脲嘧啶(uracil)合劑(UFT)、替加氟/吉美拉西(Gimeracil)/奧特拉西(Oteracil)鉀合劑(S-1)、三氟尿苷(Trifluridine)/替吡拉西(Tipiracil)合劑(朗斯弗(Lonsurf)(註冊商標))、氟鐵龍(Furtulon)、卡培他濱(Capecitabine)、吉西他濱(Gemcitabine)、阿糖胞苷(Cytosine arabinoside)、阿扎胞苷(Azacitidine)等核酸代謝拮抗劑;氨甲蝶呤(Methotrexate)、培美曲塞(Pemetrexed)等葉酸代謝拮抗劑;潑尼松龍(Prednisolone)、地塞米松(Dexamethasone)等類固醇類;
又,厄洛替尼(Erlotinib)、拉帕替尼(Lapatinib)、吉非替尼(Gefitinib)、阿法替尼(Afatinib)、奧希替尼(Osimertinib)、阿昔替尼(Axitinib)、舒尼替尼(Sunitinib)、索拉非尼(Sorafenib)、瑞戈非尼(Regorafenib)、樂伐替尼(Lenvatinib)、阿來替尼(Alectinib)、克唑替尼(Crizotinib)、帕唑帕尼(Pazopanib)等酪胺酸激酶抑制劑;硼替佐米(Bortezomib)、卡非佐米(Carfilzomib)、伊克薩姆畢(Ixazomib)等蛋白酶體
(proteasome)抑制劑;哌柏西利(Palbociclib)等細胞週期蛋白依賴性激酶抑制劑;依維莫司(Everolimus)、坦西羅莫司(Temsirolimus)等mTOR抑制劑;曲妥珠單抗(Trastuzumab)、西妥昔單抗(Cetuximab)、耐昔妥珠單抗(Necitumumab)、貝伐珠單抗(Bevacizumab)、帕尼單抗(Panitumumab)、雷莫蘆單抗(Ramucirumab)等抗成長因子(受體)抗體。除此之外亦可使用公知之抗腫瘤劑。
其他抗腫瘤劑較佳為以醫藥上之有效量並以公知之用法來組合使用。
對於本發明,若作為非小細胞肺癌之治療劑適用時,較佳係與公知之治療方法組合來應用。較佳為例如將紫杉醇、白蛋白懸濁紫杉醇(亞伯杉(註冊商標))、歐洲紫杉醇、替加氟/吉美拉西/奧特拉西鉀合劑(S-1)、吉西他濱、培美曲塞、長春瑞濱、吉非替尼、厄洛替尼、阿法替尼、奧希替尼、耐昔妥珠單抗等作為併用藥劑來組合適用。亦較佳為對於此等抗腫瘤劑再將順鉑或卡鉑之抗腫瘤性鉑錯合物予以組合之化學療法組合。更佳為紫杉醇與抗腫瘤性鉑錯合物之併用、白蛋白懸濁紫杉醇(亞伯杉(註冊商標))與抗腫瘤性鉑錯合物之併用、培美曲塞與抗腫瘤性鉑錯合物之併用、替加氟/吉美拉西/奧特拉西鉀合劑(S-1)與抗腫瘤性鉑錯合物之併用。此等併用之其他抗腫瘤劑,較佳係以經確認於非小細胞肺癌為有效性之用法用量來適用。
[實施例]
以下,藉由實施例更詳細地說明本發明。實施例中使用之材料係如下述般取得而供於各試驗。
(1)腫瘤細胞
小鼠黑色素瘤B16-F0係從ATCC(美國典型培養物保藏中心,The American Type Culture Collection)取得。使用將此於含有10%牛胎兒血清(Corning
International,Inc.)及100μg/mL卡那黴素硫酸鹽(Kanamycin sulfate)之DMEM(Thermo Fisher Scientific Inc.)中,於CO2培養箱內(37℃、5%二氧化碳下)培養而成者。
小鼠結腸腺癌細胞株MC38係從GenOway S.A.取得。使用將此於含有10%牛胎兒血清(Corning International,Inc.)、2mM L-麩醯胺酸(Thermo Fisher Scientific Inc.)、10mM HEPES(Thermo Fisher Scientific Inc.)、1mM丙酮酸鈉(富士膠片和光純藥股份有限公司)、0.1mM MEM非必須胺基酸溶液(Thermo Fisher Scientific Inc.)、盤尼西林/鏈黴素(penicillin/streptomycin)(富士膠片和光純藥股份有限公司)之DMEM(Thermo Fisher Scientific Inc.)中,於CO2培養箱內(37℃、5%二氧化碳下)培養而成者。
(2)受測物質
烏苯美司係從日本化藥股份有限公司取得。
抗小鼠PD-1抗體(殖株(clone)J43)及同型對照抗體IgG(多殖株亞美尼亞倉鼠IgG(polyclonal Armenian Hamster IgG))係從BioXcell公司取得。
烏苯美司係溶解於注射用蒸餾水(大塚製藥工場股份有限公司)使用。抗小鼠PD-1抗體及IgG係以PBS(-)(Thermo Fisher Scientific Inc.)稀釋使用。
[實施例1]
使用小鼠黑色素瘤細胞B16-F0之皮下移植模型,評估藉由烏苯美司及抗小鼠PD-1抗體之併用投予所致之抗腫瘤效果。又,同時確認細胞激素及免疫系統標記之變動。
將2×105個B16-F0移植到雌性C57BL/6N小鼠(Charles River Laboratories Japan,Inc)之皮下,製作皮下移植模型。
對於B16-F0之皮下移植模型小鼠,將烏苯美司以5或50mg/kg之用量從移植隔日起至移植後14日為止以1日1次合計經口投予14次。於移植後4、7、11及14日,再將抗小鼠PD-1抗體以200μg/個體(body)之用量進行腹腔內投予。將作為對照之屬於抗小鼠PD-1抗體之同型對照之IgG抗體,以與抗小鼠PD-1抗體相同之條件進行投予。關於各投予群構成係統整於表1。
腫瘤之長徑及短徑係以數位卡尺(digital caliper)(Mitutoyo股份有限公司)計測,將腫瘤體積(mm3)以「長徑×短徑2/2」之公式算出。又,使用移植後15日之腫瘤體積值,將各投予群相對於對照群之相對腫瘤體積(T/C)以「受測物質投予群之平均腫瘤體積/對照群之平均腫瘤體積×100」之公式算出。
動物於最終投予隔日之移植後15日全部進行解剖檢查。於解剖檢查日,使用添加有EDTA/2K溶液之注射筒及注射針從頸靜脈進行採血,以多項目自動血球分析裝置XN-2000V(Sysmex股份有限公司)測定總白血球數。於麻醉下,從腹大動脈使用添加有肝素鈉(heparin sodium)溶液之注射筒及注射針進行採血,然後採取腫瘤。血液及腫瘤組織係用於免疫表型(Immunophenotyping)。將血液進行離心分離後獲得之血漿,係藉由ELISA法測定細胞激素。
統計分析係使用統計分析軟體EXSUS(ver.10.0,CAC Croix股份有限公司),於對照群及各投予群、併用群及各個單劑群實施Wilcoxon檢定。以顯著水準P<0.05進行雙側統計學的分析。
[實施例1.1]抗腫瘤效果
圖1表示各投予群中之腫瘤增殖推移。在相對於移植後15日之對照群(IgG投予)之相對平均腫瘤體積(T/C)中,烏苯美司5mg/kg及50mg/kg投予群及抗PD-1抗體投予群係相對於對照群而未顯示腫瘤增殖抑制效果,相對於此,烏苯美司高用量與抗PD-1抗體之併用群之T/C為68%,顯示腫瘤增殖抑制效果。由此而確認到烏苯美司與抗PD-1抗體之併用能發揮在各別單獨投予時未觀察到之腫瘤增殖抑制效果。
將實施例1.1之抗腫瘤效果以相對腫瘤體積之個別值進行解析時,移植後15日之T/C顯示未達100%之個體係於各單劑投予中為群之半數例以下,相對於此,於烏苯美司低用量與抗PD-1抗體之併用群及烏苯美司高用量與抗PD-1抗體之併用群中皆超過半數,8隻中有5隻(圖2)。
[實施例1.2]抗腫瘤性細胞激素產生
就各投予群之血漿中之抗腫瘤性細胞激素而言,使用Levis小鼠IFN-γ ELISA套組、Levis小鼠TNF-α ELISA套組(FUJIFILM Wako Shibayagi Corporation)測定IFN-γ及TNF-α濃度。結果表示於圖3及圖4。
相較於對照群、烏苯美司單劑之各投予量群及抗PD-1抗體單獨之投予群,烏苯美司高用量與抗PD-1抗體之併用群顯示明顯的IFN-γ之產生增強效果。相較於對照群及烏苯美司單劑高用量群,在烏苯美司高用量之併用群中顯著地增加(P值0.02,圖3)。
又,相較於對照群、烏苯美司單劑之各投予量群及抗PD-1抗體單獨之投予群,烏苯美司與抗PD-1抗體之併用群顯示TNF-α之產生增強效果。相較於對照群及烏苯美司單劑之高用量群,於烏苯美司高用量與抗PD-1抗體之併用群中顯著地增加(P值0.045,圖4)。
已知IFN-γ及TNF-α係將免疫系統網路予以連鎖性地活化而有助於抗腫瘤效果之抗腫瘤性細胞激素。由於烏苯美司與抗PD-1抗體之併用群係顯示腫瘤增殖抑制效果,故由此而暗示IFN-γ及TNF-α有助於腫瘤增殖抑制之可能性。
[實施例1.3]腫瘤浸潤淋巴球之免疫表型
在確認到抗腫瘤效果之後,針對由解剖檢查所採得之腫瘤組織,藉由流式細胞術法進行腫瘤浸潤淋巴球之解析。
免疫表型係使用抗小鼠CD45抗體、抗小鼠CD3抗體、抗小鼠CD4抗體、抗小鼠CD8抗體、抗小鼠/人類CD11b抗體、抗小鼠CD25抗體、抗小鼠/人類FOXP3抗體、抗小鼠CD16/32抗體(BioLegend公司)、裂解緩衝液(Lysing Buffer)(BD Biosciences)、True-Nuclear轉錄因子緩衝液套組(True-Nuclear Transcription
Factor Buffer Set(BioLegend)、腫瘤分離套組(Tumor Dissocioation Kit)、小鼠(Milteny biotec)。
將腫瘤片於腫瘤分離套組(Tumor Dissocioation Kit)之酵素液中細切,以gentleMACS Octo Dissociator進行機械性分散後,於37℃一邊緩慢振盪一邊培養40分鐘。培養完成後,再次進行機械性分散處理。添加含有10%FBS之RPMI1640,通過70μm之細胞過濾器,進行離心處理後,將細胞塊再懸濁於含有10%FBS之RPMI1640,製成將此從腫瘤片分散調製出之單細胞懸濁液。分取單細胞懸濁液之一部分,以裂解緩衝液(Lysing Buffer)進行溶血處理,以抗小鼠CD16/32抗體進行Fc受體之阻斷(Blocking)處理後,將細胞表面標記CD45、CD3、CD4、CD8、CD11b染色,以流式細胞儀LSRII(BD Biosciences)測定之。
評估係將屬於CTL之CD8陽性T細胞(CD45+、CD3+、CD8+)作為指標。CD8陽性T細胞率係使用從於流式細胞儀測定中之單細胞懸濁液中之全部生細胞部分(fraction)之計數及CD8陽性T細胞之計數所算出之CD8陽性T細胞率,計算出單細胞懸濁液中之總生細胞數之總CD8陽性T細胞數,並計算出每10000個生細胞之CD8陽性T細胞數。圖5表示各投予群中之CD8陽性T細胞數之結果。
腫瘤中之CD8陽性T細胞數,係於烏苯美司高用量與抗PD-1抗體之併用群中確認到顯示高值之個體。檢討CD8陽性T細胞數與相對腫瘤體積之關係時,在顯示顯著腫瘤增殖抑制之各併用群之個體中確認到其與顯示CD8陽性T細胞數高值之個體為一致,故認為不僅是烏苯美司高用量,於低用量之併用中亦確認到有助於腫瘤增殖抑制效果之CD8陽性T細胞的誘導作用(圖6)。
CD8陽性T細胞係作為CTL而具有傷害腫瘤細胞之作用。因此,烏苯美司與抗PD-1抗體之併用係可誘導腫瘤中之CTL並發揮腫瘤增殖抑制效果。
[實施例1.4]末梢血中淋巴球之免疫表型
在確認到抗腫瘤效果後,針對由解剖檢查所採得之血液,藉由流式細胞術法進行末梢血中淋巴球之解析。
將末梢血以裂解緩衝液(Lysing Buffer)進行溶血處理,作成末梢血單核細胞(PBMC)後,以抗小鼠CD16/32抗體將Fc受體進行阻斷,將細胞表面標記CD45、CD3、CD4、CD8、CD25染色。將PBMC固定,進行穿透處理,將核內因子FOXP3染色,以流式細胞儀LSRII(BD Biosciences)測定之。
評估係將以CD45+、CD3+、CD4+、CD25+、FOXP3鑑定之Treg作為指標。算出CD45陽性細胞中之Treg之存在比率,從總白血球數之值算出每1μL末梢血之Treg數。圖7表示各投予群中之Treg數之結果。
末梢血中之Treg數,係於抗PD-1抗體單劑投予群、烏苯美司低用量及高用量之抗PD-1抗體之併用群中為低值(圖7)。另一方面,於烏苯美司單劑投予群中未觀察到變化。觀察Treg數與相對腫瘤體積之關係時,於顯示顯著腫瘤增殖抑制之併用群之個體中確認到其與顯示Treg數低值之個體為一致,不僅是烏苯美司高用量,於低用量之併用亦確認到有助於腫瘤增殖抑制效果之Treg誘導之抑制作用(圖8)。Treg係具有顯示對於「在腫瘤免疫中具有主要功能之CTL」抑制活化或障礙性之作用。因此,Treg之降低作用有促進腫瘤免疫並有助於腫瘤增殖抑制之效果。
由免疫表型之結果可知,烏苯美司與抗PD-1抗體之併用投予群係抑制Treg之誘導且誘導腫瘤中之CTL,故能期待其可促進腫瘤局部中之腫瘤免疫作用。
由上顯示,烏苯美司與抗PD-1抗體之組合投予,係以烏苯美司所具有之淋巴球活化作用為基礎,可將腫瘤中CTL數之增加、抗腫瘤性細胞激素產生增加、腫瘤免疫耐受狀態之解除等複數種腫瘤免疫系統網路予以活化而發揮抗腫瘤效果。
[實施例2]小鼠血中濃度推移
對絕食後之9週齡雌性C57BL/6N小鼠(Charles River Laboratories Japan,Inc)將烏苯美司5mg/kg或50mg/kg於各群9隻分別單次經口投予。採血時間點為投予後5分鐘、10分鐘、30分鐘、1小時、3小時、6小時、8小時、12小時及24小時之9個時間點,投予後5分鐘至6小時為止者係於異氟烷(isoflurane)麻醉下從頸靜脈採血0.1mL,投予後8小時以後者係全都於異氟烷麻醉下從大靜脈採血。為了確保各時間點之n=3,於3個時間點從1個體採血,以3隻為1組進行動物交換之稀疏採血(Sparse blood collection)。從獲得之血液調製血漿後,將血漿中之烏苯美司濃度以液體層析質量分析計(LC/MS/MS)測定。表2表示各投予量之藥物動態參數。
Cmax係與投予量成正比,MRTinf係無關投予量而為恆定。AUCinf之50mg/5mg比顯示大於投予量比之傾向,於小鼠以5至50mg/kg之投予量可獲得大致之用量比例性。
[實施例3]抗腫瘤效果
使用小鼠結腸腺癌細胞MC38之皮下移植模型,評估藉由烏苯美司及抗小鼠PD-1抗體之併用投予所致之抗腫瘤效果。
將1×105個之MC38移稙到雌性C57BL/6N小鼠(Charles River Laboratories Japan,Inc)之皮下,製作皮下移植模型。對MC38之皮下移植模型小鼠,將烏苯美司以0.5或5mg/kg之用量從移植隔日至移植後24日為止以1日1次合計經口投予24次。再者,於移植後7、11、14、18、21及24日,將抗小鼠PD-1抗體以50μg/個體之用量進行腹腔內投予。將作為對照之屬於抗小鼠PD-1抗體之同型對照之IgG抗體,以與抗小鼠PD-1抗體相同之條件進行投予。關於各投予群構成係統整於表3。
腫瘤之長徑及短徑係以數位卡尺(Mitutoyo股份有限公司)計測,將腫瘤體積(mm3)以「長徑×短徑2/2」之公式算出。又,使用移植後25日之腫瘤體積值,將各投予群相對於對照群之相對腫瘤體積(T/C)以「受測物質投予群之平均腫瘤體積/對照群之平均腫瘤體積×100」之公式算出。
統計分析係使用統計分析軟體EXSUS(ver.10.0,EP Croix股份有限公司),於對照群與各投予群、併用群與各個單劑群中,對於移植後25日之腫瘤體積值實施Wilcoxon檢定。以顯著水準P<0.05及P<0.01進行雙側統計學的分析。
圖9表示各投予群之腫瘤增殖推移。關於移植後25日之烏苯美司單劑或抗PD-1抗體單劑投予群之相對於對照群(IgG投予)之相對平均腫瘤體
積(T/C),烏苯美司之0.5mg/kg群為62%,烏苯美司之5mg/kg群為51%,抗PD-1抗體群為33%,皆顯示抗腫瘤效果。併用群之T/C係於烏苯美司0.5mg/kg與抗PD-1抗體之併用群為37%,於烏苯美司5mg/kg與抗PD-1抗體之併用群為19%。
確認到烏苯美司之用量依存性抗腫瘤效果。又,於烏苯美司5mg/kg與抗PD-1抗體之併用群中,確認到比單劑強之效果(相對於對照群之P值:0.002,相對於烏苯美司5mg/kg群之P值:0.015,相對於烏苯美司0.5mg/kg與抗PD-1抗體之併用群之P值:0.039,圖9)。
[實施例4]細胞激素產生
使用小鼠結腸腺癌細胞MC38之皮下移植模型,評估由烏苯美司與抗小鼠PD-1抗體之併用投予所致之血漿中細胞激素推移。
將1×105個MC38移植到雌性C57BL/6N小鼠(Charles River Laboratories Japan,Inc)之皮下,製作皮下移植模型。對於MC38之皮下移植模型小鼠,將烏苯美司以5mg/kg之用量從移植隔日至移植後24日為止以1日1次合計經口投予24次。再者,於移植後7、11、14、18、21及24日,將抗小鼠PD-1抗體以50μg/個體之用量進行腹腔內投予。將作為對照之屬於抗小鼠PD-1抗體之同型對照之IgG抗體,以與抗小鼠PD-1抗體相同之條件進行投予。關於各投予群構成係統整於表4。
於移植後7、14、21或24日,使用添加有肝素鈉溶液(持田製藥股份有限公司製造)之注射筒及注射針從頸靜脈採血。將採取之血液進行離心分離,使用所得之血漿藉由ELISA法或電化學發光法測定細胞激素。IFN-γ濃度係使用Levis小鼠IFN-γ ELISA套組(富士膠片和光Shibayagi股份有限公司製造),TNF-α、IL-6、KC/GRO(IL-8)及IL-10濃度係使用V-PLEX Proinflammatory Panel 1 Mouse Kit(Meso Scale Diagnostics,LLC.)進行測定。圖10至圖14表示各自之推移。
統計分析係使用統計分析軟體EXSUS(ver.10.0,EP Croix股份有限公司),於對照群及各投予群實施Wilcoxon檢定。以顯著水準P<0.05及P<0.01進行雙側統計學的分析。
烏苯美司與抗PD-1抗體之併用群係經時性地增加細胞激素產生量。相較於對照群、烏苯美司單劑及抗PD-1抗體單劑投予群,併用群顯示IFN-γ、TNF-α、IL-6、KC/GRO(IL-8)及IL-10之明顯的產生增強效果(圖10至圖14)。
移植後21或24日,併用群相對於對照群之P值,在IFN-γ為0.003,在TNF-α為0.045,在IL-6為0.031,在IL-10為0.008。
已知IFN-γ、TNF-α、IL-6及IL-8係被認為是將免疫系統網路予以連鎖性活化而有助於抗腫瘤效果之抗腫瘤性細胞激素或炎症性細胞激素。已知IL-10係進行炎症反應調節之抗炎症性細胞激素。於實施例3中,烏苯美司與抗PD-1抗體之併用群係顯示比各單劑投予群更強的腫瘤增殖抑制效果,因此,認為烏苯美司與抗PD-1抗體之組合投予可使IFN-γ、TNF-α、IL-6及KC/GRO(IL-8)之產生增加,有助於腫瘤增殖抑制。又,IL-10係與上述細胞激素之產生增加進行反應而代償性地增加,推測為調整生體過剩之炎症反應。
Claims (12)
- 一種抗腫瘤劑,係以烏苯美司作為有效成分,該抗腫瘤劑係用以與屬於免疫檢查點抑制劑之抗PD-1抗體、抗PD-L1抗體及/或抗CTLA-4抗體組合投予。
- 如請求項1所述之抗腫瘤劑,其中,烏苯美司之用量係使單次投予時之血中濃度時間曲線下面積(AUC)成為3.00至50.00μg‧hr/mL之用量。
- 如請求項1或2所述之抗腫瘤劑,其中,烏苯美司係連日投予之用法。
- 一種抗腫瘤劑,係以選自由屬於免疫檢查點抑制劑之抗PD-1抗體、抗PD-L1抗體及抗CTLA-4抗體所構成群組中之1種作為有效成分,該抗腫瘤劑係用以與烏苯美司組合投予。
- 如請求項4所述之抗腫瘤劑,其中,烏苯美司之用量係使單次投予時之血中濃度時間曲線下面積(AUC)成為3.00至50.00μg‧hr/mL之用量。
- 一種醫藥,係以烏苯美司作為有效成分,該醫藥係藉由與屬於免疫檢查點抑制劑之抗PD-1抗體、抗PD-L1抗體及/或抗CTLA-4抗體組合投予,而用以使抗腫瘤性細胞激素的產生亢進。
- 如請求項6所述之醫藥,其中,烏苯美司之用量係使單次投予時之血中濃度時間曲線下面積(AUC)成為3.00至50.00μg‧hr/mL之用量。
- 一種醫藥,係以烏苯美司作為有效成分,該醫藥係藉由與屬於免疫檢查點抑制劑之抗PD-1抗體、抗PD-L1抗體及/或抗CTLA-4抗體組合投予,而用以使腫瘤浸潤性淋巴球增加。
- 如請求項8所述之醫藥,其中,烏苯美司之用量係使單次投予時之血中濃度時間曲線下面積(AUC)成為3.00至50.00μg‧hr/mL之用量。
- 一種醫藥,係以烏苯美司作為有效成分,該醫藥係藉由與屬於免疫檢查點抑制劑之抗PD-1抗體、抗PD-L1抗體及/或抗CTLA-4抗體組合投予,而使用於選自由小細胞肺癌、非小細胞肺癌、食道癌、頭頸部癌、腦腫瘤、結腸/直腸癌、結腸腺癌、胃癌、乳癌、肝細胞癌、胰臟癌、膽管癌、腎臟癌、前列腺癌、膀胱癌、卵巢癌、子宮頸癌、甲狀腺癌及黑色素瘤所構成群組中之惡性腫瘤之治療。
- 如請求項10所述之醫藥,其中,烏苯美司之用量係使單次投予時之血中濃度時間曲線下面積(AUC)成為3.00至50.00μg‧hr/mL之用量。
- 如請求項10或11所述之醫藥,其中,烏苯美司係連日投予之用法。
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