TW201922282A - Ｐｄ-１抗體和表觀遺傳調節劑聯合在製備治療腫瘤的藥物中的用途 - Google Patents
Ｐｄ-１抗體和表觀遺傳調節劑聯合在製備治療腫瘤的藥物中的用途 Download PDFInfo
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Abstract
本發明涉及PD-1抗體和表觀遺傳調節劑聯合在製備治療腫瘤的藥物中的用途。具體而言，本發明涉及PD-1抗體和表觀遺傳調節劑聯合在製備治療腫瘤和/或增強T-細胞活性的藥物中的用途。
Description
抗PD-1抗體和表觀遺傳調節劑聯合在製備治療腫瘤和/或增強T-細胞活性的藥物中的用途。
PD-1(程序性死亡受體1)抗體可以特異性識別並結合淋巴細胞表面PD-1，阻斷PD-1/PD-L1信號通路，進而激活T細胞對腫瘤的免疫殺傷作用，調動機體免疫系統而清除體內腫瘤細胞。表觀遺傳改變與癌症發展和耐藥性密切相關。隨著研究的深入，發現向患者重複施用PD-1抗體後存在耐藥情況。DNA甲基化抑制劑地西他濱(Dacogen®)已被批准用於血液學治療惡性腫瘤及其對實體瘤的臨床療效受到關注，各種動物模型和細胞系研究表明，地西他濱誘導控制細胞凋亡、細胞週期停滯以及腫瘤表面抗原的基因表達；藉由DNA去甲基化效應誘導主要組織相容性複合體(MHC)和共刺激分子，其結果導致地西他濱提高了抗
腫瘤免疫治療的響應率、抑制腫瘤生長。研究發現甲基化修飾以及特定基因的沉默可能對T-細胞的成熟和定型過程中發揮關鍵作用，已有報導5-阿紮胞苷可增加以PD-1/PD-L1(程序性死亡配體1)為靶點的免疫檢查點治療的敏感度，因此表觀遺傳學治療聯合免疫治療可提高腫瘤臨床治療的有效性(Cancer letters 354.1(2014)：12-20)。Riccadonna等人的研究表明去甲基化劑具有提高免疫療法對各種神經膠質瘤細胞識別和隨後的破壞，其細胞和動物試驗表明地西他濱聯合多種免疫療法對惡性膠質瘤模型具有良好抑瘤效果([J].PloS one,2016,11(8)：e0162105)；Tamas A等人的研究發現地西他濱聯合免疫檢查點抑制劑(Anti-PD-1H)，尤其是在在KBC胰腺癌模型小鼠中可顯著提高抑瘤效率，在地西他濱給藥後發現顯著升高T細胞PD-1H的表達，地西他濱接續抗PD-1H治療可顯著延長小鼠生存期([J].Gastroenterology,2017,152(5)：S42-S43)；WO2015035112公開了一種表觀遺傳調節劑聯合免疫調節劑用於治療腫瘤，其中表觀遺傳調節劑選自地西他濱，免疫調節劑可選自PD-1/PD-L1抗體。
目前臨床研究已逐步開展地西他濱聯合抗PD-1抗體的治療，PD-1抗體納武單抗(Nivolumab)聯合阿紮胞苷治療復發難治性AML(急性髓性淋巴細胞白血病)的臨床研究中有18%的患者療效評價為CR([J].Blood 2016 128：763)；Chunmeng Wang報導的PD-1抗體聯合地西他濱治療晚期和未治療的惡性腫瘤的I期臨床研究顯示入組的11名患者中
有1名患者療效評價為CR([J].Journal of Clinical Oncology 35(2017)：e14555-e14555)。PD-L1抑制劑度伐魯單抗(Durvalumab)聯合口服阿紮胞苷治療既往對地西他濱或阿紮胞苷不敏感的骨髓增生異常綜合症的II期臨床研究正在進行中(NCT02281084)；PD-1抑制劑派姆單抗(Pembrolizumab)聯合地西他濱治療復發難治性AML也正在開展中(NCT02996474)，但目前已有報導的臨床結果仍不甚理想，對於難治性腫瘤總生存期的延長並不令人滿意，而正在進行臨床研究的結果尚未可知，如何篩選最佳的PD-1/PD-L1抑制劑與DNA去甲基化抑制劑獲得最佳抑瘤效果並同時兼顧安全性仍然是臨床亟待解決的問題。
本發明提供的抗PD-1抗體，WO2015085847公開了該抗體的序列和製備方法，目前PD-1抗體正處於國內臨床I期，安全性良好，已報到的臨床研究結果已經顯示出其具有一定的抗腫瘤作用([J].Journal of Clinical Oncology 35(2017)：e15572-e15572)。
本發明提供免疫治療劑和表觀遺傳調節劑聯合在製備治療腫瘤和/或增強T-細胞的藥物中的用途，該免疫治療劑選自PD-1抗體。
PD-1抗體是已知的，較佳該PD-1抗體的輕鏈可變區包含分別如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的LCDR1、LCDR2和LCDR3。
該PD-1抗體的重鏈可變區包含分別如SEQ ID NO：1、
SEQ ID NO：2和SEQ ID NO：3所示的HCDR1、HCDR2和HCDR3。
其中，前面所述的各CDR序列如下表所示：
較佳的，該PD-1抗體為人源化抗體。
較佳的，人源化抗體輕鏈可變區序列為如SEQ ID NO：10所示的序列或其變體；該變體較佳在輕鏈可變區有0至10的胺基酸變化；更佳為A43S的胺基酸變化。該人源化抗體重鏈可變區序列為如SEQ ID NO：9所示的序列或其變體；該變體較佳在重鏈可變區有0至10的胺基酸變化；更佳為G44R的胺基酸變化。
前述的人源化抗體重、輕鏈的可變區序列如下所示：
重鏈可變區
SEQID NO：9
輕鏈可變區
SEQID NO：10
較佳的，人源化抗體輕鏈序列為如SEQ ID NO：8所示的序列或其變體；該變體較佳在輕鏈可變區有0至10的胺基酸變化；更佳為A43S的胺基酸變化。該人源化抗體重鏈序列為如SEQ ID NO：7所示的序列或其變體；該變體較佳在重鏈可變區有0至10的胺基酸變化；更佳為G44R的胺基酸變化。
特別較佳的該人源化抗體輕鏈序列為如SEQ ID NO：8所示的序列，重鏈序列為如SEQ ID NO：7所示的序列。
前述的人源化抗體重、輕鏈的序列如下所示：
重鏈
SEQID NO：7
輕鏈
SEQID NO：8
本發明較佳的實施例方案中，該表觀遺傳調節劑選自去甲基化劑、DNA甲基轉移酶(DNMT)抑制劑、組蛋白去乙醯化酶(HDAC)抑制劑的一種或多種，其中所述DNMT抑制劑選自鳥地西他濱(guadecitabine)、RX-3117、來那度胺(Lenalidomide)和阿紮胞苷複方、EPI-01、地西他濱和E-7727複方、RRx-001、替莫唑胺、CM-272、KM-101、KRX-0402、TdCyd、UVI-5008、阿紮胞苷前藥、地西他濱前藥、aza-T-dCyd、XB-05、PMX-700、CP-4200；所述HDAC抑制劑選自莫昔替諾司他(mocetinostat)、恩替諾司他(entinostat)、嘌呤諾司他(purinostat)、拉格唑拉(largazole)、拉格唑拉類似物、ACY-738、瑞斯米諾司他(resminostat)、VRx-3996、吉凡諾司他(givinostat)、MPT-0E028、突西地諾司他(tucidinostat)、TMB-ADC、羅米地辛(romidepsin)、帕
比諾司他(panobinostat)、4SC-202、艾貝諾司他(abexinostat)、CUDC-907、伏利諾司他(vorinostat)、普拉西諾司他(pracinostat)、HLY-0019、DWP-0016、瑞美替諾司他(remetinostat)、苯丁酸鈉、丙戊酸、CKD-509、CKD-504、CKD-506、CKD-581、瑞可林諾斯司他(ricolinostat)、CG-200745、AR-42、SP-2-59、西塔林諾司他(citarinostat)、伏利諾司他(vorinostat)、AP-001、喹辛諾司他(quisinostat)、SP-1-161、RCY-1497、貝里諾司他(belinostat)、曲古司他汀(trichostatin)A、TMP-195、RND-001、GSK-3117391、ACY-1083、替非諾司他(tefinostat)、替諾司他目司汀(tinostamustine)、SF-2558HA、CXD-101、JW-1521、CG-1255、LB-205、LB-201、OCID-4681、QTX-153、APH-0812、CX-1026、OBP-801、CS-3158、RG-2833、TL-112、HG-3001、KDAC-001、泰蘭迪辛(thailandepsin)B、QTX-125、RGFP-966、SP-1003、BEBT-908、BRD-3308、BEBT-201、BEBT-906、ACY-257、NMB-T-BMX-OS01、NBM-HD-1、澤布拉林(zebularine)。
本發明另外較佳的實施例方案中，該表觀遺傳調節劑選自阿紮胞苷、地西他濱、氟達拉濱(Fludarabine)、鳥地西他濱(Guadecitabine)、澤布拉林(Zebularine)、NPEOC-DAC、CP-4200、伏諾司他(Vorinostat)、羅美地辛(Romidepsin)、帕比諾司他(Panobinostat)、CI-994、5,6-二氫-5-氮雜胞苷、5-氟-2’-脫氧胞苷、RX-3117、表沒食子兒茶素沒食子酸酯(EGCG)、染料木黃酮、薑黃素、寡核苷酸類，較佳選自地西他濱、阿紮胞苷、鳥地西他濱(Guadecitabine)、羅美
地辛(Romidepsin)、氟達拉濱(Fludarabine)。
本發明較佳的實施例方案中，該腫瘤選自惡性腫瘤、良性腫瘤；該惡性腫瘤選自惡性上皮腫瘤、肉瘤、骨髓瘤、白血病、淋巴瘤、黑色素瘤、頭頸部腫瘤、腦部腫瘤、混合型腫瘤、兒童惡性腫瘤；該惡性上皮腫瘤選自肺癌、乳腺癌、肝癌、胰腺癌、結直腸癌、胃癌、胃食管腺癌、食管癌、小腸癌、賁門癌、子宮內膜癌、卵巢癌、輸卵管癌、外陰癌、睾丸癌、前列腺癌、陰莖癌、腎癌、膀胱癌、肛門癌、膽囊癌、膽管癌、畸胎瘤、心臟腫瘤；該頭頸部腫瘤選自鼻咽癌、喉癌、甲狀腺癌、舌癌、口腔癌；該肉瘤選自Askin瘤、軟骨肉瘤、尤文氏肉瘤、惡性血管內皮瘤、惡性神經鞘瘤、骨肉瘤、軟組織肉瘤；該骨髓瘤選自孤立型骨髓瘤、多髮型骨髓瘤、彌漫型骨髓瘤、白血病型骨髓瘤、髓外型骨髓瘤；該白血病選自急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性骨髓性白血病、多毛細胞性白血病、T細胞淋巴細胞白血病、大顆粒淋巴細胞性白血病、成人T細胞白血病；該淋巴瘤選自非霍奇金淋巴瘤、霍奇金淋巴瘤；該腦部腫瘤選自神經上皮組織腫瘤、顱神經和脊髓神經腫瘤、腦膜組織腫瘤；該兒童惡性腫瘤選自腎母細胞瘤、神經母細胞瘤、視網膜母細胞瘤、兒童生殖細胞腫瘤。
在本發明另外一個較佳的實施例方案中，該肺癌選自所述肺癌選自非小細胞肺癌、小細胞肺癌；該乳腺癌選自所述乳腺癌選自激素受體(HR)陽性乳腺癌、人表皮生長
因子受體-2(HER2)陽性乳腺癌、三陰乳腺癌；該腎癌選自透明腎細胞癌、乳頭狀腎細胞癌、嫌色細胞性腎細胞癌、集合管癌；該神經上皮組織腫瘤選自較佳星形細胞瘤、間變性星形細胞瘤、膠質母細胞瘤；該肝癌選自原發性肝癌、繼發性肝癌，該原發性肝癌選自肝細胞癌、膽管細胞癌、混合性肝癌；該結直腸癌選自結腸癌、直腸癌。
在本發明另外一個較佳的實施例方案中，該腫瘤選自實體瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、前列腺癌、胰腺癌、肺癌、食管癌、肝癌、膽管癌、乳腺癌、結直腸癌、胃癌、腎癌、急性髓性淋巴細胞白血病、骨髓增生異常綜合症、膠質瘤。
在本發明較佳的實施例方案中，該腫瘤由PD-1介導和/或表達PD-L1。
在本發明較佳的實施例方案中，該腫瘤選自中晚期腫瘤、復發難治性腫瘤、經化療藥物治療失敗和/或復發腫瘤、經放療失敗和/或復發腫瘤、經靶向藥物治療失敗和/或復發腫瘤、經免疫治療失敗和/或復發腫瘤。
在本發明較佳的實施例方案中，該腫瘤對免疫治療劑或免疫療法或表現為抵抗或耐藥，較佳的，該免疫治療劑是以PD-1和/或PD-L1或CTLA-4(細胞毒性T淋巴細胞相關蛋白4)為靶點；該免疫療法選自免疫檢查點阻斷(ICB)療法、嵌合抗原受體T細胞免疫療法(CAR-T療法)、自體細胞免疫療法(CIK療法)。
在本發明較佳的實施例方案中，較佳的，該免疫治療
劑選自PD-1抗體、PD-L1抗體、CTLA-4抗體，所述PD-1抗體包括但不限於匹地單抗(Pidilizumab)、MEDI-0680、AMP-224、PF-06801591、TSR-042、JS-001、GLS-010、PDR-001、杰諾單抗(Genolimzumab)、卡瑞單抗(Camrelizumab)、BGB-A317、IBI-308、REGN-2810、帕姆單抗(Pembrolizumab)、納武單抗(Nivolumab)；該PD-L1抗體包括但不限於MSB-0011359-C、CA-170、LY-3300054、BMS-936559、度伐魯單抗(Durvalumab)、阿維魯單抗(Avelumab)、阿特珠單抗(Atezolizumab)；該CTLA-4抗體包括但不限於依匹姆單抗(ipilimumab)、AK-104、JHL-1155、ATOR-1015、AGEN-1884、PRS-010、曲美木單抗(tremelimumab)、IBI-310、MK-1308、BMS-986218、SN-CA21、FPT-155、KN-044、CG-0161、ONC-392、AGEN-2041、PBI-5D3H5。
在本發明較佳的實施例方案中，提供PD-1抗體與表觀遺傳調節劑聯合在製備增強T-細胞活性藥物中的用途，該T細胞較佳外周T-細胞。
本發明較佳的實施例方案中，該PD-1抗體劑量選自1-10mg/kg，較佳選自1mg/kg、2mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg，更佳選自3mg/kg、4mg/kg、5mg/kg。
本發明較佳的實施例方案中，該PD-1抗體劑量選自50-600mg，較佳選自50mg、60mg、70mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、375mg、400mg、425mg、450mg、475mg、500mg、600mg，更佳選
自100mg、200mg、400mg。
本發明較佳的實施例方案中，該表觀遺傳調節劑劑量選自5-100mg/m2，較佳選自5mg/m2、6mg/m2、7mg/m2、8mg/m2、9mg/m2、10mg/m2、12mg/m2、15mg/m2、20mg/m2、25mg/m2、30mg/m2、35mg/m2、40mg/m2、50mg/m2、60mg/m2、75mg/m2；更佳選自7mg/m2、10mg/m2、12mg/m2、15mg/m2、20mg/m2、25mg/m2、30mg/m2、40mg/m2、50mg/m2、75mg/m2。
本發明較佳的實施例方案中，該表觀遺傳調節劑劑量選自5-500mg，較佳選自10mg、15mg、20mg、25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、400mg、500mg，更佳選自10mg、20mg、100mg、200mg、300mg。
本發明較佳的實施例方案中，該PD-1抗體與表觀遺傳調節劑的重量比選自0.01-100：1，較佳選自5：1、4：1、3：1、5：2、2：1、7：4、3：2、4：3、5：4、1：1、3：4、2：3、3：5、1：2、2：5、1：3、3：10、1：4、40：1、25：1、20：1、15：1、25：2、12：1、10：1、8：1、9：2、25：4、6：1、20：3、15：4；更佳選自5：1、4：1、3：1、5：2、2：1、1：1、2：3、4：3、40：1、20：1。
本發明較佳的實施例方案中，該聯合還包含第三組分，該第三組分選自烷化劑、鉑絡合劑、代謝拮抗劑、植物生物鹼、激素抗癌劑、蛋白酶體抑制劑、芳香化酶抑制劑、免疫調節劑、EGFR抑制劑、ALK抑制劑、PARP抑制劑VEGF抗體、VEGFR抑制劑、mTOR抑制劑的一種或多種。
較佳的，該化療藥物選自烷化劑、鉑絡合劑、代謝拮
抗劑、植物生物鹼(如長春鹼類、三尖杉酯鹼類)、激素抗癌劑、蛋白酶體抑制劑、芳香化酶抑制劑、免疫調節劑的一種或多種；在另外較佳的實施例方案中，該化療藥物包括但不限於環磷醯胺、異環磷醯胺、美法侖、白消安、尼莫司丁、雷莫司汀、達卡巴嗪、替莫唑胺、鹽酸氮芥、二溴甘露醇、順鉑、卡鉑、奧沙利鉑、奈達鉑、甲胺蝶呤、5-氟尿嘧啶、替加氟、吉西他濱、卡培他濱、氟維司群、培美曲塞、蒽環類抗生素、絲裂黴素、博萊黴素類、放線菌素、長春鹼類、喜樹鹼類、紫杉醇類、長春新鹼、長春鹼、長春地辛、依託泊苷、多西他賽、紫杉醇、白蛋白結合型紫杉醇、紫杉醇脂質體、伊立替康、長春瑞濱、米托蒽醌、長春氟寧、拓撲替康、亮丙瑞林、戈舍瑞林、度他雄胺、氟維司群、地塞米松、他莫昔芬、硼替佐米、來那度胺等、依西美坦、來曲唑、阿那曲唑。
較佳的，該靶向藥物選自EGFR抑制劑、ALK抑制劑、PARP抑制劑、VEGF抗體和VEGFR抑制劑、mTOR抑制劑、中的一種或多種治療。這些靶向藥物是本領域熟知的，例如EGFR抑制劑可以選自吉非替尼、厄洛替尼、埃克替尼、和阿法替尼、西妥昔單抗、曲妥珠單抗中的一種或幾種；ALK抑制劑可以選自克唑替尼、色瑞替尼、阿西替尼、布加尼布(Brigatinib)；VEGF抗體選自貝伐珠單抗、布洛魯單抗(Brolucizumab)、凡努單抗(Vanucizumab)、納威西單抗(Navicixizumab)、蘭尼單抗(Ranibizumab)、康柏西普(Conbercept)的一種或多種；VEGFR抑制劑選自舒尼替尼、
阿帕替尼、法米替尼中的一種或幾種；本發明較佳的實施例方案中，該第三組分選自吉西他濱、順鉑、卡鉑、紫杉醇白蛋白、紫杉醇脂質體、紫杉醇、多西他賽、環磷醯胺、多柔比星、表柔比星、長春新鹼、替吉奧、替加氟、5-氟尿嘧啶、四氫尿苷(Tetrahydrouridine)的一種或多種。
在本發明上述較佳的實施例方案中，上述第三組分可根據患者的體表面積、體重，或KPS功能狀態評分標準或ECOG體力狀況評分標準(Zubrod-ECOG-WHO)和各種腫瘤診療指南中對不同類型腫瘤化療方案推薦的劑量和給藥方案進行選擇。如紫杉醇白蛋白給藥劑量為50至500mg/m2，較佳為125mg/m2；吉西他濱給藥劑量為500至2000mg/m2，較佳為1000mg/m2；順鉑給藥劑量為25至200mg/m2，較佳為75mg/m2。
在本發明中，該治療週期可為1天、3天、1週、2週、3週、3至4週、4週，較佳3週或3至4週或4週。
在本發明中，該治療週期包括但不限於化療週期或放療週期或其他相關靶向藥物治療週期或免疫治療週期。
在本發明中，PD-1抗體與表觀遺傳調節劑聯合用於腫瘤，二者的給藥次序為表觀遺傳調節劑給藥在PD-1抗體給藥之前，或二者同時給藥，或表觀遺傳調節劑給藥在PD-1抗體給藥之後；較佳的，表觀遺傳調節劑給藥在PD-1抗體給藥之前。
在本發明中，表觀遺傳劑與PD-1抗體可在在相同或不
同的治療週期內聯合用於治療腫瘤，在治療腫瘤的過程中，表觀遺傳劑與PD-1抗體聯合給藥的同時或之前或之後還可聯合依據不同腫瘤較佳的化療方案或放療治療方案或靶向小分子藥物治療方案或免疫治療方案治療腫瘤，該免疫治療方案包括但不限於細胞免疫療法(如CAR-T療法，腫瘤疫苗、CIK療法等)；此外，表觀遺傳劑與PD-1抗體的聯合給藥也可不聯合其他治療方案單獨進行。
在本發明中，PD-1抗體與表觀遺傳調節劑在聯用的同時可進行按照各種腫瘤診療規範或指導原則所規定的不同病理分型和進展階段腫瘤的治療方案，該腫瘤診療規範或指導原則包括但不限於NCCN(美國國立綜合癌症網絡發佈各種惡性腫瘤臨床實踐指南)或中國衛生部頒佈的惡性腫瘤診療規範。
在本發明中，表觀遺傳調節劑可在傳統腫瘤治療方案(包括但不限於化療、放療、小分子靶向治療、手術切除、內窺鏡治療)之前先行在1至2個治療週期內的任意一個1至7天的時間段裡進行連續給藥，較佳在1至5天的時間段裡進行連續給藥，在此治療週期內，PD-1抗體與表觀遺傳調節劑同步給藥或在表觀遺傳調節劑之前或在表觀遺傳調節劑之後給藥，較佳的，PD-1抗體可在地西他濱給藥結束後的第1天、第2天、第3天、第4天、第5天、第6天、第7天給藥，較佳第3天、第4天、第5天給藥；較佳的，PD-1抗體可在地西他濱給藥開始前的前1天、前2天、前3天、前4天、前5天、前6天、前7天給藥，
較佳前3天、前4天、前5天給藥；該表觀遺傳調節劑選自地西他濱、阿紮胞苷；該地西他濱劑量較佳為10mg或7mg/m2。
本發明關於“聯合”是一種給藥方式，是指在一定時間期限內給予至少一種劑量的PD-1抗體和至少一種劑量的表觀遺傳調節劑，其中兩種物質都顯示藥理學作用。該時間期限可以是一個給藥週期內，較佳4週內、3週內、2週內、1週內、或24小時以內、12小時以內。可以同時或依次給予PD-1抗體和表觀遺傳調節劑。這種期限包括這樣的治療，其中藉由相同給藥途徑或不同給藥途徑給予PD-1抗體和表觀遺傳調節劑。本發明所述聯合的給藥方式選自同時給藥、獨立地配製並共給藥或獨立地配製並相繼給藥。在本發明中，本發明進一步涉及的藥物中的用途，其中PD-1抗體的給藥頻次為一日一次、一日二次、一日三次、一週一次、二週一次、三週一次、一月一次，表觀遺傳調節劑的給藥頻次為一日一次、一日二次、一日三次、一週一次、二週一次、三週一次、一月一次。
在較佳的實施方案中，以21天為一個給藥週期，每週期內5天給予地西他濱10mg/天，每週期內給予一次PD-1抗體4mg/kg；其中PD-1抗體也可固定劑量給藥，每名患者200mg或400mg(體重大於80kg者)；可按此給藥方法循環8個給藥週期。
在最較佳的實施方案中，21天為一個給藥週期，第1個給藥週期的第1-第5天給予地西他濱10mg/天；第8天
給予PD-1抗體4mg/kg；其中PD-1抗體也可固定劑量給藥，每名患者200mg或400mg(體重大於80kg者)。在本發明較佳的實施方案中，該PD-1抗體以注射的方式給藥，例如皮下或靜脈注射，注射前需將PD-1抗體配製成可注射的形式。特別較佳的PD-1抗體的可注射形式是注射液或凍乾粉針，其包含PD-1抗體、緩衝劑、穩定劑，視需要地還含有表面活性劑。緩衝劑可選自醋酸鹽、檸檬酸鹽、琥珀酸鹽、以及磷酸鹽中的一種或幾種。穩定劑可選自糖或胺基酸，較佳二糖，例如蔗糖、乳糖、海藻糖、麥芽糖。表面活性劑選自聚氧乙烯氫化蓖麻油、甘油脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯，較佳該聚氧乙烯山梨醇酐脂肪酸酯為聚山梨酯20、40、60或80，最佳維聚山梨酯20。最為佳的PD-1抗體的可注射形式包含PD-1抗體、醋酸鹽緩衝劑、海藻糖和聚山梨酯20。
本發明所述聯合的給藥途徑選自經口給藥、胃腸外給藥、經皮給藥，所述胃腸外給藥包括但不限於靜脈注射、皮下注射、肌肉注射。
本發明提供上述免疫治療劑聯合上述表觀遺傳調節劑作為治療製備治療腫瘤和/或增強T-細胞活性的藥物。
在本發明中，提供了一種治療腫瘤和/或增強T-細胞活性的辦法，包括向患者施用上述免疫治療劑和上述表觀遺傳調節劑。
本發明還提供了一種藥物套組，或者一種藥物包裝盒，其中含有前述的表觀遺傳調節劑和PD-1抗體。
本發明還提供了一種醫藥組成物，包含前述的有效量的PD-1抗體和表觀遺傳調節劑，以及一種或多種可藥用的賦型劑、稀釋劑或載體。
第1圖為PD-1抗體聯合地西他濱與PD-1抗體給藥後耐藥療效對比。
第2圖為PD-1抗體聯合地西他濱4周後腫瘤消退情況。
第3圖為PD-1抗體聯合地西他濱治療惡性實體瘤腫瘤負荷減輕情況。
第4圖為PD-1抗體聯合地西他濱治療惡性實體瘤腫瘤負荷隨治療時間變化情況。
發明詳述
一、術語
為了更容易理解本發明，以下具體定義了某些技術和科學術語。除顯而易見在本文件中的它處另有明確定義，否則本文使用的所有其它技術和科學術語都具有本發明所屬領域的一般技術人員通常理解的含義。
術語“免疫療法”指免疫療法是利用免疫系統來治療疾病，在本發明中主要指藉由提高腫瘤細胞的免疫原性和對效應細胞殺傷的敏感性，激發和增強機體抗腫瘤免疫應答，並應用免疫細胞和效應分子輸注宿主體內，協同機體免疫系統殺傷腫瘤、抑制腫瘤生長。
以下結合實施例用於進一步描述本發明，但這些實施
例並非限制本發明的範圍。
實施例1：地西他濱聯合PD-1抗體治療復發難治性霍奇金淋巴瘤
1、受試抗體和化合物
PD-1抗體按WO2015085847公開的方法製備，對應其代號為H005-1，其重、輕鏈的序列如本發明中SEQID NO：7和SEQID NO：8。批號：P1512，200mg/每瓶，配成20mg/ml備用。
市售地西他濱凍乾粉針劑，50mg/瓶，採用無菌注射用水重溶，配成約5mg/mL溶液，再按臨床需求採用生理鹽水、0.5%葡萄糖溶液或乳酸格林式液配製成0.1-1mg/mL的溶液使用。
2、入組受試者
(1)霍奇金淋巴瘤病理學確診；(2)年齡12至80歲；(3)ECOG評分小於2分；(4)預期壽命至少3個月；(5)淋巴瘤受試者由淋巴瘤反應標準定義至少一個1cm的可測病灶；(6)必須至少接受兩次化療、且已經歷至少4週的洗脫期；自體造血幹細胞移植的受試者符合條件超3個月；(7)必須具有足夠的骨髓、肝、腎、肺和心臟功能。
3、分組
截止至2017年9月27日，共入組受試者共19人，其
中10人經PD-1抗體治療耐藥，分組為經PD-1抗體治療耐藥組；9人未經PD-1抗體治療，分組為未經PD-1抗體治療組；最終有效評價對象：PD-1抗體治療耐藥組為9人，未經PD-1抗體治療組9人。經PD-1抗體耐藥組受試者中，其中有8名受試者既往接受過3至8次納武單抗(Nivolumab)的治療，1名受試者既往同時接受過納武單抗(Nivolumab)和派姆單抗(Pembrolizumab)治療；未經PD-1抗體治療組有3名受試者既往接受過CAR-T治療；在最終進行療效評價的18名患者中，有2名既往既接受納武單抗(Nivolumab)治療同時也接受過CAR-T治療。
4、給藥方法
入組受試者第1個給藥週期(21天)的第1-第5天給予地西他濱10mg/d，靜脈滴注；第8天給予PD-1抗體200mg(若體重超過80kg，給予400mg)，按此給藥方法循環8個給藥週期。
5、試驗結果
臨床研究結果顯示(見表1)，在臨床研究過程中，無嚴重不良反應發生，最常見不良反應為櫻桃狀血管瘤、發熱、噁心，皮疹，均為1至2級不良反應；地西他濱+PD-1抗體治療復發難治性霍奇金淋巴瘤總緩解率高達78%，且在經PD-1抗體治療耐藥組中仍有高達56%的客觀緩解率，無疑為經以PD-1/PD-L1為靶點治療耐藥的患者提供了一種新的治療途徑。
備註：經PD-1抗體治療耐藥組指接受PD-1抗體治療四週，且無客觀反應(CR+PR)；經PD-1抗體治療後疾病復發。
實驗結束時共入組71名病人，其中一組單獨使用PD-1抗體治療，具體結果如下：
實施例2：地西他濱聯合PD-1抗體治療復發難治性惡性腫瘤
1、受試抗體和化合物
見實施例1
2、入組受試者
(1)惡性腫瘤病理學確診；(2)年齡12至80歲；(3)ECOG評分小於2分；(4)預期壽命至少3個月；(5)由淋巴瘤反應標準定義至少一個1cm的可測病灶；(6)必須經一線化療失敗、且已經歷至少4週的洗脫期；(7)必須具有足夠的骨髓、肝、腎、肺和心臟功能。
3、分組
截止至2016年10月30日，共入組受試者共11人，包括6名彌漫性大B細胞淋巴瘤，1名B細胞淋巴瘤，1名霍奇金淋巴瘤，4名實體瘤(2名胃癌、1名食管癌)；最終可評價對象為9人。其中兩名漫性大B細胞淋巴瘤受試者接受過CAR-T治療，一名胃癌受試者既往接受CIK治療。
4、給藥方法
入組受試者第1個給藥週期(21天)的第1-第5天給予地西他濱10mg/d，靜脈滴注；第8天給予PD-1抗體
4mg/kg，按此給藥方法循環8個給藥週期。
5、試驗結果
臨床研究結果顯示(見表2)，地西他濱+PD-1抗體治療復發難治性惡性腫瘤總緩解率為7/9(78%)，其中4名受試者經PD-1抗體單藥治療進展後採用PD-1抗體聯合地西他濱治療取得了徹底緩解或部分緩解的療效評價，無疑為延續該類患者生存期提供了新的選擇。
實施例3：地西他濱聯合PD-1抗體治療復發難治性惡性腫瘤
1、受試抗體和化合物
見實施例1
2、入組受試者
(1)惡性腫瘤病理學確診；(2)年齡12至80歲；(3)ECOG評分小於2分；(4)預期壽命至少3個月；(5)由淋巴瘤反應標準定義至少一個1cm的可測病灶；(6)必須經一線化療失敗、且已經歷至少4週的洗脫期；(7)必須具有足夠的骨髓、肝、腎、肺和心臟功能。
3、分組
截止至2017年9月26日，共入組受試者共24人，包括18名霍奇金淋巴瘤，2名B細胞非霍奇金淋巴瘤；4名實體瘤(2名結直腸癌、1名腎癌、1名乳腺癌)；最終可評價對象為23人。18名霍奇金淋巴瘤受試者中有8名既往接受3至13次納武單抗(Nivolumab)或派姆單抗(Pembrolizumab)的治療，5名既往接受CAR-T治療；2名B細胞非霍奇金淋巴瘤受試者中一名既往接受13次納武單抗(Nivolumab)治療，1名既往接受CAR-T治療；4名實體瘤受試者中有2名既往分別接受2次或10次納武單抗
(Nivolumab)治療，1名既往接受4次CIK治療。
4、給藥方法
入組受試者第1個給藥週期(21天)的第1至第5天給予地西他濱10mg/d，靜脈滴注；第8天給予PD-1抗體4mg/kg，按此給藥方法循環8個給藥週期。
5、試驗結果
臨床研究結果顯示(見第3圖、第4圖)，按照抗腫瘤細胞免疫治療療效評價標準(immune-related response criteria，irRC標準)地西他濱+PD-1抗體治療復發難治性惡性腫瘤總緩解率為10/23(44%)，其中5名受試者徹底緩解(CR，與基線水平相比腫瘤負荷下降大於100%)，5名患者受試者部分緩解(PR，與基線水平相比腫瘤負荷下降大於50%)，10名受試者疾病穩定(SD，與基線水平相比腫瘤負荷下降小於25%，但增加不超過25%)，2名受試者疾病進展(PD，與基線水平相比腫瘤負荷增加超過25%)。按照irRC標準，即使患者療效評價為SD，實際上認為同樣屬臨床獲益人群，因此地西他濱+PD-1抗體治療復發難治性惡性腫瘤疾病控制率(DCR)高達21/23(91%)。藉由本發明實施例，地西他濱+PD-1抗體治療復發難治性惡性腫瘤無疑為延長經PD-1抗體治療耐受或復發以及經CAR-T治療或CIK治療耐受或復發的患者生存期提供了重要治療路徑。
<110> 江蘇恆瑞醫藥股份有限公司 中國人民解放軍總醫院
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Claims (24)
- 一種免疫治療劑和表觀遺傳調節劑聯合在製備治療腫瘤和/或增強T-細胞活性的藥物中的用途，其特徵在於，該免疫治療劑選自PD-1抗體，該PD-1抗體的輕鏈可變區包含分別如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的LCDR1、LCDR2和LCDR3；該PD-1抗體的重鏈可變區包含分別如SEQ ID NO：1、SEQ ID NO：2和SEQ ID NO：3所示的HCDR1、HCDR2和HCDR3。
- 如申請專利範圍第1項所述的用途，其中，該PD-1抗體為人源化抗體。
- 如申請專利範圍第2項所述的用途，其中，該抗PD-1人源化抗體的輕鏈可變區序列為如SEQ ID NO：10所示的序列或其變體；重鏈可變區序列為如SEQ ID NO：9所示的序列或其變體。
- 如申請專利範圍第3項所述的用途，其中，該變體在輕鏈可變區有0至10的胺基酸變化。
- 如申請專利範圍第4項所述的用途，其中，該變體在輕鏈可變區為A43S的胺基酸變化。
- 如申請專利範圍第3項所述的用途，其中，該變體在重鏈可變區有0至10的胺基酸變化。
- 如申請專利範圍第6項所述的用途，其中，該變體在重鏈可變區為G44R的胺基酸變化。
- 如申請專利範圍第1至7項中任一項所述的用途，其中，該人源化抗體輕鏈序列為如SEQ ID NO：8所示的序列， 重鏈序列為如SEQ ID NO：7所示的序列。
- 如申請專利範圍第1至8項中任一項所述的用途，其中，該表觀遺傳調節劑選自去甲基化劑、DNA甲基轉移酶(DNMT)抑制劑、組蛋白去乙醯化酶(HDAC)抑制劑的一種或多種。
- 如申請專利範圍第1至9項中任一項所述的用途，其中，該表觀遺傳調節劑選自阿紮胞苷、地西他濱、氟達拉濱(Fludarabine)、鳥地西他濱(Guadecitabine)、澤布拉林(Zebularine)、NPEOC-DAC、CP-4200、伏利諾司他(Vorinostat)、羅米地辛(Romidepsin)、帕比諾司他(Panobinostat)、CI-994、5,6-二氫-5-氮雜胞苷、5-氟-2’-脫氧胞苷、RX-3117、表沒食子兒茶素沒食子酸酯(EGCG)、染料木黃酮、薑黃素、寡核苷酸類。
- 如申請專利範圍第10項所述的用途，其中，該表觀遺傳調節劑選自地西他濱、阿紮胞苷、鳥地西他濱、羅米地辛、氟達拉濱。
- 如申請專利範圍第1至11項中任一項所述的用途，其中，該腫瘤選自惡性腫瘤、良性腫瘤；該惡性腫瘤選自惡性上皮腫瘤、肉瘤、骨髓瘤、白血病、淋巴瘤、黑色素瘤、頭頸部腫瘤、腦部腫瘤、混合型腫瘤、兒童惡性腫瘤。
- 如申請專利範圍第1至12項中任一項所述的用途，其中，該腫瘤選自實體瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、前列腺癌、胰腺癌、肺癌、食管癌、肝癌、膽管癌、 乳腺癌、結直腸癌、胃癌、腎癌、急性髓性淋巴細胞白血病、骨髓增生異常綜合症、膠質瘤。
- 如申請專利範圍第1至13項中任一項所述的用途，其中，該腫瘤由PD-1介導和/或表達PD-L1。
- 如申請專利範圍第1至14項中任一項所述的用途，其中，該腫瘤選自中晚期腫瘤、復發難治性腫瘤、經化療藥物治療失敗和/或復發腫瘤、經放療失敗和/或復發腫瘤、經靶向藥物治療失敗和/或復發腫瘤、經免疫治療失敗和/或復發腫瘤。
- 如申請專利範圍第1至15項中任一項所述的用途，其中，該腫瘤對免疫治療劑或免疫療法表現為抵抗或耐藥。
- 如申請專利範圍第1至16項中任一項所述的用途，其中，該腫瘤對以PD-1或PD-L1或CTLA-4為靶點的免疫治療劑表現為抵抗或耐藥。
- 如申請專利範圍第1至17項中任一項所述的用途，其中，該PD-1抗體劑量選自1至10mg/kg。
- 如申請專利範圍第18項所述的用途，其中，該PD-1抗體劑量選自3mg/kg、4mg/kg、5mg/kg。
- 如申請專利範圍第1至19項中任一項所述的用途，其中，該PD-1抗體劑量選自50至600mg，，其中每三週給藥一次。
- 如申請專利範圍第20項所述的用途，其中，該PD-1抗體劑量選自200mg、400mg每次。
- 如申請專利範圍第1至21項中任一項所述的用途，其中，該表觀遺傳調節劑的給藥劑量為10mg/天，其中每21天內給予5天。
- 一種藥物包裝盒，其特徵在於，包含有申請專利範圍第1至22項中任一項所述的表觀遺傳調節劑和PD-1抗體。
- 一種醫藥組成物，其特徵在於，包含有申請專利範圍第1至22項中任一項所述的有效量的PD-1抗體和表觀遺傳調節劑，以及一種或多種可藥用的賦型劑、稀釋劑或載體。
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| TW (1) | TW201922282A (zh) |
| WO (1) | WO2019072220A1 (zh) |
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| EP4650005A3 (en) | 2016-07-15 | 2026-01-28 | Viracta Subsidiary, Inc. | Histone deacetylase inhibitors for use in immunotherapy |
| US20200368280A1 (en) * | 2018-01-12 | 2020-11-26 | Viracta Therapeutics, Inc. | Epigenetic modifiers for use in cellular immunotherapy |
| TW202130349A (zh) * | 2019-09-24 | 2021-08-16 | 大陸商江蘇恆瑞醫藥股份有限公司 | Ｐｄ－１抗體聯合紫杉類化合物在製備治療三陰性乳腺癌的藥物中的用途 |
| GB201913988D0 (en) | 2019-09-27 | 2019-11-13 | Celleron Therapeutics Ltd | Novel treatment |
| CN113116879A (zh) * | 2020-01-15 | 2021-07-16 | 江苏恒瑞医药股份有限公司 | 法米替尼联合紫杉类和铂类药物在制备治疗肿瘤疾病的药物中的用途 |
| CN113413389B (zh) * | 2021-07-19 | 2024-03-15 | 成都赜灵生物医药科技有限公司 | 一种组蛋白去乙酰化酶抑制剂的制剂及其制备方法和用途 |
| CN116196415B (zh) * | 2022-12-07 | 2023-08-01 | 浙江省肿瘤医院 | 用于增敏pd-1抗体的混合制剂及其使用方法 |
| CN116650655A (zh) * | 2023-07-06 | 2023-08-29 | 浙江大学 | 一种基于mavs棕榈酰化修饰的肿瘤免疫治疗组合药物 |
| CN116763808A (zh) * | 2023-07-12 | 2023-09-19 | 复旦大学附属中山医院 | 地西他滨联合RRx-001在治疗胶质瘤中的应用 |
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| US10966998B2 (en) * | 2013-09-05 | 2021-04-06 | The Johns Hopkins University | Cancer therapy via a combination of epigenetic modulation and immune modulation |
| SG10201804945WA (en) * | 2013-12-12 | 2018-07-30 | Shanghai hengrui pharmaceutical co ltd | Pd-1 antibody, antigen-binding fragment thereof, and medical application thereof |
| US10869926B2 (en) * | 2014-07-15 | 2020-12-22 | The Johns Hopkins University | Suppression of myeloid derived suppressor cells and immune checkpoint blockade |
| US10034872B2 (en) * | 2014-08-22 | 2018-07-31 | Celgene Corporation | Methods of treating multiple myeloma with immunomodulatory compounds in combination with antibodies |
| CN106999591B (zh) * | 2015-09-28 | 2021-02-23 | 苏州盛迪亚生物医药有限公司 | 一种抗pd-1抗体制剂及其在医药上的应用 |
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- 2018-10-12 CN CN201880059360.5A patent/CN111132696B/zh active Active
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| CN111132696B (zh) | 2023-05-16 |
| CN111132696A (zh) | 2020-05-08 |
| WO2019072220A1 (zh) | 2019-04-18 |
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