CN114099670A - 酪氨酸激酶抑制剂与抗pd-1抗体联合在制备治疗肿瘤药物中的用途 - Google Patents
酪氨酸激酶抑制剂与抗pd-1抗体联合在制备治疗肿瘤药物中的用途 Download PDFInfo
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- CN114099670A CN114099670A CN202110992862.7A CN202110992862A CN114099670A CN 114099670 A CN114099670 A CN 114099670A CN 202110992862 A CN202110992862 A CN 202110992862A CN 114099670 A CN114099670 A CN 114099670A
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Abstract
本公开涉及酪氨酸激酶抑制剂与抗PD‑1抗体联合在制备治疗肿瘤药物中的用途。具体而言，本公开涉及的酪氨酸激酶抑制剂为式I所示化合物或其可药用盐，涉及的抗PD‑1抗体或其抗原结合片段的轻链可变区包含分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3；所述的抗PD‑1抗体或其抗原结合片段的重链可变区包含分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的HCDR1、HCDR2和HCDR3。
Description
技术领域
本公开属于医药领域，涉及酪氨酸激酶抑制剂与抗PD-1抗体联合在制备治疗肿瘤药物中的用途。
背景技术
根据2019年全国肿瘤登记中心对2015年恶性肿瘤登记资料研究显示，中国甲状腺癌每年新发病例数为20.1万，发病率为14.6人/每10万人。
甲状腺癌从分化来源，可以分为甲状腺滤泡细胞来源的甲状腺癌和神经内分泌C细胞来源的甲状腺癌。分化型甲状腺癌(Differentiated Thyroid Cancer,DTC)和甲状腺未分化癌(Anaplastic Thyroid Cancer，ATC)是甲状腺滤泡细胞来源的甲状腺癌。
DTC是甲状腺癌的最主要类型，约占所有新发甲状腺癌类型的90％，而且是一类预后最好的甲状腺癌。分化型甲状腺癌中分化程度较高的类型包括，乳头状甲状腺癌(Papillary Thyroid Cancer，PTC)、滤泡状甲状腺癌(Follicular Thyroid Cancer，FTC)和Hürthle细胞甲状腺癌(HürthleCell Thyroid Cancer)。低分化甲状腺癌(PoorlyDifferentiated Thyroid Cancer，PDTC)也是一种来源于滤泡的甲状腺癌，但相比于DTC更具有侵袭性。ATC占甲状腺癌的比例很低，一般＜1％，同样也是甲状腺滤泡细胞来源的甲状腺癌。
甲状腺髓样癌(Medullary Thyroid Cancer，MTC)是一类起源于神经棘演化的滤泡旁神经内分泌细胞C细胞(可以分泌降钙素)，一般占甲状腺癌的1～2％。甲状腺髓样癌一般可以分为散发性和遗传性两类，其中散发性甲状腺髓样癌约占甲状腺髓样癌患者的80％。
有近50％的ATC患者在确诊时已经发生远处转移。目前对于ATC的治疗手段比较匮乏，第1年的死亡率接近90％。ATC最容易发生转移的部位是肺(占80％)，其次是骨转移(6％～16％)和脑转移(5％～13％)。局部快速进展导致的窒息是最常见的死亡原因。对于ATC的治疗需要多学科会诊模式(MDT)，综合使用手术、放/化疗进行。但目前研究发现这种治疗模式对于晚期转移性ATC的患者无效，因此姑息治疗仍是目前对该类患者的主要治疗手段。但对于具有BRAFV600E突变的ATC患者(一般大约有20％～50％的ATC肿瘤中具有BRAFV600突变)，目前研究显示达拉非尼(Dabrafenib)联合曲美替尼(Trametinib)具有良好的效果。2018年5月4日，美国食品药品监督管理局(FDA)批准达拉非尼(Dabrafenib)联合曲美替尼(Trametinib)用于治疗具有BRAFV600E突变的ATC患者。尚无酪氨酸激酶抑制剂被批准用于治疗ATC患者。
PD-1或其配体PD-L1的免疫抑制剂(包括Nivolumab、Pembrolizumab以及Atezolizumab等)已被证实为一种很有前景的肿瘤免疫治疗途径，在包括黑色素瘤、非小细胞肺癌以及肾细胞癌等多个肿瘤中取得成功。目前已在部分ATC肿瘤表面发现PD-L1，并在其周围存在浸润淋巴细胞。Ahn等通过免疫组织化学回顾性分析了407例原发性甲状腺癌的病理组织，其中有22.2％的ATC中表达PD-L1，远高于甲状腺乳头状癌(6.1％)和甲状腺滤泡癌(7.6％)。而Wu等在评估了13例ATC患者后发现，有3例(23％)患者检测到了PD-L1表达。因此使用PD-1或其配体PD-L1的免疫抑制剂联合靶向治疗，可能会使部分ATC患者症状缓解，延长生存期。
CN101007815B公开了如下式I所示的化合物(化学名5-(2-二乙胺基-乙基)-2-(5-氟-2-氧代-1，2-二氢-吲哚-3-亚基-甲基)-3-甲基-1，5，6，7-四氢-吡咯[3，2-c]吡啶-4-酮)，公开了式II所示化合物的苹果酸盐，并公开了其具有很强的酪氨酸激酶抑制作用，
CN107629048A公开了如下式II所示的化合物及其晶型，即式I化合物L-苹果酸盐，
本公开提供了一种酪氨酸激酶抑制剂与抗PD-1抗体联合在制备预防或治疗肿瘤疾病的药物中的用途，并显示了良好的抑瘤效果。
发明内容
本公开提供了酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段联合在制备预防或治疗甲状腺癌的药物中的用途。所述的酪氨酸激酶抑制剂为式I所示化合物或其可药用盐。
本公开还提供了一种用于治疗甲状腺癌的抗PD-1抗体或其抗原结合片段，其中抗PD-1抗体或其抗原结合片段与酪氨酸激酶抑制剂联用，所述的酪氨酸激酶抑制剂为式I所示化合物或其可药用盐。
本公开还提供了一种用于治疗甲状腺癌的酪氨酸激酶抑制剂，其中酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段联用，所述的酪氨酸激酶抑制剂为式I所示化合物或其可药用盐。
所述抗PD-1抗体或其抗原结合片段的轻链可变区包含分别如SEQ ID NO:4、SEQID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3；重链可变区包含分别如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：
| 名称 | 序列 | 编号 |
| HCDR1 | SYMMS | SEQID NO：1 |
| HCDR2 | TISGGGANTYYPDSVKG | SEQID NO：2 |
| HCDR3 | QLYYFDY | SEQID NO：3 |
| LCDR1 | LASQTIGTWLT | SEQID NO：4 |
| LCDR2 | TATSLAD | SEQID NO：5 |
| LCDR3 | QQVYSIPWT | SEQID NO：6 |
在某些实施方式中，所述PD-1抗体选自人源化抗体或其片段。
在某些实施方式中，本公开中所述抗PD-1抗体或其抗原结合片段选自由Fab，Fab’-SH，Fv，scFv，和(Fab’)2片段组成的组的抗体片段。
免疫球蛋白可以来源于任何通常已知的同种型，包括但不限于IgA、分泌型IgA、IgG和IgM。IgG亚类也是本领域技术人员众所周知的，包括但不限于IgG1、IgG2、IgG3和IgG4。“同种型”是指由重链恒定区基因编码的Ab种类或亚类(例如，IgM或IgG1)。在一些可选实施方案中，本公开中所述抗PD-1抗体或其抗原结合片段包含人源IgG1、IgG2、IgG3或IgG4同种型的重链恒定区，优选包含IgG1或IgG4同种型的重链恒定区。
在某些实施方式中，所述抗PD-1抗体或其抗原结合片段包含κ或λ的轻链恒定区的轻链恒定区。
在某些实施方式中，人源化抗体轻链可变区序列为如SEQ ID NO:10所示的序列或其变体，所述变体优选在轻链可变区有0-10的氨基酸变化，更优选为A43S的氨基酸变化；所述人源化抗体重链可变区序列为如SEQ ID NO:9所示的序列或其变体，所述变体优选在重链可变区有0-10的氨基酸变化，更优选为G44R的氨基酸变化。
前述的人源化抗体重、轻链的可变区序列如下所示：
重链可变区
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS
SEQID NO：9
轻链可变区
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK
SEQID NO：10
在某些实施方式中，所述人源化抗体轻链序列为如SEQ ID NO:8所示的序列或其变体；所述变体优选在轻链可变区有0-10的氨基酸变化，更优选为A43S的氨基酸变化；所述人源化抗体重链序列为如SEQ ID NO:7所示的序列或其变体，所述变体优选在重链可变区有0-10的氨基酸变化，更优选为G44R的氨基酸变化。
在某些实施方式中，所述人源化抗体的轻链序列为如SEQ ID NO:8所示的序列，重链序列为如SEQ ID NO:7所示的序列。
所述人源化抗体重、轻链的序列如下所示：
重链
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQID NO：7
轻链
DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQID NO：8
在某些实施方式中，所述的甲状腺癌选自分化型甲状腺癌、甲状腺未分化癌、甲状腺髓样癌，优选放射性碘难治分化型甲状腺癌、不适合131I治疗的分化型甲状腺癌、甲状腺髓样癌、甲状腺未分化癌；更优选放射性碘难治分化型甲状腺癌、不适合131I治疗的分化型甲状腺癌、晚期甲状腺髓样癌、晚期甲状腺未分化癌。。
在某些实施方式中，所述分化型甲状腺癌选自放射性碘难治分化型甲状腺癌、不适合131I治疗的分化型甲状腺癌。
在某些实施方式中，所述癌症是经放射性碘治疗后仍有进展的癌症，即患有该癌症的患者至少有一个可测量病灶在放射碘治疗中完全丧失摄碘功能或在经放射性碘治疗后疾病得不到控制，仍然继续进展或转移。
在某些实施方式中，所述癌症是不适合131I治疗的癌症，即患有该癌症的患者因无法切除原发灶而不能进行131I治疗分化型甲状腺癌患者、甲状腺组织或手术切除原发灶后剩余甲状腺组织摄取131I率不高于1％的患者、或患者自身情况不适宜使用131I治疗，其中包括但不限于妊娠期妇女、手术后创面未愈者、白细胞数在3.0*109/L以下、肝功能受损者或肾功能受损者等。
在某些实施方式中，所述的甲状腺未分化癌或晚期甲状腺未分化癌选自经手术后仍有进展的甲状腺未分化癌、经化疗后仍有进展的甲状腺分化癌、经放射外照射治疗仍有进展的甲状腺未分化癌、经微波消融后仍有进展的甲状腺未分化癌或不可手术治愈的甲状腺未分化癌。
在某些实施方式中，所述的分化型甲状腺癌或晚期分化型甲状腺癌选自经手术后仍有进展的分化型甲状腺癌、经化疗后仍有进展的分化型甲状腺癌、经放射外照射治疗仍有进展的分化型甲状腺癌、经微波消融后仍有进展的甲状腺分化型甲状腺癌或不可手术治愈的分化型甲状腺癌。
在某些实施方式中，所述的甲状腺髓样癌或晚期甲状腺髓样癌选自经手术后仍有进展的甲状腺髓样癌、经化疗后仍有进展的甲状腺髓样癌、经放射外照射治疗仍有进展的甲状腺髓样癌、经微波消融后仍有进展的甲状腺髓样癌或不可手术治愈的甲状腺髓样癌。
在某些实施方式中，所述的癌症是经手术后仍有进展的癌症。即患有该癌症的患者在经过手术治疗后疾病得不到控制，仍然继续进展或转移。
在某些实施方式中，所述的癌症是经过化疗后仍然进展的癌症。即患有该癌症的患者在经过化疗后疾病得不到控制，仍然继续进展或转移。其中所述的化疗可以是使用各种常规的化疗药物治疗，例如铂络合剂(例如顺铂、卡铂、奥沙利铂等)与其他化疗药物联合，例如MVAC方案(甲氨蝶呤、长春碱、多柔比星和顺铂)以及GC方案(吉西他滨和顺铂)。
在某些实施方式中，所述的癌症是经局部治疗后仍有进展的癌症，所述的癌症还可以是经消融治疗后仍有进展的癌症。即患有该癌症的患者在经过消融治疗后疾病得不到控制，仍然继续进展或转移。消融治疗是指通过物理或化学的方法直接灭活或融解肿瘤组织的治疗方法。可分为物理消融和化学消融。物理消融是通过一些技术手段在肿瘤组织内进行加热、冷冻，从而使肿瘤组织凝固、冻融坏死。常用的物理消融方法有冷冻消融、射频消融、高能聚焦超声消融、微波消融、激光消融等。化学消融则是将各种化学制剂或药物，如无水酒精、热蒸馏水及化疗药物等注射于肿瘤内部，通过物理或化学效应使肿瘤细胞及其血管内皮细胞发生脱水、蛋白凝固等变化，从而导致肿瘤细胞变性、坏死。在某些实施方式中，消融治疗为微波消融治疗。
在某些实施方式中，所述的癌症是经放射外照射治疗仍有进展的癌症。即患有该癌症的患者在经过放射外照射治疗后疾病得不到控制，仍然继续进展或转移。
在某些实施方式中，所述酪氨酸激酶抑制剂的剂量范围选自1-1000mg，例如可以是1mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg，75mg、80mg、85mg、90mg、95mg、100mg、150mg、200mg、250mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg。酪氨酸激酶抑制剂的给药频次可以是其每日三次、每日两次、每日一次、每两日一次、每三日一次、每四日一次、每五日一次、每周一次、每两周一次、每三周一次、每四周一次、每月一次。
在某些实施方案中，所述酪氨酸激酶抑制剂的给药剂量选自1mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg，75mg、80mg、85mg、90mg、95mg、100mg，给药频率为一日一次。
在某些实施方式中，所述抗PD-1抗体或其抗原结合片段剂量为0.1～10.0mg/kg，可以为0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg。
在另一可选实施方案中，其中所述抗PD-1抗体或其抗原结合片段剂量为1～600mg，可以为1.0mg、1.2mg、1.4mg、1.6mg、1.8mg、2.0mg、2.2mg、2.4mg、2.6mg、2.8mg、3.0mg、3.2mg、3.4mg、3.6mg、3.8mg、4.0mg、4.2mg、4.4mg、4.6mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10.0mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg。
在某些实施方式中，所述抗PD-1抗体或其抗原结合片段的给药频次可以是每周给药一次、每两周给药一次、每三周给药一次、每四周给药一次、每月给药一次。
在某些实施方式中，所述抗PD-1抗体或其抗原结合片段的给药频次可以是每三周给药一次、给药剂量为200mg，静脉滴注，每次输注30min(不少于20min，不超过60min)；酪氨酸激酶抑制剂的给药频次为一日一次，给药剂量为15mg/次、20mg/次或25mg/次或30mg/次。
在某些实施方式中，所述的PD-1抗体以注射的方式给药，例如皮下或静脉注射，注射前需将PD-1抗体配制成可注射的形式。特别优选的PD-1抗体的可注射形式是注射液或冻干粉针，其包含PD-1抗体、缓冲剂、稳定剂，任选地还含有表面活性剂。缓冲剂可选自醋酸盐、柠檬酸盐、琥珀酸盐、以及磷酸盐中的一种或几种。稳定剂可选自糖或氨基酸，优选二糖，例如蔗糖、乳糖、海藻糖、麦芽糖。表面活性剂选自聚氧乙烯氢化蓖麻油、甘油脂肪酸酯、聚氧乙烯山梨醇酐脂肪酸酯，优选所述聚氧乙烯山梨醇酐脂肪酸酯为聚山梨酯20、40、60或80，最优选聚山梨酯20。最为优选的PD-1抗体的可注射形式包含PD-1抗体、醋酸盐缓冲剂、海藻糖和聚山梨酯20。
本公开还提供了一种用于治疗甲状腺癌的酪氨酸激酶抑制剂，优选治疗甲状腺未分化癌的酪氨酸激酶抑制剂，其中所述的酪氨酸激酶抑制剂为式I所示化合物或其可药用盐，优选式II所示化合物，所述酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段联合施用，所述抗PD-1抗体或其抗原结合片段的轻链可变区包含分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3；所述的抗PD-1抗体或其抗原结合片段的重链可变区包含分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的HCDR1、HCDR2和HCDR3。
本公开还提供了一种用于治疗甲状腺癌的抗PD-1抗体或其抗原结合片段，优选治疗甲状腺未分化癌的抗PD-1抗体或其抗原结合片段，其中所述抗PD-1抗体或其抗原结合片段的轻链可变区包含分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示的LCDR1、LCDR2和LCDR3；所述的抗PD-1抗体或其抗原结合片段的重链可变区包含分别如SEQ ID NO:1、SEQID NO:2和SEQ ID NO:3所示的HCDR1、HCDR2和HCDR3，所述抗PD-1抗体或其抗原结合片段与酪氨酸激酶抑制剂联合施用，所述的酪氨酸激酶抑制剂为式I所示化合物或其可药用盐。
本公开还提供了一种治疗本公开所述的甲状腺未分化癌的方法，包括向患者施用本公开所述的酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段。
本公开还涉及一种包含酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段，以及一种或多种药用载体、赋形剂、稀释剂的药物组合物。所述药物组合物可以制成药学上可接受的任一剂型。例如，可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
本公开所述的含酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段的药物组合物，可以单独给药，或者与一种或多种治疗剂联合使用。
本公开还提供了一种药物包装盒，其中包装有本公开所述的酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段。
本公开中式(I)所示化合物的可药用盐可以是盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。
在某些实施方式中，所述式I所示化合物的可药用盐为苹果酸盐，优选L-苹果酸盐，优选式II所示的化合物。
本公开所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
本公开所述联合的给药途径选自经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。
本公开所述的方案中，所述的联合任选的还包含其他组分，所述其他组分包括但不限于其他抗肿瘤药等。
待组合的各成分(例如，酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段与其他任意组分药物)可同时给药或依次顺序地分开用药。此外，待组合的各成分还可以以同一制剂形式或以分开的不同制剂的形式联合给药。
本公开所述的“联合”是一种给药方式，是指一定时间期限内给予至少一种剂量的酪氨酸激酶抑制剂，以及至少一种剂量的抗PD-1抗体或其抗原结合片段，其中给予的药物都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内，更优选12小时以内。可以同时或依次给予酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段。本公开所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。
无进展生存期(PFS)：从随机开始到首次记录肿瘤客观进展日期或到任何原因导致死亡的时间，以先出现者为准。
总生存期(OS)指从随机期至任何原因导致死亡的期。末次随访时仍存活的受试者，其OS以末次随访时间计为数据删失。失访的受试者，其OS以失访前末次证实存活时间计为数据删失。数据删失的OS定义为从随机分组到删失的时间。
客观缓解率(Objective response rate，ORR)指肿瘤缩小达到一定并且保持一定时间的病人的比例，包含了CR和PR的病例。采用实体瘤缓解评估标准(RECIST 1.1标准)来评定肿瘤客观缓解。受试者在基线时必须伴有可测量的肿瘤病灶，疗效评定标准根据RECIST 1.1标准分为完全缓解(CR)、部分缓解(PR)、稳定(SD)、进展(PD)。
疾病控制率(Disease Control Rate，DCR)指经确认的完全缓解、部分缓解和疾病稳定(≥8周)病例数在可评价疗效患者中的百分比。
完全缓解(CR)：所有靶病灶消失，全部病理淋巴结(包括靶结节和非靶结节)短直径必须减少至＜10mm。
部分缓解(PR)：靶病灶直径之和比基线水平减少至少30％。
疾病进展(PD)：以整个实验研究过程中所有测量的靶病灶直径之和的最小值为参照，直径和相对增加至少20％(如果基线测量值最小就以基线值为参照)；除此之外，必须满足直径和的绝对值增加至少5mm(出现一个或多个新病灶也视为疾病进展)。
疾病稳定(SD)：靶病灶减小的程度没达到PR，增加的程度也没达到PD水平，介于两者之间，研究时可以直径之和的最小值作为参考。
本公开将酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段联合给药，从而增强了抗肿瘤活性，以及改善了肿瘤疾病的治疗效果。
具体实施方式
实施例1：式I所示化合物的L-苹果酸盐联合抗PD-1抗体在治疗晚期甲状腺癌的安全性和疗效的临床研究
1、试验药物
药物名称：
式II所示化合物，根据CN101007815B公开的方法制备，胶囊剂，规格：15mg/粒或20mg/粒。
PD-1抗体，按照专利申请WO2017054646A中的方法制备，其重、轻链的序列如本公开中SEQ ID NO:7和SEQ ID NO:8。规格为200mg/支。
2、入组受试者
1.年龄：≥18岁，男女不限；
2.不可手术或微波消融等局部治疗手段治愈的晚期甲状腺癌患者，且病理组织学或细胞学确诊的以下三类甲状腺癌类型(满足其中一类即可)：
1)局部晚期或转移性分化型甲状腺癌，包括甲状腺乳头状癌(含滤泡亚型和低分化亚型等)和甲状腺滤泡状癌(含Hürthle细胞亚型等)；
2)局部晚期或转移性甲状腺髓样癌；
3)甲状腺未分化癌；
3.如受试者为分化型甲状腺癌患者，则需要满足放射性碘难治定义或者不适合131I治疗。放射性碘难治的定义如下(满足下述条件之一)：
a)至少有一个可测量病灶在放射碘治疗中完全丧失摄碘功能；
b)病灶虽然具有摄碘能力，但至少有一个可测量病灶，在131I治疗后仍在12个月内发生疾病进展。
c)累计接受放射碘治疗剂量≥22.2GBq(≥600mCi)，最后一次放射性碘治疗在入组前6个月内；
4.如受试者为分化型甲状腺癌患者且不属于低分化亚型，从筛选期开始，其TSH水平应在抑制层面(＜0.5mU/L)；
5.至少有一个可测量病灶(根据RECIST v1.1要求，该可测量病灶螺旋CT扫描长径≥10mm或肿大淋巴结短径≥15mm；既往接受过局部治疗的病灶，根据RECIST vl.1标准，明确进展后可作为靶病灶)；
3、给药方法：
式II所示化合物：20mg(起始剂量)，餐前或餐后口服，推荐每日固定时间、餐后0.5h内给药，每日1次；每3周(21天)为一个周期。连续服药，3周为一个周期。
PD-1抗体：每3周给药1次，窗口期为计划给药时间的±7天，PD-1抗体延迟给药超过计划给药时间7天，则当次不再给药，待下次计划给药时间继续按原给药剂量给药。
4、研究结果：
表1患者疗效情况
不适合131I治疗的分化型甲状腺癌组中，入组23例，在组16例；已评价20例，9例PR(1例未确认)，10例SD，1例PD，ORR 45.0％，DCR 95.0％。
放射性碘难治分化型甲状腺癌组：入组9例，在组7例；已评价9例，3例PR，6例SD，ORR 33.3％，DCR 100％。
甲状腺髓样癌组：入组5例，在组2例；已评价5例，1例PR，4例SD，ORR 20％，DCR100％。
甲状腺未分化癌组：入组18例，在组11例；已评价14例，9例PR，4例SD，1例PD，ORR64.3％，DCR 92.9％。
序列表
<110> 江苏恒瑞医药股份有限公司
<120> 酪氨酸激酶抑制剂与抗PD-1抗体联合在制备治疗肿瘤药物中的用途
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
<211> 5
<212> PRT
<213> 鼠源(Mus musculus)
<400> 1
Ser Tyr Met Met Ser
1 5
<210> 2
<211> 17
<212> PRT
<213> 鼠源(Mus musculus)
<400> 2
Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 3
<211> 7
<212> PRT
<213> 鼠源(Mus musculus)
<400> 3
Gln Leu Tyr Tyr Phe Asp Tyr
1 5
<210> 4
<211> 11
<212> PRT
<213> 鼠源(Mus musculus)
<400> 4
Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Thr
1 5 10
<210> 5
<211> 7
<212> PRT
<213> 鼠源(Mus musculus)
<400> 5
Thr Ala Thr Ser Leu Ala Asp
1 5
<210> 6
<211> 9
<212> PRT
<213> 鼠源(Mus musculus)
<400> 6
Gln Gln Val Tyr Ser Ile Pro Trp Thr
1 5
<210> 7
<211> 443
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> (1)..(443)
<223> 重链序列
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
115 120 125
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu
130 135 140
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
145 150 155 160
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190
Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr
195 200 205
Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro
210 215 220
Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
245 250 255
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn
260 265 270
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
290 295 300
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
305 310 315 320
Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys
325 330 335
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu
340 345 350
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
355 360 365
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
370 375 380
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
385 390 395 400
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly
405 410 415
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
420 425 430
Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 8
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> (1)..(214)
<223> 轻链序列
<400> 8
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 9
<211> 116
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> (1)..(116)
<223> 重链可变区
<400> 9
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Met Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Gly Ala Asn Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Leu Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr Val
100 105 110
Thr Val Ser Ser
115
<210> 10
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> PEPTIDE
<222> (1)..(10)
<223> 轻链可变区
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Thr Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Thr Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Val Tyr Ser Ile Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
Claims (12)
1.酪氨酸激酶抑制剂与抗PD-1抗体或其抗原结合片段联合在制备预防或治疗甲状腺癌的药物中的用途，其中所述的酪氨酸激酶抑制剂为式I所示化合物或其可药用盐，所述抗PD-1抗体或其抗原结合片段的轻链可变区包含分别如SEQ ID NO:4、SEQ ID NO:5和SEQ IDNO:6所示的LCDR1、LCDR2和LCDR3；所述的抗PD-1抗体或其抗原结合片段的重链可变区包含分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示的HCDR1、HCDR2和HCDR3，
2.根据权利要求1所述的用途，其中所述抗PD-1抗体或其抗原结合片段选自人源化抗体或其片段。
3.根据权利要求1或2所述的用途，其中所述抗PD-1抗体或其抗原结合片段包含人源IgG1、IgG2、IgG3或IgG4同种型的重链恒定区，优选包含IgG1或IgG4同种型的重链恒定区。
4.根据权利要求2所述的用途，其中所述人源化抗体的轻链可变区序列为如SEQ IDNO:10所示的序列或其变体，所述变体优选在轻链可变区有0-10的氨基酸变化，更优选为A43S的氨基酸变化；所述人源化抗体的重链可变区序列为如SEQ ID NO:9所示的序列或其变体，所述变体优选在重链可变区有0-10的氨基酸变化，更优选为G44R的氨基酸变化。
5.根据权利要求2所述的用途，其中所述人源化抗体的轻链序列为如SEQ ID NO:8所示的序列，重链序列为如SEQ ID NO:7所示的序列。
6.根据权利要求1-5中任一项所述的用途，其中所述的甲状腺癌选自分化型甲状腺癌、甲状腺未分化癌、甲状腺髓样癌；优选放射性碘难治分化型甲状腺癌、不适合131I治疗的分化型甲状腺癌、甲状腺髓样癌、甲状腺未分化癌。
7.根据权利要求6所述的用途，其中所述的甲状腺未分化癌选自经手术后仍有进展的甲状腺未分化癌、经化疗后仍有进展的甲状腺未分化癌、经放射外照射治疗仍有进展的甲状腺未分化癌、经微波消融后仍有进展的甲状腺癌。
8.根据权利要求1-7任意一项所述的用途，其中所述酪氨酸激酶抑制剂的给药剂量选自1-1000mg。
9.根据权利要求8所述的用途，其中酪氨酸激酶抑制剂的给药频次选自每日三次、每日两次、每日一次、每两日一次、每三日一次、每四日一次、每五日一次、每周一次。
10.根据权利要求1-9任意一项所述的用途，其中所述抗PD-1抗体或其抗原结合片段的给药剂量为1-600mg。
11.根据权利要求10所述的用途，其中所述抗PD-1抗体或其抗原结合片段的给药频次选自每周给药一次、每两周给药一次、每三周给药一次、每四周给药一次、每月给药一次。
12.一种药物组合，其包含式I所示化合物或其可药用盐与抗PD-1抗体或其抗原结合片段，以及一种或多种药用载体、赋形剂、稀释剂。
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| CN101007815A (zh) * | 2006-01-27 | 2007-08-01 | 上海恒瑞医药有限公司 | 吡咯并六元杂环化合物及其在医药上的用途 |
| CN111035759A (zh) * | 2018-10-11 | 2020-04-21 | 江苏恒瑞医药股份有限公司 | 阿帕替尼与抗pd-1抗体联合在制备治疗软组织肉瘤的药物中的用途 |
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| CN111035759A (zh) * | 2018-10-11 | 2020-04-21 | 江苏恒瑞医药股份有限公司 | 阿帕替尼与抗pd-1抗体联合在制备治疗软组织肉瘤的药物中的用途 |
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