CN114984227A - 抗tigit抗体在联合用药中的应用 - Google Patents
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Abstract
本发明公开了一种联合用药物,包括抗TIGIT抗体或抗原结合片段和另一种治疗剂。本发明还公开了抗TIGIT抗体或抗原结合片段在联合用药中的应用,治疗方法包括向有需要的患者给药有效量的抗TIGIT抗体或抗原结合片段和另一种治疗剂。
Description
技术领域
本发明属于生物医药领域,尤其涉及抗TIGIT抗体在联合用药中的应用。
背景技术
TIGIT(T cell immunoreceptor with Ig and ITIM domains)是一种具有免疫球蛋白(Ig)和酪氨酸抑制剂基序(ITIM)结构域的T细胞免疫受体,主要表达于激活的T细胞和NK细胞上(Yu,X.,et al.(2009)."The surface protein TIGIT suppresses T cellactivation by promoting the generation of mature immunoregulatory dendriticcells."Nature immunology10(1):48-57.)。TIGIT结构显示包含一个细胞外免疫球蛋白结构域,一个I型跨膜区和两个ITIM基序。TIGIT是共同刺激网络的一部分,这个共刺激网络主要由T细胞上的激活性受体CD226和抑制性受体TIGIT,以及在APC、肿瘤细胞、感染的细胞表面表达的配体CD155(也称为PVR,一种在人类中被PVR基因编码的脊髓灰质炎病毒受体蛋白质)和CD112组成。TIGIT与PVR或CD112结合后会引起TIGIT胞质内Tyr225被磷酸化,TIGIT和细胞自适应生长因子受体结合蛋白2(GRB2)进行结合。GRB2可以招募SHIP1抑制磷脂酰肌醇三激酶(PI3K)和促分裂原活化蛋白激酶(MAPK)信号。除此之外,磷酸化的TIGIT通过Beta抑制蛋白2(β-arrestin2)招募SHIP1和通过阻断TNF受体相关因子6(TRAF6)的自身泛素化并破坏核因子KB(NF-KB)激活,一系列的信号传导最终导致T细胞或NK细胞的功能受到抑制,细胞因子的产生受到抑制。PVR既是TIGIT的配体,又是CD226分子的配体。在和CD112或CD155结合之后,CD226的胞内结构域的Ser329和Tyr322被磷酸化;Ser329磷酸化促进蛋白激酶(PKC)的激活和CD226与淋巴细胞关联抗原1(LFA1)的相互结合。LFA1然后被用于TYN介导的Tyr322磷酸化和CD226介导的下游信号传导。一系列的信号传导最终导致T细胞或NK细胞的功能受到激活,促进细胞因子的产生。存在于T细胞或NK细胞表面的TIGIT分子与CD226分子之间也发生着相互作用,表现在TIGIT分子可以直接扰乱CD226形成正常的二聚体,从而破坏CD226的正常生理功能。TIGIT和CD226如同天平的两端,通过PVR这个支点,通过共刺激和共抑制信号的传导巧妙地调节着机体的免疫功能。
发明内容
本发明公开了一种联合用药物,包括抗TIGIT抗体或抗原结合片段和另一种治疗剂。在一些实施方案中,本发明提供了一种联合用药物,包括治疗有效量的抗TIGIT抗体或抗原结合片段和另一种治疗剂。
另一方面,本发明公开了抗TIGIT抗体或抗原结合片段用于联合治疗肿瘤或癌症的方法或用途。在一些实施方案中,所述方法或用途包括:向有需要的患者施用有效量的抗TIGIT抗体或抗原结合片段和另一种治疗剂。另一方面,本发明公开了抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段在制备与另一种治疗剂联合用于治疗肿瘤或癌症的药物中的应用。另一方面,本发明公开了抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段和另一种治疗剂在制备用于治疗肿瘤或癌症的药物中的应用。
另一方面,本发明还公开了一种试剂盒,试剂盒包含抗TIGIT抗体或抗原结合片段(或制剂)和用于指导有需要患者给药抗TIGIT抗体或抗原结合片段(或制剂)和另一种治疗剂(或制剂)的说明书。另一方面,本发明还公开了一种试剂盒,试剂盒包含抗TIGIT抗体或抗原结合片段(或制剂)、另一种治疗剂(或制剂)和用于指导有需要患者给药抗TIGIT抗体或抗原结合片段(或制剂)和另一种治疗剂(或制剂)的说明书。在一些实施方案中,本发明还公开了一种试剂盒,试剂盒包含抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物(或制剂)以及用于指导有需要患者给药抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物(或制剂)的说明书。
另一方面,本发明还公开了包含抗TIGIT抗体或抗原结合片段和另一种治疗剂的适合注射用的药物组合物,如推注型药物组合物或输液(滴注)型药物组合物。在一些实施方案中,药物组合物至少包含0.1%的抗TIGIT抗体或抗原结合片段和0.1%的另一种治疗剂。抗体和另一种治疗剂的百分比可以变化,并且为给定剂型重量的约2%和约90%之间。这种治疗上有用的药物组合物中抗TIGIT抗体或抗原结合片段和另一种治疗剂的量可以为给药的有效量。
另一方面,本发明还公开了上述药物组合物的制备方法:分别将本文所述的抗TIGIT抗体和另一种治疗剂(或抗TIGIT抗体和另一种治疗剂的组合物)与药学上可接受的适合注射用的载体(例如注射用水,生理盐水等)混合。上述抗TIGIT抗体或抗原结合片段和另一种治疗剂与药学上可接受的载体的混合方法是本领域通常已知的。
在一些实施方案中,抗TIGIT抗体或抗原结合片段联合另一种治疗剂用于治疗肿瘤或癌症。本发明将抗TIGIT抗体或抗原结合片段(或制剂)和另一种治疗剂(或制剂)用于肿瘤或癌症治疗中,可以减缓症状。
在一些实施方案中,所述另一种治疗剂为抗体或抗原结合片段或抗体药物偶联物(ADC)。
在一些实施方案中,抗TIGIT抗体或抗原结合片段(或制剂)、另一种治疗剂(或制剂)与其他治疗方法联合使用用于治疗肿瘤或癌症,例如化疗、放疗和手术治疗等。
在一些实施方案中,所述抗TIGIT抗体或抗原结合片段至少包含SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3所示的HCDR3、SEQ ID NO:4所示的LCDR1、SEQ ID NO:5所示的LCDR2、SEQ ID NO:6所示的LCDR3中一个或多个。
在一些实施方案中,所述抗TIGIT抗体或抗原结合片段包含SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3所示的HCDR3、SEQ ID NO:4所示的LCDR1、SEQ ID NO:5所示的LCDR2和SEQ ID NO:6所示的LCDR3。
在一些实施方案中,所述抗TIGIT抗体或抗原结合片段的重链可变区包含SEQ IDNO:7所示的氨基酸序列,或与SEQ ID NO:7所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗TIGIT抗体或抗原结合片段的轻链可变区包含SEQ IDNO:8所示的氨基酸序列,或与SEQ ID NO:8所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗TIGIT抗体或抗原结合片段的重链可变区包含SEQ IDNO:7所示的氨基酸序列,或与SEQ ID NO:7所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;所述抗TIGIT抗体或抗原结合片段的轻链可变区包含SEQ ID NO:8所示的氨基酸序列,或与SEQ IDNO:8所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗TIGIT抗体或抗原结合片段的重链可变区包含SEQ IDNO:7所示的氨基酸序列,所述抗TIGIT抗体或抗原结合片段的轻链可变区包含SEQ ID NO:8所示的氨基酸序列。
在一些实施方案中,所述抗TIGIT抗体的重链包含SEQ ID NO:9所示的氨基酸序列,或与SEQ ID NO:9所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗TIGIT抗体的轻链包含SEQ ID NO:10所示的氨基酸序列,或与SEQ ID NO:10所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:10所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗TIGIT抗体的重链包含SEQ ID NO:9所示的氨基酸序列,或与SEQ ID NO:9所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;所述抗TIGIT抗体的轻链包含SEQ ID NO:10所示的氨基酸序列,或与SEQ ID NO:10所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:10所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗TIGIT抗体为抗体h10D8OF或h10D8OFKF,抗体h10D8OF和h10D8OFKF的重链包含如SEQ ID NO:9所示的氨基酸序列,所述抗体h10D8OF和h10D8OFKF的轻链包含如SEQ ID NO:10所示的氨基酸序列。在一些实施方案中,抗体h10D8OF和h10D8OFKF分别含有两条序列相同的重链和两条序列相同的轻链。
抗体蛋白可以通过基因工程在CHO细胞或HEK293细胞中表达,并通过纯化获得;纯化可以采用常规方法进行,例如先离心细胞悬液并收集上清液,再次离心进一步去除杂质。ProteinA亲和柱和离子交换柱等方法可以用于纯化抗体蛋白。
在一些实施方案中,所述抗TIGIT抗体(例如抗体h10D8OFKF)或抗原结合片段的岩藻糖基化水平为0-10%。在一些实施方案中,所述抗TIGIT抗体(例如抗体h10D8OFKF)或抗原结合片段的岩藻糖基化水平为0-5%。在一些实施方案中,所述抗TIGIT抗体(例如抗体h10D8OFKF)或抗原结合片段的岩藻糖基化水平为约0、约0.1%、约0.5%、约0.8%、约1%、约1.3%、约1.6%、约2.1%、2.9%、约3%、约3.3%、3.8%、约4%、约4.2%、4.3%、约4.6%、约5%,或这些数值中任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,所述抗TIGIT抗体(例如抗体h10D8OFKF)或抗原结合片段没有结合岩藻糖。在一些实施方案中,所述抗TIGIT抗体(例如抗体h10D8OFKF)或抗原结合片段具有增强的ADCC效应(antibody-dependent cell-mediated cytotoxicity)。
在一些实施方案中,低岩藻糖基化或无岩藻糖基化的抗TIGIT抗体或抗原结合片段由α-(1,6)-岩藻糖基转移酶基因敲除的细胞系表达。在一些实施方案中,抗体h10D8OFKF由α-(1,6)-岩藻糖基转移酶基因敲除的细胞系表达,例如α-(1,6)-岩藻糖基转移酶基因敲除的CHO细胞。
在一些实施方案中,本发明公开了一种用于治疗有需要患者的肿瘤或癌症的方法,其包括施用有效量的抗TIGIT抗体或抗原结合片段和另一种治疗剂。在一些实施方案中,抗TIGIT抗体或抗原结合片段以约0.05mg至1200mg、约0.05mg至1000mg、约0.05mg至500mg、约0.05mg至100mg、约0.1mg至100mg、约0.1mg至50mg、约0.1mg至30mg、约0.1mg至10mg、约0.5mg至1mg、约9mg至1200mg、约1mg至900mg、约1mg至300mg、约1mg至100mg、约1mg至30mg、约1mg至10mg、约1mg至3mg、约3mg至900mg、约3mg至600mg、约3mg至100mg、约3mg至30mg、约3mg至10mg、约10mg至900mg、约10mg至600mg、约10mg至300mg、约10mg至100mg、约10mg至30mg、约30mg至900mg、约30mg至600mg、约30mg至300mg、约30mg至100mg、约100mg至900mg、约100mg至600mg、约100mg至300mg、约300mg至900mg、约300mg至600mg、约600mg至900mg的剂量给药。在一些实施方案中,抗TIGIT抗体或抗原结合片段以约0.001mg/kg至20mg/kg、约0.001mg/kg至2mg/kg、约0.001mg/kg至1mg/kg、约0.005mg/kg至1mg/kg、约0.01mg/kg至1mg/kg、约0.01mg/kg至20mg/kg的剂量给药。在一些实施方案中,抗TIGIT抗体或抗原结合片段施用的剂量为约0.05mg至1200mg、约0.05mg至1000mg、约0.05mg至500mg、约0.1mg至100mg、约0.1mg至50mg、约0.1mg至30mg、约0.1mg至10mg、0.5mg至1mg、约9mg至1200mg、约1mg至900mg、约1mg至300mg、约1mg至100mg、约1mg至30mg、约1mg至10mg、约1mg至3mg、约3mg至900mg、约3mg至600mg、约3mg至100mg、约3mg至30mg、约3mg至10mg、约10mg至900mg、约10mg至600mg、约10mg至300mg、约10mg至100mg、约10mg至30mg、约30mg至900mg、约30mg至600mg、约30mg至300mg、约30mg至100mg、约100mg至900mg、约100mg至600mg、约100mg至300mg、约300mg至900mg、约300mg至600mg、约600mg至900mg每个治疗周期。在一些实施方案中,抗TIGIT抗体或抗原结合片段施用的剂量为约0.001mg/kg至20mg/kg、约0.001mg/kg至2mg/kg、约0.001mg/kg至1mg/kg、约0.005mg/kg至1mg/kg、约0.01mg/kg至1mg/kg、约0.01mg/kg至20mg/kg每个治疗周期。在一些实施方案中,一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,抗TIGIT抗体或抗原结合片段每天给药一次至每7周给药一次。
在一些实施方案中,抗TIGIT抗体或抗原结合片段每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次。在一些实施方案中,所述抗TIGIT抗体为抗体h10D8OF或h10D8OFKF。
在一些实施方案中,可以分别将抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段和另一种治疗剂(或抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物)配制成药物组合物,并以适合于所选给药途径的多种形式向患者给药,例如通过肠胃外、静脉内(iv)、肌肉内、局部或皮下途径。在一些实施方案中,可以分别将抗TIGIT抗体或抗原结合片段和另一种治疗剂(或抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物)静脉输注。抗TIGIT抗体或抗原结合片段和另一种治疗剂的量将取决于药物的性质,细胞表面触发药物的内在化,运输和释放的程度,所治疗的疾病,患者的状况(如年龄,性别,体重等)。
在一些实施方案中,每次施用的抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段约0.001mg/kg至20mg/kg或含此剂量抗TIGIT抗体或抗原结合片段的制剂。在一些实施方案中,每次施用的抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段约0.01mg/kg至20mg/kg或含此剂量抗TIGIT抗体或抗原结合片段的制剂。含抗TIGIT抗体或抗原结合片段的制剂可以为适于注射用途的制剂包括无菌水性溶液(在此是水溶性的)或分散体以及用于即时制备无菌注射液或分散体的无菌粉末。对于静脉内施用,合适的载体包括生理盐水、抑菌水或磷酸盐缓冲盐水(PBS)、乙醇、多元醇(例如,甘油、丙二醇和液体聚乙二醇等)的溶剂或分散介质,及其适宜的混合物。在一些实施方案中,制剂至少包含0.1%的抗TIGIT抗体或抗原结合片段。抗体的百分比可以变化,并且为给定剂型重量可以约2%至90%之间。
在一些实施方案中,每次施用的抗TIGIT抗体或抗原结合片段为约0.001mg/kg,约0.002mg/kg,约0.003mg/kg,约0.004mg/kg,约0.005mg/kg,约0.006mg/kg,约0.007mg/kg,约0.008mg/kg,约0.009mg/kg,约0.01mg/kg,约0.012mg/kg,约0.015mg/kg,约0.018mg/kg,约0.02mg/kg,约0.03mg/kg,约0.04mg/kg,约0.05mg/kg,约0.06mg/kg,约0.07mg/kg,约0.08mg/kg,约0.1mg/kg,约0.3mg/kg,约0.5mg/kg,约0.8mg/kg,约0.9mg/kg,约1mg/kg,约2mg/kg,约3mg/kg,约4mg/kg,约5mg/kg,约6mg/kg,约7mg/kg,约8mg/kg,约9mg/kg,约10mg/kg,约12mg/kg,约14mg/kg,约15mg/kg,约18mg/kg,约20mg/kg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量抗TIGIT抗体或抗原结合片段的制剂。在一些实施方案中,抗TIGIT抗体(如抗体h10D8OF或h10D8OFKF)或抗原结合片段每次施用的剂量为约0.001mg/kg至20mg/kg、约0.001mg/kg至2mg/kg、约0.001mg/kg至1mg/kg、约0.005mg/kg至1mg/kg、约0.01mg/kg至1mg/kg、约0.01mg/kg至20mg/kg每天给药一次至每7周给药一次;或者每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次;或者每2、3或4周给药一次。在一些实施方案中,抗TIGIT抗体(如抗体h10D8OF或h10D8OFKF)或抗原结合片段每次施用的剂量为约0.001mg/kg,约0.002mg/kg,约0.003mg/kg,约0.004mg/kg,约0.005mg/kg,约0.006mg/kg,约0.007mg/kg,约0.008mg/kg,约0.009mg/kg,约0.01mg/kg,约0.012mg/kg,约0.015mg/kg,约0.018mg/kg,约0.02mg/kg,约0.03mg/kg,约0.04mg/kg,约0.05mg/kg,约0.06mg/kg,约0.07mg/kg,约0.08mg/kg,约0.1mg/kg,约0.3mg/kg,约0.5mg/kg,约0.8mg/kg,约0.9mg/kg,约1mg/kg,约2mg/kg,约3mg/kg,约4mg/kg,约5mg/kg,约6mg/kg,约7mg/kg,约8mg/kg,约9mg/kg,约10mg/kg,约12mg/kg,约14mg/kg,约15mg/kg,约18mg/kg,约20mg/kg每2、3或4周给药一次。
在一些实施方案中,抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段施用的剂量为每剂约0.05mg至1200mg。在一些实施方案中,抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段施用的剂量为每剂约9mg至1200mg。在一些实施方案中,抗PD-1抗体或抗原结合片段施用的剂量为每剂约1mg至600mg。在一些实施方案中,抗PD-1抗体或抗原结合片段施用的剂量为每剂约50mg至600mg。在一些实施方案中,抗TIGIT抗体(如抗体h10D8OF或h10D8OFKF)或抗原结合片段施用的剂量为每次约0.05mg至1200mg、约0.05mg至500mg、约0.05mg至100mg、约0.1mg至100mg、约0.1mg至50mg、约0.1mg至30mg、约0.1mg至10mg、约0.5mg至1mg、约9mg至1200mg、约1mg至900mg、约1mg至300mg、约1mg至100mg、约1mg至30mg、约1mg至10mg、约1mg至3mg、约3mg至900mg、约3mg至600mg、约3mg至100mg、约3mg至30mg、约3mg至10mg、约10mg至900mg、约10mg至600mg、约10mg至300mg、约10mg至100mg、约10mg至30mg、约30mg至900mg、约30mg至600mg、约30mg至300mg、约30mg至100mg、约100mg至900mg、约100mg至600mg、约100mg至300mg、约300mg至900mg、约300mg至600mg、约600mg至900mg每天给药一次至每7周给药一次;或者每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次;或者每2、3或4周给药一次。在一些实施方案中,抗TIGIT抗体或抗原结合片段每次施用的剂量为约0.05mg、约0.08mg、约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约30mg、约40mg、约50mg、约100mg、约300mg、约600mg、约900mg、约1000mg、约1200mg每2、3或4周给药一次。在一些实施方案中,抗TIGIT抗体或抗原结合片段每次施用的剂量为约0.05mg、约0.08mg、约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约30mg、约100mg、约300mg、约600mg或约900mg每2、3或4周给药一次。在一些实施方案中,抗TIGIT抗体或抗原结合片段每次施用的剂量为约600mg至1200mg每2、3或4周给药一次。在一些实施方案中,抗TIGIT抗体或抗原结合片段每次施用的剂量为约700mg、约800mg、900mg或约1200mg每2、3或4周给药一次。
在一些实施方案中,采用治疗有效量的另一种治疗剂和抗TIGTI抗体或抗原结合片段分别或者同时施加在患者上。另一种治疗剂和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。在一些实施方案中,抗TIGIT抗或抗原结合片段和另一种治疗剂是通过皮下(s.c.)注射、腹膜内(i.p.)注射、肠胃外注射、动脉内注射或静脉内(i.v.)注射或输液等方式进行给药。抗TIGIT抗体或抗原结合片段和另一种治疗剂可以通过相同或者不同方式进行给药。
在一些实施方案中,抗TIGIT抗体或抗原结合片段是通过静脉内(i.v.)输液方式进行给药。
在一些实施方案中,所述抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段和所述另一种治疗剂分别为独立的给药单元,联合用药。在一些实施方案中,所述抗TIGIT抗体或抗原结合片段可以在施加所述另一种治疗剂之前给药,也可以在施加所述另一种治疗剂之后给药,也可以与所述另一种治疗剂同时给药。
在一些实施方案中,所述抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段和所述另一种治疗剂同时形成组合给药单元,联合用药。
在一些实施方案中,患者患有肿瘤或癌症。在一些实施方案中,肿瘤和癌症包括但不限于血液癌症、实体瘤。在一些实施方案中,血液癌症包括但不限于白血病、淋巴瘤和骨髓瘤。在一些实施方案中,白血病包括急性淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)和骨髓性增生疾病/肿瘤(MPDS)。在一些实施方案中,淋巴瘤包括霍奇金淋巴瘤、无痛性和侵袭性非霍奇金淋巴瘤、伯基特淋巴瘤和滤泡性淋巴瘤(小细胞和大细胞)。在一些实施方案中,骨髓瘤包括多发性骨髓瘤(MM)、巨细胞骨髓瘤、重链骨髓瘤和轻链或本斯-琼斯骨髓瘤。在一些实施方案中,实体瘤包括乳腺癌、卵巢癌、胰腺癌、前列腺癌、黑素瘤、结直肠癌、结肠癌、肺癌、头颈癌、膀胱癌、食道癌、肝癌和肾癌。在一些实施方案中,肿瘤和癌症为尚无有效治疗手段的经病理学确诊的局部晚期或转移性恶性实体肿瘤。
在一些实施方案中,所述另一种治疗剂选自以下针对靶点的抗体或抗原结合片段或抗体药物偶联物(ADC):EGFR(表皮生长因子受体)、VEGF(血管内皮生长因子)、VEGFR2(血管内皮生长因子受体2)、CTLA-4(细胞毒性T淋巴细胞相关蛋白4)、PD-1(程序性死亡受体-1)、PD-L1(程序性死亡配体-1)、HER2(人表皮生长因子受体2)、CD20(分化簇20)、Trop2(人滋养层细胞表面抗原2)、Lag3(淋巴细胞活化基因-3分子)、CD27(分化簇27)、OX40(肿瘤坏死因子受体超家族成员4)、ICOS(inducible costimulator)、BTLA(B和T淋巴细胞弱化因子)、TIM3(T细胞免疫球蛋白黏液素3)、BCMA(B细胞成熟抗原)、c-MET(间质表皮转化因子)和TAA-1/2/3(肿瘤相关抗原)。在一些实施方案中,所述抗体为抑制型抗体或激动型抗体。
在一些实施方案中,所述另一种治疗剂选自抗EGFR抗体、抗VEGF抗体、抗VEGFR2抗体、抗CTLA-4抗体、抗PD-1抗体、抗PD-L1抗体、抗HER2抗体、抗CD20抗体、抗Trop2抗体、抗OX40抗体和抗ICOS抗体。
在一些实施方案中,所述另一种治疗剂为靶向T淋巴细胞相关抗原4(CTLA-4)抗体(抗CTLA-4抗体)或抗原结合片段,如伊匹单抗(YervoyTM或其生物类似物)或去岩藻糖基化伊匹单抗,如WO2014089113所述。在一些实施方案中,抗CTLA-4抗体的重链包含如SEQ IDNO:17所示的氨基酸序列,抗CTLA-4抗体的轻链包含如SEQ ID NO:18所示的氨基酸序列;抗CTLA-4抗体含有两条序列相同的重链和两条序列相同的轻链。
在一些实施方案中,抗CTLA-4抗体或抗原结合片段由CHO细胞表达。在一些实施方案中,抗CTLA-4抗体或抗原结合片段由α-(1,6)-岩藻糖基转移酶基因敲除的细胞系(如CHO细胞)表达。
在一些实施方案中,所述抗CTLA-4抗体或抗原结合片段的高甘露糖糖型总量<5%和/或唾液酸化糖型总量<3%。在一些实施方案中,抗CTLA-4抗体或抗原结合片段的高甘露糖糖型总量为约0.1%、约0.3%、约0.9%、约1.18%、约1.7%、约2.6%、约3.3%、约4.1%、约4.9%、约4.99%,或这些数值中任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,所述抗CTLA-4抗体或抗原结合片段的唾液酸化糖型总量为约0.1%、0.2%、约0.36%、约0.8%、约1.5%、约2.2%、约2.7%、约2.9%、2.99%,或这些数值中任何两个值之间的范围(包括端点)或其中任何值。
在一些实施方案中,所述抗CTLA-4抗体或抗原结合片段的高甘露糖糖型总量<2%和/或唾液酸化糖型总量<1%。
在一些实施方案中,所述抗CTLA-4抗体或抗原结合片段的岩藻糖基化水平为0-10%。在一些实施方案中,所述抗CTLA-4抗体或抗原结合片段的岩藻糖基化水平为0-5%。在一些实施方案中,所述抗CTLA-4抗体或抗原结合片段的岩藻糖基化水平为约0、约0.1%、约0.3%、约0.4%、约0.6%、约1.3%、约1.9%、约2.2%、约2.8%、约3.3%、约3.7%、约4.1%、约4.5%、约5%,或这些数值中任何两个值之间的范围(包括端点)或其中任何值。
在一些实施方案中,伊匹单抗施用的剂量为约30mg至300mg每个治疗周期。在一些实施方案中,一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,伊匹单抗施用的剂量为1mg/kg,3mg/kg或10mg/kg每3周、6周、或12周给药一次。在一些实施方案中,伊匹单抗施用的剂量为1mg/kg每3周或6周给药一次。在一些实施方案中,伊匹单抗施用的剂量为3mg/kg每3周或6周给药一次。在一些实施方案中,伊匹单抗施用的剂量为10mg/kg每3周或每12周给药一次。
在一些实施方案中,每次施用的伊匹单抗为约0.5mg/kg至10mg/kg或含此剂量伊匹单抗的制剂。在一些实施方案中,每次施用的伊匹单抗为约0.5mg/kg,约1mg/kg,约1.2mg/kg,约2mg/kg,约2.4mg/kg,约3mg/kg,约3.6mg/kg,约4mg/kg,约4.8mg/kg,约5mg/kg,约5.5mg/kg,约6mg/kg,约6.9mg/kg,约7mg/kg,约8.4mg/kg,约9mg/kg,约10mg/kg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量伊匹单抗的制剂。
在一些实施方案中,采用治疗有效量的伊匹单抗和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。伊匹单抗和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。
在一些实施方案中,所述另一种治疗剂为抗PD-1抗体或抗原结合片段。在一些实施方案中,所述抗PD-1抗体为纳武利尤单抗(nivolumab;如欧狄沃或OPDIVO或其生物类似物)、帕博利单抗(pembrolizumab;如可瑞达或Keytruda或其生物类似物)、卡瑞利珠单抗(camrelizumab;如艾瑞卡或其生物类似物)、信迪利单抗(sintilimab;如或其生物类似物)、特瑞普利单抗(toripalimab;如拓益或其生物类似物)或替雷利珠单抗(tislelizumab;如称或其生物类似物)。
在一些实施方案中,所述抗PD-1抗体或抗原结合片段包含SEQ ID NO:21所示的HCDR1、SEQ ID NO:22所示的HCDR2、SEQ ID NO:23所示的HCDR3、SEQ ID NO:24所示的LCDR1、SEQ ID NO:25所示的LCDR2和SEQ ID NO:26所示的LCDR3。
在一些实施方案中,所述抗PD-1抗体或抗原结合片段的重链可变区包含SEQ IDNO:27所示的氨基酸序列,或与SEQ ID NO:27所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:27所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗PD-1抗体或抗原结合片段的轻链可变区包含SEQ IDNO:28所示的氨基酸序列,或与SEQ ID NO:28所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:28所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,所述抗PD-1抗体或抗原结合片段的重链可变区包含SEQ IDNO:27所示的氨基酸序列,或与SEQ ID NO:27所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:27所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;所述抗PD-1抗体或抗原结合片段的轻链可变区包含SEQ ID NO:28所示的氨基酸序列,或与SEQ ID NO:28所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:28所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
在一些实施方案中,抗PD-1抗体的重链包含如SEQ ID NO:19所示的氨基酸序列,抗PD-1抗体的轻链包含如SEQ ID NO:20所示的氨基酸序列。在一些实施方案中,其可以通过基因工程在细胞(如CHO)中表达,并通过纯化获得。
在一些实施方案中,抗PD-1抗体为替雷利珠单抗。
在一些实施方案中,抗PD-1抗体或抗原结合片段以每个治疗周期约1mg至600mg、约1mg至300mg、约1mg至100mg、约10mg至100mg、约10mg至50mg、约15mg至35mg、约50mg至600mg的剂量给药。在一些实施方案中,抗PD-1抗体或抗原结合片段以每个治疗周期约0.01mg/kg至10mg/kg、约0.1mg/kg至10mg/kg、约0.1mg/kg至1mg/kg、约1mg/kg至10mg/kg的剂量给药。在一些实施方案中,抗PD-1抗体或抗原结合片段施用的剂量为约1mg至600mg、约50mg至600mg、约1mg至300mg、约1mg至100mg、约10mg至100mg、约10mg至50mg、约15mg至35mg每个治疗周期。在一些实施方案中,抗PD-1抗体或抗原结合片段施用的剂量为约0.01mg/kg至10mg/kg、约1mg/kg至10mg/kg、约0.1mg/kg至10mg/kg、约0.1mg/kg至1mg/kg每个治疗周期。在一些实施方案中,一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,抗PD-1抗体或抗原结合片段每次施用的剂量为约1mg至600mg、约50mg至600mg、约1mg至300mg、约1mg至100mg、约10mg至100mg、约10mg至50mg、约15mg至35mg每天给药一次至每7周给药一次,或者每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次;或者每2周或每3周给药一次。在一些实施方案中,抗PD-1抗体或抗原结合片段每次施用的剂量为约0.01mg/kg至10mg/kg、约1mg/kg至10mg/kg、约0.1mg/kg至10mg/kg、约0.1mg/kg至1mg/kg每天给药一次至每7周给药一次,或者每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次;或者每2周或每3周给药一次。在一些实施方案中,抗PD-1抗体或抗原结合片段每次施用的剂量为约0.01mg/kg,约0.02mg/kg,约0.03mg/kg,约0.04mg/kg,约0.05mg/kg,约0.06mg/kg,约0.07mg/kg,约0.08mg/kg,约0.09mg/kg,约0.1mg/kg,约0.2mg/kg,约0.3mg/kg,约0.4mg/kg,约0.5mg/kg,约0.6mg/kg,约0.7mg/kg,约0.8mg/kg,约0.9mg/kg,约1mg/kg,约2mg/kg,约3mg/kg,约4mg/kg,约5mg/kg,约6mg/kg,约7mg/kg,约8mg/kg,约9mg/kg,约10mg/kg(或这些数值中的任何两个值之间的范围(包括端点)或其中任何值)每2周或每3周给药一次。在一些实施方案中,抗PD-1抗体或抗原结合片段每次施用的剂量为约10mg至约600mg每2、3或4周给药一次。在一些实施方案中,抗PD-1抗体或抗原结合片段每次施用的剂量为约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg、约20mg、约30mg、约33mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约200mg、约300mg、约400mg、约500mg、约600mg(或这些数值中的任何两个值之间的范围(包括端点)或其中任何值)每2、3或4周给药一次。
在一些实施方案中,每次施用的抗PD-1抗体或抗原结合片段为约0.1mg/kg至10mg/kg或含此剂量抗PD-1抗体或抗原结合片段的制剂。在一些实施方案中,每次施用的抗PD-1抗体或抗原结合片段为约1mg/kg至10mg/kg或含此剂量抗PD-1抗体或抗原结合片段的制剂。在一些实施方案中,每次施用的抗PD-1抗体或抗原结合片段为约0.1mg/kg,约0.2mg/kg,约0.3mg/kg,约0.4mg/kg,约0.5mg/kg,约0.6mg/kg,约0.7mg/kg,约0.8mg/kg,约0.9mg/kg,约1mg/kg,约1.2mg/kg,约2mg/kg,约2.4mg/kg,约3mg/kg,约3.6mg/kg,约4mg/kg,约4.8mg/kg,约5mg/kg,约5.5mg/kg,约7mg/kg,约10mg/kg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量抗PD-1抗体或抗原结合片段的制剂。
在一些实施方案中,每次施用的替雷利珠单抗为100mg-300mg。在一些实施方案中,每次施用的替雷利珠单抗为约200mg。在一些实施方案中,每2-4周施用一次替雷利珠单抗。在一些实施方案中,约每3周施用一次替雷利珠单抗。
在一些实施方案中,采用治疗有效量的抗PD-1抗体或抗原结合片段和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。抗PD-1抗体或抗原结合片段和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。
在一些实施方案中,所述另一种治疗剂为是靶向PD-L1的抗体(抗PD-L1抗体)或抗原结合片段,如阿特珠单抗(Atezolizumab,如或其生物类似物),或度伐利尤单抗(Durvalumab,如或其生物类似物)。阿特珠单抗及Durvalumab可以通过基因工程在细胞(如CHO)中表达,并通过纯化获得;纯化可以采用常规方法进行。
在一些实施方案中,所述另一种治疗剂为阿特珠单抗,阿特珠单抗包括TecentriqTM其生物类似物或ADCC效应增强单抗或去岩藻糖基化单抗。在一些实施方案中,阿特珠单抗施用的剂量为约60mg至1200mg每个治疗周期。在一些实施方案中,一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,阿特珠单抗施用的剂量为约1200mg每3周给药一次。
在一些实施方案中,每次施用的阿特珠单抗为约1mg/kg至20mg/kg或含此剂量阿特珠单抗的制剂。在一些实施方案中,每次施用的阿特珠单抗为约1mg/kg,约1.2mg/kg,约2mg/kg,约2.4mg/kg,约3mg/kg,约3.6mg/kg,约4mg/kg,约4.8mg/kg,约5mg/kg,约5.5mg/kg,约6mg/kg,约9mg/kg,约12mg/kg,约15mg/kg,约18mg/kg,约20mg/kg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量阿特珠单抗的制剂。
在一些实施方案中,所述另一种治疗剂为Durvalumab,包括IMFINZITM,其生物类似物,或ADCC效应增强单抗或去岩藻糖基化单抗。在一些实施方案中,Durvalumab施用的剂量为约60mg至900mg每个治疗周期。在一些实施方案中,一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,Durvalumab施用的剂量为约5mg/kg到15mg/kg每2周或每3周给药一次。在一些实施方案中,Durvalumab施用的剂量为约10mg/kg每2周给药一次。
在一些实施方案中,每次施用的Durvalumab为约1mg/kg至10mg/kg或含此剂量Durvalumab的制剂。在一些实施方案中,每次施用的Durvalumab为约1mg/kg,约1.2mg/kg,约2mg/kg,约2.4mg/kg,约3mg/kg,约3.6mg/kg,约4mg/kg,约4.8mg/kg,约5mg/kg,约5.5mg/kg,约6mg/kg,约9mg/kg,约10mg/kg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量Durvalumab的制剂。
在一些实施方案中,采用治疗有效量的抗PD-L1抗体或抗原结合片段和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。抗PD-L1抗体或抗原结合片段和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。
在一些实施方案中,所述另一种治疗剂为与表皮生长因子受体2(HER2)的细胞外二聚化结构域(亚结构域II)发生特异性结合的单克隆抗体(抗HER2抗体),如帕妥珠单抗。帕妥珠单抗可以通过基因工程在细胞(如CHO)中表达,并通过纯化获得。
在一些实施方案中,所述另一种治疗剂为帕妥珠单抗,帕妥珠单抗包括perjetaTM或其生物类似物或ADCC效应增强单抗或去岩藻糖基化单抗。在一些实施方案中,帕妥珠单抗施用的剂量为约40mg至900mg每个治疗周期。在一些实施方案中,一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,帕妥珠单抗施用的剂量为约初始840mg,之后420mg每3周给药一次。
在一些实施方案中,每次施用的帕妥珠单抗为约1mg/kg至12mg/kg或含此剂量帕妥珠单抗的制剂。在一些实施方案中,每次施用的帕妥珠单抗为约1mg/kg,约1.2mg/kg,约2mg/kg,约2.4mg/kg,约3mg/kg,约3.6mg/kg,约4mg/kg,约4.8mg/kg,约5mg/kg,约5.5mg/kg,约6mg/kg,约6.9mg/kg,约7mg/kg,约8.4mg/kg,约9mg/kg,约11mg/kg,约12mg/kg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量帕妥珠单抗的制剂。
在一些实施方案中,采用治疗有效量的帕妥珠单抗和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。帕妥珠单抗和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。
在一些实施方案中,所述另一种治疗剂是一种重组人源化免疫球蛋白G1(IgG1)单克隆抗体,可以结合VEGF-A,抑制其与VEGF受体-2(VEGFR-2)结合(抗VEGF抗体),如贝伐珠单抗。贝伐珠单抗可以通过基因工程在细胞(如CHO)中表达,并通过纯化获得。
在一些实施方案中,贝伐珠单抗施用的剂量为约50mg至400mg每个治疗周期。在一些实施方案中,一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,贝伐珠单抗施用的剂量为约5mg/kg到15mg/kg每2周或每3周给药一次。在一些实施方案中,贝伐珠单抗施用的剂量为约5mg/kg,7.5mg/kg,10mg/kg,或15mg/kg每2周或每3周给药一次。在一些实施方案中,贝伐珠单抗施用的剂量为约5mg/kg每2周给药一次,10mg/kg每2周给药一次,7.5mg/kg每3周给药一次,15mg/kg每3周给药一次。
在一些实施方案中,每次施用的贝伐珠单抗为约1mg/kg至9mg/kg或含此剂量贝伐珠单抗的制剂。在一些实施方案中,每次施用的贝伐珠单抗为约1mg/kg,约1.2mg/kg,约2mg/kg,约2.4mg/kg,约3mg/kg,约3.6mg/kg,约4mg/kg,约4.8mg/kg,约5mg/kg,约5.5mg/kg,约6mg/kg,约6.9mg/kg,约7mg/kg,约8.4mg/kg,约9mg/kg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量贝伐珠单抗的制剂。
在一些实施方案中,采用治疗有效量的贝伐珠单抗和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。贝伐珠单抗和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。
在一些实施方案中,所述另一种治疗剂为是靶向CD20的抗体(抗CD20抗体),如奥法木单抗,或obinutuzumab。奥法木单抗及obinutuzumab可以通过基因工程在细胞(如CHO)中表达,并通过纯化获得。
在一些实施方案中,所述另一种治疗剂为奥法木单抗,奥法木单抗包括ArzerraTM或其生物类似物或ADCC效应增强单抗或去岩藻糖基化单抗,如CN109096399A公开的BAT4406F。在一些实施方案中,奥法木单抗施用的剂量为约10mg至2000mg每个治疗周期。在一些实施方案中,一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,奥法木单抗施用的剂量为约20mg每周或每月给药一次。在一些实施方案中,奥法木单抗施用的剂量为约初始300mg,1周后1000mg,之后1000mg每4周或每8周给药一次。在一些实施方案中,奥法木单抗施用的剂量为约初始300mg,1周后2000mg,之后2000mg每1周或每4周给药一次。
在一些实施方案中,每次施用的奥法木单抗为约0.5mg/kg至18mg/kg或含此剂量奥法木单抗的制剂。在一些实施方案中,每次施用的奥法木单抗为约0.5mg/kg,约1mg/kg,约1.2mg/kg,约2mg/kg,约2.4mg/kg,约3mg/kg,约3.6mg/kg,约4mg/kg,约4.8mg/kg,约5mg/kg,约5.5mg/kg,约6mg/kg,约6.9mg/kg,约7mg/kg,约8.4mg/kg,约9mg/kg,约11mg/kg,约13mg/kg,约14mg/kg,约15mg/kg,约17mg/kg,约18mg/kg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量奥法木单抗的制剂。
在一些实施方案中,采用治疗有效量的奥法木单抗和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。奥法木单抗和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。
在一些实施方案中,所述另一种治疗剂为obinutuzumab,包括其生物类似物,或ADCC效应增强单抗或去岩藻糖基化单抗,如CN109096399A所述BAT4306F。在一些实施方案中,obinutuzumab施用的剂量为约10mg至2000mg每个治疗周期。在一些实施方案中,一个治疗周期为1周、2周、3周、4周、1个月、5周、6周、7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,obinutuzumab施用的剂量为第1天100mg,第2天900mg,第8天、第15天1,000mg,之后1,000mg每疗程。在一些实施方案中,obinutuzumab施用的有效量为第1天、第8天、第15天各1,000mg,之后1,000mg每疗程。每疗程可以是1个月或2个月。
在一些实施方案中,每次施用的obinutuzumab为约0.5mg/kg至15mg/kg或含此剂量obinutuzumab的制剂。在一些实施方案中,每次施用的obinutuzumab为约0.5mg/kg,约1mg/kg,约1.2mg/kg,约2mg/kg,约2.4mg/kg,约3mg/kg,约3.6mg/kg,约4mg/kg,约4.8mg/kg,约5mg/kg,约5.5mg/kg,约6mg/kg,约6.9mg/kg,约7mg/kg,约8.4mg/kg,约9mg/kg,约11mg/kg,约13mg/kg,约14mg/kg,约15mg/kg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量obinutuzumab的制剂。
在一些实施方案中,采用治疗有效量的obinutuzumab和抗TIGIT抗体或抗原结合片段分别或者同时施加在患者上。obinutuzumab和抗TIGIT抗体或抗原结合片段的给药周期可以相同或者不同。
在一些实施方案中,所述另一种治疗剂为抗HER2抗体药物偶联物(HER2-ADC)或抗Trop2抗体药物偶联物(Trop2-ADC),例如ado-trastuzumab emtansine(T-DM1),trastuzumab deruxtecan(DS-8201),CN103333246B及CN109078181A所述抗体药物偶联物。
在一些实施方案中,本发明公开了一种治疗肿瘤或癌症的方法,其包括向有需要的患者施用有效量的抗TIGIT抗体或抗原结合片段(或制剂)和另一种治疗剂(或制剂)。在一些实施方案中,抗TIGIT抗体或抗原结合片段以约0.05mg至1200mg的剂量施用。在一些实施方案中,抗TIGIT抗体或抗原结合片段的有效量为单次给药约9mg至1200mg(或含此剂量抗TIGIT抗体的制剂)。在一些实施方案中,另一种治疗剂为抗PD-1抗体或抗原结合片段。在一些实施方案中,所述抗PD-1抗体包含SEQ ID NO:21所示的HCDR1、SEQ ID NO:22所示的HCDR2、SEQ ID NO:23所示的HCDR3、SEQ ID NO:24所示的LCDR1、SEQ ID NO:25所示的LCDR2和SEQ ID NO:26所示的LCDR3。在一些实施方案中,所述抗PD-1抗体或抗原结合片段的重链可变区包含SEQ ID NO:27所示的氨基酸序列,或与SEQ ID NO:27所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:27所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或所述抗PD-1抗体或抗原结合片段的轻链可变区包含SEQ ID NO:28所示的氨基酸序列,或与SEQ ID NO:28所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:28所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。在一些实施方案中,所述抗PD-1抗体的重链包含如SEQ ID NO:19所示的氨基酸序列,抗PD-1抗体的轻链包含如SEQ ID NO:20所示的氨基酸序列。在一些实施方案中,抗PD-1抗体或抗原结合片段的有效量为单次给药约1mg至600mg(或含此剂量抗PD-1抗体或抗原结合片段的制剂)。剂量时间表和给药方式取决于某些患者群中的抗PD-1抗体或抗原结合片段(或制剂)、抗TIGIT抗体或抗原结合片段(或制剂)的获益风险评估和一般临床实践指南。
在一些实施方案中,患者每个治疗周期内抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段施用的剂量为约0.05mg至1200mg(或含此剂量抗TIGIT抗体或抗原结合片段的制剂),患者每个治疗周期内抗PD-1抗体或抗原结合片段施用的剂量为约1mg至600mg(或含此剂量抗PD-1抗体或抗原结合片段的制剂)。
在一些实施方案中,患者每个治疗周期内抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段施用的剂量为约9mg至1200mg(或含此剂量抗TIGIT抗体或抗原结合片段的制剂),患者每个治疗周期内抗PD-1抗体或抗原结合片段施用的剂量为约50mg至600mg(或含此剂量抗PD-1抗体或抗原结合片段的制剂)。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量是约0.05mg、约0.08mg、约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约12mg、约20mg、约30mg、约50mg、约60mg、约80mg、约100mg、约120mg、约200mg、约250mg、约290mg、约300mg、约330mg、约380mg、约400mg、约434mg、约480mg、约500mg、约567mg、约580mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量抗TIGIT抗体或抗原结合片段的制剂。在一些实施方案中,一个治疗周期为1周至7周给药一次。在一些实施方案中,每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量是约0.05mg至1200mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约1mg至30mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量是9mg至100mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约100mg至约300mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、或约4周。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约300mg至约600mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、或约4周。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约600mg至约900mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、或约4周。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约30mg、约50mg、约74mg、约100mg、约110mg、约120mg、约130mg、约140mg、约150mg、约160mg、约170mg、约180mg、约190mg、约200mg、约260mg、约300mg、约350mg、约400mg、约430mg、约460mg、约520mg、约600mg、约900mg,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约0.8mg至2mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;比如约1mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约1mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约2mg至5mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;比如约3mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约3mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约7mg至20mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;比如约10mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约10mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约23mg至50mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;比如约30mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约30mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约75mg至150mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;比如约100mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约100mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约167mg至250mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;比如约200mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约200mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约267mg至354mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;比如约300mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约300mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约347mg至430mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;比如约400mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约400mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约557mg至650mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;比如约600mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约600mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约877mg至950mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;比如约900mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗TIGIT抗体或抗原结合片段的剂量为约900mg,或含此剂量抗TIGIT抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约0.05mg至1200mg每3周给药一次。在一些实施方案中,抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约1mg至900mg每3周给药一次。在一些实施方案中,抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段的剂量为约10mg至900mg每3周给药一次。在一些实施方案中,抗TIGIT抗体或抗原结合片段的剂量为约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约30mg、约100mg、约200mg、约300mg、约400mg、约500mg、约600mg、约700mg、约800mg或约900mg每3周给药一次。在一些实施方案中,抗TIGIT抗体或抗原结合片段的剂量为约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约30mg、约100mg、约300mg、约600mg或约900mg每3周给药一次。
在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量是约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg、约20mg、约30mg、约33mg、约40mg、约50mg、约60mg、约80mg、约120mg、约200mg、约250mg、约290mg、约300mg、约330mg、约380mg、约400mg、约434mg、约480mg、约500mg、约567mg、约580mg、约600mg,或这些数值中任何两个值之间的范围(包括端点)或其中任何值,或含此剂量抗PD-1抗体或抗原结合片段的制剂。在一些实施方案中,一个治疗周期为1周至7周给药一次。在一些实施方案中,每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量是15mg至35mg、10mg至50mg、10mg至100mg、1mg至100mg、50mg至600mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量是10mg至200mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约10mg至约300mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、或约4周。在一些实施方案中,每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量是100mg至200mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、约4周、约5周、约6周、约7周,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。在一些实施方案中,一个治疗周期为约1周、约2周、约3周或约4周。在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约200mg至约300mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周、或约4周。在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg、约20mg、约30mg、约33mg、约40mg、约50mg、约60mg、约80mg、约100mg、约110mg、约120mg、约130mg、约140mg、约150mg、约160mg、约170mg、约180mg、约190mg、约200mg,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约10mg至20mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;比如约16mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约16mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约20mg至45mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;比如约33mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约33mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约45mg至80mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;比如约50mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约50mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约87mg至130mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;比如约100mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约100mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约180mg至230mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;比如约200mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约200mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约267mg至343mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;比如约300mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约300mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约300mg至700mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;比如约600mg给药一次。在一些实施方案中,患者每个治疗周期内施用抗PD-1抗体或抗原结合片段的剂量为约600mg,或含此剂量抗PD-1抗体或抗原结合片段的制剂;其中,一个治疗周期为约1周、约2周、约3周或约4周。
在一些实施方案中,患者每个治疗周期内分别给药一次抗TIGIT抗体或抗原结合片段和另一种治疗剂(或给药一次抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物)。在一些实施方案中,每个治疗周期内多次分别给药抗TIGIT抗体或抗原结合片段和另一种治疗剂(或抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物),例如2次、3次、4次或5次。在一些实施方案中,患者每个治疗周期只能给药一次或四次。
在一些实施方案中,患者接受一个治疗周期治疗。在一些实施方案中,患者接受多个(例如2个、3个或4个)治疗周期治疗。在一些实施方案中,患者接受治疗直至病症得到缓解而不再需要治疗。
在一些实施方案中,本发明公开了一种用于治疗肿瘤或癌症的方法,所述方法包括:向有需要的患者给予约0.05mg至10mg、约10mg至100mg、约100mg至300mg、约300mg至600mg或约600mg至1200mg,比如约0.05mg、约0.08mg、约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约0.6mg、约0.7mg、约0.8mg、约0.9mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约20mg、约30mg、约100mg、约120mg、约200mg、约300mg、约600mg或约900mg的抗TIGIT抗体(例如抗体h10D8OF或h10D8OFKF)或抗原结合片段,含此剂量抗TIGIT抗体或抗原结合片段的制剂;还向有需要的患者给予约1mg至10mg、约10mg至50mg、约50mg至100mg、约100mg至200mg、约200mg至400mg或约400mg至600mg,比如约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg、约20mg、约30mg、约33mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约120mg、约150mg、约200mg或约250mg的抗PD-1抗体或抗原结合片段,含此剂量抗PD-1抗体或抗原结合片段的制剂。在一些实施方案中,患者接受单剂量抗TIGIT抗体或抗原结合片段的治疗,以及单剂量抗PD-1抗体或抗原结合片段的治疗。在一些实施方案中,患者接受单剂量抗TIGIT抗体或抗原结合片段和抗PD-1抗体或抗原结合片段组合物的治疗。
在一些实施方案中,每3周一次给药抗TIGIT抗体或抗原结合片段和抗PD-1抗体或抗原结合片段。
在一些实施方案中,单剂量给药后,患者的症状得到缓解。在一些实施方案中,单剂量给药后,患者后的症状未得到预期缓解,再对患者分别给药约0.05mg至1200mg抗TIGIT抗体或抗原结合片段和约1mg至600mg抗PD-1抗体或抗原结合片段。在一些实施方案中,单剂量给药后,患者的症状得到缓解。在一些实施方案中,单剂量给药后,患者后的症状未得到预期缓解,再对患者分别给药约9mg至1200mg抗TIGIT抗体或抗原结合片段和约50mg至600mg抗PD-1抗体或抗原结合片段。
在一些实施方案中,抗TIGIT抗体或抗原结合片段(或制剂)、抗PD-1抗体或抗原结合片段(或制剂)是通过皮下(s.c.)注射、腹膜内(i.p.)注射、肠胃外注射、动脉内注射或静脉内(i.v.)注射等方式进行给药。在一些实施方案中,抗TIGIT抗体或抗原结合片段(或制剂)、抗PD-1抗体或抗原结合片段(或制剂)是输液方式进行给药。在一些实施方案中,抗TIGIT抗体或抗原结合片段(或制剂)、抗PD-1抗体或抗原结合片段(或制剂)是推注方式进行给药。
在一些实施方案中,抗TIGIT抗体或抗原结合片段(或制剂)、抗PD-1抗体或抗原结合片段(或制剂)是通过静脉内(i.v.)输液方式进行给药。在一些实施方案中,静脉内输液持续时间为约50分钟、约55分钟、约60分钟、约65分钟、约70分钟、约75分钟、约81分钟、约87分钟、约90分钟、约95分钟,或这些数值中任何两个值之间的范围(包括端点)或其中任何值。
在一些实施方案中,在抗TIGIT抗体或抗原结合片段(或制剂)给药后,进行抗PD-1抗体或抗原结合片段(或制剂)给药。在一些实施方案中,在抗TIGIT抗体或抗原结合片段(或制剂)给药约15-60分钟(如约30分钟)后进行抗PD-1抗体或抗原结合片段(或制剂)给药。
附图说明
图1示抗体抑制肿瘤体生长;其中横坐标表示给药的天数,纵坐标表示肿瘤体积。
图2示抗体小鼠体重的影响;其中横坐标表示给药的天数,纵坐标表示小鼠体重。
术语
除非另作说明,否则下列的每一个术语应当具有下文所述的含义。
定义
应当注意的是,术语“一种”实体是指一种或多种该实体,例如“一种抗体”应当被理解为一种或多种抗体,因此,术语“一种”(或“一个”)、“一种或多种”和“至少一种”可以在本文中互换使用。
本文所用的术语“包含”或“包括”意味着组合物和方法等包括所列举的元素,例如组份或步骤,但不排除其它。“基本上由……组成”意味着组合物和方法排除对组合的特征有根本影响的其它元素,但不排除对组合物或方法无本质上影响的元素。“由……组成”意味着排除未特别列举的元素。
术语“多肽”旨在涵盖单数的“多肽”以及复数的“多肽”,并且是指由通过酰胺键(也称为肽键)线性连接的氨基酸单体构成的分子。术语“多肽”是指两个或更多个氨基酸的任何单条链或多条链,并且不涉及产物的特定长度。因此,“多肽”的定义中包括肽、二肽、三肽、寡肽、“蛋白质”、“氨基酸链”或用于指两个或多个氨基酸链的任何其他术语,并且术语“多肽”可以用来代替上述任何一个术语,或者与上述任何一个术语交替使用。术语“多肽”也意在指多肽表达后修饰的产物,包括但不限于糖基化、乙酰化、磷酸化、酰胺化、通过已知的保护/封闭基团衍生化、蛋白水解切割或非天然发生的氨基酸修饰。多肽可以源自天然生物来源或通过重组技术产生,但其不必从指定的核酸序列翻译所得,它可能以包括化学合成的任何方式产生。
“氨基酸”是指既含氨基又含羧基的有机化合物,比如α-氨基酸,其可直接或以前体的形式由核酸编码。单个氨基酸由三个核苷酸(所谓的密码子或碱基三联体)组成的核酸编码。每一个氨基酸由至少一个密码子编码。相同氨基酸由不同密码子编码称为“遗传密码的简并性”。氨基酸包括天然氨基酸和非天然氨基酸。天然氨基酸包括丙氨酸(三字母代码:ala,一字母代码:A)、精氨酸(arg,R)、天冬酰胺(asn,N)、天冬氨酸(asp,D)、半胱氨酸(cys,C)、谷氨酰胺(gln,Q)、谷氨酸(glu,E)、甘氨酸(gly,G)、组氨酸(his,H)、异亮氨酸(ile,I)、亮氨酸(leu,L)、赖氨酸(lys,K)、甲硫氨酸(met,M)、苯丙氨酸(phe,F)、脯氨酸(pro,P)、丝氨酸(ser,S)、苏氨酸(thr,T)、色氨酸(trp,W)、酪氨酸(tyr,Y)和缬氨酸(val,V)。
“保守氨基酸取代”是指一个氨基酸残基被另一个含有化学性质(例如电荷或疏水性)相似的侧链(R基团)的氨基酸残基所取代。一般而言,保守氨基酸取代不大会在实质上改变蛋白质的功能性质。含有化学性质相似侧链的氨基酸类别的实例包括:1)脂族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;2)脂族羟基侧链:丝氨酸和苏氨酸;3)含酰胺的侧链:天冬酰胺和谷氨酰胺;4)芳族侧链:苯丙氨酸、酪氨酸和色氨酸;5)碱性侧链:赖氨酸、精氨酸和组氨酸;6)酸性侧链:天冬氨酸和谷氨酸。
“VL、VH的保守氨基酸取代”的氨基酸数目可为约1个、约2个、约3个、约4个、约5个、约6个、约8个、约9个、约10个、约11个、约13个、约14个、约15个保守氨基酸取代,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。“重链或轻链的保守氨基酸取代”的氨基酸数目可为约1个、约2个、约3个、约4个、约5个、约6个、约8个、约9个、约10个、约11个、约13个、约14个、约15个、约18个、约19个、约22个、约24个、约25个、约29个、约31个、约35个、约38个、约41个、约45个保守氨基酸取代,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。
术语“编码”应用于多聚核苷酸时,是指被称为“编码”多肽的多聚核苷酸,在其天然状态或当通过本领域技术人员公知的方法操作时,经转录和/或翻译可以产生该多肽和/或其片段。
本发明公开的抗体、抗原结合片段或衍生物包括但不限于多克隆、单克隆、多特异性、全人源、人源化、灵长类化、嵌合抗体、单链抗体、表位结合片段(例如类Fab、类Fab'和类F(ab')2)、类单链Fvs(scFv)。
术语“重组”涉及多肽或多聚核苷酸,意指天然不存在的多肽或多聚核苷酸的形式,不受限制的实施例可以通过组合产生通常并不存在的多聚核苷酸或多肽。
“同源性”或“同一性”或“相似性”是指两个肽之间或两个核酸分子之间的序列相似性。可以通过比较每个序列中可以比对的位置来确定同源性。当被比较的序列中的位置被相同的碱基或氨基酸占据时,则分子在该位置是同源的。序列之间的同源程度是由序列共有的匹配或同源位置的数目组成的一个函数。
“至少80%同一性”为约80%同一性、约81%同一性、约82%同一性、约83%同一性、约85%同一性、约86%同一性、约87%同一性、约88%同一性、约90%同一性、约91%同一性、约92%同一性、约94%同一性、约95%同一性、约98%同一性、约99%同一性,或这些数值中的任何两个值之间的范围(包括端点)或其中任何值。
多聚核苷酸或多聚核苷酸序列(或多肽或抗体序列)与另一序列有具有一定百分比(例如90%、95%、98%或者99%)的“同一性”或“序列同一性”是指当序列比对时,所比较的两个序列中该百分比的碱基(或氨基酸)相同。可以使用目测或本领域已知的软件程序来确定该比对同一性百分比或序列同一性,比如Ausubel et al.eds.(2007)在CurrentProtocols in Molecular Biology中所述的软件程序。优选使用默认参数进行比对。其中一种比对程序是使用默认参数的BLAST,例如BLASTN和BLASTP,两者使用下列默认参数:Geneticcode=standard;filter=none;strand=both;cutoff=60;expect=10;Matrix=BLOSUM62;Descriptions=50sequences;sortby=HIGHSCORE;Databases=non-redundant;GenBank+EMBL+DDBJ+PDB+GenBankCDStranslations+SwissProtein+SPupdate+PIR。生物学上等同的多聚核苷酸是具有上述指定百分比的同一性并编码具有相同或相似生物学活性的多肽的多聚核苷酸。
“抗体”、“抗原结合片段”是指特异性识别和结合抗原的多肽或多肽复合物。抗体可以是完整的抗体及其任何抗原结合片段或其单链。因此术语“抗体”包括分子中含有具有与抗原结合的生物学活性的免疫球蛋白分子的至少一部分的任何蛋白质或肽。抗体和抗原结合片段包括但不局限重链或轻链或其配体结合部分的互补决定区(CDR)、重链可变区(VH)、轻链可变区(VL)、重链恒定区(CH)、轻链恒定区(CL)、框架区(FR)或其任何部分,或结合蛋白的至少一部分。CDR区包括轻链的CDR区(LCDR1-3)和重链的CDR区(HCDR1-3)。
术语“抗体”包括可以在生物化学上区分的各种广泛种类的多肽。本领域技术人员将会理解,重链的类别包括gamma、mu、alpha、delta或epsilon(γ、μ、α、δ、ε),其中还有一些亚类(例如γ1-γ4)。该链的性质决定了抗体的“种类”分别为IgG、IgM、IgA、IgG或IgE。免疫球蛋白亚类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgG5等已被充分表征并且赋予的功能特异性也已知。所有的免疫球蛋白种类都在本发明公开的保护范围内。在一些实施方案中,免疫球蛋白分子为IgG种类。
轻链可以分为kappa(κ)或lambda(λ)。每个重链可以与κ或λ轻链结合。一般来说,当由杂交瘤,B细胞或基因工程宿主细胞生产免疫球蛋白时,其轻链和重链通过共价键结合,两条重链的“尾巴”部分通过共价二硫键或非共价键结合。在重链中,氨基酸序列从Y构型的叉状末端的N末端延伸至每条链底部的C末端。免疫球蛋白κ轻链可变区为Vκ;免疫球蛋白λ轻链可变区为Vλ。
轻链和重链都分成结构和功能同源性的区域。术语“恒定的”和“可变的”根据功能被使用。轻链可变区(VL)和重链可变区(VH)决定了抗原识别和特异性。轻链恒定区(CL)和重链恒定区(CH)赋予重要的生物学性质,如分泌、经胎盘移动、Fc受体结合、补体结合等。按照惯例,恒定区的编号随着它们变得更远离抗体的抗原结合位点或氨基末端而增加。N端部分是可变区,C端部分是恒定区;CH3和CL结构域实际上分别包含重链和轻链的羧基端。
在本领域中使用和/或接受的术语有两个或多个定义的情况下,除非明确地对立指出,否则本文使用的术语的定义包括所有这些含义。一个具体的例子是使用“互补决定区”(“CDR”)一词来描述在重链和轻链多肽的可变区内发现的非连续的抗原结合位点。这一特定区域在Kabat et al.,U.S.Dept.of Health and Human Services,Sequences ofProteins of Immunological Interest(1983)和Chothia等在J.Mol.Biol.196:901-917(1987)有相关描述,其通过引用全部并入本文。
根据Kabat和Chothia定义的CDR包括相互比较时的氨基酸残基的重叠或子集。尽管如此,应用任一定义来指代抗体或其变体的CDR都在本发明范围内。包含特定CDR的确切残基编号将根据CDR的序列和大小而变化。本领域技术人员通常可以根据抗体的可变区氨基酸序列确定出CDR包含哪些特定的残基。
Kabat等人还定义了适用于任何抗体的可变区序列的编号系统。本领域普通技术人员可以不依赖于序列本身以外的其他实验数据将该“Kabat编号”系统应用到任何可变区序列。“Kabat编号”是指由Kabat et al.,U.S.Dept.of Health and Human Services在“Sequence of Proteinsof Immunological Interest”(1983)提出的编号系统。抗体还可以用EU或Chothia编号系统。
本发明中术语“抗体药物偶联物”或“ADC”是指与一个或多个化学药物(其可以任选地是治疗剂或细胞毒性剂)化学连接的抗体或其抗原结合片段。在一些实施方案中,ADC包括抗体、细胞毒性或治疗药物和使得药物能够与抗体连接或偶联的接头。ADC通常具有与抗体偶联的1、2、3、4、5、6、7、8、9或10个数的药物。可以包括在ADC中的药物有但不限于:有丝分裂抑制剂、抗肿瘤抗生素、免疫调节剂、基因治疗的载体、烷化剂、抗血管生成剂、抗代谢物、含硼试剂、化疗保护剂、激素、抗激素剂、皮质类固醇、光活性治疗剂、寡核苷酸、放射性核素试剂、拓扑异构酶抑制剂、酪氨酸激酶抑制剂和放射致敏剂。在一些实施方案中,包括在ADC中的药物可以是类美登素药物。在一些实施方案中,包括在ADC中的药物可以是如本申请所述的如式Ⅰ所示的化合物或其药学上可接受的盐。在一些实施方案中,在ADC中,抗体通过自身半胱氨酸或疏基化的氨基酸如疏基化赖氨酸,形成二硫键,与药物偶联。
“治疗”是指治疗性治疗和预防性或防治性措施,其目的是预防、减缓、改善和停止不良的生理改变或紊乱,例如疾病的进程,包括但不限于以下无论是可检测还是不可检测的结果,症状的缓解、疾病程度的减小、疾病状态的稳定(即不恶化)、疾病进展的延迟或减缓、疾病状态的改善或缓和,减轻或消失(无论是部分还是全部)、延长与不接受治疗时预期的生存期限等。需要治疗的患者包括已经患有病症或紊乱的患者,容易患有病症或紊乱的患者,或者需要预防该病症或紊乱的患者,可以或预期从施用本发明公开的抗体或组合物用于检测、诊断过程和/或治疗中受益的患者。
“患者”指需要诊断、预后或治疗的任何哺乳动物,包括人类、狗、猫、豚鼠、兔子、大鼠、小鼠、马、牛等。在一些实施方案中,患者为人。
“约”指相关技术领域技术人员容易知道的相应数值的常规误差范围。在一些实施方式中,本文中提到“约”指所描述的数值以及其±10%、±5%或±1%的范围。
“有效量”是指活性化合物或药剂的量,其能引起组织、系统、动物、个体或人类的生物学或医学反应;有效量由研究人员、兽医、医生或其他临床医生寻求的。
如本文所用,短语“有需要”是指已将患者鉴定为需要特定方法或治疗。在一些实施例中,可以通过任何诊断方式进行识别。在本文描述的任何方法和治疗中,患者可能需要。
“联合用药物”包括两种或两种以上药物,所述药物可以分别形成独立的给药单元或共同形成组合的给药单元。在一些实施例中,联合用药物包括分开的抗TIGIT抗体或抗原结合片段和另一种治疗剂。在一些实施例中,联合用药物包括抗TIGIT抗体或抗原结合片段和另一种治疗剂的组合物。在一些实施例中,在施用联合用药物时,不同的药物可以同时或分别给药。
可以按常规方法根据本文所述抗体氨基酸序列设计合成编码抗体的DNA,将其置入表达载体中,然后转染宿主细胞,在培养基中培养被转染的宿主细胞产生单克隆抗体。在一些实施方案中,表达抗体载体包括至少一个启动子元件,抗体编码序列,转录终止信号和polyA尾。其他元件包括增强子,Kozak序列及插入序列两侧RNA剪接的供体和受体位点。可以通过SV40的前期和后期启动子,来自逆转录病毒的长末端重复序列如RSV、HTLV1、HIVI及巨细胞病毒的早期启动子来获得高效的转录,也可应用其它一些细胞的启动子如肌动蛋白启动子。合适的表达载体可包括pIRES1neo,pRetro-Off,pRetro-On,PLXSN,或者pLNCX,pcDNA3.1(+/-),pcDNA/Zeo(+/-),pcDNA3.1/Hygro(+/-),PSVL,PMSG,pRSVcat,pSV2dhfr,pBC12MI和pCS2等。常使用的哺乳动物细胞包括HEK293细胞,Cos1细胞,Cos7细胞,CV1细胞,鼠L细胞和CHO细胞等。
“IC50”表示50%抑制浓度,即对指定的生物过程抑制一半时所需的药物或者抑制剂的浓度。
本文中引用的所有出版物,专利,和专利申请全部内容通过参考并入本文用于所有目的。
具体实施方式
以下通过具体的实施例进一步说明本发明的技术方案,具体实施例不代表对本发明保护范围的限制。其他人根据本发明理念所做出的一些非本质的修改和调整仍属于本发明的保护范围。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1抗体的制备方法
根据抗体的重链和轻链氨基酸序列构建重链和轻链的DNA序列,用PCR引物修饰DNA序列的5’端,在轻链和重链DNA序列的5’端添加kozak序列及信号肽DNA序列。构建好的序列再克隆到现有表达载体中,通过测序分析验证重组质粒的正确构建。将上述重组质粒转染表达细胞中进行表达,收集上清液、纯化获得抗体蛋白样品,并用于下面各种实施例。
其中,1)抗体h10D8OF制备过程中,采用的表达载体为pCDNA3.1TM(+)(Invitr ogen公司,货号为V79020),表达细胞为CHO细胞;2)抗体h10D8OFKF制备过程中,采用的表达载体为pCDNA3.1TM(+),表达细胞为α-(1,6)-岩藻糖基转移酶基因敲除的CHO细胞,经测试岩藻糖基化水平约为0;3)抗CTLA-4抗体制备过程中,采用的表达载体为pCDNA3.1TM(+),表达细胞为α-(1,6)-岩藻糖基转移酶基因敲除的CHO细胞,经测试岩藻糖基化水平约为0;4)抗PD-1抗体制备过程中,采用的表达载体为pCDNA3.1TM(+),表达细胞为CHO细胞;5)参照抗体Tiragolumab制备过程中,采用的表达载体为pCDNA3.1TM(+),表达细胞为CHO细胞。上述抗体的氨基酸序列见表1-4;其中,抗体h10D8OF和h10D8OFKF的氨基酸序列是相同的。抗体的DNA序列见表5;其中,抗体h10D8OF和h10D8OFKF的DNA序列是相同的。
抗体h10D8OF、抗体h10D8OFKF、抗CTLA-4抗体和抗PD-1抗体的轻链DNA序列的5’端添加的DNA序列均为gccgccaccatggactttcaggtgcagatcatctccttcctgctgatcagcgcctccgtgatcatgtccaggggc,如SEQ ID NO:35所示,kozak序列用下划线示出,信号肽用斜体示出;抗体h10D8OF、抗体h10D8OFKF、抗CTLA-4抗体和抗PD-1抗体的重链DNA序列的5’端添加的DNA序列均为gccgccaccatgggctggagcctgatcctgctgttcctggtggccgtggccaccagagtgctgtcc,如SEQ ID NO:36所示,kozak序列用下划线示出,信号肽用斜体示出。参照抗体Tiragolumab的轻链DNA序列的5’端添加的DNA序列为gccgccaccatggacatgagggtgctggcccagctgctgggactgctgctgctgtgcttcccaggcgccagatgc,如SEQ ID NO:37所示,kozak序列用下划线示出,信号肽用斜体示出;重链DNA序列的5’端添加的DNA序列为gccgccaccatggagtttgggctgagctgggttttccttgttgctatattaaaaggtgtccagtgt,如SEQ ID NO:38所示,kozak序列用下划线示出,信号肽用斜体示出。
表1抗体h10D8OF和h10D8OFKF的氨基酸序列
表2参照抗体Tiragolumab的氨基酸序列
表3抗CTLA-4抗体的氨基酸序列
表4抗PD-1抗体的氨基酸序列
表5抗体的DNA序列
实施例2阻断TIGIT与配体PVR结合试验
采用流式细胞术检测抗TIGIT抗体阻断游离的PVR-Fc与TIGIT-Jurkat细胞表面的TIGIT的结合。试验步骤为:取活力良好(细胞活力大于90%)的TIGIT-Jurkat细胞,离心后用PBS重悬为密度1000万/ml,加入到96孔尖底板中,每孔50μl,即每孔细胞数量为50万;取适量的生物素化的PVR-Fc(即PVR-Fc-bio),用PBS(磷酸缓冲液)进行稀释,配制成PVR-Fc-bio稀释液,终浓度为12.5nM;取适量抗TIGIT抗体或参照抗体Tiragolumab,用PVR-Fc-bio稀释液进行稀释,抗体起始浓度为200nM,2倍梯度稀释,共10个浓度梯度,每个浓度点设3个复孔;2-8℃条件下孵育1个小时,然后用PBS洗涤2次,加入1:1000稀释的荧光二抗Streptavidin-PE(eBioscience,CAT#12-4317-87)稀释液,每孔100μl,2-8℃孵育30min;然后PBS洗涤2次,采用流式分析仪检测荧光强度(Mean PE-A)。
PVR-Fc-bio的制备方法为:人PVR胞外区的核酸序列添加酶切位点(HindIII和EcoRI),通过连接子与人IgG1重链恒定区的核酸序列进行融合;融合之后的序列被插入到pCDNA3.1(+)载体中,然后瞬时转染HEK293F细胞;培养完成的细胞上清通过ProteinA亲和层析纯化,纯化得到的融合蛋白命名为PVR-Fc;取适量PVR-Fc蛋白,使用Thermoscientific公司的生物素标记试剂盒(HSulfo-NHS-LC-Biotinylation Kit,货号:21435),按照说明书中的操作步骤对PVR-Fc进行生物素化标记,标记后的蛋白命名为PVR-Fc-bio。其中,人PVR胞外区的氨基序列如SEQ ID NO:13所示,连接子的基因序列如SEQID NO:14所示,连接子的氨基酸序列如SEQ ID NO:39所示,人IgG1重链恒定区的氨基酸序列如SEQ ID NO:15所示,PVR-Fc的氨基酸序列如SEQ ID NO:40所示(见表6)。
TIGIT-Jurkat细胞的制备方法为:用人全长TIGIT基因替换pCMV2-CFD-Flag(义翘神州,货号:HG10160-M-F)上的目的基因得到重组质粒,用限制性内切酶ClaI(Bsu15I)将重组质粒线性化之后采用电穿孔法进行转染Jurkat细胞系(ATCC,Clone E6-1,TIB-152TM)。筛选压为潮霉素,得到阳性细胞株再进行亚克隆进而得到可以稳定表达人TIGIT细胞系,即:TIGIT-Jurkat细胞。其中,人全长TIGIT基因的序列如SEQ ID NO:16所示(见表6)。
1)在同样条件下,抗体h10D8OF和抗体Tiragolumab均可以有效地阻断TIGIT与PVR-Fc的结合,两者的IC50值分别为0.4409nM和2.820nM;抗体h10D8OF的阻断能力要优于抗体Tiragolumab。
2)在同样条件下,抗体h10D8OFKF和抗体Tiragolumab均可以有效地阻断TIGIT与PVR-Fc的结合,两者的IC50值分别为0.742nM和2.820nM;抗体h10D8OFKF的阻断能力要优于抗体Tiragolumab。
表6相关序列
实施例3抗体h10D8OFKF体内药效试验
人源化小鼠BALB/c-hPD1/hTIGIT(江苏集萃药康生物科技股份有限公司)皮下接种CT26结肠癌肿瘤细胞;接种肿瘤细胞后,当小鼠的平均肿瘤体积为79.65mm3时,进行分组,每组10只。分组当天定义为D0天,并于D0天、D4天、D7天、D11天、D14天、D18天采用腹腔注射(I.P.)方式进行给药,给药的剂量为10mg/kg或30mg/kg。给药方案见表7。
表7给药方案
细胞接种后,每周常规监测肿瘤对动物正常行为的影响;具体指标包括:小鼠的活动性,摄食和饮水情况,体重增加或降低情况,眼睛、被毛及其它异常情况。肿瘤体积(mm3)为0.5×(肿瘤长径×肿瘤短径2),各组小鼠的肿瘤体积以平均值±标准误差(mean±SEM)表示。TGItw(肿瘤重量的抑制率)计算公式为:
TGItw=(1-(mean TW给药组)/(mean TW对照组))×100%;Mean TW给药组:给药组小鼠终点处理时肿瘤重量的平均值,Mean TW对照组:对照组小鼠终点处理时肿瘤重量的平均值。
1)抗体h10D8OF和抗体Tiragolumab都可以抑制CT26结肠癌增长,并且抗体h10D8OF抑制肿瘤增长的效果优于抗体Tiragolumab;在30mg/kg剂量下,试验终点(D20天)时相对肿瘤抑制率TGItw(%)h10D8OF为92.89%,Tiragolumab为71.07%。
2)抗体h10D8OFKF和抗体Tiragolumab都可以抑制CT26结肠癌增长,并且抗体h10D8OFKF抑制肿瘤增长的效果优于抗体Tiragolumab。h10D8OFKF在10mg/kg和30mg/kg剂量下以及Tiragolumab在30mg/kg剂量下,试验终点时(D20天)相对肿瘤抑制率TGItw(%)分别为92.39%、95.94%和71.07%。
实施例4抗体h10D8OFKF与抗PD-1抗体联合给药抑制癌细胞的增殖
本研究评价了测试药物抗体h10D8OFKF和抗PD-1抗体(实施例1制备)在免疫检查点人源化小鼠BALB/c-hPD1/hTIGIT(江苏集萃药康生物科技有限公司)皮下接种CT26.WT结肠癌细胞中的药效。
1)肿瘤细胞接种
小鼠结肠癌细胞复苏,收集对数生长期的细胞,去除培养液并用PBS洗两次后接种,接种量为5×106/100μL/只,接种位置为小鼠右后肢。
2)分组给药
等肿瘤体积达到89.19mm3时,40只小鼠根据肿瘤体积随机分成4组,每组10只。分组当天定义为D0天,并于D0天开始给药;分组给药方案见表8,给药日期为:D0天、D4天、D7天、D11天、D14天、D18天、D21天(G3组在D22天进行给药,G4组在D21天和D22天均进行给药)、D25天。
3)实验观察和数据采集
细胞接种后,每周常规监测肿瘤对动物正常行为的影响。具体指标包括小鼠的活动性,摄食和饮水情况,体重增加或降低情况,眼睛、被毛及其它异常情况。
开始给药后,于D0天、D4天、D6天、D8天、D11天、D13天、D15天、D18天、D20天、D22天、D25天、D27天、D29天观测肿瘤大小并称量小鼠体重。肿瘤体积计算方式为:肿瘤体积(mm3)=0.5×(肿瘤长径×肿瘤短径2)。
4)统计
各组小鼠的肿瘤体积、小鼠体重、肿瘤重量等实验结果以平均值±标准误差(mean±SEM)表示。采用独立样本T检验比较不同给药组与对照组相比有无显著性差异。数据采用SPSS进行分析。P<0.05为具有显著性差异。
TGItv(相对肿瘤体积的抑制率)计算公式:
RTVn=Vnt/Vn0;Vnt:编号为n的小鼠在第t天的肿瘤体积,Vn0:编号为n的小鼠在第0天的肿瘤体积,RTVn:编号为n的小鼠在第t天的肿瘤相对体积
TGItv=(1-(mean RTV给药组)/(mean RTV对照组))×100%;mean RTV给药组:给药组RTV平均值,mean RTV对照组:对照组RTV平均值。
表8给药方案
备注:单药组给药体积:10μL/g(小鼠给药体积=10μL/g×小鼠体重(g))
如图1所示,与对照组相比,单药抗体h10D8OFKF和单药抗PD-1抗体能抑制肿瘤生长,抗体h10D8OFKF和抗PD-1抗体联合给药组有显著的抗肿瘤药效,且抗肿瘤效果优于单药抗体h10D8OFKF和抗PD-1抗体的抗肿瘤效果(G1、G2组未发现小鼠肿瘤完全消退,G3组有2只小鼠的肿瘤完全消退,G4组有1只小鼠的肿瘤完全消退);与G2和G3单药组相比,G4组肿瘤抑制率(TGItv)明显提高,抗体h10D8OFKF和抗PD-1抗体联合具有协同抗肿瘤作用。如图2所示,各组之间的小鼠体重未发现明显差异,表明小鼠对当前体系中的药物耐受性良好。
实施例5临床研究
本研究是一项评价抗体h10D8OFKF注射液单药或联合替雷利珠单抗在晚期恶性实体肿瘤患者中的安全性、耐受性、药代动力学特征和初步临床有效性的多中心、开放的I期临床研究。
研究分为两部分:
第一部分:单药剂量递增研究。采用加速滴定和“3+3”的剂量递增规则来探索抗体h10D8OFKF的安全性、耐受性和药代动力学特征。
共设置8个剂量组,分别设置1mg(起始剂量)组、3mg组、10mg组、30mg组、100mg组、300mg组、600mg组以及900mg组。总体分为两个阶段。第一阶段:1mg组、3mg组、10mg组采用加速滴定方法进行剂量递增。第二阶段:30mg组、100mg组、300mg组、600mg组、900mg组按标准“3+3”规则进行剂量递增研究。
第二部分:抗体h10D8OFKF联合替雷利珠单抗联合给药剂量递增研究。研究抗体h10D8OFKF单药或联合替雷利珠单抗的安全性和临床有效性。
给药方案:
抗体h10D8OFKF给药方案:静脉输注给药,建议输注时长≥60分钟,研究用药暂定每3周给药一次(Q3W)。如果患者出现输液相关反应并能够继续治疗,则研究者基于既往经验和临床实际情况可以考虑使用如苯海拉明或对乙酰氨基酚等进行预防给药。如果未观察到输液相关反应,后续的输注时间可由研究者根据临床实际情况酌情调整到30分钟~2小时完成输液均可。
替雷利珠单抗给药方案:抗体h10D8OFKF输注完毕30分钟后开始静脉输注给药,建议输注时长30~60分钟,每3周给药一次(Q3W)。详细给药方案参照替雷利珠单抗注射液药品说明书执行。
DLT定义:不良事件(AE)将基于CTCAEv5.0进行评估。剂量限制性毒性(DLT)定义为在DLT观察期发生并被认为至少可能与研究药物相关的AE,具体如下:
■5级毒性;
■血液学毒性:
●4级贫血;
●4级血小板减少症持续≥7天;
●伴有出血(≥2级)或需进行血小板输注的3级血小板减少症;
●4级中性粒细胞减少症≥7天或3级的中性粒细胞减少伴感染≥7天;
●≥3级的中性粒细胞减少伴发热;
■非血液学毒性:
●≥3级非血液学毒性(非单纯实验室检查发现的AE);
●符合任一以下条件的、因临床实验室检查发现的3、4级非血液学毒性:①需要进行临床干预;②导致住院治疗;③任何导致第2周期给药延迟超过2周的治疗相关毒性;
以下AE不被定义为DLT:
●3级的内分泌毒性经激素替代治疗后可有效控制的;
●3级的癌性疼痛;
●3级的皮疹;
●3级的输液反应在6小时内经处理能缓解的;
●3级的恶心、呕吐或腹泻经处理或支持治疗后在72小时内下降至≤2级的;
●3级的疲乏持续≤7天的;
●3级或以上的电解质紊乱在72小时内自行缓解或经处理后缓解的;
MTD定义:MTD被定义为某一剂量组在DLT评估期内观察到≤1/6的受试者中探索到的DLT的最高剂量水平。
耐受性与安全性评价:
耐受性评价指标:剂量限制性毒性(DLT)事件及其发生率。
安全性评价指标:生命体征与体格检查、实验室检查(血常规、血生化、甲状腺功能、凝血常规、尿常规、便常规、妊娠试验)、ECOG评分、心电图、不良事件(包括免疫相关不良事件)等。
药代动力学评价:
所有剂量组的受试者在治疗期间(前6个治疗周期)的规定时间点需要收集血样,在给药前2小时内监测血浆浓度(Ctrough)。每个时间点计划采3.5mL血样,检测血清药物的浓度水平,研究药代动力学(PK)特征。
通过实际给药剂量、实际采样时间和非房室模型计算下述PK参数:
单次给药:CmaxTmax、T1/2、CL、Vd、Ke、MRT、AUC(0-τ)、AUC(0-∞);
多次给药:Cmax,ss、Cavg,ss、Cmin,ss、AUC(0-τ)ss、AUC(0-∞)ss、Tmax,ss、T1/2,ss、CL、Vss、Ke、MRT、蓄积指数(Rac)、波动指数DF。
药效学受体占有率(RO)研究:
抗体h10D8OFKF注射液的受体占有率研究是通过检测外周血中T细胞表面TIGIT受体结合来实现的。药效学受体占有率研究只在剂量递增的受试者中开展,受试者在治疗期间的特定时间点收集血样。每个时间点计划采集2mL血样,分别于第1、3周期给药前、给药结束时、168h、336h及504h密集采样,第2、4、5、6个周期给药前采样。
临床有效性评价:根据RECIST1.1定义的客观缓解率(ORR)、缓解持续时间(DOR)、疾病控制率(DCR)、无进展生存期(PFS)及总生存期(OS)。
序列表
<110> 百奥泰生物制药股份有限公司
<120> 抗TIGIT抗体在联合用药中的应用
<150> PCT/CN2021/078725
<151> 2021-03-02
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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> 11
<211> 456
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Glu Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
20 25 30
Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Lys Thr Tyr Tyr Arg Phe Lys Trp Tyr Ser Asp Tyr Ala
50 55 60
Val Ser Val Lys Gly Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn
65 70 75 80
Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val
85 90 95
Phe Tyr Cys Thr Arg Glu Ser Thr Thr Tyr Asp Leu Leu Ala Gly Pro
100 105 110
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser
115 120 125
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
130 135 140
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
195 200 205
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val
210 215 220
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
225 230 235 240
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
245 250 255
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
260 265 270
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
275 280 285
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
290 295 300
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
305 310 315 320
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
325 330 335
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
340 345 350
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
355 360 365
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
370 375 380
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
385 390 395 400
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
420 425 430
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
435 440 445
Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 12
<211> 220
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Thr Val Leu Tyr Ser
20 25 30
Ser Asn Asn Lys Lys Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Asn Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 13
<211> 343
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Met Ala Arg Ala Met Ala Ala Ala Trp Pro Leu Leu Leu Val Ala Leu
1 5 10 15
Leu Val Leu Ser Trp Pro Pro Pro Gly Thr Gly Asp Val Val Val Gln
20 25 30
Ala Pro Thr Gln Val Pro Gly Phe Leu Gly Asp Ser Val Thr Leu Pro
35 40 45
Cys Tyr Leu Gln Val Pro Asn Met Glu Val Thr His Val Ser Gln Leu
50 55 60
Thr Trp Ala Arg His Gly Glu Ser Gly Ser Met Ala Val Phe His Gln
65 70 75 80
Thr Gln Gly Pro Ser Tyr Ser Glu Ser Lys Arg Leu Glu Phe Val Ala
85 90 95
Ala Arg Leu Gly Ala Glu Leu Arg Asn Ala Ser Leu Arg Met Phe Gly
100 105 110
Leu Arg Val Glu Asp Glu Gly Asn Tyr Thr Cys Leu Phe Val Thr Phe
115 120 125
Pro Gln Gly Ser Arg Ser Val Asp Ile Trp Leu Arg Val Leu Ala Lys
130 135 140
Pro Gln Asn Thr Ala Glu Val Gln Lys Val Gln Leu Thr Gly Glu Pro
145 150 155 160
Val Pro Met Ala Arg Cys Val Ser Thr Gly Gly Arg Pro Pro Ala Gln
165 170 175
Ile Thr Trp His Ser Asp Leu Gly Gly Met Pro Asn Thr Ser Gln Val
180 185 190
Pro Gly Phe Leu Ser Gly Thr Val Thr Val Thr Ser Leu Trp Ile Leu
195 200 205
Val Pro Ser Ser Gln Val Asp Gly Lys Asn Val Thr Cys Lys Val Glu
210 215 220
His Glu Ser Phe Glu Lys Pro Gln Leu Leu Thr Val Asn Leu Thr Val
225 230 235 240
Tyr Tyr Pro Pro Glu Val Ser Ile Ser Gly Tyr Asp Asn Asn Trp Tyr
245 250 255
Leu Gly Gln Asn Glu Ala Thr Leu Thr Cys Asp Ala Arg Ser Asn Pro
260 265 270
Glu Pro Thr Gly Tyr Asn Trp Ser Thr Thr Met Gly Pro Leu Pro Pro
275 280 285
Phe Ala Val Ala Gln Gly Ala Gln Leu Leu Ile Arg Pro Val Asp Lys
290 295 300
Pro Ile Asn Thr Thr Leu Ile Cys Asn Val Thr Asn Ala Leu Gly Ala
305 310 315 320
Arg Gln Ala Glu Leu Thr Val Gln Val Lys Glu Gly Pro Pro Ser Glu
325 330 335
His Ser Gly Ile Ser Arg Asn
340
<210> 14
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
attgaaggta gaatggat 18
<210> 15
<211> 330
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 16
<211> 735
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
atgcgctggt gtctgctgct gatttgggcc cagggactga gacaggctcc tctggcttca 60
ggaatgatga ccggcaccat cgagaccacc ggaaacatca gcgccgagaa gggaggaagc 120
atcatcctcc agtgccacct gagtagcaca accgcacagg tcacccaggt caattgggag 180
cagcaggacc agctgctggc catttgcaac gccgatctgg gttggcacat ctctcctagc 240
ttcaaggaca gagtggcccc aggaccagga ctgggactga cactgcagag tctgaccgtg 300
aacgacaccg gcgagtactt ctgcatctac cacacctacc cagacggcac ctacacagga 360
cggatcttcc tggaggtgct ggagtctagc gtggcagagc acggagccag attccagatc 420
cctctgctgg gagctatggc agctacactg gtcgtgatct gcaccgcagt gatcgtggtc 480
gtggctctga cacggaagaa gaaggccctg agaatccaca gcgtggaggg agacctgaga 540
agaaagagcg ccggacagga ggagtggtct cctagcgctc cttctcctcc aggctcttgt 600
gtgcaggcag aagcagctcc agcaggtctc tgcggagaac agagaggaga ggattgcgcc 660
gagctgcacg actacttcaa cgtgctgagc taccggagcc tgggcaattg cagcttcttc 720
accgagaccg gatga 735
<210> 17
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Thr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Thr Phe Ile Ser Tyr Asp Gly Asn Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Trp Leu Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 18
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Phe Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 19
<211> 447
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Arg Asp Tyr Arg Leu Asp Met Gly Phe Glu Phe Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 20
<211> 218
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ala Tyr
85 90 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 21
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Asn Tyr Tyr Met Tyr
1 5
<210> 22
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe Lys
1 5 10 15
Asn
<210> 23
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Arg Asp Tyr Arg Leu Asp Met Gly Phe Glu Phe
1 5 10
<210> 24
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Arg Ala Ser Lys Gly Val Ser Thr Ser Gly Tyr Ser Tyr Leu His
1 5 10 15
<210> 25
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Leu Ala Ser Tyr Leu Glu Ser
1 5
<210> 26
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Gln His Ala Tyr Asp Leu Pro Leu Thr
1 5
<210> 27
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Gln Val Gln Leu Val Gln Ser Gly Val Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Asn Pro Ser Asn Gly Gly Thr Asn Phe Asn Glu Lys Phe
50 55 60
Lys Asn Arg Val Thr Leu Thr Thr Asp Ser Ser Thr Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Lys Ser Leu Gln Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Arg Asp Tyr Arg Leu Asp Met Gly Phe Glu Phe Trp Gly Gln
100 105 110
Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 28
<211> 111
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Gly Val Ser Thr Ser
20 25 30
Gly Tyr Ser Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
35 40 45
Arg Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Ala Tyr
85 90 95
Asp Leu Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 29
<211> 1350
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 29
caggtgcagc tggtggagtc cggcggcgga gtggtgcagc ctggaaggtc cctgagactg 60
gactgtaagg ccagcggctt cacctttagc agctacggca tgagctgggt gagacaggcc 120
cctggcaagg gcctggagct ggtggctacc atcaatagca atggcggcag cacctactac 180
cccgacagcg tgaagggcag attcactatc agcagagaca actccaagaa taccctgttc 240
ctgcagatga atagcctgag agccgaggac accgccgtgt actactgcgc caggctgggc 300
accggcaccc tgggatttgc ctactggggc cagggtaccc tggttaccgt tagcagcgcg 360
agcaccaaag gcccgagcgt gtttccgctg gccccgagca gcaaaagcac cagcggtggc 420
accgcagcgc tgggttgcct ggtgaaagat tatttcccgg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagaaagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggatgagctg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaatga 1350
<210> 30
<211> 645
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 30
gagatcgtga tgacccagag ccccgccacc ctgtccctga gcccaggaga gagagccacc 60
ctgagctgca aggcctccca ggacgtgaag accgccgtga gctggtatca acagaagcct 120
ggccaggccc ccagactgct gatctactgg gcctccacca gggccaccgg catccctgct 180
agattcagcg gctccggctc cggcaccgat tacaccctga ccatcagcag cctggagcct 240
gaggatttcg ccgtgtacta ctgtcagcag cactactcca ccccttggac cttcggccag 300
ggcaccaagg tggagatcaa gcgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttga 645
<210> 31
<211> 1344
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 31
caggtccagc tggtcgaatc tggcggcggc gtcgtccagc ctggaagatc tctgagactg 60
tcttgcgctg cttctggctt taccttctct tcttacacaa tgcattgggt cagacaggct 120
cctggtaaag gtctggagtg ggtcacattc atctcttacg acggcaacaa caagtactac 180
gccgattctg tcaagggcag attcaccatc tccagagaca actccaagaa caccctgtac 240
ctgcagatga actctctgag agctgaggat accgctatct actattgcgc tagaacaggc 300
tggctgggac cttttgatta ctggggacag ggaacactgg tcacagtctc ttctgcttct 360
accaaaggac cttctgtctt tcctctggct ccttcttcta agtctacctc tggcggaaca 420
gctgctctgg gttgtctggt caaggattac ttccctgaac cggtgacagt gtcttggaat 480
tctggagctc tgacctcagg agtccataca tttcctgctg tcctgcagtc ttctggcctg 540
tattctctgt cctctgtggt gacagtccct tcttcttctc tgggaacaca gacctacatc 600
tgcaacgtca accacaagcc ttccaacacc aaggtcgaca agagagtgga gcctaagtct 660
tgcgacaaga cacatacatg tccaccgtgc ccagcacctg aactcctggg gggaccgtca 720
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 780
acatgcgtgg tggtggacgt gagccacgaa gaccctgagg tcaagttcaa ctggtacgtg 840
gacggcgtgg aggtgcataa tgccaagaca aagccgcggg aggagcagta caacagcacg 900
taccgtgtgg tcagcgtcct caccgtcctg caccaggact ggctgaatgg caaggagtac 960
aagtgcaagg tctccaacaa agccctccca gcccccatcg agaaaaccat ctccaaagcc 1020
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga tgagctgacc 1080
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct atcccagcga catcgccgtg 1140
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacgcctcc cgtgctggac 1200
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1260
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1320
agcctctccc tgtctccggg taaa 1344
<210> 32
<211> 645
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 32
gaaattgtcc tgacacagtc tcctggaaca ctgtctctgt ctcctggaga gagagctaca 60
ctgtcttgta gggcttctca gtctgtggga tcttcttacc tggcttggta tcagcagaaa 120
cctggacagg ctcctagact gctgatctac ggcgcttttt ctagagctac cggaatccct 180
gacagattct ctggatctgg ctctggaacc gatttcaccc tgaccatctc tagactggaa 240
cctgaggact ttgctgtcta ctactgtcag cagtacggct cttctccttg gacatttgga 300
cagggaacca aggtcgagat caagcgtacg gtggctgcac catctgtctt catcttcccg 360
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645
<210> 33
<211> 1341
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 33
caggtgcagc tggtgcagtc cggcgtggag gtgaagaagc ctggcgccag cgtgaaggtg 60
tcctgtaagg ccagcggcta caccttcacc aattactata tgtattgggt gcggcaggcc 120
cccggccagg gactggagtg gatgggaggc atcaatccca gcaacggcgg caccaacttc 180
aatgagaagt ttaagaaccg ggtgaccctg accaccgata gcagcaccac caccgcttac 240
atggagctga agagcctgca gtttgacgat accgctgtgt actattgcgc tgcccgggat 300
tacaggctgg acatgggctt cgagttctgg ggccagggta ccaccgtgac cgtgtccagc 360
gctagcacca agggcccttc cgtgttcccc ctggccccct gtagccggtc cacctctgag 420
agcaccgctg ctctgggctg tctggtgaag gattactttc ccgaaccggt gaccgtgtca 480
tggaactccg gggctctgac atccggtgtc cacacttttc ctgcagtgct gcagtcatcc 540
ggcctgtaca gcctgagctc tgtggtcaca gtcccaagtt catccctggg aaccaagaca 600
tatacttgca acgtggatca taaacccagc aatactaagg tcgacaaacg agtggagtct 660
aagtacggac caccttgccc accatgtcca gcacctgagt tcctgggagg accaagcgtg 720
ttcctgtttc ctccaaagcc taaagatacc ctgatgatca gtcggactcc cgaggtcacc 780
tgcgtggtcg tggacgtgtc ccaggaggac cctgaagtcc agttcaactg gtacgtggac 840
ggcgtcgaag tgcacaatgc taagacaaaa cctcgagagg aacagtttaa ctccacatac 900
cgtgtcgtga gcgtcctgac tgtgctgcat caggattggc tgaacggcaa ggagtataag 960
tgcaaagtga gcaataaggg actgccaagc tctatcgaga aaactatttc taaggctaaa 1020
ggacagccta gggaaccaca ggtgtacacc ctgcccccta gtcaggagga aatgactaag 1080
aaccaggtct cactgacctg tctggtgaaa gggttctatc cttcagatat tgcagtggag 1140
tgggaatcca atggtcagcc agagaacaat tacaagacaa ctccacccgt gctggacagc 1200
gatgggtctt tctttctgta ttctagactg accgtggaca aaagtcgctg gcaggagggt 1260
aatgtctttt cttgtagtgt gatgcacgaa gccctgcaca accactacac tcagaaaagc 1320
ctgtcactgt ccctgggtaa a 1341
<210> 34
<211> 654
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 34
gagatcgtgc tgacccagtc ccccgctacc ctgagcctgt cccccggaga gcgggctacc 60
ctgtcttgtc gggcctccaa gggcgtgagc accagcggat actcctatct gcactggtac 120
cagcagaagc ccggccaggc tcccaggctg ctgatctacc tggcttccta cctggagagc 180
ggcgtgcccg ctaggtttag cggcagcggc agcggaaccg atttcaccct gaccatcagc 240
tccctggagc ccgaggattt tgccgtgtac tactgccagc acgcttacga cctgcccctg 300
acctttggcg gcggcaccaa ggtggagatc aagcgtacgg tggctgcacc atctgtcttc 360
atcttcccgc catctgatga gcagttgaaa tctggaactg cctctgttgt gtgcctgctg 420
aataacttct atcccagaga ggccaaagta cagtggaagg tggataacgc cctccaatcg 480
ggtaactccc aggagagtgt cacagagcag gacagcaagg acagcaccta cagcctcagc 540
agcaccctga cgctgagcaa agcagactac gagaaacaca aagtctacgc ctgcgaagtc 600
acccatcagg gcctgagctc gcccgtcaca aagagcttca acaggggaga gtgt 654
<210> 35
<211> 75
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 35
gccgccacca tggactttca ggtgcagatc atctccttcc tgctgatcag cgcctccgtg 60
atcatgtcca ggggc 75
<210> 36
<211> 66
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 36
gccgccacca tgggctggag cctgatcctg ctgttcctgg tggccgtggc caccagagtg 60
ctgtcc 66
<210> 37
<211> 75
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 37
gccgccacca tggacatgag ggtgctggcc cagctgctgg gactgctgct gctgtgcttc 60
ccaggcgcca gatgc 75
<210> 38
<211> 66
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 38
gccgccacca tggagtttgg gctgagctgg gttttccttg ttgctatatt aaaaggtgtc 60
cagtgt 66
<210> 39
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Ile Glu Gly Arg Met Asp
1 5
<210> 40
<211> 659
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Trp Pro Pro Pro Gly Thr Gly Asp Val Val Val Gln Ala Pro Thr Gln
1 5 10 15
Val Pro Gly Phe Leu Gly Asp Ser Val Thr Leu Pro Cys Tyr Leu Gln
20 25 30
Val Pro Asn Met Glu Val Thr His Val Ser Gln Leu Thr Trp Ala Arg
35 40 45
His Gly Glu Ser Gly Ser Met Ala Val Phe His Gln Thr Gln Gly Pro
50 55 60
Ser Tyr Ser Glu Ser Lys Arg Leu Glu Phe Val Ala Ala Arg Leu Gly
65 70 75 80
Ala Glu Leu Arg Asn Ala Ser Leu Arg Met Phe Gly Leu Arg Val Glu
85 90 95
Asp Glu Gly Asn Tyr Thr Cys Leu Phe Val Thr Phe Pro Gln Gly Ser
100 105 110
Arg Ser Val Asp Ile Trp Leu Arg Val Leu Ala Lys Pro Gln Asn Thr
115 120 125
Ala Glu Val Gln Lys Val Gln Leu Thr Gly Glu Pro Val Pro Met Ala
130 135 140
Arg Cys Val Ser Thr Gly Gly Arg Pro Pro Ala Gln Ile Thr Trp His
145 150 155 160
Ser Asp Leu Gly Gly Met Pro Asn Thr Ser Gln Val Pro Gly Phe Leu
165 170 175
Ser Gly Thr Val Thr Val Thr Ser Leu Trp Ile Leu Val Pro Ser Ser
180 185 190
Gln Val Asp Gly Lys Asn Val Thr Cys Lys Val Glu His Glu Ser Phe
195 200 205
Glu Lys Pro Gln Leu Leu Thr Val Asn Leu Thr Val Tyr Tyr Pro Pro
210 215 220
Glu Val Ser Ile Ser Gly Tyr Asp Asn Asn Trp Tyr Leu Gly Gln Asn
225 230 235 240
Glu Ala Thr Leu Thr Cys Asp Ala Arg Ser Asn Pro Glu Pro Thr Gly
245 250 255
Tyr Asn Trp Ser Thr Thr Met Gly Pro Leu Pro Pro Phe Ala Val Ala
260 265 270
Gln Gly Ala Gln Leu Leu Ile Arg Pro Val Asp Lys Pro Ile Asn Thr
275 280 285
Thr Leu Ile Cys Asn Val Thr Asn Ala Leu Gly Ala Arg Gln Ala Glu
290 295 300
Leu Thr Val Gln Val Lys Glu Gly Pro Pro Ser Glu His Ser Gly Ile
305 310 315 320
Ser Arg Asn Ile Glu Gly Arg Met Asp Ala Ser Thr Lys Gly Pro Ser
325 330 335
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
340 345 350
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
355 360 365
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
370 375 380
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
385 390 395 400
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
405 410 415
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
420 425 430
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
435 440 445
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
450 455 460
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
465 470 475 480
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
485 490 495
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
500 505 510
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
515 520 525
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
530 535 540
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
545 550 555 560
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
565 570 575
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
580 585 590
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
595 600 605
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
610 615 620
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
625 630 635 640
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
645 650 655
Pro Gly Lys
Claims (24)
1.一种联合用药物,包括抗TIGIT抗体或抗原结合片段和另一种治疗剂;
所述抗TIGIT抗体或抗原结合片段包含SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3所示的HCDR3、SEQ ID NO:4所示的LCDR1、SEQ ID NO:5所示的LCDR2和SEQ ID NO:6所示的LCDR3。
2.如权利要求1所述的联合用药物,所述抗TIGIT抗体或抗原结合片段包含重链可变区和轻链可变区,其中:
所述重链可变区包含SEQ ID NO:7所示的氨基酸序列,或与SEQ ID NO:7所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或
所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列,或与SEQ ID NO:8所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
3.如权利要求1或2所述的联合用药物,所述抗TIGIT抗体的重链包含SEQ ID NO:9所示的氨基酸序列,或与SEQ ID NO:9所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:9所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或
所述抗TIGIT抗体的轻链包含SEQ ID NO:10所示的氨基酸序列,或与SEQ ID NO:10所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:10所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
4.如权利要求1-3任一项所述的联合用药物,所述另一种治疗剂选自针对以下靶点的抗体或抗原结合片段或抗体药物偶联物:EGFR、VEGF、VEGFR2、CTLA-4、PD-L1、PD-1、HER2、CD20、Trop2、Lag3、TIGIT、CD27、OX40、ICOS、BTLA、TIM3、BCMA、c-MET和TAA-1/2/3;或者,所述另一种治疗剂为抗PD-1抗体或抗原结合片段;或者,所述抗PD-1抗体为纳武利尤单抗、帕博利单抗、卡瑞利珠单抗、信迪利单抗、特瑞普利单抗或替雷利珠单抗;或者,所述抗PD-1抗体或抗原结合片段包含SEQ ID NO:21所示的HCDR1、SEQ ID NO:22所示的HCDR2、SEQ IDNO:23所示的HCDR3、SEQ ID NO:24所示的LCDR1、SEQ ID NO:25所示的LCDR2和SEQ ID NO:26所示的LCDR3。
5.如权利要求4所述的联合用药物,所述抗PD-1抗体或抗原结合片段包含重链可变区和轻链可变区,其中:
所述重链可变区包含SEQ ID NO:27所示的氨基酸序列,或与SEQ ID NO:27所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:27所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或
所述轻链可变区包含SEQ ID NO:28所示的氨基酸序列,或与SEQ ID NO:28所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:28所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
6.如权利要求4或5所述的联合用药物,所述抗PD-1抗体的重链包含SEQ ID NO:19所示的氨基酸序列,或与SEQ ID NO:19所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:19所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或
所述抗PD-1抗体的轻链包含SEQ ID NO:20所示的氨基酸序列,或与SEQ ID NO:20所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:20所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
7.如权利要求1-6任一项所述的联合用药物,所述抗TIGIT抗体或抗原结合片段和另一种治疗剂分别或同时给药。
8.如权利要求1-7任一项所述的联合用药物,所述抗TIGIT抗体或抗原结合片段和另一种治疗剂的质量比为0.01:10-1:1;或者为0.01:1-1:1;或者为0.1:3。
9.权利要求1-8任一项所述的联合用药物在制备用于治疗肿瘤或癌症的药物中的应用。
10.如权利要求9所述的应用,所述肿瘤或癌症为血液癌症或实体瘤;或者,所述肿瘤或癌症选自于急性淋巴细胞性白血病、急性骨髓性白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病、骨髓性增生疾病/肿瘤、霍奇金淋巴瘤、无痛性和侵袭性非霍奇金淋巴瘤、伯基特淋巴瘤、滤泡性淋巴瘤、多发性骨髓瘤、巨细胞骨髓瘤、重链骨髓瘤、轻链或本斯-琼斯骨髓瘤、乳腺癌、卵巢癌、胰腺癌、前列腺癌、黑素瘤、结直肠癌、结肠癌、肺癌、头颈癌、膀胱癌、食道癌、肝癌和肾癌。
11.一种用于治疗肿瘤或癌症的方法,其包括:向有需要的患者给药有效量的抗TIGIT抗体或抗原结合片段和另一种治疗剂;
所述抗TIGIT抗体或抗原结合片段包含SEQ ID NO:1所示的HCDR1、SEQ ID NO:2所示的HCDR2、SEQ ID NO:3所示的HCDR3、SEQ ID NO:4所示的LCDR1、SEQ ID NO:5所示的LCDR2和SEQ ID NO:6所示的LCDR3。
12.如权利要求11所述的方法,所述抗TIGIT抗体或抗原结合片段包含重链可变区和轻链可变区,其中:
所述重链可变区包含SEQ ID NO:7所示的氨基酸序列,或与SEQ ID NO:7所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:7所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或
所述轻链可变区包含SEQ ID NO:8所示的氨基酸序列,或与SEQ ID NO:8所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:8所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
13.如权利要求11或12所述的方法,所述抗TIGIT抗体的重链包含SEQ ID NO:9所示的氨基酸序列,或与SEQ ID NO:9所示序列相比具有至少80%同一性的氨基酸序列,或与SEQID NO:9所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或
所述抗TIGIT抗体的轻链包含SEQ ID NO:10所示的氨基酸序列,或与SEQ ID NO:10所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:10所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
14.如权利要求11-13任一项所述的方法,所述另一种治疗剂选自针对以下靶点的抗体或抗原结合片段或抗体药物偶联物:EGFR、VEGF、VEGFR2、CTLA-4、PD-L1、PD-1、HER2、CD20、Trop2、Lag3、TIGIT、CD27、OX40、ICOS、BTLA、TIM3、BCMA、c-MET和TAA-1/2/3;或者,所述另一种治疗剂为抗PD-1抗体或抗原结合片段。
15.如权利要求14所述的方法,所述抗PD-1抗体为纳武利尤单抗、帕博利单抗、卡瑞利珠单抗、信迪利单抗、特瑞普利单抗或替雷利珠单抗;或者,所述抗PD-1抗体或抗原结合片段包含SEQ ID NO:21所示的HCDR1、SEQ ID NO:22所示的HCDR2、SEQ ID NO:23所示的HCDR3、SEQ ID NO:24所示的LCDR1、SEQ ID NO:25所示的LCDR2和SEQ ID NO:26所示的LCDR3。
16.如权利要求15所述的方法,所述抗PD-1抗体或抗原结合片段包含重链可变区和轻链可变区,其中:
所述重链可变区包含SEQ ID NO:27所示的氨基酸序列,或与SEQ ID NO:27所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:27所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或
所述轻链可变区包含SEQ ID NO:28所示的氨基酸序列,或与SEQ ID NO:28所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:28所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
17.如权利要求15或16所述的方法,所述抗PD-1抗体的重链包含SEQ ID NO:19所示的氨基酸序列,或与SEQ ID NO:19所示序列相比具有至少80%同一性的氨基酸序列,或与SEQID NO:19所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列;和/或
所述抗PD-1抗体的轻链包含SEQ ID NO:20所示的氨基酸序列,或与SEQ ID NO:20所示序列相比具有至少80%同一性的氨基酸序列,或与SEQ ID NO:20所示序列相比具有一个或多个保守氨基酸取代的氨基酸序列。
18.如权利要求11-17任一项所述的方法,所述抗TIGIT抗体或抗原结合片段以0.05mg至1200mg、0.05mg至1000mg、0.05mg至500mg、0.05mg至100mg、0.1mg至100mg、0.1mg至50mg、0.1mg至30mg、0.1mg至10mg、0.5mg至1mg、9mg至1200mg、1mg至900mg的剂量给药;或者,所述抗TIGIT抗体或抗原结合片段以0.001mg/kg至20mg/kg、0.001mg/kg至2mg/kg、0.001mg/kg至1mg/kg、0.005mg/kg至1mg/kg、0.01mg/kg至1mg/kg、0.01mg/kg至20mg/kg的剂量给药;或者,每个治疗周期内抗TIGIT抗体或抗原结合片段给药的剂量为0.05mg至1200mg、0.05mg至1000mg、0.05mg至500mg、0.05mg至100mg、0.1mg至100mg、0.1mg至50mg、0.1mg至30mg、0.1mg至10mg、0.5mg至1mg、9mg至1200mg、1mg至900mg;或者,每个治疗周期内抗TIGIT抗体或抗原结合片段给药的剂量为0.001mg/kg至20mg/kg、0.001mg/kg至2mg/kg、0.001mg/kg至1mg/kg、0.005mg/kg至1mg/kg、0.01mg/kg至1mg/kg、0.01mg/kg至20mg/kg;或者,所述抗TIGIT抗体或抗原结合片段的每次给药量为0.05mg至1200mg、9mg至1200mg、1mg至900mg;或者,所述抗TIGIT抗体或抗原结合片段的每次给药量为0.001mg/kg至20mg/kg、0.01mg/kg至20mg/kg。
19.如权利要求15-18任一项所述的方法,所述抗PD-1抗体或抗原结合片段以1mg至600mg、50mg至600mg、1mg至300mg、1mg至100mg、10mg至100mg、10mg至50mg、15mg至35mg的剂量给药;或者,所述抗PD-1抗体或抗原结合片段以0.01mg/kg至10mg/kg、1mg/kg至10mg/kg、0.1mg/kg至10mg/kg、0.1mg/kg至1mg/kg的剂量给药;或者,每个治疗周期内抗PD-1抗体或抗原结合片段给药的剂量为1mg至600mg、50mg至600mg、1mg至300mg、1mg至100mg、10mg至100mg、10mg至50mg、15mg至35mg;或者,每个治疗周期内抗PD-1抗体或抗原结合片段给药的剂量为0.01mg/kg至10mg/kg、1mg/kg至10mg/kg、0.1mg/kg至10mg/kg、0.1mg/kg至1mg/kg;或者,所述抗PD-1抗体或抗原结合片段的每次给药量为1mg至600mg、50mg至600mg;或者,所述抗PD-1抗体或抗原结合片段的每次给药量为0.01mg/kg至10mg/kg、1mg/kg至10mg/kg。
20.如权利要求11-19任一项所述的方法,所述抗TIGIT抗体或抗原结合片段和另一种治疗剂分别或同时给药。
21.如权利要求11-20任一项所述的方法,所述抗TIGIT抗体或抗原结合片段每天给药一次至每7周给药一次,或者所述抗TIGIT抗体或抗原结合片段每周给药三次、每周给药两次、每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次;和/或,所述抗PD-1抗体或抗原结合片段每天给药一次至每7周给药一次,或者所述抗PD-1抗体或抗原结合片段每周给药三次、每周给药两次、每周给药一次、每2周给药一次、每3周给药一次、每4周给药一次、每5周给药一次、每6周给药一次或每7周给药一次。
22.如权利要求11-21任一项所述的方法,所述抗TIGIT抗体或抗原结合片段和另一种治疗剂给药的质量比为0.01:10-1:1;或者为0.01:1-1:1;或者为0.1:3。
23.如权利要求11-22任一项所述的方法,所述肿瘤或癌症为血液癌症或实体瘤;或者,所述肿瘤或癌症选自于急性淋巴细胞性白血病、急性骨髓性白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病、骨髓性增生疾病/肿瘤、霍奇金淋巴瘤、无痛性和侵袭性非霍奇金淋巴瘤、伯基特淋巴瘤、滤泡性淋巴瘤、多发性骨髓瘤、巨细胞骨髓瘤、重链骨髓瘤、轻链或本斯-琼斯骨髓瘤、乳腺癌、卵巢癌、胰腺癌、前列腺癌、黑素瘤、结直肠癌、结肠癌、肺癌、头颈癌、膀胱癌、食道癌、肝癌和肾癌。
24.一种试剂盒,其包含权利要求1-8任一项所述的联合用药物和用于指导有需要患者给药权利要求1-8任一项所述的联合用药物的说明书。
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EP3347379B9 (en) * | 2016-08-17 | 2020-03-25 | Compugen Ltd. | Anti-tigit antibodies, anti-pvrig antibodies and combinations thereof |
CN110997720A (zh) * | 2017-07-27 | 2020-04-10 | Iteos治疗公司 | 抗tigit抗体 |
MX2020008795A (es) * | 2018-02-28 | 2020-10-08 | Yuhan Corp | Anti cuerpos anti tigit y usos de los mismos. |
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