CN114650815A - 癌症治疗的方法及组成物 - Google Patents
癌症治疗的方法及组成物 Download PDFInfo
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- CN114650815A CN114650815A CN202080076324.7A CN202080076324A CN114650815A CN 114650815 A CN114650815 A CN 114650815A CN 202080076324 A CN202080076324 A CN 202080076324A CN 114650815 A CN114650815 A CN 114650815A
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Abstract
在一方面,提供治疗例如实体瘤的肿瘤形成的方法及组成物,所述方法及组成物包含a)一种或多种化疗剂,例如检查点抑制剂或多柔比星和/或环磷酰胺;b)单乙酰基二酰基甘油化合物,例如1‑棕榈酰基‑2‑亚油酰基‑3‑乙酰基甘油(PLAG)。
Description
技术领域
在一方面,提供治疗例如肿瘤的肿瘤形成的方法及组成物,所述方法及组成物包含a)一种或多种化疗剂,例如AC-疗法以及b)单乙酰基二酰基甘油化合物,例如1-棕榈酰基-2-亚油酰基-3-乙酰甘油(PLAG)。
背景技术
癌症的特征在于异常且不受控制的细胞生长。癌症涉及身体中的任何组织,并可扩散到起源的组织以外。不受控制的增生和其他细胞异常可导致癌性肿瘤的形成。肿瘤可在它们起源的组织中,中断所述组织的功能并将其破坏,并且,当癌细胞转移时,续发肿瘤可在原发生长的部位附近或不同部位发展。癌症的原因与各种化学物质、病毒、细菌和环境暴露有关。
因此,需要改善的癌症疗法。
发明内容
在一个方面,我们现在提供患有癌症的患者的治疗和预防的新疗法。
在一个方面,提供减少或抑制患者中肿瘤生长的方法及组成物,其包括一种或多种化疗剂与式(I)的单乙酰基二酰基甘油化合物的同时施用,其中,所述式(I)的化合物是不同于所述一种或多种化疗剂。
我们惊奇地发现,式(I)的单乙酰基二酰基甘油化合物和一种或多种化疗剂的协调给药能对减小肿瘤尺寸/负荷产生协同效应。例如,参见以下实施例1和3的结果。
在一个方面,本揭露的方法包括向具有肿瘤或其他肿瘤形成的受试者,例如人类,施用治疗有效量的:
a)一种或多种化疗剂;以及
b)式(I)的单乙酰基二酰基甘油化合物:
其中,R1和R2独立地是包含14至20个碳原子的脂肪酸基团。b)式(I)的化合物是不同于所述a)一种或多种化疗剂。所述a)一种或多种化疗剂和b)式(I)的化合物是以组合或其他协调方式适当地施用予患者。
在优选的方面,所述b)单乙酰基二酰基甘油是式(II)的化合物:
所述式(II)的化合物在本文中也是指PLAG(1-棕榈酰基-2-亚油酰基-3-乙酰甘油)、PLAG或EC-18。
在优选的方面,除了PLAG之外,一种或多种化疗剂包括一种或多种免疫检查点抑制剂化合物或药剂。在一些实施例中,所述免疫检查点抑制剂是抗体或其片段,包括单克隆抗体或其片段。
用于本揭露的组成物及方法的优选的检查点抑制剂,包括PD-1抑制剂,例如派姆单抗(Pembrolizumab)(Keytruda)、尼鲁单抗(Nivolumab)(Opdivo);以及西米普利单抗(Cemiplimab)(Libtayo)。用于本揭露的组成物及方法的其他优选检查点抑制剂包括PD-L1抑制剂,例如阿替珠单抗(Atezolizumab)(Tecentriq);阿维单抗(Avelumab)(Bavencio);以及德瓦鲁单抗(Imfinzi)。其他用于本揭露的组成物及方法的优选的检查点抑制剂,包括CTLA-4抑制剂,例如伊派利单抗(Ipilmumab)(Yervoy)。
在某些优选的方面,所述检查点抑制剂是PD-L1抑制剂。
我们惊奇地发现式(I)的单乙酰基二酰基甘油化合物以及检查点抑制剂的一者或多者的协调给药,可在癌症治疗效果中产生协同效应,包括减小肿瘤尺寸/负荷。参见以下实施例3。
在某些优选的方面,一种或多种化疗剂包括多柔比星(doxorubicin)。
在另外优选的方面,一种或多种化疗剂包括环磷酰胺。
在某些方面,一种或多种化疗剂包括多柔比星和环磷酰胺两者,其中,这些药剂可至少实质上同时或依序施用。
在另外优选的方面,一种或多种化疗剂包括5-FU(5-氟尿嘧啶)和/或顺铂(cisplatin)。
在特别优选的方面,一种或多种化疗剂包括AC疗法,其包括多柔比星,例如多柔比星盐酸盐(阿德力霉素(Adriamycin))和环磷酰胺。
在特别优选的方面,一种或多种化疗剂包括AC-T或AC-紫杉醇疗法,其包括多柔比星,例如多柔比星盐酸盐(阿德力霉素)和环磷酰胺,后续使用紫杉醇(太平洋紫杉醇(paclitaxel))治疗。
根据本揭露的方法的可投予受试者的其他化疗剂,包括例如环磷酰胺、依托泊苷(etoposide)、异环磷酰胺(ifosfamide)、美司钠(mesna)、吉西他滨(gemcitabine)和/或他莫昔芬(tamoxifen),或一种或多种其他化疗剂。
在某些实施例中,本发明的治疗途径也可与以下疗法的任一者组合:放射、化疗、手术、治疗抗体、免疫调节剂、蛋白酶体抑制剂、广泛性DAC抑制剂、H-DAC抑制剂、检查点抑制剂、包含CAR T及NK细胞疗法的过继细胞疗法和/或疫苗。
在本发明的某些方面,a)一种或多种化疗剂不包括粒细胞集落刺激因子(G-CSF)。在某些方面,不向受试者施用粒细胞集落刺激因子(G-CSF)作为本文所揭露的方法、组成物或试剂盒的一部分或与本文所揭露的方法、组成物或试剂盒结合。在某些方面,在使用如本文所揭露的a)一种或多种化疗剂以及b)式(I)的化合物治疗之前,受试者至少有0.5、1、2、3、4、6、8周或更久未施用粒细胞集落刺激因子(G-CSF),和/或在使用如本文所揭露的a)一种或多种化疗剂以及b)式(I)的化合物治疗之后,受试者至少有0.5、1、2、3、4、6、8周或更久未施用粒细胞集落刺激因子(G-CSF)。
在另一方面,提供医药组成物,其包含a)一种或多种化疗剂,例如多柔比星和/或一种或多种检查点抑制剂化合物;以及b)单乙酰基二酰基甘油化合物,例如PLAG(1-棕榈酰基-2-亚油酰基-3-乙酰甘油),其不同于所述a)一种或多种化疗剂。
在又一方面,提供用于治疗或预防包括实体瘤的肿瘤形成的试剂盒。本发明的试剂盒可适当地包含a)一种或多种化疗剂;以及b)单乙酰基二酰基甘油化合物,例如PLAG(1-棕榈酰基-2-亚油酰基-3-乙酰甘油),其不同于所述a)一种或多种化疗剂。优选地,试剂盒将包含治疗有效量的a)一种或多种化疗剂以及b)例如PLAG的单乙酰基二酰基甘油化合物的各者。优选的试剂盒也可包括a)一种或多种化疗剂以及b)例如PLAG的单乙酰基二酰基甘油化合物于治疗如实体瘤包括乳腺癌的肿瘤形成的使用说明书。所述说明书可适当地为书面形式,包括作为产品标签。
本发明的方法、组成物和试剂盒可治疗患有多种类型的肿瘤形成和癌症的受试者。在某些方面,所述方法、组成物和试剂盒可治疗患有乳腺癌的受试者。
在某些方面,本发明的方法包括鉴定和选择患有例如实体瘤或乳腺癌的肿瘤形成的受试者,接着向所选的受试者施用a)一种或多种化疗剂以及b)单乙酰基二酰基甘油化合物,例如PLAG。
如所讨论的,在某些方面,本文所揭露的组成物和试剂盒不包括粒细胞集落刺激因子(G-CSF)。
本发明的其他方面在下文中揭露。
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专利或申请文件包含至少一幅以彩色执行的附图。本专利或专利申请出版物的彩色附图副本将由专利局依要求提供并支付必要的费用。
图1显示研究使用PLAG和AC-疗法的同时治疗,对肿瘤治疗功效的协同效应的示例性实验设计。
图2A至2J显示共同施用PLAG和AC-疗法的协同效应。与阳性对照相比:*P<0.05、***P<0.001(各自实验n=5)。与疗法治疗组相比:#P<0.05、##P<0.01(各自实验n=5)。N.S.,不显著)
图2A显示在AC-疗法治疗(2/20)和PLAG联合治疗期间,异种移植小鼠的各周记录的肿瘤重量的变化。
图2B显示在牺牲日所测量的来自图2A组各自的肿瘤重量的分析。
图2C显示图2A中所示的AC-疗法(2/20)和PLAG联合治疗期间,异种移植小鼠中的肿块。
图2D显示图2A的AC-疗法治疗(2/20)和PLAG联合治疗之后,牺牲小鼠中肿瘤组织的染色和细胞凋亡相关(apoptosis-related)的蛋白质表现。
图2E显示在图2A中所示的AC-疗法(2/20)和PLAG联合治疗之后,在牺牲小鼠肿瘤组织中细胞凋亡相关蛋白质表现量的变化。
图2F显示在AC-疗法治疗(5/50)和PLAG联合治疗期间,异种移植小鼠中各周记录的肿块的变化。
图2G显示在牺牲日所测量的来自图2F组各自的肿瘤重量的分析。
图2H显示图2F所示的AC-疗法(5/50)和PLAG联合治疗期间,异种移植小鼠中的肿块。
图2I显示AC-疗法治疗(5/50)和PLAG联合治疗之后,牺牲小鼠中肿瘤组织的染色和细胞凋亡相关蛋白质表现。
图2J显示图2F中所示的AC-疗法(5/50)和PLAG联合治疗之后,在牺牲小鼠肿瘤组织中细胞凋亡相关蛋白质表现量的变化。##P<0.01(各自实验n=5)。N.S.,不显著。
图3A至图3D显示在共同施用PLAG和AC-疗法期间,中性粒细胞(neutrophil)趋化性的阻抑或抑制。
图3A显示使用带有抗体的免疫组织化学对肿瘤浸润中性粒细胞的验证。使用抗-Ly6C+/Ly6G+抗体和仅抗-Ly6G+抗体。
图3B显示肿瘤浸润中性粒细胞的评价。与阴性对照相比:*P<0.05、**P<0.01、***P<0.001(各自实验n=5)。N.S.,不显著。与AC-疗法组相比:#P<0.05、##P<0.01、###P<0.001(各自实验n=5)。N.S.’,不显著。
图3C显示与血液中具有中性粒细胞趋化性相关的分泌趋化因子的评价:*P<0.05、**P<0.01、***P<0.001(各自实验n=5)。N.S.,不显著。与AC-疗法对照组相比:#P<0.05、##P<0.01、###P<0.001(各自实验n=5)。N.S.’,不显著。
图3D显示血液中的中性粒细胞的评价:*P<0.05、**P<0.01、***P<0.001(各自实验n=5)。N.S.,不显著。与AC-疗法对照组相比:#P<0.05、##P<0.01、###P<0.001(各自实验n=5)。N.S.',不显著。
图4A至图4G显示由PLAG治疗癌症的生长抑制。
图4A显示PLAG对异种移植小鼠中肿块的影响。
图4B显示牺牲日异种移植小鼠中肿瘤重量的验证。与阳性对照相比:*P<0.05、***P<0.001(各自实验n=5)。
图4C显示PLAG治疗的异种移植小鼠中各周计数的肿块的变化。
图4D显示使用免疫组织化学对肿瘤浸润中性粒细胞的验证。与阳性对照相比:*P<0.05、**P<0.01(各自实验n=5)。
图4E显示与血液中具有中性粒细胞趋化性相关的分泌趋化因子的评价:与阴性对照相比;*P<0.05、**P<0.01、***P<0.001(各自实验n=5)。N.S.,不显著。与阳性对照相比;#P<0.05、##P<0.01、###P<0.001(各自实验n=5)。N.S.',不显著。
图4F显示使用免疫组织化学验对肿瘤中的中性粒细胞趋化性相关趋化因子表达的验证。
图4G显示使用免疫组织化学对肿瘤中的肿瘤细胞周期诱导因子表达的验证。
图5A至图5D显示由PLAG治疗对癌症生长和中性粒细胞浸润的抑制。
图5A显示PLAG对异种移植小鼠中肿块的影响。
图5B显示在牺牲日异种移植小鼠中肿瘤重量的验证。与阳性对照相比:*P<0.05、**P<0.01(各自实验n=5)。N.S.,不显著。
图5C显示PLAG治疗的异种移植小鼠中各周计数的肿块的变化。
图5D显示使用免疫组织化学对肿瘤浸润中性粒细胞的验证。
图6A和图6B显示通过增强的PAR2降解抑制癌症的增殖。
图6A显示通过使用剂量依赖性方式的PLAG治疗,对中性粒细胞活化的MDA-MB-231乳腺癌细胞的细胞生长的抑制。各周与阴性对照相比:*P<0.05、**P<0.01、***P<0.001(各自实验n=5)。N.S.,不显著。与各周仅刺激中性粒细胞的组相比:#P<0.05、##P<0.01、###P<0.001(各自实验n=5)。N.S.,不显著。
图6B显示中性粒细胞活化的癌细胞中的细胞周期活性的PLAG的抑制作用。
图6C显示通过PCR和蛋白质印迹法,在中性粒细胞和PLAG治疗的细胞中,评价细胞周期相关基因和蛋白质的表现量。
图6D显示使用蛋白质印迹法,对PLAG和中性粒细胞共同治疗的活化癌细胞中与PAR2降解相关的蛋白质表现和磷酸化的验证。
图6E显示使用免疫沉淀测定法对PAR2结合蛋白的鉴定。
图6F显示通过使用抗PAR2抗体的泛素化测定,在PLAG和中性粒细胞共同治疗的癌细胞中用泛素活性验证PAR2的降解。
图7显示示例性实验设计,以研究实施例3中的MB49膀胱癌模型中PLAG对PD-L1免疫检查点药物治疗的协同效应。
图8A显示估计3天间隔的各组中肿瘤尺寸变化的分析。
图8B显示牺牲当天小鼠的形态及肿瘤尺寸的变化。
图8C显示在牺牲日所评价的PLAG或aPD-L1联合治疗小鼠中的肿瘤重量分析。
在图8A至图8C中:与阳性对照相比:#P<0.05、###<0.001;与仅aPD-L1治疗组相比:$P<0.05、$$$P<0.001(各自实验n=6)。N.S.,不显著。平均值±标准差(Mean±SD)。
图9A显示通过全血细胞计数(CBC)分析的PLAG调节中性粒细胞计数。
图9B显示根据PLAG和aPD-L1治疗的血液Ly6G和CD11b阳性细胞分选结果的分析。
图9C显示根据PLAG和aPD-L1治疗的组织浸润的Ly6G和CD11b阳性细胞分选结果的分析。
图9D显示代表图9B(血液)和图9C(肿瘤)的图。
图9E显示通过IHC染色对肿瘤组织中由PLAG治疗的中性粒细胞浸润控制效果的分析。(Ly6G:中性粒细胞群;中性粒细胞弹性蛋白酶:活性中性粒细胞)。
在图9A至图9E中:与阴性对照相比:***P<0.001;与阳性对照相比:#P<0.05,##P<0.01、###P<0.001;与仅aPD-L1治疗组相比:$$P<0.01、$$$P<0.001(各自实验n=3)。N.S.,不显著。平均值±标准差。
图10A显示通过全血细胞计数(CBC)分析的PLAG调节淋巴细胞计数。
图10B显示根据PLAG治疗的血液中NLR含量的定量分析。
图10C和图10D显示根据PLAG和aPD-L1治疗的血液CD4和CD8阳性细胞分选结果的分析。
图10E和10F显示根据PLAG和aPD-L1治疗的肿瘤组织浸润CD4和CD8阳性细胞分选结果的分析。
图10G显示通过IHC染色对肿瘤组织中由PLAG治疗的淋巴细胞浸润效果的分析。
在图10A至图10F中:与阴性对照相比:***P<0.001;与阳性对照相比:#P<0.05、##P<0.01、###P<0.001;与仅aPD-L1治疗组相比:$$P<0.01、$$$P<0.001(各自实验n=3)。N.S.,不显著。平均值±标准差。
图11A和图11B显示与中性粒细胞浸润和活性有关的趋化因子和生长因子分泌变化。
图11C和图11D显示与T细胞极性有关的趋化因子和细胞因子分泌变化。
图11E显示与淋巴细胞的形成和活性有关的细胞因子分泌的变化。
在图11A至图11E中:与阴性对照相比:*P<0.05、P<0.01、***P<0.001;与阳性对照相比:#P<0.05、##P<0.01、###P<0.001;与仅aPD-L1治疗组相比:$P<0.05、$$P<0.01、$$$P<0.001(各自实验n=6)。N.S.,不显著。平均值±标准差。
图12显示在实施例4中的LLC-1模型中PLAG对PD-L1免疫检查点抑制剂治疗的协同效应的示例性实验设计。
图13A显示估计3天间隔的各组中肿瘤尺寸变化的分析。
图13B显示牺牲当天小鼠的形态和肿瘤尺寸的变化。
图13C显示在牺牲日所评价的PLAG或aPD-1联合治疗小鼠中的肿瘤重量分析。
在图13A至图13C中:与阳性对照相比:###P<0001;与仅aPD-1治疗组相比:$P<0.05、$$P<0.05、$$$P<0.001(各自实验n=6)。N.S.,不显著。平均值±标准差。
图14A显示通过全血细胞计数(CBC)分析PLAG调节免疫细胞计数。
图14B显示根据PLAG和aPD-1治疗的血液/肿瘤CD4或CD8阳性细胞分选结果的分析。
图14C显示根据PLAG和aPD-1治疗的血液/组织浸润的Ly6G阳性细胞分选结果的分析。
图14D显示通过IHC染色对在肿瘤组织中由PLAG治疗中性粒细胞浸润控制效果的分析。
在图14A中:与阴性对照相比:***P<0.001;与阳性对照相比:#P<0.05、##P<0.01、###P<0.001;与仅aPD-1治疗组相比:$$P<0.01、$$$P<0.001(各自实验n=6)。N.S.,不显著。平均值±标准差。
图15A和图15B显示根据PLAG和aPD-1治疗的血液/肿瘤Th17细胞群分选结果的分析。
在图15B中,与阴性对照相比:***P<0.001;与阳性对照相比:###P<0.001;与仅aPD-1治疗组相比:$P<0.01(各自实验n=3)。N.S.,不显著。平均值±标准差。
图16A显示每周牺牲小鼠的形态和肿瘤尺寸的变化。
图16B显示通过全血细胞计数(CBC)分析调节免疫细胞计数的化合物。
图16C显示根据化合物治疗的血液/组织浸润的Ly6G阳性细胞分选结果的分析。
图16D显示根据PLAG和aPD-1治疗的血液/肿瘤Th 17细胞群分选结果的分析。
在图16A至图16D中:各自实验n=6。纳瓦利辛(Navarixin):CXCR 2拮抗剂;aLy6G:抗-Ly6G抗体治疗。与阴性对照相比:***P<0.001;与阳性对照相比:#P<0.05、##P<0.01、###P<0.001;与仅aPD-1治疗组相比:$$P<0.01、$$$P<0.001(各自实验n=6)。N.S.,不显著。平均值±标准差。
图17A显示根据PLAG和aPD-1治疗的牺牲日在血浆中的腺苷浓度的分析。
图17B显示根据化合物治疗每周牺牲的在血浆中的腺苷浓度的分析。纳瓦利辛:CXCR2拮抗剂;aLy6G:抗-Ly6G抗体治疗。与阴性对照相比:***P<0.001;与阳性对照相比:#P<0.05、##P<0.01、###P<0.001;与仅aPD-1治疗组相比:$$P<0.01、$$$P<0.001(各自实验n=6)。N.S.,不显著。平均值±标准差。
具体实施方式
术语PLAG、EC-18和1-棕榈酰基-2-亚油酰基-3-乙酰甘油在本文中可互换使用并在本文中指代相同的化合物。
定义
本文所使用的缩写具有它们在化学和生物学领域内的常规含义。本文所述的化学结构和化学式是根据化学领域中已知的化学价(chemical valency)的标准规则所构建的。
对于本领域技术人员显而易见的是,本文所揭露的某些化合物可以互变异构(tautomeric)形式存在,所述化合物的所有此类互变异构形式都在本发明的范围内。
如本文所用,术语“一个”或“一种”是指一者或多者。例如,单数形式的“一”、“一者”和“所述”也旨在包括复数形式,除非上下文另有明确说明。将进一步理解的是,当在本说明书中使用术语“包括”、“包含”、“具有”等时,指定了所陈述的特征、区域、整数、步骤、制程、操作、元件和/或组件的存在,但不排除存在或添加其他特征、区域、整数、步骤、制程、操作、元件、组件及/其组合的一者或多者。
“药学上可接受的赋形剂”和“药学上可接受的载体”是指一种有助于将活性剂施用于受试者且被受试者吸收的物质,且可包括在本发明的组成物中,而不会对患者造成显著的不良毒理作用。药学上可接受的赋形剂的非限制性实例包括水、NaCl、生理盐水溶液、乳酸林格氏液、标准蔗糖、标准葡萄糖、粘结剂、填充剂、崩解剂、润滑剂、包衣料、甜味剂、风味剂、盐溶液(如林格氏液)、醇、油、明胶、碳水化合物如乳糖、直链淀粉或淀粉、脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷和颜料等。此类制剂可被灭菌,且若需要,可与不和本发明的化合物发生有害反应的辅助剂混合,所述辅助剂例如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、用于影响渗透压的盐、缓冲剂、着色剂和/或芳香物质等。本领域技术人员将认识到,本发明可使用其他药物赋形剂。
如本文所用,“治疗”和“疗法”包括预防性治疗。治疗方法包括将治疗有效量的活性剂施用于受试者。给药步骤可由单次给药组成或可包括一系列给药。治疗期的长度取决于多种因素,例如病症的严重程度、患者的年龄、活性剂的浓度、治疗中所使用的组成物的活性或其组合。还应当理解,在特定治疗或预防疗法的过程中,可增加或减少使用于治疗或预防的药剂的有效剂量。通过本领域已知的标准诊断测定,可产生剂量的变化并变得明显。在某些情况下,可能需要长期给药。例如,以足以治疗受试者的量和持续时间,将组成物施用于患者。术语“治疗”及其结合词,可包括预防损伤、病理、病症或疾病。在实施例中,治疗是预防。在实施方案中,治疗不包括预防。
术语“预防”是指减少在患者中的疾病症状的发生。如上所述,预防可为完全的(例如,没有检测到的症状)或部分的,因此与未治疗时可能发生的症状相比,所观察到的症状较少。
“患者”、“受试者”、“有需要的患者”和“有需要的受试者”在本文中可互换使用,是指可通过如本文所提供的医药组成物的施用,对患有或易于患有疾病或病症给予治疗的生物体。非限制性实例包括人类、其他哺乳动物、牛、大鼠、小鼠、狗、猴、山羊、绵羊、牛、鹿和其他非哺乳动物。在一些实施例中,患者或受试者是人类。
“有效量”或“治疗有效量”,是相对于化合物的不存在而言,足以使化合物实现所陈述的目的的量(例如,治疗疾病、降低酶活性、增加酶活性、降低分解代谢酶活性或减少疾病或病症的一种或多种症状,以实现给药的效果)。“有效量”的一个实例是足以有助于治疗、预防或减轻疾病的一种或多种症状的量,其也可称为“治疗有效量”。一种或多种症状(以及此短语的语法等效物)的“减少”,意味着症状的严重性或频率的减少,或消除症状。药物的“预防有效量”,是当药物被施用于受试者时,将具有所预期的预防效果的量,例如,预防或延迟损伤、疾病、病理或病症的发作(或复发),或降低伤害、疾病、病理或状况或其症状发作(或复发)的可能性。通过一剂给药,不一定会发生全面的预防效果,且可能发生仅在一系列剂量的给药之后。因此,可在给药一次或多次后施用预防有效量。如本文所用,“活性降低量”是指与不存在拮抗剂相比,降低酶活性所需的拮抗剂的量。如本文所用,“功能破坏量”是指与不存在拮抗剂相比,破坏酶或蛋白质功能所需的拮抗剂的量。确切的量将取决于治疗的目的,且可由本领域技术人员使用已知技术确定(参见,例如,Lieberman,Pharmaceutical Dosage Forms(vols.1-3,1992);Lloyd,The Art,Science andTechnology of Pharmaceutical Compounding(1999);Pickar,Dosage Calculations(1999);以及Remington:The Science and Practice of Pharmacy,20th Edition,2003,Gennaro,Ed.,Lippincott,Williams&Wilkins)。
如本文所用,在对于受试者的疗法的给药的上下文中,术语“联合”是指用以获得治疗益处的一者以上的疗法的使用。在给药的上下文中,术语“联合”也可指当与额外的疗法的至少一者一起使用时,对受试者的疗法的预防性使用。术语“联合”的使用不限于将疗法(例如,第一和第二疗法)施用于受试者的顺序。可对曾具有、具有或易患癌症的受试者,包括已被诊断为患有实体瘤的受试者,在施予第二疗法(例如i)式(I)的单乙酰基二酰基甘油化合物,诸如PLAG的施用或ii))之前(例如,1分钟、5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时或长达约1周之前)、同时或后续(例如,1分钟、5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时或长达约1周之后)施予第一疗法(例如i)一种或多种化疗剂或ii)式(I)的单乙酰基二酰基甘油化合物,诸如PLAG的施用)。按顺序和时间间隔对受试者施用治疗,以使治疗可共同起作用。在一具体的实施方案中,按顺序并在时间间隔内对受试者施用治疗,以使它们提供与若以其他方式施用时相比增加的益处。任何额外的疗法可与其他额外的疗法以任何顺序施用。
术语“增殖性失调(proliferative disorder)”和“增殖性疾病(proliferativedisease)”是指与异常细胞增殖相关的疾病,例如癌症。
如本文所使用的“肿瘤”和“赘生物(neoplasm)”或类似术语,是指由细胞过度生长或增殖所引起的良性或恶性的任何组织的块(mass),包括癌前病变。
“肿瘤形成(neoplasia)”是指以过度增殖或减少的细胞凋亡为特征的疾病或病症。本发明的示例性肿瘤可包括但不限于癌症,包括实体瘤。本发明的进一步示例性肿瘤可包括但不限于膀胱癌、白血病(例如,急性白血病、急性淋巴细胞白血病、急性髓细胞白血病、急性成髓细胞白血病、急性早幼粒细胞白血病、急性髓单核细胞白血病、急性单核细胞白血病、急性红白血病、慢性白血病、慢性髓细胞白血病、慢性淋巴细胞白血病)、真性红细胞增多症、淋巴瘤(霍奇金氏病(Hodgkin's disease)、非霍奇金氏病(non-Hodgkin'sdisease))、瓦尔登斯特伦氏巨球蛋白血症(Waldenstrom's macroglobulinemia)、重链疾病和实体瘤,诸如肉瘤和上皮癌(例如,纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因氏瘤(Ewing's tumor)、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、乳腺癌、卵巢癌、前列腺癌、胃和食道癌、头和颈癌、直肠癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝细胞瘤、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、肾母细胞瘤(Wilm's tumor)、子宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮性癌、神经胶质瘤、胶质母细胞瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、神经鞘瘤、脑膜瘤、黑素瘤、神经母细胞瘤和视网膜母细胞瘤)。在特定实施例中,肿瘤形成是多发性骨髓瘤(multiplemyeloma)、β细胞淋巴瘤(beta-cell lymphoma)、尿路上皮/膀胱癌(urothelial/bladdercarcinoma)或黑素瘤(melanoma)。
“化疗剂”是用于癌症治疗的化合物。化疗剂的实施例包括厄洛替尼(Erlotinib)(TARCEVATM,Genentech/OSI Pharm.)、硼替佐米(Bortezomib)(VELCADETM,MillenniumPharm.)、氟维司群(Fulvestrant)(FASLODEXTM,Astrazeneca)、舒尼替尼(Sutent)(SU11248,Pfizer)、来曲唑(Letrozole)(FEMARATM,Novartis)、甲磺酸伊马替尼(Imatinibmesylate)(GLEEVECTM,Novartis)、PTK787/ZK 222584(Novartis)、奥沙利铂(Oxaliplatin)(EloxatinTM,Sanofi)、5-FU(5-氟尿嘧啶)、甲酰四氢叶酸(Leucovorin)、雷帕霉素((Rapamycin)、西罗莫司(Sirolimus)(RAPAMUNETM,Wyeth)、拉帕替尼(Lapatinib)(GSK572016,GlaxoSmithKline)、洛那法尼(Lonafarnib)(SCH 66336)、索拉非尼(Sorafenib)(BAY43-9006,Bayer Labs.)和吉非替尼(Gefitinib)(IRESSATM,Astrazeneca)、AG1478、AG1571(SU 5271;Sugen)、烷化剂,例如噻替派(Thiotepa)和CYTOXANTM环磷酰胺;烷基磺酸盐,例如白消安、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶类(aziridines),例如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);乙烯亚胺(ethylenimine)和甲基胺基吖啶(methylamelamine),包括六甲蜜胺(altretamine)、三乙撑蜜胺(triethylenemelamine)、三亚乙基磷酰胺(triethylenephosphoramide)、三乙撑硫代磷酰胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylolmelamine);番荔枝内酯(acetogenins)(尤其是布拉它辛(bulatacin)和布拉它辛酮(bulatacinone));喜树碱(包括合成的类似物托泊替康(topotecan));苔藓抑素(bryostatin);卡莉司汀(callystatin);CC-1065(包括其阿多来新(adozcicsin)、卡折来新(carzcicsin)和比折来新(bizcicsin)合成类似物);隐藻素(cryptophycins)(特别是隐藻素1和隐藻素8);多拉司他丁(dolastatin);多卡霉素(duocarmycin)(包括合成类似物,KW-2189和CB1-TM1);软珊瑚醇(eleutherobin);潘拉司他汀(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥(nitrogen mustard),例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、甲氮芥(mechlorethamine)、盐酸氧甲氮芥(mechlorethamine oxidehydrochloride)、美法仑(melphalan)、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶芥(uracilmustard);亚硝脲(nitrosureas),例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷尼司汀(ranimnustine);抗生素,例如烯二炔抗生素(例如,卡奇霉素(calicheamicin),尤其是卡奇霉素γ1和卡奇霉素Ω1(Angew Chem.Intl.Ed.Engl.(1994)33:183-186);达内霉素(dynemicin),包括达内霉素A;双膦酸盐,例如氯膦酸盐(clodronate);埃斯波霉素(esperamicin);以及新制癌菌素生色团(neocarzinostatinchromophore)相关的色素蛋白烯二炔抗生素生色团(chromoprotein enediyneantibiotic chromophores))、阿克拉霉素(aclacinomysins)、放线菌素(actinomycin)、蒽霉素(anthramycin)、重氮丝氨酸(azaserine)、博来霉素(bleomycins)、放线菌素(cactinomycin)、卡比霉素(carabicin)、卡米诺霉素(caminomycin)、嗜癌素(carzinophilin)、色霉素(chromomycinis)、更生霉素(dactinomycin)、柔红霉素(daunorubicin)、去托比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸(6-diazo-5-oxo-L-norleucine)、ADRIAMYCINTM多柔比星(包括吗啉代-多柔比星(morpholino-doxorubicin)、氰基吗啉代-多柔比星(cyanomorpholino-doxorubicin)、2-吡咯啉代-多柔比星(2-pyrrolino-doxorubicin)和脱氧多柔比星(deoxydoxorubicin))、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycins)如丝裂霉素C、霉酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泼非霉素(potfiromycin)、嘌呤霉素(puromycin)、奎那霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(strcptonigrin)、链佐星(strcptozocin)、杀结核菌素(tubcrcidin)、乌苯美司(ubenimcx)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物,例如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,如二甲叶酸(denopterin)、甲氨蝶呤、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,例如氟达拉滨(fludarabine)、6-巯基嘌呤(6-mercaptopurine)、噻咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物,例如安西他滨(ancitabine)、阿扎胞苷(azacytidine)、6-氮尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、多西氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄性激素,例如卡鲁睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺素(anti-adrenals),例如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂(folic acid replenisher)如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);贝斯布西(bestrabucil);比生群(bisantrene;);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);亚胺醌(diaziquone);鸟氨酸(elfornithine);依利醋铵(elliptinium acetate);埃坡霉素(epothilone);依托格鲁(etoglucid);硝酸镓(gallium nitrate);羟基脲(hydroxyurea);香菇多醣(lentinan);洛尼达宁(lonidainine);类美登素(maytansinoids),例如美登素(maytansine)和安丝菌素(ansamitocins);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);二胺硝吖啶(nitraerine);喷司他汀(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基酰肼(2-ethylhydrazide);丙卡巴肼(procarbazine);PSKTM多醣复合物(JHS NaturalProducts);雷佐生(razoxane);根霉素(rhizoxin);西唑呋喃(sizofuran);螺旋锗(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2”-三氯三乙胺(2,2',2”-trichlorotriethylamine);单端孢菌素(trichothecenes)(尤其是T-2毒素、疣孢菌素A(verracurin A)、杆孢菌素A(roridin A)和蛇形菌素(anguidine));脲烷(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);加胞嘧啶(gacytosinc);阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺(cyclophosphamidc);噻替哌(thiotepa);紫杉醇(taxoids),例如TAXOLTM帕利他塞(paclitaxel)、(ABRAXANETM Cremophor-free)、白蛋白改造的紫杉醇纳米颗粒制剂和TAXOTERETM多西他塞(doxetaxel);苯丁酸氮芥(chloranbucil);GEMZARTM吉西他滨(gemcitabine);6-硫鸟嘌呤(6-thioguanine);巯基嘌呤(mercaptopurine);甲氨蝶呤(methotrexate);铂类似物(platinum analogs),例如顺铂(cisplatin)和卡铂(carboplatin);长春碱(vinblastine);铂(platinum);依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine);NAVELBINETM长春瑞滨(vinorelbine);能灭瘤(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基蝶呤(aminopterin);希罗达(xeloda);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂(topoisomerase inhibitor)RFS 2000;二氟甲基鸟氨酸(difluoromethylornithine)(DMFO);维A酸(retinoids),如视黄酸(retinoic acid);卡培他滨(capecitabine);和上述药学上可接受的盐或酸的任一者。
“化疗剂”的定义在此还包括为:(i)用于调节或抑制激素对肿瘤的作用的抗激素剂,例如抗雌激素和选择性雌激素受体调节剂(SERM),包含,例如,他莫昔芬(NOLVADEX)、雷洛昔芬、屈洛昔芬、4-羟基他莫昔芬(4-hydroxytamoxifen)、曲沃昔芬、克昔芬(keoxifene)、LY117018、奥纳普利司通(onapristone)和FARESTONTM(托瑞米芬);(ii)抑制芳香酶的芳香酶抑制剂,芳香酶调节肾上腺中的雌激素产生,诸如,例如,4(5)-咪唑、氨鲁米特(aminoglutethimide)、MEGASETM(醋酸甲地孕酮(megestrol acetate))、AROMASINTM(依西美坦)、福美斯坦、法屈唑、RIVISORTM(伏罗唑)、FEMARATM(来曲唑)和ARIMIDEXTM(阿那曲唑);(iii)抗雄激素,例如氟他胺、尼鲁胺、比卡鲁胺、亮脯利特(leuprolide)和戈舍瑞林;以及曲沙他滨(一种1,3-二氧戊环核苷胞嘧啶类似物);(iv)芳构化酶(aromatase)抑制剂;(v)蛋白激酶抑制剂;(vi)脂质激酶抑制剂;(vii)反义寡核苷酸,特别是那些抑制与异常细胞增殖有关的信号通路中基因表达的那些,诸如,例如,PKC-α、Ralf和H-Ras;(viii)核酶,例如VEGF表达抑制剂(例如,ANGIOZYMETM(核酶))和HER2表达抑制剂;ix)基因治疗疫苗等疫苗,例如ALLOVECTINTM疫苗、LEUVECTINTM疫苗和VAXIDTM疫苗;PROLEUKINTM rIL-2;LURTOTECANTM拓扑异构酶1抑制剂;ABARELIXTM rmRH;(x)抗血管生成剂,例如贝伐珠单抗(AVASTINTM);(xi)上述药学上可接受的盐或酸的任一者。
如所讨论的,在某些方面,优选的化疗剂包括免疫检查点抑制剂。例如,用于本方法及组成物的合适且优选的检查点抑制剂,包括程序性死亡-配体1(PD-L1,也称为B7-H1、CD274)、程序性死亡1(PD-1)、CTLA-4、PD-L2(B7-DC、CD273)、LAG3、TIM3、2B4、A2aR、B7H1、B7H3、B7H4、BTLA、CD2、CD27、CD28、CD30、CD40、CD70、CD80、CD86、CD137、CD160、CD226、CD276、DR3、GAL9、GITR、HAVCR2、HVEM、IDO1、IDO2、ICOS(诱导型T细胞共刺激物)、KIR、LAIR1、LIGHT、MARCO(具有胶原结构的巨噬细胞受体)、PS(磷脂酰丝氨酸)、OX-40、SLAM、TIGHT、VISTA、VTCN1或其任意组合。在一些实施方案中,免疫检查点抑制剂是IDO1、CTLA4、PD-1、LAG3、PD-L1、TIM3或其组合的抑制剂。
在某些优选的组成物及方法中,免疫检查点抑制剂是PD-L1的抑制剂。在某些优选的组成物及方法的一些实施例中,免疫检查点抑制剂是PD-1抑制剂。在某些优选的组成物及方法中,免疫检查点抑制剂是CTLA-4的抑制剂。在某些优选的组成物及方法中,免疫检查点抑制剂是LAG3的抑制剂。在某些优选的组成物及方法中,免疫检查点抑制剂是TIM3抑制剂。在某些优选的组成物及方法中,免疫检查点抑制剂是IDO1抑制剂。
本发明的方法及组成物可有效地减少或抑制患者中的肿瘤生长,例如接受a)一种或多种化疗剂和b)式(I)的单乙酰基二酰基甘油化合物,例如PLAG的治疗的癌症患者。与PLAG和不同的一种或多种化疗剂联合治疗可导致肿瘤体积减少5%、10%、15%、20%、25%、30%、35%、40%、45%或50%或更多。
使用本方法及组成物可治疗多种类型的癌症。例如,待治疗的癌症可为实体瘤。可使用本发明的示例性癌症包括,但不限于,乳腺癌、白血病(例如,kemia、急性白血病、急性淋巴细胞白血病、急性髓细胞白血病、急性成髓细胞白血病、急性早幼粒细胞白血病、急性髓单核细胞白血病、急性单核细胞白血病、急性红白血病、慢性白血病、慢性髓细胞白血病、慢性淋巴细胞白血病)、真性红细胞增多症、淋巴瘤(霍奇金氏病、非霍奇金氏病)、瓦尔登斯特伦氏巨球蛋白血症(Waldenstrom's macroglobulinemia)、重链疾病和实体瘤,诸如肉瘤和上皮癌(例如,纤维肉瘤、粘液肉瘤、脂肪肉瘤、软骨肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤因氏瘤、平滑肌肉瘤、横纹肌肉瘤、结肠癌、胰腺癌、卵巢癌、前列腺癌、胃和食道癌、头和颈癌、直肠癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓样癌、支气管癌、肾细胞癌、肝细胞瘤、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、肾母细胞瘤(Wilm's tumor)、子宫颈癌、子宫癌、睾丸癌、肺癌、小细胞肺癌、膀胱癌、上皮性癌、神经胶质瘤、胶质母细胞瘤、星形细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突神经胶质瘤、神经鞘瘤、脑膜瘤、黑素瘤、神经母细胞瘤和视网膜母细胞瘤)。
例如,在韩国注册专利第10-0789323号和第10-1278874号中显示用于式(I)的单乙酰基二酰基甘油化合物的制备的化学合成方法,其内容通过引用并入本文。例如,PLAG可通过用乙酰基、棕榈酰基和亚油酰基官能团酰化甘油的羟基来合成。
从细胞培养测定中可最初确定式(I)的单乙酰基二酰基甘油化合物例如PLAG和不同的一种或多种化疗剂的治疗有效量。如使用本文所述或本领域已知的方法所测量的,目标浓度将是能够实现本文所述方法的活性化合物的那些浓度。之前也已报导,式(I)的单乙酰基二酰基甘油化合物例如PLAG和不同的一种或多种化疗剂的治疗量。
如本领域公知的,从动物模型中也可确定用于人类的治疗有效量。例如,用于人类的剂量可配制为达到已发现在动物中有效的浓度。如上所述,可通过监测化合物的有效性和向上或向下调整剂量来调整人体中的剂量。基于上述方法和其他方法调整剂量以在人体中实现最大功效,完全在普通技术人员的能力范围内。
剂量可根据患者的需要和所使用的化合物而变化。在本发明的上下文中,给予患者的剂量应足以随时间在患者中产生有益的治疗反应。剂量的大小也将取决于任何不良副作用的存在、性质和程度。为特定情况确定合适的剂量是在从业者的技能范围内。通常,以小于化合物最佳剂量的较小剂量开始治疗。此后,剂量以小的增量增加,直到达到环境下的最佳效果。可单独调整剂量和间隔以提供对所治疗的特定临床适应症有效的给药化合物水平。这将提供与受试者疾病状态的严重程度相称的治疗方案。
利用本文提供的教导,可计划有效的预防性或治疗性治疗方案,该方案不会引起明显的毒性,但仍能有效治疗特定患者表现出的临床症状。该计划应包括,通过考虑诸如化合物效力、相对生物利用度、患者体重、不良副作用的存在和严重程度、优选的给药方式和所选药物的毒性特征等因素,来仔细选择活性化合物。
给予哺乳动物的剂量和频率(单剂量或多剂量)可根据多种因素而变化,例如,无论哺乳动物是否患有另一种疾病及其给药途径;接受者的大小、年龄、性别、健康状况、体重、体重指数和饮食;所治疗的疾病症状的性质和程度、同时治疗的种类、所治疗的疾病的并发症或其他与健康有关的问题。其他治疗方案或药剂可与申请人发明的方法和化合物结合使用。已确定的剂量(例如频率和持续时间)的调整和操作完全在本领域技术人员的能力范围内。
本发明的组成物的给药频率没有特别限制,可一天一次或一天数次分次给药。
需要式(I)或式(II)的化合物(即EC-18)的治疗的患者,例如人,示例性日剂量包括在0.0001mg/kg和4mg/kg之间的体重,或在0.01mg/kg和4mg/kg之间的体重,例如,高达或大约0.001、0.003、0.005、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、2、3或4mg/kg的受试者的体重,例如有需要的人类患者的体重。例如,在一些实施例中,式(I)或式(II)的化合物的有效各周剂量可在0.1μg/kg体重和400μg/kg体重之间,例如有需要的人类患者。在优选的方面,使用口服制剂,例如含有250至1000mg,例如500mg,的式(I)或式(II)的化合物的片剂或胶囊剂(例如软明胶胶囊)。对于特定患者或确定的患者的组,也可凭经验确定最佳剂量。
也可变化且可凭经验确定不同化疗剂的示例性有效每日剂量。若所述药剂已在临床上用于抗癌治疗,则在一方面,所述药剂可使用与之前未使用EC-18的药剂相同或相似的剂量。在某些方面,不同化疗剂的示例性每日剂量可在例如0.1μg/kg和100μg/kg体重之间,例如0.1、0.3、0.5、1、5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或99μg/kg体重。
式(I)的单乙酰基二酰基甘油化合物例如PLAG和一种或多种化疗剂,可通过多种途径中的任一者施用于受试者,例如局部接触、口服、静脉内、腹膜内、肌肉内、病灶内、鞘内、鼻内或皮下给药,或向受试者植入缓释装置,例如微型渗透泵。肠胃外给药包括,例如,静脉内、肌肉内、小动脉内、皮内、皮下、腹膜内、心室内和颅内。
医药组成物可包括包含治疗有效量的式(I)的单乙酰基二酰基甘油化合物,例如PLAG,以及一种或多种化疗剂的其中一者或两者,即以有效实现其预期目的的量包含。对特定应用有效的实际量尤其取决于所治疗的病症。当在治疗疾病的方法中施用时,此类组成物将包含有效量的活性成分以达到所欲的结果,例如调节靶分子的活性和/或减少、消除或减缓疾病症状的进展。
对于每种制剂,医药组成物可与额外的药学上可接受的载体一起制造。如本文所用,术语“药学上可接受的载体”可指不刺激生物体且不抑制注射化合物的生物活性和特征的载体或稀释剂。可用于本发明的载体的种类没有特别限制,可使用工业领域中常用的和药学上可接受的任何载体。
盐水、无菌水、静脉输液、缓冲盐水、白蛋白注射液、葡萄糖溶液、麦芽糖糊精溶液、甘油、乙醇是可用载体的非限制性实例。这些载体可单独或两者或更多者组合使用。所述载体可包括非天然存在的载体。如果需要,可添加和使用其他常规使用的添加剂,如抗氧化剂、缓冲剂和/或抑菌剂。可与稀释剂、分散剂、表面活性剂、粘合剂、润滑剂等配制成水溶液、混悬剂、乳剂等注射液,以及丸剂、胶囊剂、颗粒剂或片剂等。
当需要或希望肠胃外施用时,用于医药组成物中所含化合物的特别合适的混合物,可为可注射的、无菌溶液、油性或水溶液,以及悬浮液、乳液或植入物,包括栓剂。特别地,用于肠胃外给药的载体包括右旋糖、盐水、纯水、乙醇、甘油、丙二醇、花生油、芝麻油、聚氧乙烯嵌段聚合物等的水溶液。安瓿是方便的单位剂量。适合用于本文所呈现的医药组成物中的药物混合物,可包括例如在Pharmaceutical Sciences(第17版,Mack Pub.Co.,Easton,PA)和WO 96/05309中所描述的那些,两者的教导特此皆通过引用并入。
如所讨论的,还提供套件。例如,在此方面,式(I)的单乙酰基二酰基甘油化合物,例如PLAG,以及一种或多种化疗剂,各自合适地包装在标记为特定治疗的合适容器中。所述容器视预期用途而定,可包括PLAG化合物或组成物、一种或多种化疗剂以及合适的稳定剂的一者或多者、载体分子和/或类似物。在其他实施例中,所述试剂盒还包含预期治疗的治疗剂的一者或多者,例如额外一种或多种化疗剂。产品可包括容器(例如,小瓶、罐、瓶、袋等),其含有PLAG化合物或组成物和/或一种或多种化疗剂。此外,制品或试剂盒可进一步包括,例如,包装材料、使用说明、注射器、递送装置、治疗或监测需要预防或治疗的病症。
产品可进一步包括图例(例如,印刷的标签或插件或描述产品用途的其他介质(例如,录音带或录像带))。图例可与容器相关(例如,贴在容器上)且可描述其中的组成物所应施用的方式(例如,施用的频率和途径)、其适应症和其他用途。可备好给药(例如,以剂量适当的单位存在)的组成物,且可包括额外的药学上可接受的佐剂、载体或其他稀释剂和/或额外的治疗剂的一者或多者。或者,组成物可例如以浓缩形式提供,具有稀释剂和稀释说明。
如所讨论的,单乙酰基二酰基甘油化合物,如PLAG,以及不同一种或多种化疗剂,合适地以联合方式施用,例如,同时或依顺序施用。例如,单乙酰基二酰基甘油化合物,如PLAG,以不同一种或多种化疗剂,合适地在数小时内,可实质上同时施用于受试者,或可在不同时间施用这些药剂于受试者,即便分开施用之间的较长时间也可适用。
实施例
为了清楚理解的目的,尽管已通过说明和实施例的方式对前述部分进行一些详细的描述,但对于本领域技术人员而言,根据上述教导将实施某些小的改变和修改是显而易见的。因此,描述和实施例不应被解释为限制本文描述的任何发明的范围。
本文引用的所有参考文献,包括专利申请和出版物,均通过引用整体并入本文。
实施例1:在异种移植小鼠模型中,PLAG与AC-疗法组合的抗癌作用
使用MDA-MB-231乳腺癌异种移植模型。在单独的AC-疗法和PLAG联合治疗的动物中评价肿瘤生长。AC-疗法为使用2/20和5/50mph(多柔比星/环磷酰胺)的剂量,每周两次通过腹腔注射,且PLAG为使用100和250mpk每天施用。以3天的间隔计算肿瘤生长。中性粒细胞趋化性相关趋化因子、CXCL1/2/8和循环中性粒细胞也在2周内进行评价。通过免疫组织化学(IHC)分析肿瘤病灶中凋亡分子标志物Bax/Bak和肿瘤浸润性中性粒细胞(TIN)的表达。
PLAG具有降低以PLAG和AC-疗法共疗法共治疗的异种移植小鼠的肿瘤负荷的协同效应。在使用2/20或5/50mpk治疗组的AC-疗法中,通过计算肿瘤尺寸观察到肿瘤生长的延迟,且通过TUNEL证明所处理的细胞凋亡,并使用AC-疗法回归肿瘤负荷中细胞凋亡相关蛋白的表达。也检测到取决于肿块的来自肿瘤负荷和随后的中性粒细胞募集的调节趋化因子表达。在PLAG联合治疗组中,直到牺牲为止,持续观察到比单独AC-疗法更小的肿瘤负荷。还证实,与单独AC-疗法组(p<0.05)相比,使用5/50AC-疗法与PLAG联合治疗组的肿瘤负荷以浓度依赖性方式显著降低。尤其是在250mpkPLAG联合治疗组中,在牺牲日并未发现试验小鼠中的肿瘤组织。通过IHC和趋化因子分析,证明PLAG添加组中趋化因子表达和TIN显著降低。此外,在PLAG单独治疗组中,观察到肿瘤生长中断、趋化因子表达和TIN降低。总之,PLAG对在使用AC-疗法联合治疗的受试者中的肿瘤负荷的消退具有协同效应。使用IHC分析肿瘤组织显示,PLAG联合治疗组的TIN显著降低。结果也列出于图1、图2(包括图2A至图2J)和图3(包括图3A至图3D)中。
实施例2:PLAG的抗癌作用
图4(包括图4A至图4G)、5(包括图5A至图5D)和图6(包括图6A和图6B)显示使用PLAG对癌症的治疗。这些结果表明,使用PLAG治疗可有效调节中性粒细胞趋化因子在癌组织中的表达,从而控制中性粒细胞的过度浸润。这些结果表明,单独施用PLAG(没有额外的化疗剂)可通过抑制癌组织的细胞周期来调节过度生长。这些结果也表明,PLAG的施用可通过诱导癌组织中的PAR2降解,来抑制细胞周期和趋化因子的表达。
实施例3:PLAG对MB49膀胱癌同系(syngeneic)模型中PD-L1免疫检查点药物治疗的影响
第四代抗癌药,免疫检查点药物的研制,是抗癌研究的重大突破。使用免疫检查点药物的癌症治疗仍在扩大。为了提高免疫检查点药物的疗效,实质上需要肿瘤微环境的调节。在本实验中,我们检测了1-棕榈酰基-2-亚油酰基-3-乙酰甘油(PLAG)的提高的抗癌功效,PLAG已被证明,与PD-L1免疫检查点抑制剂共同治疗,可减弱肿瘤中的肿瘤浸润性中性粒细胞(TIN)。
方法
使用同系模型(n=6)以研究加入PLAG后PD-L1抗体的抗肿瘤作用增强。将MB49鼠膀胱癌细胞为皮下植入C57BL/6小鼠中并饲养5周。肿瘤植入一周后,使用或不使用5mpkPD-L1抗体(10F.9G2),每天口服不同剂量(50/100mpk)的PLAG,持续4周。每周一次通过IP注射递送PD-L1抗体。(图7,表1)
表1
结果
PLAG治疗组证明,肿瘤负荷以浓度依赖性方式降低。与阳性对照相比,在50和100mpk的PLAG治疗小鼠中,肿瘤负荷降低至显著值(p<0.05)。在单独使用PD-L1抗体治疗的组中,下降的肿瘤的生长速度直至约2周。在同时使用PLAG和PD-L1抗体治疗的组中,与单独使用PD-L1抗体治疗的组相比,肿瘤的生长显著减少。图8A至图8C中显示,通过PLAG治疗增加的aPD-L1对肿瘤进展的抑制作用。
PLAG治疗对中性粒细胞群和肿瘤浸润的控制显示在图9A至图9E中,且PLAG治疗对淋巴细胞群和肿瘤浸润的控制显示在图10A至图10G中。每两周计算一次中性粒细胞和淋巴细胞的结果是,与单独使用PD-L1抗体治疗的组相比,使用PLAG和PD-L1治疗的组的中性粒细胞与淋巴细胞比率(NLR)含量显著降低。此外,单独通过PLAG治疗即可有效减少TIN的数量。
在图11A至图11E中证实,通过PLAG治疗参与免疫细胞群的细胞因子和趋化因子分泌。在PLAG治疗的组中,也观察到肿瘤生长中断和趋化因子分泌减少。总之,我们的数据建议,通过减少TIN的数量,PLAG提供增强的PD-L1抗体对同系小鼠模型中肿瘤负荷消退的影响。
结论
PLAG可提高PD-L1抗体在减少破坏性肿瘤微环境中的肿瘤负担方面的功效。PLAG不仅更有效地增加aPD-L1的抗肿瘤作用,还可自行抑制肿瘤进展。特别是,由PLAG有效地减少了增加肿瘤进展的肿瘤浸润性中性粒细胞(TIN)。通过PLAG有效减少TINs的数量,进一步增强了细胞毒性T淋巴细胞(CTLs)的抗肿瘤作用。
实施例4:PLAG对LLC-1同系模型中的PD-1免疫检查点抑制剂治疗的协同抗癌作用
背景
尽管针对各种适应症的免疫检查点抑制剂(ICI)疗法的使用一直在增加,但已证明一些不同类型癌症的患者对ICI没有反应。为了提高ICI反应率,可能需要针对其他机制的联合疗法,通过调节肿瘤微环境来防止肿瘤免疫逃避。
方法
为了研究抗PD-1抗体(aPD-1添加1-棕榈酰基-2-亚油酰基-3-乙酰甘油(PLAG)后增强的抗肿瘤作用,使用同系模型(n=6/组),将LLC-1肺癌经皮下植入至C57BL/6小鼠体内。使用或不使用aPD-1(RMP 1-14),每天施用PLAG,持续4周。aPD-1每周一次通过IP注射递送。分析在牺牲日的肿瘤和血液中淋巴细胞群和中性粒细胞的浸润程度(图12、表2)。
表2
结果
在PLAG治疗的50和100mpk小鼠组中,与阳性对照p 0 05相比,肿瘤负荷显著降低。在单独使用aPD-1治疗的组中,与阳性对照相比,肿瘤生长减少约65。然而,与单独使用aPD-1相比,在使用PLAG联合治疗的小鼠中,肿瘤显著减少18。PLAG与抗PD-1抗体(aPD-1)的协同抗肿瘤作用如图13A至图13D所示。
与单独使用aPD-1相比,使用PLAG联合治疗的组的中性粒细胞与淋巴细胞比率含量显著降低。特别是,PLAG治疗有效降低肿瘤中的中性粒细胞浸润程度。PLAG和aPD-1治疗对免疫细胞群和肿瘤浸润的影响显示在图14A至图14D中,并且PLAG和aPD-1治疗对Th17群的调节和肿瘤浸润的影响显示在图15A和图15B中。如图16A至图16D所示,PLAG可作为调节剂,而不是中性粒细胞浸润和迁移的抑制剂。进一步如图17A和图17B所示,PLAG可通过快速去除DAMP来防止由于肿瘤进展而增加的DAMP。
与单独使用aPD-1相比,使用PLAG联合治疗的组的肿瘤中,细胞毒性T淋巴细胞(CTL)的活性和浸润有效增加。与阳性对照相比,这种改善是由诱导肿瘤中大量中性粒细胞浸润的Th17群体的显著减少所引起的。
结论
PLAG通过减少肿瘤浸润性中性粒细胞和Th17群同时增加CTL,协同增强aPD-1对肿瘤负荷消退的抗癌作用。因此,将具有优异安全性的aPD-1与PLAG结合,可有助于增强aPD-1的抗肿瘤反应,同时通过减少ICI的剂量来降低免疫相关毒性。
PLAG不仅与使用aPD-1对肿瘤进展具有协同抗肿瘤作用,且其本身也可抑制肿瘤进展。PLAG通过快速去除源自肿瘤的DAMP(腺苷),来减少肿瘤浸润性中性粒细胞(TIN)。通过PLAG去除最初的DAMP(腺苷),中性粒细胞不会大量浸润到肿瘤区域。PLAG减少Th17群体和肿瘤浸润Th17细胞,这些细胞参与了过度中性粒细胞浸润到肿瘤部位。
因此,与单独的aPD-1相比,aPD-1和PLAG的组合可改善aPD-1的治疗结果,通过对抑制性肿瘤微环境(TME)进行治疗,有助于增强抗肿瘤免疫反应。据推测,PLAG治疗可通过中性粒细胞募集到TME的抑制以及T细胞的抗肿瘤免疫的增强,将免疫抑制性TME转变为免疫增强型TME。
应当理解,本文描述的实例和实施例仅用于说明目的,并且将向本领域的技术人员提出根据其的各种修改或改变,并且将被包括在本申请的精神和范围内以及本申请所附的权利要求书的范围内。本文引用的所有出版物、专利和专利申请均出于所有目的通过引用整体并入本文。
Claims (29)
2.根据权利要求1所述的方法,其中,所述a)一种或多种化疗剂包含免疫检查点抑制剂。
3.根据权利要求2所述的方法,其中,所述一种或多种免疫检查点抑制剂包含派姆单抗、尼鲁单抗、西米普利单抗、阿替珠单抗、阿维单抗、德瓦鲁单抗和/或伊派利单抗。
4.根据权利要求2或3所述的方法,其中,所述一种或多种免疫检查点抑制剂包含PD-L1抑制剂。
5.根据权利要求1至4中任一项所述的方法,其中,所述a)一种或多种化疗剂包含多柔比星。
6.根据权利要求1至5中任一项所述的方法,其中,所述a)一种或多种化疗剂包含环磷酰胺。
7.根据权利要求1至6中任一项所述的方法,其中,所述a)一种或多种化疗剂包含AC-疗法。
8.根据权利要求1至7中任一项所述的方法,其中,所述a)一种或多种化疗剂是5-FU、顺铂、依托泊苷、异环磷酰胺、美司钠、吉西他滨和/或他莫昔芬。
10.根据权利要求1至9中任一项所述的方法,其中,所述a)一种或多种化疗剂以及b)式(I)的化合物实质上同时施用。
11.根据权利要求1至10中任一项所述的方法,其中,所述a)一种或多种化疗剂以及b)式(I)化合物依序施用。
12.根据权利要求1至11中任一项所述的方法,其中,所述受试者患有乳腺癌。
13.根据权利要求1至12中任一项所述的方法,其中,所述受试者具有实体瘤。
15.根据权利要求14所述的方法,其中,向所述受试者施用AC-疗法。
17.根据权利要求14至16中任一项所述的方法,其中,所述a)多柔比星和/或环磷酰胺以及b)式(I)的化合物实质上同时施用。
18.根据权利要求14至17中任一项所述的方法,其中,所述a)多柔比星和/或环磷酰胺以及b)式(I)的化合物依序施用。
19.根据权利要求1至18中任一项所述的方法,其中,所述施用导致肿瘤细胞的数量减少。
20.根据权利要求1至19中任一项所述的方法,其中,所述受试者是人类。
21.根据权利要求1至20中任一项所述的方法,其中,所述受试者亦使用放射、额外的化疗、手术、治疗抗体、免疫调节剂、蛋白酶体抑制剂、广泛性DAC抑制剂、H-DAC抑制剂、检查点抑制剂、包含CAR T及NK细胞疗法的过继细胞疗法和/或疫苗来治疗。
23.根据权利要求22所述的试剂盒,其中,所述a)一种或多种化疗剂包含免疫检查点抑制剂。
24.根据权利要求23所述的试剂盒,其中,所述一种或多种免疫检查点抑制剂包含派姆单抗、尼鲁单抗、西米普利单抗、阿替珠单抗、阿维单抗、德瓦鲁单抗和/或伊派利单抗。
25.根据权利要求23或24所述的试剂盒,其中,所述一种或多种免疫检查点抑制剂包含PD-L1抑制剂。
27.根据权利要求22至26中任一项所述的试剂盒,进一步包含癌症治疗的说明书。
28.根据权利要求27所述的试剂盒,其中,所述说明是书面产品插件或产品标签。
29.根据权利要求27或28所述的试剂盒,其中,所述说明用于乳腺癌的治疗。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1946392A (zh) * | 2004-04-24 | 2007-04-11 | 金尚姬 | 含有单乙酰基二酰基甘油衍生物的免疫调节剂、抗癌剂和健康食品 |
CN106535887A (zh) * | 2014-05-15 | 2017-03-22 | 株式会社Enzychem生命科学 | 治疗白细胞减少症和血小板减少症的方法 |
CN109476748A (zh) * | 2016-08-08 | 2019-03-15 | 豪夫迈·罗氏有限公司 | 用于癌症的治疗和诊断方法 |
CA3084594A1 (en) * | 2017-11-30 | 2019-06-06 | Enzychem Lifesciences Corporation | Compositions for prevention or treatment of acute radiation syndrome |
CN113613670A (zh) * | 2019-01-16 | 2021-11-05 | Enzychem生命科学株式会社 | 治疗癌症的方法和组合物 |
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WO2005112912A1 (en) * | 2004-04-24 | 2005-12-01 | Sang-Hee Kim | Immunomoduating agent, anti-cancer agent and health food containing monoacetyldiacylglycerol derivatives |
KR101621851B1 (ko) * | 2013-08-19 | 2016-05-31 | 한국생명공학연구원 | 모노아세틸디아실글리세롤 화합물을 유효성분으로 함유하는 혈액암 또는 암전이 억제용 조성물 |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1946392A (zh) * | 2004-04-24 | 2007-04-11 | 金尚姬 | 含有单乙酰基二酰基甘油衍生物的免疫调节剂、抗癌剂和健康食品 |
CN106535887A (zh) * | 2014-05-15 | 2017-03-22 | 株式会社Enzychem生命科学 | 治疗白细胞减少症和血小板减少症的方法 |
CN109476748A (zh) * | 2016-08-08 | 2019-03-15 | 豪夫迈·罗氏有限公司 | 用于癌症的治疗和诊断方法 |
CA3084594A1 (en) * | 2017-11-30 | 2019-06-06 | Enzychem Lifesciences Corporation | Compositions for prevention or treatment of acute radiation syndrome |
CN113613670A (zh) * | 2019-01-16 | 2021-11-05 | Enzychem生命科学株式会社 | 治疗癌症的方法和组合物 |
Non-Patent Citations (2)
Title |
---|
JINSEON JEONG ET AL: "1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation", 《CELL & BIOSCIENCE》, vol. 9, pages 1 - 15, XP055819793, DOI: 10.1186/s13578-018-0266-7 * |
MYUNG-HWAN KIM ET AL: "EC-18, a Synthetic Monoacetyldiacylglyceride, Inhibits Hematogenous Metastasis of KIGB-5 Biliary Cancer Cell in Hamster Model", 《JOURNAL OF KOREAN MEDICAL SCIENCE》, vol. 24, pages 474 - 480, XP055321285, DOI: 10.3346/jkms.2009.24.3.474 * |
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