CN112469429A - Ccr5抑制剂在癌症治疗中的应用 - Google Patents
Ccr5抑制剂在癌症治疗中的应用 Download PDFInfo
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Abstract
本发明提供治疗癌症的方法,其包括向对象施用CCR5抑制剂。
Description
相关申请的交叉引用
本申请要求在2018年5月28日提交的第62/677,114号美国临时专利申请和在2019年1月15日提交的第62/792,600号美国临时专利申请的权益和优先权,其均通过引用的方式整体并入本文中。
技术领域
本申请涉及治疗癌症的方法。
背景技术
趋化因子和趋化因子受体已涉及多种疾病。一种趋化因子可以结合到几种趋化因子受体上,反之亦然,从而它们就形成一个繁复系统。
在已知的趋化因子受体中,C-C趋化因子受体5型(CCR5)已被鉴定为介导HIV进入的共受体。CCR5在细胞表面存在至少两种构象,在对它们存在的可能解释中,一种构象由G蛋白偶联的CCR5组成,另一种由G蛋白未偶联的CCR5组成。C-C趋化因子CCL3、CCL4和CCL5是主要的CCR5内源性激动剂。CCL5,也称为RANTES(在活化时被调节,正常T细胞表达和分泌),除了CCR5外,已经显示其还与C-C趋化因子受体1型(CCR1)和C-C趋化因子受体3型(CCR3)相互作用。
内源性CCR5激动剂的参与导致了全部细胞内信号传导通路的活化,这些通路广泛定义为G蛋白依赖性和G蛋白非依赖性信号传导通路。G蛋白依赖性信号传导的一种表现是诱导细胞内钙流。G蛋白非依赖性信号传导的一种表现是诱导受体内化,导致细胞内受体隐蔽(receptor sequestration)。
CCR5属于G蛋白偶联受体超家族。对于该超家族的成员,已经鉴定了能够优先活化G蛋白依赖性信号传导通路或G蛋白非依赖性信号传导通路的配体。这些配体,统称为“偏向性配体(biased ligand)”,已经证明具有令人感兴趣的药理学和制药学特性,能够选择性地活化或抑制某些病理学感兴趣的通路。
CCR5由某些癌细胞表达,其中其活化被认为提供了存活和转移信号。此外,CCR5在浸润肿瘤并抑制抗肿瘤免疫应答的免疫调节白细胞(M2巨噬细胞和调节T细胞)上表达。
马拉韦罗(Maraviroc,MVC)是目前批准用于治疗HIV感染的CCR5抑制剂。此外,马拉韦罗还显示在体外(Pervaiz A.et al.Med Oncol.2015;32(5):158;ZiJ.et al.Am J Cancer Res.2017;7(4):869-80)和体内癌症模型(Ward S.T.et al.Br JCancer.2015;112(2):319-28;Tanabe Y.et al.Oncotarget.2016;7(30):48335-45)中均具有活性。
此外,接受口服马拉韦罗的转移性结直肠癌(mCRC)患者显示出可能抑制肿瘤生长或转移的肿瘤微环境变化的证据。在一些情况下,患者也经历了对马拉韦罗治疗的临床应答,包括转移性疾病的消退(Halama N.et al.Cancer Cell.2016;29(4):587-601)。
发明内容
在一个方面,提供一种治疗癌症的方法,所述方法包含向对象施用CCR5抑制剂,其中所述CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列(signature sequence)QGP[P或L],且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同。
在本发明所述方法的一个实施方案中,所述CCR5抑制剂抑制HIV进入细胞,且相较于CCR1和CCR3,所述CCR5抑制剂是CCR5选择性的。
在本发明所述方法的一个实施方案中,所述CCR5抑制剂仅抑制CCR5细胞内信号传导通路的亚组(subset)。
在本发明所述方法的一个实施方案中,所述CCR5抑制剂抑制或减少CCR5的炎性作用,例如,当在钙流信号传导测定中以300nM的浓度测试时,导致信号传导应答为PSC-RANTES引发的最大应答(Emax)的30%或更低。
在本发明所述方法的一个实施方案中,所述特征序列为QGP[P或L][L或G或S或M][M或D或S或Q或G]。
在本发明所述方法的一个实施方案中,所述特征序列为QGP[P或L][L或G或S或M][M或D或S或Q或G]XX[Q或G或L或A或T或S]X,其中X表示任何天然的或修饰的氨基酸。
在本发明所述方法的一个实施方案中,所述特征序列为QGP[P或L]LM或QGPPG[D或S]。
在本发明所述方法的一个实施方案中,所述特征序列为QGPPLM或QGPPGD。
在本发明所述方法的一个实施方案中,所述特征序列为QGP[P或L][L或M][M或Q][A或W或G或Q或N]X[Q或G或L][S或V或T或G],其中X表示任何天然的或修饰的氨基酸。
在本发明所述方法的一个实施方案中,所述特征序列为QGPPLM[A或W][L或T或M][Q或G][S或V或T或G]。
在本发明所述方法的一个实施方案中,所述特征序列为QGPP[G或L][M或Q]XX[Q或S][S或V],其中X表示任何天然的或修饰的氨基酸。
在本发明所述方法的一个实施方案中,所述特征序列选自QGPPLMALQS(SEQ IDNO:2)、QGPPLMWMQV(SEQ ID NO:3)、QGPPLMWLQV(SEQ ID NO:4)、QGPPLMWTQS(SEQ ID NO:5)、QGPPLMWLQT(SEQ ID NO:6)、QGPPLMWTQV(SEQ ID NO:7)、QGPPLMWMQS(SEQ ID NO:8)、QGPPLMATQS(SEQ ID NO:9)、QGPPLMWLQS(SEQ ID NO:10)、QGPPLMALQV(SEQ ID NO:11)、QGPPLMWLGG(SEQ ID NO:12)、QGPPLMWRGS(SEQ ID NO:13)、QGPLLMWLQV(SEQ ID NO:14)、QGPPLMQTTP(SEQ ID NO:15)、QGPPLSWLQV(SEQ ID NO:30)、QGPPLSWLQS(SEQ ID NO:31)、QGPPGQWSQV(SEQ ID NO:32)、QGPPMMAGLS(SEQ ID NO:33)、QGPPLSWQQS(SEQ ID NO:34)、QGPPGMWSQS(SEQ ID NO:35)、QGPPLQWRQS(SEQ ID NO:36)、QGPPLMGTQS(SEQ ID NO:37)、QGPPLMQLQV(SEQ ID NO:38)、QGPPLSWSQV(SEQ ID NO:39)、QGPPMSWSQS(SEQ ID NO:40)、QGPPLMNLQV(SEQ ID NO:41)、QGPPMSAYQV(SEQ ID NO:42)和QGPPMQGGLS(SEQ ID NO:43)。
在本发明所述方法的一个实施方案中,所述特征序列选自QGPPLMALQS(SEQ IDNO:2)、QGPPLMWMQV(SEQ ID NO:3)、QGPPLMWLQV(SEQ ID NO:4)、QGPPLMWTQS(SEQ ID NO:5)、QGPPLMWLQT(SEQ ID NO:6)、QGPPLMWTQV(SEQ ID NO:7)、QGPPLMWMQS(SEQ ID NO:8)、QGPPLMATQS(SEQ ID NO:9)、QGPPLMWLQS(SEQ ID NO:10)、QGPPLMALQV(SEQ ID NO:11)、QGPPLMWLGG(SEQ ID NO:12)、QGPPLMWRGS(SEQ ID NO:13)、QGPLLMWLQV(SEQ ID NO:14)和QGPPLMQTTP(SEQ ID NO:15)。
在本发明所述方法的一个实施方案中,所述特征序列为QGPPLMATQS(SEQ ID NO:9)。
在本发明所述方法的一个实施方案中,所述特征序列位于最N末端。
在本发明所述方法的一个实施方案中,所述C末端部分与SEQ ID NO:1相同。
在本发明所述方法的一个实施方案中,其中所述CCR5抑制剂包含SEQ ID NO:70的氨基酸序列。
在本发明所述方法的一个实施方案中,所述癌症为结直肠癌、乳腺癌、肺癌、前列腺癌、卵巢癌、胰腺癌、食管癌、胃癌、肝癌或白血病。
在本发明所述方法的一个实施方案中,其中所述癌症是转移性的。
在本发明所述方法的一个实施方案中,其中所述癌症是化疗或放疗难治性的和/或对化疗或放疗具有抗性的。
对本领域普通技术人员而言,在结合附图阅读本发明具体实施方案的下述描述之后,本发明的其他方面和特征将是明显的。
附图说明
图1示出了与各种已知的CCR5抑制剂相比,5P12-RANTES在抑制通过人CCR5的信号传导中的效力。
图2示出了5P12-RANTES与AZT和MVC的抗HIV效力的比较。
图3示出了5P12-RANTES既不拮抗CCR1也不拮抗CCR3。
图4示出了5P12-RANTES在结直肠癌动物模型中的功效。“QD”表示每日给药,“Q3D”表示每三天给药。
具体实施方式
本发明人惊奇地发现,N-末端修饰的RANTES变体,即5P12-RANTES(SEQ ID NO:70),在抑制CCR5信号传导和/或HIV-1复制方面相对于马拉韦罗(MVC)更加有效。本发明人进一步证实,与MVC一样,相较于CCR1和CCR3,5P12-RANTES是CCR5选择性的。此外,在5P12-RANTES的临床前评价中,该化合物以20mg/kg的剂量以单剂量静脉输注施用给食蟹猴(cynomolgus macaque)和大鼠,没有任何不良事件。这些发现表明,与已知对几种类型的癌症治疗有效的MVC相比,这种N-末端修饰的RANTES变体及其结构相关的类似物具有增强的功效,且具有非常小的副作用。本发明人已经证明了5P12-RANTES在结直肠癌动物模型中的功效。
因此,本发明的方法涉及通过向对象施用CCR5抑制剂、特别是包含N-末端部分和C-末端部分的多肽来治疗癌症,其中所述N-末端部分包含特征序列QGP[P或L],即特征序列的第四位置为P或L,且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同。
不受理论限制,认为本文提供的CCR5抑制剂能够抑制癌细胞生长和/或重编程免疫调节白细胞(例如诱导“肿瘤-浸润巨噬细胞从免疫抑制(M2)表型到免疫刺激(M1)表型”的表型转变)。还认为本文提供的CCR5抑制剂对肿瘤突变负荷不敏感。
CCR5抑制剂
本发明所用术语“CCR5抑制剂”是指抑制由CCR5诱导的一种或多种生物和/或病理活动的分子或化合物。CCR5抑制剂可以通过实现部分或完全占据CCR5上它们相互作用所需的一个或多个位点来阻止配体或病原体的结合(正构抑制剂)。或者,CCR5抑制剂可以通过占有CCR5上的其他位点并诱导CCR5采取配体或病原体不能识别的一种或多种构象来阻止配体或病原体的结合(变构抑制剂)。CCR5抑制剂可抑制CCR5细胞内信号传导通路的全部或仅亚组。CCR5抑制剂也可以通过引发CCR5的长期细胞内隔离而起作用,使得其不能被胞外配体或病原体接近。CCR5抑制剂也可以通过特异性抑制或去除CCR5基因的表达而起作用。CCR5抑制剂也可以通过与一种或多种配体或病原体结合,从而使它们不能与CCR5结合而起作用。
可用于本发明方法的CCR5抑制剂是HIV进入细胞的高效抑制剂,即具有高的抗HIV效力,且相较于受体CCR1和CCR3,CCR5抑制剂是CCR5选择性的;并且还可具有结合多种细胞表面构象的CCR5的能力,和/或仅引发低度的促炎信号传导,和/或仅抑制全部CCR5细胞内信号传导通路的亚组,和/或引发CCR5内化到细胞中(受体隐蔽、下调或下行性调节)。
在本发明的上下文中,对于具有IC50值的CCR5抑制剂使用表述“高抗HIV效力”、“高的效力”或“高效”,如通过美国专利第8,686,111号的材料和方法部分中所述的细胞融合或HIV复制测定所测量的,为1000pM(1nM)或更低,例如低于900、800、700、600、500、400、300、200、150、140、130、120、110、100、90、80、70、60、50、40、30或20pM。在一些实施方案中,通过如实施例1所述的CCR5信号传导测定或如本申请实施例2所述的HIV复制测定所测量的,可用于本发明方法的CCR5抑制剂比MVC更有效,例如比MVC更有效至少2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、11倍、12倍、13倍、14倍、15倍、16倍、17倍、18倍、19倍、20倍、21倍、22倍、23倍、24倍、25倍、26倍、27倍、28倍、29倍或30倍。
在本发明的上下文中,如果CCR5抑制剂基本上不活化CCR1和/或CCR3,则与CCR1和/或CCR3以及CCR5结合的CCR5抑制剂仍被认为相较于CCR1和/或CCR3,对CCR5具有选择性。在一些实施方案中,可用于本发明方法的CCR5抑制剂基本上不结合也基本上不活化CCR1和CCR3。在本发明的上下文中,如果CCR5抑制剂对于CCR1和/或CCR3结合的IC50值大于50nM,例如大于60、70、80、90、100、110、120、130、140、150、200、300、400、500、600、700、800、900或1000nM,则认为CCR5抑制剂基本上不结合CCR1和/或CCR3,如使用美国专利第8,686,111号材料和方法部分中所述的CCR1偏爱结合(Discrimination Binding Assay)测定和/或CCR3偏爱结合测定所测量的。相较于CCR1和/或CCR3活化的选择性CCR5活化可通过美国专利第8,686,111号材料和方法部分所述的钙流测定来评价。在本发明的上下文中,如果通过美国专利号第8,686,111号的材料和方法部分中所述的钙流测定所测量的,如果CCR5抑制剂的信号传导活性低于该受体由天然RANTES/CCL5引发的Emax的30%,例如低于26%、22%、20%、18%、16%、14%、12%、10%、8%、6%、4%、2%或1%,则认为其基本上不活化CCR1和/或CCR3。
在本发明上下文中,如果CCR5抑制剂与CCR5的结合不受不可水解的GTP类似物如GTPγS(鸟苷5'-O-(γ-硫代)-三磷酸)或Gpp(NH)p(鸟苷5'-(β,γ-酰亚胺)三磷酸)的存在或不存在的影响,则认为CCR5抑制剂以G蛋白偶联和未偶联的构象与CCR5结合。如果特异性结合的放射性标记的抑制剂在存在或不存在Gpp(NH)P或存在100μM Gpp(NH)P下差异相差小于20%,例如小于18%、16%、14%、12%、10%、8%、6%、5%、4%、3%、2%或1%,则认为CCR5抑制剂与CCR5的结合不受存在或不存在不可水解的GTP类似物的影响,如通过放射性配体结合测定所测量的,如Colin P.et al.Proc Natl Acad Sci U S A 2013;110(23):9475–9480的图3D和图3E中以及在支持信息(Supporting Information)中所述的。
在本发明上下文中,具有“低信号传导活性”的CCR5抑制剂,即它们的施用和/或与CCR5结合仅在靶细胞中引起低度的促炎信号传导,当在美国专利第8,686,111号的材料和方法部分中所述的钙流信号传导测定中以300nM的浓度测试时,导致信号传导应答为PSC-RANTES引发的最大应答(Emax)的30%或更低。例如,本发明所述方法中使用的CCR5抑制剂可具有信号传导活性,如在钙流信号传导测定中所测量的,低于PSC-RANTES引发的最大应答(Emax)的30%、26%、22%、20%、18%、16%、14%、12%、10%、8%、6%、4%、2%或1%。PSC-RANTES的序列为R1-SSDTTPCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTRKNRQVCANPEKKWVREYINSLEMS,其中R1=Nα-(正壬酰基)-脱-Ser1-[L-硫代脯氨酰基2,L-环己基甘氨酰基3]。
[A]在本发明的上下文中,具有“高受体隐蔽活性”的CCR5抑制剂,即它们的施用和/或与CCR5结合引起高度受体隐蔽(所述隔离可以是受体内化、下调或下行性调节),当在如美国专利第8,686,111号的材料和方法部分所述的CCR5表面下行性调节/受体隐蔽测定中测试时,导致对照水平的表面CCR5分子的至少50%的隔离。例如,CCR5抑制剂可具有超过对照水平的表面CCR5的50%、55%、60%、65%、70%、80%、85%、90%或95%的受体隐蔽活性。
在一些实施方案中,可用于本发明方法的CCR5抑制剂是美国专利第8,686,111号中公开的那些,即包含N-末端部分和C-末端部分的多肽,其中所述N-末端部分包含特征序列QGP[P或L],即特征序列的第四位置可为P或L,且所述C-末端部分的氨基酸序列与SEQ IDNO:1至少70%相同。
美国专利第8,686,111号中公开的CCR5抑制剂可将高抗HIV效力与低信号传导活性组合,或将高抗HIV效力与高受体隐蔽活性组合。在一些实施方案中,可用于本发明方法的CCR5抑制剂组合了高抗HIV效力与低信号传导和高受体隐蔽活性。在一些实施方案中,可用于本发明方法的CCR5抑制剂组合了高抗HIV效力与低信号传导活性,而非高受体隐蔽活性。
在一些实施方案中,可用于本发明方法的CCR5抑制剂的特征在于高水平的抗HIV效力(IC50水平,例如0.02和1nM之间,或0.02和0.15nM之间,如通过美国专利第8,686,111号的材料和方法部分中所述的细胞融合测定所测量的)与低水平的信号传导活性(例如,不超过15%、不超过10%或不超过5%,如通过美国专利第8,686,111号的材料和方法部分中所述的钙流测定所测量的)和低水平的受体隐蔽活性(例如,不超过20%或不超过10%,如通过美国专利第8,686,111号的材料和方法部分中所述的CCR5表面下行性调节测定所测量的)的组合。
在一些实施方案中,可用于本发明方法的CCR5抑制剂的特征在于高水平的抗HIV效力(IC50水平,例如0.02和1nM之间,或0.02和0.15nM之间,如通过美国专利第8,686,111号的材料和方法部分中所述的细胞融合测定所测量的)与高水平的信号传导活性(例如至少60%,或至少85%,如通过美国专利第8,686,111号的材料和方法部分中所述的钙流测定所测量的)和高水平的受体隐蔽活性(例如至少60%,或至少70%,如通过美国专利第8,686,111号的材料和方法部分中所述的CCR5表面下行性调节测定所测量的)的组合。
在一些实施方案中,可用于本发明方法的CCR5抑制剂的特征在于高水平的抗HIV效力(IC50水平,例如0.02和1nM之间,或0.02和0.15nM之间,如通过美国专利第8,686,111号的材料和方法部分中所述的细胞融合测定所测量的)与低水平的信号传导活性(例如,不超过30%,或不超过20%,不超过15%,或不超过10%,如通过美国专利第8,686,111号的材料和方法部分中所述的钙流测定所测量的)和中等水平的受体隐蔽活性(例如,20%和50%之间,或30%和50%之间,如通过美国专利第8,686,111号的材料和方法部分中所述的CCR5表面下行性调节测定所测量的)的组合。
在一些实施方案中,可用于本发明方法的CCR5抑制剂的特征在于高水平的抗HIV效力(IC50水平,例如0.02和1nM之间,或0.02和0.15nM之间,如通过美国专利第8,686,111号的材料和方法部分中所述的细胞融合测定所测量的)与低水平的信号传导活性(例如,不超过30%,或不超过20%,不超过15%,或不超过10%,如通过美国专利第8,686,111号的材料和方法部分中所述的钙流测定所测量的)和高水平的受体隐蔽活性(例如,至少50%,如通过美国专利第8,686,111号的材料和方法部分中所述的CCR5表面下行性调节测定所测量的)的组合。
在一些实施方案中,可用于本发明方法的CCR5抑制剂的特征在于高水平的抗HIV效力(IC50水平,例如0.02和1nM之间,或0.02和0.15nM之间,如通过美国专利第8,686,111号的材料和方法部分中所述的细胞融合测定所测量的)与中等水平的信号传导活性(例如30%和50%之间,或30%和45%之间,如通过美国专利第8,686,111号的材料和方法部分中所述的钙流测定所测量的)和高水平的受体隐蔽活性(例如至少50%,如通过美国专利第8,686,111号的材料和方法部分中所述的CCR5表面下行性调节测定所测量的)的组合。
在一些实施方案中,可用于本发明方法的CCR5抑制剂的特征在于中等水平的抗HIV效力(IC50水平,例如0.02和1nM之间,或0.02和0.15nM之间,如通过美国专利第8,686,111号的材料和方法部分中所述的细胞融合测定所测量的)与中等水平的信号传导活性(例如30%和50%之间,或30%和45%之间,如通过美国专利第8,686,111号的材料和方法部分中所述的钙流测定所测量的)和中等水平的受体隐蔽活性(例如20%和50%之间,或30%和50%之间,如通过美国专利第8,686,111号的材料和方法部分中所述的CCR5表面下行性调节测定所测量的)的组合。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列为:QGP[P或L][L或G或S或M][M或D或S或Q或G];QGP[P或L][L或G][M或D或S];QGP[P或L][L或G或S或M][M或D或S或Q或G]XX[Q或G或L或A或T或S]X,其中X表示任何天然的或修饰的氨基酸;QGP[P或L][L或G][M或D或S]XX[Q或L]X,其中X表示任何天然的或修饰的氨基酸;QGP[P或L]LM;QGPPG[D或S];QGPPLM;或QGPPGD。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列为:QGP[P或L][L或M][M或Q][A或W或G或Q或N]X[Q或G或L][S或V或T或G],其中X表示任何天然的或修饰的氨基酸;QGP[P或L][L或M][M或Q][A或W或G或Q或N][L或T或M或S或G或Q或R或Y][Q或G或L][S或V或T或G];QGP[P或L]LM[A或W][L或T或M][Q或G][S或V或T或G];或QGPPLM[A或W][L或T或M][Q或G][S或V或T或G]。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列为:QGP[P或L][L或G或S][D或S或G或Q]XX[L或A或T或Q][W或A或V],其中X表示任何天然的或修饰的氨基酸;QGP[P或L][L或G或S][D或S或G或Q][T或I或S或W或Q][V或L或A或S或G][L或A或T或Q][W或A或V];QGPPG[D或S][T或I]VL[W或A];或QGPPGD[T或I]VL[W或A]。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列为:QGPP[G或L][M或Q]XX[Q或S][S或V],其中X表示任何天然的或修饰的氨基酸;QGPP[G或L][M或Q][S或G或W或A或T][L或F或T或S或G或Y][Q或S][S或V];或QGPPLM[S或G][L或F或T]Q[S或V]。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列选自QGPPLMALQS、QGPPLMWMQV、QGPPLMWLQV、QGPPLMWTQS、QGPPLMWLQT、QGPPLMWTQV、QGPPLMWMQS、QGPPLMATQS、QGPPLMWLQS、QGPPLMALQV、QGPPLMWLGG、QGPPLMWRGS、QGPLLMWLQV、QGPPLMQTTP、QGPPLSWLQV、QGPPLSWLQS、QGPPGQWSQV、QGPPMMAGLS、QGPPLSWQQS、QGPPGMWSQS、QGPPLQWRQS、QGPPLMGTQS、QGPPLMQLQV、QGPPLSWSQV、QGPPMSWSQS、QGPPLMNLQV、QGPPMSAYQV和QGPPMQGGLS。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列选自QGPPLMALQS、QGPPLMWMQV、QGPPLMWLQV、QGPPLMWTQS、QGPPLMWLQT、QGPPLMWTQV、QGPPLMWMQS、QGPPLMATQS、QGPPLMWLQS、QGPPLMALQV、QGPPLMWLGG、QGPPLMWRGS、QGPLLMWLQV和QGPPLMQTTP。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列选自QGPPGDTVLW、QGPPGDIVLA、QGPPGSYDYS、QGPPGDGGSV、QGPLSGQSTP、QGPPGDWLQV、QGPPLMSLAV、QGPPLMSLTV、QGPLSGWAQV、QGPLSQSSQV、QGPLSSQSQV和QGPLGQQGQV。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列选自QGPPGDTVLW、QGPPGDIVLA、QGPPGSYDYS、QGPPGDGGSV、QGPLSGQSTP和QGPPGDWLQV。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列选自QGPPLMSFQS、QGPPLMSTQS、QGPPLMSLQV、QGPPLMGLQV、QGPLSGWLQV、QGPPLQWFQV、QGPPLQWTQV、QGPPLMALSV、QGPPLMWSQV、QGPPGQWGQV、QGPPGSWSQV、QGPPLMSSQS、QGPPLMGLSV、QGPPLMTLQV和QGPPGQWYQS。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列选自QGPPLMSFQS、QGPPLMSTQS、QGPPLMSLQV、QGPPLMGLQV和QGPLSGWLQV。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列选自QGPPLMSVLA、QGPPGSWSSV、QGPPLGSMGP、QGPPLQWMQA、QGPPLQWMQV、QGPPLMSTQV、QGPPLMSLSV、QGPPLMSLQS、QGPPLMSLQA、QGPPLMSVQS、QGPPLMSAQS、QGPPLMSGQS和QGPPLMSGQV。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列选自QGPPLMSVLA、QGPPGSWSSV和QGPPLGSMGP。
在一些实施方案中,可用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同,其中所述特征序列选自表1中列出的特征序列:
表1
SEQ ID NO特征序列
SEQ ID NO:2QGPPLMALQS
SEQ ID NO:3QGPPLMWMQV
SEQ ID NO:4QGPPLMWLQV
SEQ ID NO:5QGPPLMWTQS
SEQ ID NO:6QGPPLMWLQT
SEQ ID NO:7QGPPLMWTQV
SEQ ID NO:8QGPPLMWMQS
SEQ ID NO:9QGPPLMATQS
SEQ ID NO:10QGPPLMWLQS
SEQ ID NO:11QGPPLMALQV
SEQ ID NO:12QGPPLMWLGG
SEQ ID NO:13QGPPLMWRGS
SEQ ID NO:14QGPLLMWLQV
SEQ ID NO:15QGPPLMQTTP
SEQ ID NO:16QGPPGDTVLW
SEQ ID NO:17QGPPGDIVLA
SEQ ID NO:18QGPPGSYDYS
SEQ ID NO:19 QGPPGDGGSV
SEQ ID NO:20 QGPLSGQSTP
SEQ ID NO:21 QGPPGDWLQV
SEQ ID NO:22 QGPPLMSFQS
SEQ ID NO:23 QGPPLMSTQS
SEQ ID NO:24 QGPPLMSLQV
SEQ ID NO:25 QGPPLMGLQV
SEQ ID NO:26 QGPLSGWLQV
SEQ ID NO:27 QGPPLMSVLA
SEQ ID NO:28 QGPPGSWSSV
SEQ ID NO:29 QGPPLGSMGP
SEQ ID NO:30 QGPPLSWLQV
SEQ ID NO:31 QGPPLSWLQS
SEQ ID NO:32 QGPPGQWSQV
SEQ ID NO:33 QGPPMMAGLS
SEQ ID NO:34 QGPPLSWQQS
SEQ ID NO:35 QGPPGMWSQS
SEQ ID NO:36 QGPPLQWRQS
SEQ ID NO:37 QGPPLMGTQS
SEQ ID NO:38 QGPPLMQLQV
SEQ ID NO:39 QGPPLSWSQV
SEQ ID NO:40 QGPPMSWSQS
SEQ ID NO:41 QGPPLMNLQV
SEQ ID NO:42 QGPPMSAYQV
SEQ ID NO:43 QGPPMQGGLS
SEQ ID NO:44 QGPPLMSLAV
SEQ ID NO:45 QGPPLMSLTV
SEQ ID NO:46 QGPLSGWAQV
SEQ ID NO:47 QGPLSQSSQV
SEQ ID NO:48 QGPLSSQSQV
SEQ ID NO:49 QGPLGQQGQV
SEQ ID NO:50QGPPLQWFQV
SEQ ID NO:51QGPPLQWTQV
SEQ ID NO:52QGPPLMALSV
SEQ ID NO:53QGPPLMWSQV
SEQ ID NO:54QGPPGQWGQV
SEQ ID NO:55QGPPGSWSQV
SEQ ID NO:56QGPPLMSSQS
SEQ ID NO:57QGPPLMGLSV
SEQ ID NO:58QGPPLMTLQV
SEQ ID NO:59QGPPGQWYQS
SEQ ID NO:60QGPPLQWMQA
SEQ ID NO:61QGPPLQWMQV
SEQ ID NO:62QGPPLMSTQV
SEQ ID NO:63QGPPLMSLSV
SEQ ID NO:64QGPPLMSLQS
SEQ ID NO:65QGPPLMSLQA
SEQ ID NO:66QGPPLMSVQS
SEQ ID NO:67QGPPLMSAQS
SEQ ID NO:68QGPPLMSGQS
SEQ ID NO:69QGPPLMSGQV
在一个实施方案中,用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列QGPPLMATQS,且C-末端部分的氨基酸序列与SEQ IDNO:1至少70%相同。
[B]在一个实施方案中,用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列QGPPGDIVLA,且C-末端部分的氨基酸序列与SEQID NO:1至少70%相同。
在一个实施方案中,用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列QGPPLMSLQV,且C-末端部分的氨基酸序列与SEQ IDNO:1至少70%相同。
在一个实施方案中,用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分由特征序列QGPPLMATQS组成,且C-末端部分的氨基酸序列为SEQID NO:1。
在一个实施方案中,用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分由特征序列QGPPGDIVLA组成,且所述C-末端部分的氨基酸序列为SEQ ID NO:1。
在一个实施方案中,用于本发明方法的CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分由特征序列QGPPLMSLQV组成,且所述C-末端部分的氨基酸序列为SEQ ID NO:1。
在一个实施方案中,用于本发明方法的CCR5抑制剂包含SEQ ID NO:70的氨基酸序列。
在一个实施方案中,用于本发明方法的CCR5抑制剂包含SEQ ID NO:71的氨基酸序列。
在一个实施方案中,用于本发明方法的CCR5抑制剂包含SEQ ID NO:72的氨基酸序列。
段落[A]至段落[B]中所述的CCR5抑制剂的N-末端部分可由不超过15、14、13、12、11或10个氨基酸组成。在一个实施方案中,所述N-末端部分由10个氨基酸组成。
在段落[A]至段落[B]中所述的CCR5抑制剂中,所述C-末端部分的N-末端可直接邻接所述N-末端部分的C-末端,即N-末端部分和C-末端部分直接邻接。
段落[A]至段落[B]中所述的CCR5抑制剂的C末端部分可与SEQ ID NO:1具有大于70%、75%、80%、85%、90%、95%、98%、99%、99.9%或100%的序列相同性。
本文所用的术语“序列相同性”具有本领域的标准含义。如本领域已知的,可以使用许多不同的程序来鉴定多核苷酸或多肽是否与已知序列具有序列相同性或相似性。序列相同性或相似性可以使用本领域已知的标准技术测定,包括但不限于Smith&Waterman,Adv.Appl.Math.2:482(1981)的局部序列相同性算法、通过Needleman&Wunsch、J.Mol.Biol.48:443(1970)的序列相同性比对算法、通过检索Pearson&Lipman、Proc.Natl.Acad.Sci.USA 85:2444(1988)的相似性方法、通过计算机实现这些算法(Wisconsin Genetics Software Package中的GAP、BESTFIT、FASTA和TFASTA,GeneticsComputer Group,575Science Drive,Madison,WI)、Devereux et al.,Nucl.Acid Res.12:387(1984)所述的最佳拟合序列程序,优选使用默认设置,或通过检查。
段落[A]至段落[B]中所述的CCR5抑制剂的特征序列可以位于多肽的N-末端附近。例如,所述特征序列的位置可以使得所述特征序列的起点位于多肽N-末端的15、12、10、8、6、5、4、3、2或1个残基内。本文所述“特征序列的起点”是指所述特征序列的N-末端。所述特征序列也可位于多肽的最N-末端,即,作为整体的多肽的N-末端,并且特征序列可一致。
在一些实施方案中,编码本文提供的所述多肽的核酸可用于本发明的方法中。本领域技术人员知道如何根据遗传密码设计或鉴定编码所述多肽的核酸。这样的核酸可以包含编码本文提供的一种或多种多肽的一个或多个节段。这样的核酸可以是RNA或DNA。这样的核酸可以是载体,即编码本文提供的所述多肽的核酸可以掺入载体中。
在一些实施方案中,可以将编码本文提供的所述多肽的核酸掺入病毒中。因此,在病毒基因组内含有编码本文提供的一种或多种多肽的一个或多个节段的病毒可用于本发明的方法中。
如本文所用的术语“蛋白质”、“肽”或“多肽”可互换使用并且是指任何长度的氨基酸聚合物。所述聚合物可以是线性或支链的,它可以包含修饰的氨基酸,并且它可以被非氨基酸中断。该术语还涵盖已经天然或通过干预修饰的氨基酸聚合物;例如,二硫键形成、糖基化、脂质化、乙酰化、磷酸化或任何其他操作或修饰,例如与标记组分缀合。该定义内还包括例如含有一个或多个氨基酸类似物(包括例如非天然氨基酸等)以及本领域已知的其他修饰的多肽。多肽可作为单链或相关链存在。本发明的多肽可以是天然或非天然糖基化的(即,该多肽具有与在相应的天然存在的多肽中发现的糖基化模式不同的糖基化模式)。
药物组合物和剂型
本发明提供了组合物,例如药物组合物,其包含如本文描述的CCR5抑制剂。如本文所用的术语“药物组合物”和“组合物”可根据上下文需要互换使用。本文所述的药物组合物可以以治疗有效量施用给对象。如本文使用的“治疗有效量”是指有效地为对象提供治疗、预防或诊断益处的组合物或治疗剂的量。在一些实施方案中,组合物的治疗有效量是在特定疾病或病症的治疗中能够在对象中诱导临床应答的量。组合物的治疗有效量的确定完全在本领域技术人员的能力范围内,特别是根据本文提供的公开内容。所述治疗有效量可以根据多种因素例如对象的状况、体重、性别和年龄而变化。
本文提供的药物组合物还可包含药学上可接受的载剂、赋形剂和/或稳定剂(参见Remington:The Science and practice of Pharmacy 20th Ed.,2000,LippincottWilliams and Wilkins,Ed.K.E.Hoover)。可接受的载剂、赋形剂或稳定剂在剂量和浓度下对受者无毒性,并且可包含缓冲剂如磷酸盐、柠檬酸盐和其他有机酸;抗氧化剂,包括抗坏血酸和甲硫氨酸;防腐剂(例如氯化十八烷基二甲基苄基铵(octadecyldimethylbenzylammonium chloride));氯化六烃季铵(hexamethonium chloride);氯化苯甲烃铵(benzalkonium chloride)、氯化苄乙氧铵(benzethonium chloride);苯酚(phenol)、丁基(butyl)或苯甲醇(benzyl alcohol);alkyl parabens例如甲基(methyl)或对羟基苯甲酸丙酯(propyl paraben);苯磷二酚(catechol);间苯二酚(resorcinol);环己醇(cyclohexanol);3-戊醇(3-pentanol);和间甲酚(m-cresol));低分子量(少于约10个残基)多肽;蛋白质,例如血清白蛋白、明胶或免疫球蛋白;亲水聚合物例如聚乙烯吡咯烷酮(polyvinylpyrrolidone);氨基酸,例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖类、二糖类和其他碳水化合物,包括葡萄糖、甘露糖或葡聚糖;螯合剂例如EDTA;糖类,例如蔗糖、甘露醇、海藻糖或山梨糖醇;成盐对离子如钠;金属络合物(例如,Zn-蛋白络合物);和/或非离子表面活性剂,例如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。
在一些实施方案中,本文提供的药物组合物可包含多于一种本文所述的CCR5抑制剂,例如两种或更多种CCR5抑制剂。在一些实施方案中,本文提供的药物组合物可包含已知具有针对癌症的治疗效果的第二治疗剂。本文所用的术语“治疗剂”是能够在疾病、病症或状况的治疗或预防中提供治疗活性、应答或作用的任何分子、物质或化合物,包括诊断剂和预防剂。
本文提供的药物组合物可以制备成各种药物剂型,例如即时释放、控释、缓释或靶向药物递送系统。通常使用的剂型包括例如溶液和混悬液、(微)乳液、软膏、凝胶、乳膏、糊剂、泡沫、栓剂、胚珠、埋植剂、贴剂、脂质体、片剂、糖衣丸、锭剂、软壳或硬壳胶囊、无定形或结晶粉末、泡腾粉或片剂、气雾剂和冻干制剂。根据所用的施用途径,可能需要特殊的装置来施加或施用剂型,例如注射器和针头、吸入器、泵、注射笔、涂药器、专用瓶或其他也可以植入体内的施用装置。
本文提供的药物剂型可以通过本领域熟知的任何方法制备,例如通过常规混合、过筛、溶解、熔融、制粒、制备糖衣丸、压片、混悬、挤出、喷雾干燥、水飞、乳化、(纳米/微米)包封、包埋或冻干方法。
对于本发明的方法,本文提供的CCR5抑制剂、药物组合物或剂型可通过常规技术施用给对象,例如静脉内(作为推注或通过在一段时间内连续输注)、肌内、透粘膜、腹膜内、脑内、皮下、关节内、滑膜内、鞘内、鼻腔、口服、表面或通过吸入。其他合适的施用途径可包括病灶内或或病灶周途径。
例如,对于静脉注射,如果需要,可以将本文提供的药物组合物在水溶液中配制,使用生理相容性缓冲剂,包括例如用于调节制剂pH的磷酸盐、组氨酸或柠檬酸盐,以及张度剂,例如氯化钠或右旋糖。对于经粘膜或鼻腔施用,半固体、液体制剂或贴剂可能是优选的,可能含有渗透促进剂。这种渗透剂通常是本领域已知的。对于口服施用,本文提供的药物组合物可以配制成液体或固体剂型,并且任选地以即时或控释/缓释制剂。用于对象口服摄取的合适剂型包括片剂、胶囊、丸剂、糖衣丸、硬壳和软壳胶囊、液体、凝胶、糖浆、浆剂、混悬液和乳液。
固体口服剂型可以使用赋形剂获得,所述赋形剂可以包括惰性稀释剂、填充剂、崩解剂、粘合剂(干的和湿的)、溶解阻滞剂、润滑剂、助流剂、抗粘附剂、阳离子交换树脂、润湿剂、抗氧化剂、防腐剂、着色剂、甜味剂和调味剂。这些赋形剂可为合成或天然来源。这些赋形剂的实例包括纤维素衍生物、柠檬酸、磷酸二钙、明胶、碳酸镁、月桂基硫酸镁/钠、甘露醇、聚乙二醇、聚乙烯吡咯烷酮、硅酸盐、二氧化硅、苯甲酸钠、山梨醇、淀粉、硬脂酸或其盐、糖类(即右旋糖、蔗糖、乳糖等)、滑石、西黄蓍胶浆、植物油(氢化的)和蜡。乙醇和水可作为造粒助剂。在某些情况下,需要用例如掩蔽气味的膜、耐胃酸膜或延迟释放膜对片剂包衣。通常使用天然和合成聚合物(联用着色剂、糖和有机溶剂或水)以包衣片剂,得到糖衣丸。当相对于片剂优选胶囊时,可以在相容的硬壳或软壳胶囊中递送药物粉末、混悬液或其溶液。
合适的惰性稀释剂包括碳酸钠和碳酸钙、磷酸钠和磷酸钙以及乳糖。玉米淀粉和海藻酸是合适的崩解剂。粘合剂可以包括淀粉和明胶。如果存在润滑剂,则其通常为硬脂酸镁、硬脂酸或滑石。如果需要,所述片剂可以用诸如单硬脂酸甘油酯(glycerylmonostearate)或二硬脂酸甘油酯(glyceryl distearate)的材料包衣,以延迟在胃肠道中的吸收。
用于口服使用的胶囊包括硬明胶胶囊和软明胶胶囊,在硬明胶胶囊中活性成分与固体稀释剂混合,在软明胶胶囊中活性成分与水或油如花生油、液体石蜡或橄榄油混合。
在一些实施方案中,本文提供的CCR5抑制剂可表面给药,通过皮肤或粘膜施用,例如通过皮肤贴剂、半固体或液体制剂,例如凝胶、(微)乳液、软膏、溶液、(纳米/微米)混悬液或泡沫。活性成分向对象的皮肤或粘膜和皮下组织的渗透可以例如使用渗透增强剂来调节;适当选择和组合亲脂性、亲水性和两亲性赋形剂,包括水、有机溶剂、蜡、油、合成的和天然的聚合物、表面活性剂、乳化剂;通过pH调节;以及络合剂的使用。
在一些实施方案中,本文提供的CCR5抑制剂可通过吸入给药,或以溶液、混悬液、乳液或来自加压包装的半固体气溶胶或雾化器的形式施用给鼻,通常使用推进剂,例如衍生自甲烷和乙烷、二氧化碳或任何其他合适气体的卤化碳。对于表面气雾剂,烃如丁烷、异丁烯和戊烷是有用的。在加压气雾剂的情况下,可以通过提供阀门来确定合适的剂量单位以递送计量的量。可配制用于吸入器或吹入器的胶囊和药筒例如明胶。这些通常含有活性成分和合适的粉末基质如乳糖或淀粉的粉末混合物。
用于通过注射肠胃外施用而配制的组合物通常是无菌的,并且可以以单位剂型存在,例如,在安瓿、注射器、注射笔中,或在多剂量容器中,后者通常含有防腐剂。适于胃肠外施用的药物组合物可以采取诸如在油性或水性媒介物中的混悬液、溶液或乳剂的形式,并且可以含有配制剂,例如缓冲剂、张度剂、粘度增强剂、表面活性剂、混悬和分散剂、抗氧化剂、生物相容性聚合物、螯合剂和防腐剂。取决于注射部位,所述媒介物可以含有水、合成或植物油和/或有机共溶剂。在某些情况下,例如使用冻干产品或浓缩物,肠胃外制剂在施用前将被重构或稀释。提供活性剂的控释或缓释的储存制剂可以包括纳米/微米颗粒或纳米/微米或非微粉化晶体的可注射混悬液。除了本领域熟知的其他物质之外,聚合物如聚(乳酸)、聚(乙醇酸)或其共聚物,可用作控释/缓释基质。其他储存递送系统可以以需要切口的埋植剂和泵的形式存在。
本文提供的用于静脉内注射CCR5抑制剂的合适载剂是本领域熟知的,包括含有碱例如氢氧化钠(以形成离子化物质)、蔗糖或氯化钠作为张度剂的水基溶液。水基溶液可以包括含有磷酸盐或组氨酸的缓冲剂。可以加入共溶剂,例如聚乙二醇(polyethyleneglycols)。这些水基体系在溶解剂方面是有效的,并且在全身施用时产生低毒性。溶液体系的组分的比例可以相当地变化,而不破坏溶解性和毒性特征。此外,组分本身可以改变。例如,可以使用低毒性的表面活性剂,例如聚山梨酸酯(polysorbates)或泊洛沙姆(poloxamers),也可以加入聚乙二醇或其他共溶剂、生物相容性聚合物例如聚乙烯吡咯烷酮(polyvinyl pyrrolidone),并且其他糖类和多元醇可以代替右旋糖。
治疗适应症
本文提供的CCR5抑制剂、药物组合物和剂型可应用于其中期望将治疗剂施用给对象以治疗或预防癌症的任何情况。本文所使用的“个体”或“对象”为哺乳动物,例如人。哺乳动物还包括但不限于畜牧动物、运动动物、宠物、灵长类动物和马。
本文所使用的“治疗”或“治疗...的”或“预防”或“预防...的”是指用于获得有益或期望的结果的方法。有益或期望的结果可以包括但不限于缓解或改善一种或多种症状或状况、减轻疾病程度、稳定疾病状态、预防疾病的发展、预防疾病的扩散、延迟或减缓疾病进程(例如抑制)、延迟或减缓疾病发作、赋予针对致病原的保护性免疫和改善或缓和疾病状态。“治疗”或“预防”也可以指延长患者的存活超过没有治疗所预期的存活,并且也可以指暂时抑制疾病的进展或预防疾病的发生,例如通过预防对象的感染。
“治疗”可与“预防”区别在于“治疗”通常发生在已经患有疾病或病症或已知已经暴露于传染原的对象中,而“预防”通常发生在没有疾病或病症发生或未知已经暴露于传染原的对象中。如将理解的,在治疗和预防中可能存在重叠。例如,可以“治疗”对象的疾病,而同时“预防”疾病的症状或进展。
如本文所用,术语“癌症”是指细胞以异常高且控制弱或不受控制的速率增殖的状况,所述速率超过周围正常组织的速率且与周围正常组织的速率不协调。癌症可以是原发性或转移性的。癌症可以从其开始的地方扩散到身体的另一部分。原始癌症被称为原发性肿瘤。身体另一部分的癌症称为转移性癌症。
可通过本发明方法治疗的癌症可为常规治疗如化疗或放疗难治性的或对常规治疗如化疗或放疗具有抗性的。术语“难治性或抗性”是指癌症对治疗无反应的情况。所述癌症在治疗开始时可能是抗性的,或者在治疗期间可能变成抗性的。
癌症的具体实例包括但不限于皮肤癌,例如黑素瘤和基底细胞癌;淋巴结癌;乳腺癌;宫颈癌;子宫癌;胃肠道癌,诸如胃(胃部)和胃肠道基质肿瘤;肺癌;卵巢癌;前列腺癌;结肠癌;直肠癌;口腔癌;脑癌;头颈癌;咽喉癌;甲状腺癌;睾丸癌;肾癌;胰腺癌;骨癌;脾癌;肝癌;膀胱癌;喉癌;鼻道癌;AIDS相关癌症;肉瘤,如软组织肉瘤、脂肪肉瘤和骨肉瘤;和血液以及骨髓的癌症,例如多发性骨髓瘤、骨髓增生性疾病和急性以及慢性白血病,例如成淋巴细胞性白血病、髓性白血病、淋巴细胞性白血病和髓细胞性白血病。
其他具体的癌症包括但不限于,晚期恶性肿瘤、淀粉样变性病、成神经细胞瘤、脑膜瘤、血管外皮细胞瘤、多发性脑转移瘤、多形性胶质母细胞瘤、胶质母细胞瘤、脑干胶质瘤、不良预后的恶性脑肿瘤、恶性胶质瘤、复发性恶性胶质瘤、间变性星形细胞瘤、间变性少突神经胶质瘤、神经内分泌肿瘤、直肠腺癌、Dukes C&D结直肠癌、不可切除性结直肠癌、转移性肝细胞癌、Kaposi's肉瘤、核型急性原始粒细胞性白血病、慢性淋巴细胞白血病(CLL)、霍奇金(Hodgkin's)淋巴瘤、非霍奇金淋巴瘤、外周T细胞淋巴瘤(包括间变性大细胞淋巴瘤、血管免疫母细胞性T细胞淋巴瘤、和皮肤T细胞淋巴瘤)、皮肤B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、小淋巴细胞淋巴瘤、Castleman病、转移性黑素瘤(局部黑素瘤、包括但不限于、眼黑色素瘤)、恶性间皮瘤、恶性胸腔积液间皮瘤综合征、腹膜癌、乳头状浆液性癌、妇科肉瘤、软组织肉瘤、硬皮病、皮肤血管炎、朗格汉斯细胞组织细胞增多症、平滑肌肉瘤、进行性骨化性纤维发育不良、激素难治性前列腺癌、切除的高危软组织肉瘤、不可挽救的(unrescectabie)肝细胞癌、Waldenstrom巨球蛋白血症、阴燃骨髓瘤、无痛性骨髓瘤、输卵管癌、雄激素非依赖性前列腺癌、雄激素依赖性IV期非转移性前列腺癌、激素不敏感的前列腺癌、化疗不敏感的前列腺癌、甲状腺乳头状癌、滤泡性甲状腺癌、甲状腺髓样癌、和平滑肌瘤。
可用本发明方法治疗的癌症的特征可在于表达CCR5的肿瘤细胞和/或由表达CCR5的白细胞浸润的实体瘤。
在一个具体的实施方案中,所述癌症为结直肠癌。结肠癌的组织学类型包括以下:腺癌(大多数结肠癌),其包括粘液性(胶样)腺癌和印戒腺癌(signet ringadenocarcinoma);硬性肿瘤;和神经内分泌(具有神经内分泌分化的肿瘤通常比纯腺癌变型具有更差的预后)。通过本发明的方法治疗的结直肠癌可以是转移性的、化疗或放疗或两者难治性的或对化疗或放疗或两者具有抗性的。
在一个具体的实施方案中,所述癌症为乳腺癌。在所有患乳腺癌的女性中,5%-10%可能具有BRCA1和BRCA2基因的种系突变。估计具有BRCA1和BRCA2突变的女性发展出乳腺癌的终生风险为40%至85%。分子谱在乳腺癌中的应用包括以下:雌激素受体(ER)和孕酮受体(PR)状态检测;HER2/neu受体状态检测;和通过微阵列分析或逆转录-聚合酶链式反应(例如MammaPrint,Oncotype DX)进行的基因谱检测。基于ER、PR和HER2/neu结果,乳腺癌被分类为以下类型之一:激素受体阳性;HER2/neu阳性;和三阴性(ER、PR和HER2/neu阴性)。ER、PR和HER2状态在确定预后和预测对内分泌和HER2方向治疗的应答是重要的。例如,激素受体(ER和/或PR)-阳性患者将接受激素疗法;HER2过表达意味着使用辅助的曲妥珠单抗(trastuzumab),通常与化疗联合;并且当HER2过表达和激素受体都不存在时(即三阴性乳腺癌),辅助治疗依赖于化疗方案,其可与研究性靶向方法联合。辅助治疗选项可包括以下:他莫昔芬(tamoxifen);芳香酶抑制剂(AI)治疗;卵巢功能抑制;和化疗。通过本发明的方法治疗的乳腺癌可以是转移性的(例如,乳腺癌可以转移到肺、肝、骨或脑中)、化疗或放疗或两者难治性的或对化疗或放疗或两者具有抗性的。
在一个具体的实施方案中,所述癌症为肺癌。两种主要类型的肺癌为小细胞肺癌(SCLC)和非小细胞肺癌(NSCLC);NSCLC占所有肺癌病例的大约85%。SCLC包括小细胞癌和复合型小细胞癌,即,SCLC与赘生性鳞状和/或腺状成分组合。NSCLC最常见的类型是鳞状细胞癌、大细胞癌和腺癌。通过本发明的方法治疗的肺癌可以是转移性的、化疗或放疗或两者难治性的或对化疗或放疗或两者具有抗性的。SCLC中的转移部位包括肝、骨、脑和肺。NSCLC中的转移部位包括骨、肺、脑、肝和肾上腺。
在一个具体的实施方案中,所述癌症为前列腺癌。超过95%的原发性前列腺癌为腺癌。前列腺腺癌通常是多灶性的,并且在分化模式中是异质的。前列腺上皮内瘤病([PIN]良性表现腺泡内的非侵袭性非典型上皮细胞)通常与前列腺腺癌相关存在。PIN被细分为低级别和高级别。高级形式可以是腺癌的前体。研究还估计在诊断的五年内,10-20%患有前列腺癌的男性将发展为去势抵抗性前列腺癌(CRPC),其进一步显著降低了存活率。通过本发明的方法治疗的前列腺癌可以是转移性的、化疗或放疗或两者难治性的或对化疗或放疗或两者具有抗性的。
在一个具体的实施方案中,所述癌症为卵巢癌。卵巢癌包括卵巢上皮癌、输卵管癌(FTC)和原发性腹膜癌(PPC)。卵巢上皮癌、输卵管癌和原发性腹膜癌可在组织学上分为浆液性囊瘤、粘液性囊瘤、子宫内膜样肿瘤(类似于子宫内膜中的腺癌)和透明细胞(中肾样(mesonephroid))肿瘤。通过本发明的方法治疗的卵巢癌可以是转移性的、化疗或放疗或两者难治性的或对化疗或放疗或两者具有抗性的。
在一个具体实施方案中,所述癌症是胰腺癌。通过本发明的方法治疗的胰腺癌可以是转移性的、化疗或放疗或两者难治性的或对化疗或放疗或两者具有抗性的。
在一个具体实施方案中,所述癌症为食管癌。占主要恶性食管赘生物的两种组织学类型:腺癌和鳞状细胞癌。腺癌通常开始于食管下段,并且鳞状细胞癌可以发展至整个食管。通过本发明的方法治疗的食管癌可以是转移性的、化疗或放疗或两者难治性的或对化疗或放疗或两者具有抗性的。
在一个具体实施方案中,所述癌症是胃癌。存在两种主要类型的胃腺癌,肠型和弥漫型。肠型腺癌高度分化,并且细胞倾向于将它们自己排列在管状或腺状结构中。术语管状、乳头状和粘液性指各种类型的肠型腺癌。腺鳞癌很少发生。弥漫型腺癌是未分化的或低分化的,并且它们缺乏腺体形成。临床上,弥漫型腺癌可以引起胃壁的浸润(即,皮革胃)。一些肿瘤可具有肠型和弥漫型的混合特征。通过本发明的方法治疗的胃癌可以是转移性的、化疗或放疗或两者难治性的或对化疗或放疗或两者具有抗性的。
在一个具体实施方案中,所述癌症是白血病。白血病可以分为急性白血病或慢性白血病。白血病还可以通过受影响的血细胞的类型分类,即成淋巴细胞性白血病或淋巴细胞白血病,或髓样白血病或髓性白血病。通过本发明的方法治疗的白血病可以是急性成淋巴细胞性白血病(ALL)。ALL是一种侵袭型白血病,其特征在于在骨髓和外周血中存在太多的成淋巴细胞或淋巴细胞。通过本发明的方法治疗的白血病可以是转移性的、化疗或放疗或两者难治性的或对化疗或放疗或两者具有抗性的。它可以扩散到淋巴结、脾、肝、中枢神经系统(CNS)和其他器官。
在一个具体实施方案中,所述癌症是肝癌。肝脏的恶性原发性肿瘤由两种主要细胞类型组成,它们是肝细胞癌(90%的病例)和胆管上皮癌。肝肿瘤的组织学分类包括肝细胞癌(HCC)、HCC的纤维板层变型、胆管上皮癌(肝内胆管癌)、混合性肝细胞性胆管上皮癌、未分化肿瘤和肝母细胞癌。通过本发明的方法治疗的肝癌可以是转移性的、化疗或放疗或两者难治性的或对化疗或放疗或两者具有抗性的。原发性肝癌转移的部位包括肺、门静脉和肝门淋巴结。
在一些实施方案中,通过本发明的方法治疗癌症可以导致癌细胞生长或增殖的抑制。在一些实施方案中,通过本发明的方法治疗癌症可以导致癌细胞迁移的抑制。在一些实施方案中,通过本发明的方法治疗癌症可以导致血管生成的抑制。在一些实施方案中,通过本发明的方法治疗癌症可以导致免疫调节性白细胞的重编程。
根据一些实施方案,在癌症症状出现之前施用本文提供的CCR5抑制剂、药物组合物或剂型。根据一些实施方案,可以长期治疗对象以预防转移和由其引起的损伤。根据一些实施方案,在对常规治疗如化疗或放疗有抗性和/或不敏感的患者中治疗癌症。根据一些实施方案,癌症症状通过本文提供的CCR5抑制剂、药物组合物或剂型治疗。
本文提供的CCR5抑制剂、药物组合物和剂型可通过实现其预期目的任何方式施用。例如,施用途径可以通过口服、舌下、含服、表面、直肠、经由吸入、经皮、皮下、静脉内、动脉内或肌内、经由心内施用、骨内、皮内、腹膜内、大脑内、经粘膜、阴道、玻璃体内、表皮、关节内、膀胱内、鞘内、关节周或局部进行。施用剂量将取决于对象的年龄、健康和体重、同时进行的治疗的种类(如果有的话)、治疗的频率、和期望效果的性质。
根据一些实施方案,本文提供的CCR5抑制剂可经口施用,可能以片剂、胶囊、粉末、糖锭剂、软明胶胶囊、糖浆、液体混悬液或锭剂的形式施用。根据一些实施方案,本文提供的CCR5抑制剂可以肠胃外制剂的形式施用,例如皮下肌内或静脉内施用。根据其他实施方案,本文提供的CCR5抑制剂可通过任何合适的鼻腔施用、肺施用、表面施用或任何合适的皮肤病学施用。
根据一些实施方案,本文提供的CCR5抑制剂可与任何合适的无毒药物载剂一起施用。所述载剂可以是气体、固体或液体。根据一些实施方案,所述载剂选自盐水溶液、水、任何合适的乳液或分散体或其任何组合。
根据一些实施方案,本文提供的CCR5抑制剂可与任何适合调节CCR5抑制剂从包含CCR5抑制剂的剂型中释放的成分一起施用。例如,可以使用延时物质,例如肠溶包衣的明胶胶囊。
根据一些实施方案,在治疗癌症的方法中,本文提供的CCR5抑制剂、药物组合物或剂型可以与已知对癌症具有治疗功效的任何第二活性剂一起施用。第二活性剂可以是大分子(例如蛋白质)或小分子(例如合成的无机、有机金属或有机分子)。
大分子活性剂的实例包括但不限于造血生长因子、细胞因子以及单克隆和多克隆抗体。活性剂的具体实例是抗CD40单克隆抗体(例如SGN-40);检查点抑制剂(例如,抗CTLA4抗体,例如伊匹木单抗(ipilimumab);抗PD-1抗体,例如纳武单抗(nivolumab)和派姆单抗(pembrolizumab);和抗PD-L-1抗体,如阿妥珠单抗(atezolizumab)、阿维单抗(avelumab)和度伐单抗(durvalumab));组蛋白脱乙酰酶抑制剂(例如,SAHA和LAQ 824);热休克蛋白-90抑制剂(例如17-AAG);胰岛素样生长因子-1受体激酶抑制剂;血管内皮生长因子受体激酶抑制剂(例如PTK787);胰岛素生长因子受体抑制剂;溶血磷脂酸酰基转移酶抑制剂;IkB激酶抑制剂;p38MAPK抑制剂;EGFR抑制剂(例如吉非替尼(gefitinib)和盐酸厄洛替尼(erlotinib HCL))HER-2抗体(例如,曲妥珠单抗和培妥珠单抗(OmnitargTM));VEGFR抗体(例如贝伐珠单抗(AvastinTM));VEGFR抑制剂(例如flk-1特异性激酶抑制剂SU5416和ptk787/zk222584);PI3K抑制剂(例如渥曼青霉素(wortmannin));C-Met抑制剂(例如PHA 665752);单克隆抗体(例如利妥昔单抗托西莫单抗依屈洛单抗和G250);和抗TNF-α抗体。小分子活性剂的实例包括但不限于抗癌剂和抗生素(例如,克拉霉素)。
可与本文提供的CCR5抑制剂联用的具体第二活性化合物根据待治疗、预防或管理的具体适应症而变化。
例如,第二活性剂包括但不限于:司马沙尼(semaxanib);环孢素(cyclosporin);依那西普(etanercept);多西环素(doxycycline);硼替佐米(bortezomib);拉帕替尼(lapatinib);阿西维辛(acivicin);阿柔比星(aclarubicin);阿考达唑(acodazolehydrochloride);阿克罗宁(acronine);阿多来新(adozelesin);阿地白介素(aldesleukin);六甲蜜胺(altretamine);安波霉素(ambomycin);醋酸阿美蒽醌(ametantrone acetate);安吖啶(amsacrine);阿那曲唑(anastrozole);氨茴霉素(anthramycin);门冬酰胺酶(asparaginase);曲林菌素(asperlin);阿扎胞苷(azacitidine);阿扎替派(azetepa);阿佐霉素(azotomycin);巴马司他(batimastat);苯佐替派(benzodepa);比卡鲁胺(bicalutamide);盐酸比生群(bisantrenehydrochloride);二甲磺酸双奈法德(bisnafide dimesylate);比折来新(bizelesin);硫酸博来霉素(bleomycin sulfate);布喹那钠(brequinar sodium);溴匹立明(bropirimine);白消安(busulfan);放线菌素(cactinomycin);卡普睾酮(calusterone);卡醋胺(caracemide);卡贝替姆(carbetimer);卡铂(carboplatin);亚硝脲氮芥(carmustine);盐酸卡柔比星(carubicin hydrochloride);卡折来新(carzelesin);西地芬戈(cedefingol);塞来昔布(celecoxib);苯丁酸氮芥(chlorambucil);西罗霉素(cirolemycin);顺铂(cisplatin);克拉屈滨(cladribine);甲磺酸克立那托(crisnatolmesylate);环磷酰胺(cyclophosphamide);阿糖胞苷(cytarabine);达卡巴嗪(dacarbazine);更生霉素(dactinomycin);盐酸柔红霉素(daunorubicinhydrochloride);地西他滨(decitabine);右奥马铂(dexormaplatin);地扎胍宁(dezaguanine);甲磺酸地扎胍宁(dezaguanine mesylate);地吖醌(diaziquone);多西他赛(docetaxel);多柔比星(doxorubicin);盐酸多柔比星(doxorubicin hydrochloride);屈洛西芬(droloxifene);柠檬酸屈洛昔芬(droloxifene citrate);丙酸屈他雄酮(dromostanolone propionate);达佐霉素(duazomycin);伊达曲沙(edatrexate);盐酸依氟鸟氨酸(eflomithine hydrochloride);依沙芦星(elsamitrucin);恩洛铂(enloplatin);恩普氨酯(enpromate);依匹哌啶(epipropidine);盐酸表柔比星(epirubicin hydrochloride);厄布洛唑(erbulozole);盐酸依索比星(esorubicinhydrochloride);雌氮芥(estramustine);雌二醇氮芥磷酸钠(estramustine phosphatesodium);依他硝唑(etanidazole);依托泊苷(etoposide);磷酸依托泊苷(etoposidephosphate);氯苯乙嘧胺(etoprine);盐酸法罗唑(fadrozole hydrochloride);法扎拉滨(fazarabine);芬维A胺(fenretinide);氟尿苷(floxuridine);磷酸氟达拉滨(fludarabine phosphate);氟尿嘧啶(fluorouracil);氟西他滨(flurocitabine);磷喹酮(fosquidone);福司曲星钠(fostriecin sodium);吉西他滨(gemcitabine);盐酸吉西他滨(gemcitabine hydrochloride);羟基脲(hydroxyurea);盐酸伊达比星(idarubicinhydrochloride);异环磷酰胺(ifosfamide);伊莫福新(ilmofosine);异丙铂(iproplatin);伊立替康(irinotecan);盐酸伊立替康(irinotecan hydrochloride);醋酸兰瑞肽(lanreotide acetate);来曲唑(letrozole);醋酸亮丙瑞林(leuprolideacetate);盐酸利阿唑(liarozole hydrochloride);洛美曲索钠(lometrexol sodium);洛莫司汀(lomustine);盐酸洛索蒽醌(losoxantrone hydrochloride);马索罗酚(masoprocol);美坦辛(maytansine);盐酸氮芥(mechlorethamine hydrochloride);醋酸甲地孕酮(megestrol acetate);醋酸美仑孕酮(melengestrol acetate);美法仑(melphalan);美诺立尔(menogaril);巯嘌呤(mercaptopurine);甲氨喋呤(methotrexate);甲氨蝶呤钠(methotrexate sodium);氯苯氨(metoprine);美妥替哌(meturedepa);米丁度胺(mitindomide);米托克星(mitocarcin);丝裂红素(mitocromin);米托洁林(mitogillin);米托马星(mitomalcin);丝裂霉素(mitomycin);米托司培(mitosper);米托坦(mitotane);盐酸米托蒽醌(mitoxantrone hydrochloride);霉酚酸(mycophenolic acid);诺考达唑(nocodazole);诺拉霉素(nogalamycin);奥马铂(ormaplatin);奥昔舒仑(oxisuran);紫杉醇(paclitaxel);培门冬酶(pegaspargase);培利霉素(peliomycin);戊氮芥(pentamustine);硫酸培洛霉素(peplomycin sulfate);培磷酰胺(perfosfamide);哌泊溴烷(pipobroman);哌泊舒凡(piposulfan);盐酸吡罗蒽醌(piroxantrone hydrochloride);普卡霉素(plicamycin);普洛美坦(plomestane);卟菲尔钠(porfimer sodium);泊非霉素(porfiromycin);泼尼氮芥(prednimustine);盐酸丙卡巴肼(procarbazine hydrochloride);嘌呤霉素(puromycin);盐酸嘌呤霉素(puromycinhydrochloride);吡唑呋喃菌素(pyrazofurin);利波腺苷(riboprine);沙芬戈(safingol);盐酸沙芬戈(safingol hydrochloride);司莫司汀(semustine);辛曲秦(simtrazene);磷乙酰天冬氨酸钠(sparfosate sodium);司帕霉素(sparsomycin);盐酸锗螺胺(spirogermanium hydrochloride);螺莫司汀(spiromustine);螺铂(spiroplatin);链黑霉素(streptonigrin);链脲菌素(streptozocin);磺氯苯脲(sulofenur);他利霉素(talisomycin);替可加兰钠(tecogalan sodium);泰索帝(taxotere);喃氟啶(tegafur);盐酸替洛蒽醌(teloxantrone hydrochloride);替莫泊芬(temoporfin);替尼泊苷(teniposide);替罗昔隆(teroxirone);睾内脂(testolactone);硫咪嘌呤(thiamiprine);硫鸟嘌呤(thioguanine);噻替派(thiotepa);噻唑呋林(tiazofurin);替拉扎明(tirapazamine);枸橼酸托瑞米芬(toremifene citrate);醋酸曲托龙(trestoloneacetate);磷酸曲西立滨(triciribine phosphate);三甲曲沙(trimetrexate);葡糖醛酸三甲曲沙(trimetrexate glucuronate);曲普瑞林(triptorelin);盐酸妥布氯唑(tubulozole hydrochloride);尿嘧啶氮芥(uracil mustard);乌瑞替派(uredepa);伐普肽(vapreotide);维替泊芬(verteporfin);硫酸长春碱(vinblastine sulfate);硫酸长春新碱(vincristine sulfate);长春地辛(vindesine);硫酸长春地辛(vindesinesulfate);硫酸长春匹定(vinepidine sulfate);硫酸长春甘酯(vinglycinate sulfate);硫酸长春罗新(vinleurosine sulfate);酒石酸长春瑞滨(vinorelbine tartrate);硫酸长春罗定(vinrosidine sulfate);硫酸长春利定(vinzolidine sulfate);伏氯唑(vorozole);折尼铂(zeniplatin);净司他丁(zinostatin);和盐酸佐柔比星(zorubicinhydrochloride)。
其他第二剂包括但不限于:20-表-l,25-二羟基维生素D3(20-epi-l,25dihydroxyvitamin D3);5-乙炔基尿嘧啶(5-ethynyluracil);阿比特龙(abiraterone);阿柔比星(aclarubicin);酰基富烯(acylfulvene);腺环戊醇(adecypenol);阿多来新(adozelesin);阿地白介素(aldesleukin);ALL-TK拮抗剂;六甲蜜胺(altretamine);氨莫司汀(ambamustine);amidox;氨磷汀(amifostine);氨基乙酰丙酸(aminolevulinicacid);氨柔比星(amrubicin);安吖啶(amsacrine);阿那格雷(anagrelide);阿那曲唑(anastrozole);穿心莲内酯(andrographolide);血管生成抑制剂(angiogenesisinhibitors);拮抗剂D(antagonist D);拮抗剂G(antagonist G);安雷利克斯(antarelix);抗背侧形态发生蛋白1(anti-dorsalizing morphogenetic protein-1);抗雄激素(antiandrogen),前列腺癌(prostatic carcinoma);抗雌激素(antiestrogen);抗瘤酮(antineoplaston);反义寡核苷酸(antisense oligonucleotides);甘氨酸阿非科林(aphidicolin glycinate);凋亡基因调节剂(apoptosis gene modulators);凋亡调节剂(apoptosis regulators);脱嘌呤核酸(apurinic acid);ara-CDP-DL-PTBA;精氨酸脱氨基酶(arginine deaminase);asulacrine;阿他美坦(atamestane);阿莫司汀(atrimustine);axinastatin 1;axinastatin 2;axinastatin 3;阿扎司琼(azasetron);阿扎毒素(azatoxin);重氮酪氨酸(azatyrosine);baccatin III衍生物;balanol;巴马司他(batimastat);BCR/ABL拮抗剂;benzochlorins;苯酰星孢素(benzoylstaurosporine);β-内酰胺衍生物(beta lactam derivatives);beta-alethine;贝克拉霉素B(betaclamycinB);桦木酸(betulinic acid);bFGF抑制剂;比卡鲁胺(bicalutamide);比生群(bisantrene);双吖丙啶基精胺(bisaziridinylspermine);双奈法德(bisnafide);bistratene A;比折来新(bizelesin);breflate;溴匹立明(bropirimine);布度钛(budotitane);丁胱亚磺酰亚胺(buthionine sulfoximine);卡泊三醇(calcipotriol);calphostin C;喜树碱衍生物(camptothecin derivatives);卡培他滨(capecitabine);甲酰胺-氨基-三唑(carboxamide-amino-triazole);羧酰胺基三唑(carboxyamidotriazole);CaRest M3;CARN700;软骨衍生的抑制剂(cartilage derivedinhibitor);卡折来新(carzelesin);酪蛋白激酶抑制剂(ICOS);澳栗精胺(castanospermine);杀菌肽B(cecropin B);西曲瑞克(cetrorelix);chlorins;4-氨基-N-(5-氯-2-喹喔啉)苯磺酰胺(chloroquinoxaline sulfonamide);西卡前列素(cicaprost);顺式-卟啉(cis-porphyrin);克拉屈滨(cladribine);氯米芬(clomifene)类似物;克霉唑(clotrimazole);collismycin A;collismycin B;考布他汀A4(combretastatin A4);考布他汀(combretastatin)类似物;conagenin;crambescidin 816;克立那托(clotrimazole);cryptophycin 8;cryptophycin A衍生物;curacin A;cyclopentanthraquinones;cycloplatam;cypemycin;阿糖胞苷十八烷基磷酸盐(cytarabine ocfosfate);溶细胞因子(cytolytic factor);磷酸己烷雌酚(cytostatin);达昔单抗(dacliximab);地西他滨(decitabine);dehydrodidemnin B;地落瑞林(deslorelin);地塞米松(dexamethasone);右异环磷酰胺(dexifosfamide);右雷佐生(dexrazoxane);右维拉帕米(dexverapamil);地吖醌(diaziquone);didemnin B;didox;diethylnorspermine;二氢-5-氮胞苷(dihydro-5-azacytidine);9-二氢紫杉醇(dihydrotaxol,9-);dioxamycin;联苯螺莫司汀(diphenylspiromustine);多西他赛(docetaxel);二十二醇(docosanol);多拉司琼(dolasetron);去氧氟尿苷(doxifluridine);多柔比星(doxorubicin);屈洛西芬(droloxifene);屈大麻酚(dronabinol);多卡米星SA(duocarmycin SA);依布硒(ebselen);依考莫司汀(ecomustine);依地福新(edelfosine);依屈洛单抗(edrecolomab);依氟鸟氨酸(eflornithine);榄香烯(elemene);乙嘧替氟(emitefur);表柔比星(epirubicin);依立雄胺(epristeride);雌氮芥类似物(estramustine analogue);雌激素激动剂(estrogenagonists);雌激素拮抗剂(estrogen antagonists);依他硝唑(etanidazole);磷酸依托泊苷(etoposide phosphate);依西美坦(exemestane);法倔唑(fadrozole);法扎拉滨(fazarabine);芬维A胺(fenretinide);非格司亭(filgrastim);非那雄胺(finasteride);flavopiridol;氟卓司汀(flezelastine);fluasterone;氟达拉滨(fludarabine);fluorodaunorunicin hydrochloride;福酚美克(forfenimex);福美坦(formestane);福司曲星(fostriecin);福莫司汀(fotemustine);gadolinium texaphyrin;硝酸镓(galliumnitrate);加洛他滨(galocitabine);加尼瑞克(ganirelix);明胶酶抑制剂(gelatinaseinhibitors);吉西他滨(gemcitabine);谷胱甘肽抑制剂(glutathione inhibitors);hepsulfam;神经生长因子(heregulin);六亚甲基二乙酰胺(hexamethylenebisacetamide);金丝桃素(hypericin);依班膦酸(ibandronic acid);伊达比星(idarubicin);艾多昔芬(idoxifene);伊决孟酮(idramantone);伊莫福新(ilmofosine);伊洛马司他(ilomastat);伊马替尼咪喹莫特(imiquimod);免疫刺激肽(immunostimulant peptides);胰岛素样生长因子-1受体抑制剂(insulin-like growthfactor-1receptor inhibitor);干扰素激动剂(interferon agonists);干扰素(interferons);白细胞介素(interleukins);碘苄胍(iobenguane);碘多柔比星(iododoxorubicin);4-依波米醇(ipomeanol,4-);伊罗普拉(iroplact);伊索拉定(irsogladine);isobengazole;isohomohalicondrin B;依他司琼(itasetron);jasplakinolide;kahalalide F;lamellarin-N triacetate;兰瑞肽(lanreotide);leinamycin;来格斯汀(lenograstim);硫酸香菇多糖(lentinan sulfate);leptolstatin;来曲唑(letrozole);白血病抑制因子;白细胞α干扰素;leuprolide+雌激素+孕酮(leuprolide+estrogen+progesterone);亮丙瑞林(leuprorelin);左旋咪唑(levamisole);利阿唑(liarozole);直链多胺类似物;亲脂二糖肽;亲脂铂化合物;lissoclinamide 7;洛铂(lobaplatin);蚯蚓磷脂(lombricine);洛美曲索(lometrexol);氯尼达明(lonidamine);洛索蒽醌(losoxantrone);罗唑利宾(loxoribine);勒托替康(lurtotecan);lutetium texaphyrin;lysofylline;裂解肽;美坦辛(maitansine);mannostatin A;马立马司他(marimastat);马索罗酚(masoprocol);乳腺丝氨酸蛋白酶抑制物(maspin);基质溶解因子(matrilysin)抑制剂;基质金属蛋白酶抑制剂;美诺立尔(menogaril);merbarone;美替瑞林(meterelin);甲硫氨酸酶;甲氧氯普胺(metoclopramide);MIF抑制剂;米非司酮(mifepristone);米替福新(miltefosine);米立司亭(mirimostim);米托胍腙(mitoguazone);二溴卫矛醇(mitolactol);丝裂霉素类似物;米托萘胺(mitonafide);mitotoxin fibroblast growth factor-saporin;米托蒽醌(mitoxantrone);莫法罗汀(mofarotene);莫拉司亭(molgramostim);爱必妥,人绒毛膜促性腺激素(Erbitux,human chorionic gonadotropin);单磷酰脂质A+分枝杆菌细胞壁sk;莫哌达醇(mopidamol);芥抗癌剂;mycaperoxide B;分枝杆菌细胞壁提取物;myriaporone;N-乙酰地那林(N-acetyldinaline);N-取代苯酰胺(N-substituted benzamides);那法瑞林(nafarelin);nagrestip;纳洛酮+喷他佐新(naloxone+pentazocine);napavin;萘萜二醇(naphterpin);那托司亭(nartograstim);奈达铂(nedaplatin);奈莫柔比星(nemorubicin);奈立膦酸(neridronic acid);尼鲁米特(nilutamide);nisamycin;一氧化氮调节剂;一氧化二氮(nitroxide)抗氧化剂;nitrullyn;奥利美生(oblimersen,);O6-苄基鸟嘌呤(O6-benzylguanine);奥曲肽(octreotide);okicenone;寡核苷酸;奥那司酮(onapristone);恩丹西酮(ondansetron);oracin;口服细胞因子诱导剂;奥马铂(ormaplatin);奥沙特隆(osaterone);奥沙利铂(oxaliplatin);oxaunomycin;紫杉醇(paclitaxel);紫杉醇类似物;紫杉醇衍生物;palauamine;棕榈酰根霉素(palmitoylrhizoxin);帕米膦酸(pamidronic acid);人参三醇(panaxytriol);帕诺米芬(panomifene);副球菌素(parabactin);帕折普汀(pazelliptine);培门冬酶(pegaspargase);培地辛(peldesine);戊聚糖多硫酸钠(pentosan poly sulfatesodium);喷司他丁(pentostatin);pentrozole;全氟溴烷(perflubron);培磷酰胺(perfosfamide);紫苏子醇(perillyl alcohol);phenazinomycin;乙酸苯酯(phenylacetate);磷酸酶抑制剂;溶血性链球菌制剂(picibanil);盐酸毛果芸香碱(pilocarpine hydrochloride);吡柔比星(pirarubicin);吡曲克辛(piritrexim);placetin A;placetin B;血纤蛋白溶酶原活化物抑制剂;铂络合物(platinum complex);铂化合物;铂三胺络合物(platinum-triamine complex);卟菲尔钠(porfimer sodium);泊非霉素(porfiromycin);泼尼松(prednisone);丙基双吖啶酮(propyl bis-acridone);前列腺素J2(prostaglandin J2);蛋白酶体抑制剂;基于蛋白A的免疫调节剂;蛋白激酶C抑制剂;蛋白激酶C抑制剂类;microalgal;蛋白酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;羟基茜草素(purpurins);吡唑啉吖啶(pyrazoloacridine);吡哆血红蛋白聚氧乙烯共轭物(pyridoxylated hemoglobin polyoxyethylene conjugate);raf拮抗剂;雷替曲塞(raltitrexed);雷莫司琼(ramosetron);ras法尼基转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;脱甲基瑞替普汀(retelliptine demethylated);羟乙磷酸铼-186(rhenium-186etidronate);根霉素(rhizoxin);核酶;R2视黄酰胺(R2 retinamide);rohitukine;罗莫肽(romurtide);罗喹美克(roquinimex);rubiginone Bl;ruboxyl;沙芬戈(safingol);saintopin;SarCNU;sarcophytol A;沙格司亭(sargramostim);Sdi1模拟物;司莫司汀(semustine);衰老衍生抑制剂1(senescence derived inhibitor 1);有义寡核苷酸;信号传导抑制剂;西佐喃(sizofiran);索布佐生(sobuzoxane);硼卡钠(sodium borocaptate);苯乙酸钠(sodium phenylacetate);solverol;生长调节素(somatomedin)结合蛋白;索纳明(sonermin);膦门冬酸(sparfosic acid);spicamycin D;螺莫司汀(spiromustine);splenopentin;海绵抑制素1(spongistatin 1);角鲨胺(squalamine);stipiamide;基质降解酶(stromelysin)抑制剂;sulfmosine;超活性血管活性肠肽拮抗剂;suradista;舒拉明(suramin);苦马豆素(swainsonine);他莫司汀(tallimustine);甲碘他莫昔芬(tamoxifenmethiodide);牛磺莫司汀(tauromustine);他扎罗汀(tazarotene);替可加兰钠(tecogalan sodium);喃氟啶(tegafur);tellurapyrylium;端粒酶抑制剂;替莫泊芬(temoporfin);替尼泊苷(teniposide);tetrachlorodecaoxide;tetrazomine;thaliblastine;噻可拉林(thiocoraline);血小板生成素;血小板生成素模拟物;胸腺法新(thymalfasin);胸腺生成素(thymopoietin)受体激动剂;胸腺曲南(thymotrinan);促甲状腺激素;tin ethyl etiopurpurin;替拉扎明(tirapazamine);titanocene bichloride;topsentin;托瑞米芬(toremifene);翻译抑制剂;维甲酸;三乙酰尿苷(triacetyluridine);曲西立滨(triciribine);三甲曲沙(trimetrexate);曲普瑞林(triptorelin);托烷司琼(tropisetron);妥罗特来(turosteride);酪氨酸激酶抑制剂;酪氨酸磷酸化抑制剂(tyrphostins);UBC抑制剂;乌苯美司(ubenimex);衍生自泌尿生殖窦的生长抑制因子;尿激酶受体拮抗剂;伐普肽(vapreotide);variolin B;维拉雷琐(velaresol);藜芦明(veramine);verdin;维替泊芬(verteporfin);长春瑞滨(vinorelbine);vinxaltine;vitaxin;伏罗唑(vorozole);扎诺特隆(zanoterone);折尼铂(zeniplatin);zilascorb;和净司他丁斯酯(zinostatin stimalamer)。
具体的第二活性剂包括但不限于2-甲氧基雌二醇、telomestatin、多发性骨髓瘤细胞中的细胞凋亡诱导剂(例如TRAIL)、他汀类药物、司马沙尼、环孢素、依那西普、多西环素、硼替佐米、奥利美生(Genasense 1Remicade、多西他赛、塞来昔布、美法仑、地塞米松类固醇类、吉西他滨、顺铂、替莫唑胺、依托泊苷、环磷酰胺、替莫唑胺、卡铂、丙卡巴肼、gliadel、他莫昔芬、托泊替康(topotecan)、甲氨蝶呤、taxol、泰索帝、氟尿嘧啶、甲酰四氢叶酸(leucovorin)、伊立替康、希罗达(xeloda)、CPT-11、干扰素α、聚乙二醇化干扰素α(例如PEG INTRON-A)、卡培他滨、顺铂、噻替派、氟达拉滨、卡铂、脂质体柔红霉素(liposomal daunorubicin)、阿糖胞苷(cytarabine)、多西他赛(doxetaxol)、紫杉醇、长春碱、IL-2、GM-CSF、达卡巴嗪、长春瑞滨、唑来膦酸、palmitronate、biaxin、白消安、泼尼松、二磷酸盐、三氧化二砷、长春新碱、多柔比星紫杉醇、更昔洛韦、阿霉素(adriamycin)、雌莫司汀磷酸钠舒林酸(sulindac)和依托泊苷。
用于治疗结肠直肠癌的具体的第二活性剂包括但不限于瑞戈非尼(regorafenib)、ziv-阿柏西普(ziv-aflibercept)和tipiracil/曲氟尿苷(trifluridine);罗米地新(romidepsin)用于治疗外周T细胞淋巴瘤和皮肤T细胞淋巴瘤;brentuximab vedotin用于治疗霍奇金淋巴瘤和间变性大细胞淋巴瘤;匹克生琼(pixantrone)和利妥昔单抗(rituximab)用于治疗非霍奇金淋巴瘤;idelalisib用于治疗慢性淋巴细胞性白血病、滤泡性淋巴瘤和小淋巴细胞性淋巴瘤;mogamulizumab用于治疗血管免疫母细胞性T细胞淋巴瘤;贝林司他(belinostat)用于治疗外周T细胞淋巴瘤;依鲁替尼(ibrutinib)用于治疗套细胞淋巴瘤和Waldenstrom's巨球蛋白血症;硼替佐米(bortezomib)用于治疗套细胞淋巴瘤;chidamide用于治疗外周T细胞淋巴瘤;纳武单抗(nivolumab)用于治疗霍奇金淋巴瘤;司妥昔单抗(siltuximab)用于治疗Castleman病;奥拉帕利(olaparib)、贝伐珠单抗(bevacizumab)和rucaparib用于治疗卵巢癌;贝伐珠单抗(bevacizumab)用于治疗宫颈癌;vismodegib和sonidegib用于治疗基底细胞癌;ruxolitinib用于治疗骨髓增生性疾病;雷莫芦单抗(ramucirumab)用于治疗胃癌;卡非佐米(carfilzomib)、泊马度胺(pomalidomide)、达雷木单抗(daratumumab)、ixazomib、帕比司他(panobinostat)和伊洛珠单抗(elotuzumab)用于治疗多发性骨髓瘤;醋酸阿比特龙(abiraterone acetate)、安扎鲁胺(enzalutamide)和镭223二氯(radium-223dichloride)用于治疗前列腺癌;米法莫肽(mifamurtide)、曲贝替定(trabectedin)、艾立布林(eribulin)和olaratumab用于治疗肉瘤;crizotinib、afatinib、阿来替尼(alectinib)、ceritinib、雷莫芦单抗(ramucirumab)、纳武单抗(nivolumab)、派姆单抗(pembrolizumab)、奈昔木单抗(necitumumab)、奥西替尼(osimertinib)、吉非替尼(gefitinib)和atezolizumab用于治疗肺癌;波舒替尼(bosutinib)、美琥他辛(omacetaxine mepesuccinate)和radotinib用于治疗慢性髓性白血病;阿托珠单抗(obinutuzumab)用于治疗慢性淋巴细胞性白血病和滤泡性淋巴瘤;泊那替尼(ponatinib)用于治疗慢性髓性白血病和急性成淋巴细胞性白血病;兰妥莫单抗(blinatumomab)用于治疗急性成淋巴细胞性白血病;依鲁替尼(ibrutinib)、奥法木单抗(ofatumumab)和venetoclax用于治疗慢性淋巴细胞白血病;瑞戈非尼(regorafenib)用于治疗胃肠道基质肿瘤;凡德他尼(vandetanib)、卡博替尼(cabozantinib)和乐伐替尼(lenvatinib)用于治疗甲状腺癌;dinutuximab用于治疗成神经细胞瘤;阿妥珠单抗(atezolizumab)用于治疗膀胱癌;纳武单抗(nivolumab)和派姆单抗(pembrolizumab)用于治疗头颈癌;伊立替康脂质体(irinotecan liposome)用于治疗胰腺癌;阿昔替尼(axitinib)、纳武单抗(nivolumab)、乐伐替尼(lenvatinib)和卡博替尼(cabozantinib)用于治疗肾癌;培妥珠单抗(pertuzumab)、ado-trastuzumab emtansine和帕博西尼(palbociclib)用于治疗乳腺癌;以及伊匹木单抗(ipilimumab)、维罗非尼(vemurafenib)、曲美替尼(trametinib)、达拉非尼(dabrafenib)、派姆单抗(pembrolizumab)、纳武单抗(nivolumab)、cobimetinib和T-Vec用于治疗黑素瘤。
如本领域技术人员所知,根据本发明方法施用的本文提供的CCR5抑制剂的量将会随之变化,这取决于施用途径、赋形剂使用以及与包括使用其他治疗剂在内的其他疗法治疗共同使用的可能性。
根据一些实施方案,本文所述的CCR5抑制剂可以约0.1mg至约400mg的量施用。根据一些实施方案,本文所述的CCR5抑制剂可以约1mg至约100mg的量施用。根据一些实施方案,本文所述的CCR5抑制剂可以约4mg至约40mg的量施用。
根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约300mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约200mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约100mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约95mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约90mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约85mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约80mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约75mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约70mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约65mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约60mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约55mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约50mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约45mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约40mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约35mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约30mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约25mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约20mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约15mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约10mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约5mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约0.1mg至约1mg的量施用。
根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约400mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约300mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约200mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约95mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约90mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约85mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约80mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约75mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约70mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约65mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约60mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约55mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约50mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约45mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约40mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约35mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约30mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约25mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约20mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约15mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约10mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约1mg至约5mg的量施用。
根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约400mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约300mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约200mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约100mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约95mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约90mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约85mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约80mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约75mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约70mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约65mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约60mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约55mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约50mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约45mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约40mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约35mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约30mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约25mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约20mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约15mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约5mg至约10mg的量施用。
根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约400mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约300mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约200mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约100mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约95mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约90mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约85mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约80mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约75mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约70mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约65mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约60mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约55mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约50mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约45mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约40mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约35mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约30mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约25mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约20mg的量施用。根据一些实施方案,本文所提供的CCR5抑制剂可以约10mg至约15mg的量施用。
根据一些实施方案,本文所提供的CCR5抑制剂可以约400mg、约350mg、约300mg、约250mg、约200mg、约150mg、约100mg、约95mg、约90mg、约85mg、约80mg、约75mg、约70mg、约65mg、约60mg、约55mg、约50mg、约45mg、约40mg、约35mg、约30mg、约25mg、约20mg、约19mg、约18mg、约17mg、约16mg、约15mg、约14mg、约13mg、约12mg、约11mg、约10mg、约9mg、约8mg、约7mg、约6mg、约5mg、约4mg、约3mg、约2mg、约1mg、约0.5mg或约0.1mg的量施用。
根据一些实施方案,本文提供的CCR5抑制剂、药物组合物或剂型可一天施用一次或以每天2、3、4、5或6个相等剂量单独施用。根据其他实施方案,本文提供的CCR5抑制剂、药物组合物或剂型可每天施用两次、三次、四次、五次、六次或更多次。
根据一些实施方案,本文提供的CCR5抑制剂、药物组合物或剂型可长期施用。根据一些实施方案,本文提供的CCR5抑制剂、药物组合物或剂型可施用一、二、三、四、五、六或七天;施用一、二、三或四周;施用一、二、三、四、五、六、七、八、九、十、十一、十二个月或更长时间。
对于长期施用,本文提供的CCR5抑制剂、药物组合物或剂型可以每日、一周六次、一周五次、一周四次、一周三次、一周两次、一周一次、每两周一次、每三周一次、每四周一次、每五周一次、每六周一次、每七周一次、每八周一次、每九周一次、每十周一次、一月两次、一月一次、每两月一次或每三月一次的频率施用。
在一些实施方案中,施用或提供本文提供的CCR5抑制剂、药物组合物或剂型,其与其他药理活性化合物分开、依次或同时联合施用。在一些实施方案中,本文提供的CCR5抑制剂、药物组合物或剂型与其他药理活性化合物联合使用。或者,本文提供的CCR5抑制剂、药物组合物或剂型的治疗性施用可在其他药理活性化合物治疗之前或之后间隔几分钟至几周。在其中本文提供的CCR5抑制剂、药物组合物或剂型和其他的药理活性化合物分开施用的实施方案中,本领域技术人员通常将确保在每次递送之间没有经过显著时间,使得本文提供的CCR5抑制剂、药物组合物或剂型和药理活性化合物将仍然能够对对象产生有利的组合作用。在这种情况下,可以预期,本领域技术人员可以在彼此相隔约12-24小时内,更优选地,在彼此相隔约6-12小时内施用两种形式。在一些情况下,可能期望显著延长施用的时间期限,其中在各次施用之间经过数天(2、3、4、5、6或7)至数周(1、2、3、4、5、6、7或8)。
可以施用本文所述的CCR5抑制剂、药物组合物或剂型,直至有需要的对象不需要治疗、预防或改善癌症。
然而,应当理解,用于任何特定对象的具体剂量和治疗方案将取决于多种因素,包括所用具体化合物的活性、年龄、体重、总体健康、性别、饮食、施用时间、排泄速率、药物组合和治疗医师的判断以及所治疗具体病症的严重程度。CCR5抑制剂的量还可取决于与CCR5抑制剂共同施用的治疗剂或预防剂(如果有的话)。
实施方案
本发明的具体实施方案包括但不限于以下:
1.一种治疗癌症的方法,所述方法包含向对象施用CCR5抑制剂,其中所述CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列QGP[P或L],且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同。
2.如实施方案1所述的方法,其中所述CCR5抑制剂抑制HIV进入细胞,且相较于CCR1和CCR3,所述CCR5抑制剂是CCR5选择性的。
3.如实施方案1或2所述的方法,其中所述CCR5抑制剂仅抑制CCR5细胞内信号传导通路的亚组。
4.如实施方案1-3任一项所述的方法,其中所述CCR5抑制剂抑制或减少CCR5的炎性作用,例如,当在钙流信号传导测定中以300nM的浓度测试时,导致信号传导应答为PSC-RANTES引发的最大应答(Emax)的30%或更低。
5.如实施方案1-4任一项所述的方法,其中所述CCR5抑制剂以G蛋白偶联和未偶联的构象结合CCR5。
6.如实施方案1-5任一项所述的方法,其中所述CCR5抑制剂不诱导CCR5内化。
7.如实施方案6所述的方法,如通过CCR5表面下行性调节测定所测量的,其中所述CCR5抑制剂导致20%或更低的受体隐蔽活性。
8.根据实施方案1所述的方法,其中所述特征序列是QGP[P或L][L或G或S或M][M或D或S或Q或G]。
9.根据实施方案1所述的方法,其中所述特征序列是QGP[P或L][L或G][M或D或S]。
10.根据实施方案1所述的方法,其中所述特征序列是QGP[P或L][L或G或S或M][M或D或S或Q或G]XX[Q或G或L或A或T或S]X,其中X表示任何天然的或修饰的氨基酸。
11.根据实施方案1所述的方法,其中所述特征序列是QGP[P或L][L或G][M或D或S]XX[Q或G或L]X,其中X表示任何天然的或修饰的氨基酸。
12.根据实施方案1所述的方法,其中所述特征序列是QGP[P或L]LM或QGPPG[D或S]。
13.根据实施方案1所述的方法,其中所述特征序列是QGPPLM或QGPPGD。
14.根据实施方案1所述的方法,其中所述特征序列是QGP[P或L][L或M][M或Q][A或W或G或Q或N]X[Q或G或L][S或V或T或G],其中X表示任何天然的或修饰的氨基酸。
15.根据实施方案1所述的方法,其中所述特征序列是QGP[P或L][L或M][M或Q][A或W或G或Q或N][L或T或M或S或G或Q或R或Y][Q或G或L][S或V或T或G]。
16.根据实施方案1所述的方法,其中所述特征序列是QGP[P或L]LM[A或W][L或T或M][Q或G][S或V或T或G]。
17.根据实施方案1所述的方法,其中所述特征序列是QGPPLM[A或W][L或T或M][Q或G][S或V或T或G]。
18.根据实施方案1所述的方法,其中所述特征序列是QGPP[G或L][M或Q]XX[Q或S][S或V],其中X表示任何天然的或修饰的氨基酸。
19.根据实施方案1所述的方法,其中所述特征序列是QGPP[G或L][M或Q][S或G或W或A或T][L或F或T或S或G或Y][Q或S][S或V]。
20.根据实施方案1所述的方法,其中所述特征序列选自QGPPLMALQS(SEQ ID NO:2)、QGPPLMWMQV(SEQ ID NO:3)、QGPPLMWLQV(SEQ ID NO:4)、QGPPLMWTQS(SEQ ID NO:5)、QGPPLMWLQT(SEQ ID NO:6)、QGPPLMWTQV(SEQ ID NO:7)、QGPPLMWMQS(SEQ ID NO:8)、QGPPLMATQS(SEQ ID NO:9)、QGPPLMWLQS(SEQ ID NO:10)、QGPPLMALQV(SEQ ID NO:11)、QGPPLMWLGG(SEQ ID NO:12)、QGPPLMWRGS(SEQ ID NO:13)、QGPLLMWLQV(SEQ ID NO:14)、QGPPLMQTTP(SEQ ID NO:15)、QGPPLSWLQV(SEQ ID NO:30)、QGPPLSWLQS(SEQ ID NO:31)、QGPPGQWSQV(SEQ ID NO:32)、QGPPMMAGLS(SEQ ID NO:33)、QGPPLSWQQS(SEQ ID NO:34)、QGPPGMWSQS(SEQ ID NO:35)、QGPPLQWRQS(SEQ ID NO:36)、QGPPLMGTQS(SEQ ID NO:37)、QGPPLMQLQV(SEQ ID NO:38)、QGPPLSWSQV(SEQ ID NO:39)、QGPPMSWSQS(SEQ ID NO:40)、QGPPLMNLQV(SEQ ID NO:41)、QGPPMSAYQV(SEQ ID NO:42)和QGPPMQGGLS(SEQ ID NO:43)。
21.根据实施方案1所述的方法,其中所述特征序列选自QGPPLMALQS(SEQ ID NO:2)、QGPPLMWMQV(SEQ ID NO:3)、QGPPLMWLQV(SEQ ID NO:4)、QGPPLMWTQS(SEQ ID NO:5)、QGPPLMWLQT(SEQ ID NO:6)、QGPPLMWTQV(SEQ ID NO:7)、QGPPLMWMQS(SEQ ID NO:8)、QGPPLMATQS(SEQ ID NO:9)、QGPPLMWLQS(SEQ ID NO:10)、QGPPLMALQV(SEQ ID NO:11)、QGPPLMWLGG(SEQ ID NO:12)、QGPPLMWRGS(SEQ ID NO:13)、QGPLLMWLQV(SEQ ID NO:14)和QGPPLMQTTP(SEQ ID NO:15)。
22.根据实施方案1所述的方法,其中所述特征序列是QGPPLMATQS(SEQ ID NO:9)。
23.根据实施方案1-22任一项的所述方法,其中所述特征序列位于最N末端。
24.根据实施方案1-23任一项所述的方法,其中所述C-末端部分与SEQ ID NO:1相同。
25.根据实施方案1-24任一项所述的方法,其中所述癌症是结直肠癌、乳腺癌、肺癌、前列腺癌、卵巢癌、胰腺癌、食管癌、胃癌、肝癌或白血病。
26.根据实施方案1-25任一项所述的方法,其中所述癌症是结直肠癌。
27.根据实施方案1-25任一项所述的方法,其中所述癌症是乳腺癌。
28.根据实施方案1-25任一项所述的方法,其中所述癌症是肺癌。
29.根据实施方案1-25任一项所述的方法,其中所述癌症是前列腺癌。
30.根据实施方案1-25任一项所述的方法,其中所述癌症是卵巢癌。
31.根据实施方案1-25任一项所述的方法,其中所述癌症是胰腺癌。
32.根据实施方案1-25任一项所述的方法,其中所述癌症是食管癌。
33.根据实施方案1-25任一项所述的方法,其中所述癌症是胃癌。
34.根据实施方案1-25任一项所述的方法,其中所述癌症是肝癌。
35.根据实施方案1-25任一项所述的方法,其中所述癌症是白血病。
36.根据实施方案35所述的方法,其中所述癌症是急性成淋巴细胞性白血病(ALL)。
37.根据实施方案1-36任一项所述的方法,其中所述癌症是转移性的。
38.根据实施方案1-36任一项所述的方法,其中所述癌症是化疗或放疗难治性的和/或对化疗或放疗具有抗性的。
39.根据实施方案37所述的方法,其中所述癌症是化疗或放疗难治性的和对化疗或放疗具有抗性的。
40.根据实施方案1-39任一项所述的方法,其中所述CCR5抑制剂与第二活性剂一起施用。
41.根据实施方案40所述的方法,其中所述第二活性剂具有针对癌症的治疗功效。
42.根据实施方案1-41任一项所述的方法,其中所述CCR抑制剂在癌症症状出现之前施用。
43.根据实施方案1-42任一项所述的方法,其中口服、舌下、含服、表面、直肠、经由吸入、经皮、皮下、静脉内、动脉内或肌内、经由心内施用、骨内、皮内、腹膜内、大脑内、经粘膜、阴道、玻璃体内、表皮、关节内、膀胱内、鞘内、关节周或局部施用所述CCR5抑制剂。
44.根据实施方案1-43任一项所述的方法,其中静脉内、口服或经由吸入施用所述CCR5抑制剂。
45.根据实施方案1-44任一项所述的方法,其中静脉内施用所述CCR5抑制剂,例如经由可注射的控释储存装置。
46.根据实施方案1-45任一项所述的方法,其中所述CCR5抑制剂与药物载剂一起施用。
47.根据实施方案1-46任一项所述的方法,其中所述CCR5抑制剂以约0.1mg至约400mg的量施用。
48.根据实施方案47所述的方法,其中所述CCR5抑制剂以约1mg的量施用。
49.根据实施方案47所述的方法,其中所述CCR5抑制剂以约2mg的量施用。
50.根据实施方案47所述的方法,其中所述CCR5抑制剂以约3mg的量施用。
51.根据实施方案47所述的方法,其中所述CCR5抑制剂以约5mg的量施用。
52.根据实施方案47所述的方法,其中所述CCR5抑制剂以约10mg的量施用。
53.根据实施方案47所述的方法,其中所述CCR5抑制剂以约20mg的量施用。
54.根据实施方案47所述的方法,其中所述CCR5抑制剂以约40mg的量施用。
55.根据实施方案1-54任一项所述的方法,其中所述CCR5抑制剂一天施用一次或以每天2、3、4、5或6个相等剂量分开施用。
56.根据实施方案1-55任一项所述的方法,其中所述CCR5抑制剂长期施用。
57.根据实施方案56所述的方法,其中所述CCR5抑制剂施用一、二、三、四、五、六或七天;施用一、二、三或四周;施用约一、二、三、四、五、六、七、八、九、十、十一、十二个月或更长时间。
58.根据实施方案57所述的方法,其中所述CCR5抑制剂施用24周或更长时间。
59.根据实施方案58所述的方法,其中所述CCR5抑制剂施用28周或更长时间。
60.根据实施方案56-59任一项所述的方法,其中以每日、一周六次、一周五次、一周四次、一周三次、一周两次、一周一次、每两周一次、每三周一次、每四周一次、每五周一次、每六周一次、每七周一次、每八周一次、每九周一次、每十周一次、一月两次、一月一次、每两月一次或每三月一次的频率施用所述CCR5抑制剂。
61.根据实施方案60所述的方法,其中每日施用所述CCR5抑制剂。
62.根据实施方案60所述的方法,其中一周施用一次所述CCR5抑制剂。
63.根据实施方案1-61任一项所述的方法,其中施用或提供所述CCR5抑制剂,其与其他药理活性化合物分开、依次或同时联合施用。
64.CCR5抑制剂用于治疗癌症的用途,其中所述CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列QGP[P或L],且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同。
65.如实施方案64所述的用途,其中所述CCR5抑制剂抑制HIV进入细胞,且相较于CCR1和CCR3,所述CCR5抑制剂是CCR5选择性的。
66.如实施方案64或65所述的用途,其中所述CCR5抑制剂仅抑制CCR5细胞内信号传导通路的亚组。
67.如实施方案64-66任一项所述的用途,其中所述CCR5抑制剂抑制或减少CCR5的炎性作用,例如,当在钙流信号传导测定中以300nM的浓度测试时,导致信号传导应答为PSC-RANTES引发的最大应答(Emax)的30%或更低。
68.如实施方案64-67任一项所述的用途,其中所述CCR5抑制剂以G蛋白偶联和未偶联的构象结合CCR5。
69.如实施方案64-68任一项所述的用途,其中所述CCR5抑制剂不诱导CCR5内化。
70.如实施方案69所述的用途,如通过CCR5表面下行性调节测定所测量的,其中所述CCR5抑制剂导致20%或更低的受体隐蔽活性。
71.根据实施方案64所述的用途,其中所述特征序列是QGP[P或L][L或G或S或M][M或D或S或Q或G]。
72.根据实施方案64所述的用途,其中所述特征序列是QGP[P或L][L或G][M或D或S]。
73.根据实施方案64所述的用途,其中所述特征序列是QGP[P或L][L或G或S或M][M或D或S或Q或G]XX[Q或G或L或A或T或S]X,其中X表示任何天然的或修饰的氨基酸。
74.根据实施方案64所述的用途,其中所述特征序列是QGP[P或L][L或G][M或D或S]XX[Q或G或L]X,其中X表示任何天然的或修饰的氨基酸。
75.根据实施方案64所述的用途,其中所述特征序列是QGP[P或L]LM或QGPPG[D或S]。
76.根据实施方案64所述的用途,其中所述特征序列是QGPPLM或QGPPGD。
77.根据实施方案64所述的用途,其中所述特征序列是QGP[P或L][L或M][M或Q][A或W或G或Q或N]X[Q或G或L][S或V或T或G],其中X表示任何天然的或修饰的氨基酸。
78.根据实施方案64所述的用途,其中所述特征序列是QGP[P或L][L或M][M或Q][A或W或G或Q或N][L或T或M或S或G或Q或R或Y][Q或G或L][S或V或T或G]。
79.根据实施方案64所述的用途,其中所述特征序列是QGP[P或L]LM[A或W][L或T或M][Q或G][S或V或T或G]。
80.根据实施方案64所述的用途,其中所述特征序列是QGPPLM[A或W][L或T或M][Q或G][S或V或T或G]。
81.根据实施方案64所述的用途,其中所述特征序列是QGPP[G或L][M或Q]XX[Q或S][S或V],其中X表示任何天然的或修饰的氨基酸。
82.根据实施方案64所述的用途,其中所述特征序列是QGPP[G或L][M或Q][S或G或W或A或T][L或F或T或S或G或Y][Q或S][S或V]。
83.根据实施方案64所述的用途,其中所述特征序列选自QGPPLMALQS(SEQ ID NO:2)、QGPPLMWMQV(SEQ ID NO:3)、QGPPLMWLQV(SEQ ID NO:4)、QGPPLMWTQS(SEQ ID NO:5)、QGPPLMWLQT(SEQ ID NO:6)、QGPPLMWTQV(SEQ ID NO:7)、QGPPLMWMQS(SEQ ID NO:8)、QGPPLMATQS(SEQ ID NO:9)、QGPPLMWLQS(SEQ ID NO:10)、QGPPLMALQV(SEQ ID NO:11)、QGPPLMWLGG(SEQ ID NO:12)、QGPPLMWRGS(SEQ ID NO:13)、QGPLLMWLQV(SEQ ID NO:14)、QGPPLMQTTP(SEQ ID NO:15)、QGPPLSWLQV(SEQ ID NO:30)、QGPPLSWLQS(SEQ ID NO:31)、QGPPGQWSQV(SEQ ID NO:32)、QGPPMMAGLS(SEQ ID NO:33)、QGPPLSWQQS(SEQ ID NO:34)、QGPPGMWSQS(SEQ ID NO:35)、QGPPLQWRQS(SEQ ID NO:36)、QGPPLMGTQS(SEQ ID NO:37)、QGPPLMQLQV(SEQ ID NO:38)、QGPPLSWSQV(SEQ ID NO:39)、QGPPMSWSQS(SEQ ID NO:40)、QGPPLMNLQV(SEQ ID NO:41)、QGPPMSAYQV(SEQ ID NO:42)和QGPPMQGGLS(SEQ ID NO:43)。
84.根据实施方案64所述的用途,其中所述特征序列选自QGPPLMALQS(SEQ ID NO:2)、QGPPLMWMQV(SEQ ID NO:3)、QGPPLMWLQV(SEQ ID NO:4)、QGPPLMWTQS(SEQ ID NO:5)、QGPPLMWLQT(SEQ ID NO:6)、QGPPLMWTQV(SEQ ID NO:7)、QGPPLMWMQS(SEQ ID NO:8)、QGPPLMATQS(SEQ ID NO:9)、QGPPLMWLQS(SEQ ID NO:10)、QGPPLMALQV(SEQ ID NO:11)、QGPPLMWLGG(SEQ ID NO:12)、QGPPLMWRGS(SEQ ID NO:13)、QGPLLMWLQV(SEQ ID NO:14)和QGPPLMQTTP(SEQ ID NO:15)。
85.根据实施方案64所述的用途,其中所述特征序列是QGPPLMATQS(SEQ ID NO:9)。
86.根据实施方案64-85任一项的所述用途,其中所述特征序列位于最N末端。
87.根据实施方案64-86任一项所述的用途,其中所述C-末端部分与SEQ ID NO:1相同。
88.根据实施方案64-87任一项所述的用途,其中所述癌症是结直肠癌、乳腺癌、肺癌、前列腺癌、卵巢癌、胰腺癌、食管癌、胃癌、肝癌或白血病。
89.根据实施方案64-88任一项所述的用途,其中所述癌症是结直肠癌。
90.根据实施方案64-88任一项所述的用途,其中所述癌症是乳腺癌。
91.根据实施方案64-88任一项所述的用途,其中所述癌症是肺癌。
92.根据实施方案64-88任一项所述的用途,其中所述癌症是前列腺癌。
93.根据实施方案64-88任一项所述的用途,其中所述癌症是卵巢癌。
94.根据实施方案64-88任一项所述的用途,其中所述癌症是胰腺癌。
95.根据实施方案64-88任一项所述的用途,其中所述癌症是食管癌。
96.根据实施方案64-88任一项所述的用途,其中所述癌症是胃癌。
97.根据实施方案64-88任一项所述的用途,其中所述癌症是肝癌。
98.根据实施方案64-88任一项所述的用途,其中所述癌症是白血病。
99.根据实施方案98所述的用途,其中所述癌症是急性成淋巴细胞性白血病(ALL)。
100.根据实施方案64-99任一项所述的用途,其中所述癌症是转移性的。
101.根据实施方案64-100任一项所述的用途,其中所述癌症是化疗或放疗难治性的和/或对化疗或放疗具有抗性的。
102.根据实施方案101所述的用途,其中所述癌症是化疗或放疗难治性的和对化疗或放疗具有抗性的。
103.根据实施方案64-102任一项所述的用途,其中所述CCR5抑制剂与第二活性剂一起施用。
104.根据实施方案103所述的用途,其中所述第二活性剂具有针对癌症的治疗功效。
105.根据实施方案64-104任一项所述的用途,其中所述CCR抑制剂在癌症症状出现之前施用。
106.根据实施方案64-105任一项所述的用途,其中口服、舌下、含服、表面、直肠、经由吸入、经皮、皮下、静脉内、动脉内或肌内、经由心内施用、骨内、皮内、腹膜内、大脑内、经粘膜、阴道、玻璃体内、表皮、关节内、膀胱内、鞘内、关节周或局部施用所述CCR5抑制剂。
107.根据实施方案64-106任一项所述的用途,其中静脉内、口服或经由吸入施用所述CCR5抑制剂。
108.根据实施方案64-107任一项所述的用途,其中静脉内施用所述CCR5抑制剂,例如经由可注射的控释储存装置。
109.根据实施方案64-108任一项所述的用途,其中所述CCR5抑制剂与药物载剂一起施用。
110.根据实施方案64-109任一项所述的用途,其中所述CCR5抑制剂以约0.1mg至约400mg的量施用。
111.根据实施方案110所述的用途,其中所述CCR5抑制剂以约1mg的量施用。
112.根据实施方案110所述的用途,其中所述CCR5抑制剂以约2mg的量施用。
113.根据实施方案110所述的用途,其中所述CCR5抑制剂以约3mg的量施用。
114.根据实施方案110所述的用途,其中所述CCR5抑制剂以约5mg的量施用。
115.根据实施方案110所述的用途,其中所述CCR5抑制剂以约10mg的量施用。
116.根据实施方案110所述的用途,其中所述CCR5抑制剂以约20mg的量施用。
117.根据实施方案110所述的用途,其中所述CCR5抑制剂以约40mg的量施用。
118.根据实施方案64-117任一项所述的用途,其中所述CCR5抑制剂一天施用一次或以每天2、3、4、5或6个相等剂量分开施用。
119.根据实施方案64-118任一项所述的用途,其中所述CCR5抑制剂长期施用。
120.根据实施方案119所述的用途,其中所述CCR5抑制剂施用一、二、三、四、五、六或七天;施用一、二、三或四周;施用约一、二、三、四、五、六、七、八、九、十、十一、十二个月或更长时间。
121.根据实施方案120所述的用途,其中所述CCR5抑制剂施用24周或更长时间。
122.根据实施方案121所述的用途,其中所述CCR5抑制剂施用28周或更长时间。
123.根据实施方案119-122任一项所述的用途,其中以每日、一周六次、一周五次、一周四次、一周三次、一周两次、一周一次、每两周一次、每三周一次、每四周一次、每五周一次、每六周一次、每七周一次、每八周一次、每九周一次、每十周一次、一月两次、一月一次、每两月一次或每三月一次的频率施用所述CCR5抑制剂。
124.根据实施方案123所述的用途,其中每日施用所述CCR5抑制剂。
125.根据实施方案123所述的用途,其中一周施用一次所述CCR5抑制剂。
126.根据实施方案64-125任一项所述的用途,其中施用或提供所述CCR5抑制剂,其与其他药理活性化合物分开、依次或同时联合施用。
127.根据实施方案63的方法,其中所述其他药理活性化合物是检查点抑制剂。
128.根据实施方案127的方法,其中所述其他药理活性化合物是抗PD-1抗体。
129.根据实施方案127的方法,其中所述其他药理活性化合物是抗CTLA-4抗体。
130.根据实施方案126的用途,其中所述其他药理活性化合物是检查点抑制剂。
131.根据实施方案130的用途,其中所述其他药理活性化合物是抗PD-1抗体。
132.根据实施方案130的用途,其中所述其他药理活性化合物是抗CTLA-4抗体。
实施例
实施例1:5P12-RANTES在抑制通过人CCR5的信号传导方面比几种其他CCR5抑制剂更有效。
用所示的抑制剂以递增的浓度处理中国仓鼠卵巢细胞,该中国仓鼠卵巢细胞通过工程化手段以表达人CCR5加上水母荧光素钙传感器以检测受体信号传导活性,然后用天然CCR5激动剂人MIP-1β/CCL4处理。在各抑制剂浓度下在细胞中测量的信号传导活性表示为在不存在抑制剂的情况下由激动剂引发的信号的百分比(n=2)(图1A、1B和1C)。在图1A中,拟合的剂量-抑制曲线(GraphPadPrism)表明马拉韦罗和5P12-RANTES的IC50值分别为2.7nM和0.12nM。在图1B中,拟合的剂量-抑制曲线(GraphPadPrism)表明cencriviroc、BMS-0813160、马拉韦罗和5P12-RANTES的IC50值分别为51nM、5.7nM、4.3nM和0.3nM。在图1C中,拟合的剂量-抑制曲线(GraphPadPrism)表明PRO-140、马拉韦罗和5P12-RANTES的IC50值分别为5.6nM、2.6nM和0.2nM。
实施例2:5P12-RANTES与MVC的抗逆转录病毒效力的比较
在使用来自一组美国供体(代表高加索人、黑种人、亚洲人和拉美裔)的外周血单个核细胞的复制测定中,将5P12-RANTES针对HIV-1BaL的抗逆转录病毒效力(log IC50)与参照化合物AZT和马拉韦罗(MVC)进行比较(图2)。对于每个供体,每个化合物在9个浓度下一式三份进行评价。每个点代表单个供体的log IC50。BD:低于(即,更有效于)测定检测限。这些数据表明,5P12-RANTES在抑制HIV-1复制方面的效力比MVC强10-30倍。
实施例3:5P12-RANTES对人CCR1和CCR3的抑制活性的测定
使用GTPγ35S功能测定,以剂量应答并一式两份,检测5P12-RANTES对重组人CCR1受体(FAST-058G)和CCR3受体(FAST-061G)的抑制活性。
测定缓冲剂为20mM HEPES pH 7.4;200mM NaCl,10μg/ml皂苷(saponin),对于具体受体浓度最佳的MgCl2,0.1%BSA。表达重组人受体的CHO-K1细胞膜提取物在冰上解冻,在测定缓冲剂中稀释并保存在冰上。GDP在测定缓冲剂中稀释,以得到具体受体的最佳浓度。珠子是PVT-WGA(PerkinElmer,RPNQ001),在测定缓冲剂中稀释到具体受体的最佳浓度。GTPγ35S(PerkinElmer NEG030X)在测定缓冲剂中稀释至0.1nM。
对于抑制检测,将膜与GDP混合,并在冰上孵育至少15分钟。平行地,临在开始反应之前,将GTPγ35S与珠子混合。将下列试剂接连加入Optiplate(PerkinElmer)的孔中:50μL检测或参考配体,20μL膜:GDP混合物,10μL历史EC80的参考激动剂和20μL GTPγ35S:珠子混合物。
将板用顶部密封覆盖,在定轨摇床上混合2min,然后在室温孵育1小时。然后将板以2000rpm离心10分钟,室温孵育1小时,用PerkinElmer TopCount计数仪以1min/孔计数。
在实验的每一天和在检测化合物之前,将参照化合物(对于CCR1为J113863;对于CCR3为UCB35625)在几个浓度下一式两份(n=2)检测,得到剂量-应答曲线和估计的EC50/IC50值。
将由此获得的用于检测的参考值与从相同受体获得的历史值(CCR1为4.89nM;CCR3为213nM)进行比较,并用于验证测定过程。只有当发现参考值在距离历史值0.5-log间隔内时,测定过程才被认为有效。
对于重复测定,测试中容忍的最大差异性约为重复平均值+/-20%。
使用应用于S形剂量-应答模型的非线性回归,用XLfit(IDBS)软件分析剂量-应答数据。在最高浓度下,5P12-RANTES在该测定中显示中等水平的CCR1信号传导增强,但没有拮抗作用(图3A)。5P12-RANTES也没有显示CCR3的拮抗作用(图3B)。
实施例4:5P12-RANTES在结直肠癌动物模型中的功效
在一个实验中,用CT-26结直肠癌细胞系皮下接种BALB/c小鼠。接种后三天,用5P12-RANTES、鼠抗PD-1抗体、5P12-RANTES+抗PD-1、或盐水安慰剂开始腹膜内处理。每天或每三天给予这种处理。如图4A所示,单独用5P12-RANTES处理导致在多个时间点统计学上显著延迟的肿瘤生长,并且在动物接受5P12-RANTES和抗PD-1抗体的联合队列中观察到在对平均肿瘤体积减小中的更深远的影响(P>0.05)。在处理过程中没有观察到明显的不良事件。
在另一个实验中,用CT-26结直肠癌细胞系皮下接种BALB/c小鼠。接种十天后,用5P12-RANTES、抗CTLA-4抗体、5P12-RANTES+抗CTLA-4、或盐水安慰剂开始腹膜内处理。5P12-RANTES处理一周给予五次。如图4B所示,单独用5P12-RANTES处理导致多个时间点肿瘤生长延迟,在动物接受5P12-RANTES和抗CTLA-4抗体的联合队列中观察到在对平均肿瘤体积减小中的更深远的影响。在处理过程中没有观察到明显的不良事件。
本说明书中引用的所有出版物和专利申请通过引用并入本文,正如具体地和单独地将各出版物或专利申请纳入本文作为参考的那样通过引用并入本文。任何出版物的引用是由于其公开早于提交日,并且不应将其解释为承认本发明无权凭借在先发明而早于该出版物。
尽管为了清楚理解的目的,已经通过说明和实施例详细描述了前述发明,但是本领域普通技术人员根据本发明的教导可容易地理解,在不背离所附权利要求的范围的情况下,可以对本发明进行某些变化和修改。
应当理解,任何数值固有地包括一些从各测试测量中发现的标准偏差必然产生的误差。此外,如本文所用,术语“约”通常是指在给定值或范围的10%、5%、1%或0.5%内。或者,当本领域普通技术人员所考虑时,术语“约”指在平均数的可接受标准误差内。除非做出相反表示,否则本发明和所附权利要求中阐述的数值参数是可以根据需要变化的近似值。至少,每个数值参数应该至少根据所记录的有效数位的值并通过应用普通舍入技术而理解。
必须注意到用于此说明书和所附权利要求的单数形式″一(a)″、″一个(an)″和″该(the)″包括复数形式,除非上下文清楚地另外指示.。除非另有定义,否则本文所用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
在说明书和权利要求书中使用的短语“和/或”应当理解为表示这样结合的要素中的“任一个或二者”,即,在一些情况下联合性地存在而在其他情况下分开地存在的要素。用“和/或”列出的多个要素应当以相同的方式来解释,即,这样结合起来的要素中的“一个或多个”。"和/或"术语特别指出的要素之外的其他要素可以任选存在,无论与特别指出的那些要素相关还是不相关。因此,作为非限制性实例,提及“A和/或B”在结合诸如“包括”等开放式语言使用时在一个实施方案中可仅指A(任选地包括除B以外的要素);在另一个实施方案中,仅指B(任选地包括除A以外的要素);在又一个实施方案中,指A和B(任选地包括其他要素);等等。
如本文在说明书和权利要求书中所使用的,“或”应当被理解为包括与如上所定义的“和/或”相同的含义。例如,当在列表中分列项目时,“或”或“和/或”应被解释为包括性的,即包括多个或一系列要素中的至少一个,但也包括多于一个,并且任选地包括另外的未列出的项目。
如本文所用,无论是在说明书中还是在所附权利要求中,过渡术语”包括“、”包含“、”带有“、”具有“、”含有“、”涉及“等应理解为包括性的或开放式的(即,表示包括但不限于),并且它们不排除未列举的要素、材料或方法步骤。只有过渡短语”由……组成“和”基本上由……组成“分别是对于权利要求和本文的示例性实施方案段落封闭或半封闭的过渡短语。过渡短语”由……组成“排除了没有具体叙述的任何要素、步骤或成分。过渡短语”基本上由……组成“将范围限制到指定的要素、材料或步骤以及那些本质上不影响本文所公开和/或要求保护的本发明的(一个或多个)基本特征的要素、材料或步骤。
序列表
<110> 奥立安生物技术瑞士有限责任公司
<120> CCR5抑制剂在癌症治疗中的应用
<130> 85279715
<150> 62/677114
<151> 2018-05-28
<150> 62/792600
<151> 2019-01-15
<160> 72
<170> PatentIn version 3.5
<210> 1
<211> 59
<212> PRT
<213> Homo sapiens
<400> 1
Cys Cys Phe Ala Tyr Ile Ala Arg Pro Leu Pro Arg Ala His Ile Lys
1 5 10 15
Glu Tyr Phe Tyr Thr Ser Gly Lys Cys Ser Asn Pro Ala Val Val Phe
20 25 30
Val Thr Arg Lys Asn Arg Gln Val Cys Ala Asn Pro Glu Lys Lys Trp
35 40 45
Val Arg Glu Tyr Ile Asn Ser Leu Glu Met Ser
50 55
<210> 2
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
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Gln Gly Pro Pro Leu Met Ala Leu Gln Ser
1 5 10
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<220>
<223> synthetic
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Gln Gly Pro Pro Leu Met Trp Met Gln Val
1 5 10
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<211> 10
<212> PRT
<213> Artificial Sequence
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<223> synthetic
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Gln Gly Pro Pro Leu Met Trp Leu Gln Val
1 5 10
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Gln Gly Pro Pro Leu Met Trp Thr Gln Ser
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Gln Gly Pro Pro Leu Met Trp Leu Gln Thr
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Gln Gly Pro Pro Leu Met Trp Thr Gln Val
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Gln Gly Pro Pro Leu Met Trp Met Gln Ser
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Gln Gly Pro Pro Leu Met Ala Thr Gln Ser
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Gln Gly Pro Pro Leu Met Trp Leu Gln Ser
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Gln Gly Pro Pro Leu Met Ala Leu Gln Val
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Gln Gly Pro Pro Leu Met Trp Leu Gly Gly
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Gln Gly Pro Pro Leu Met Trp Arg Gly Ser
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Gln Gly Pro Leu Leu Met Trp Leu Gln Val
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Gln Gly Pro Pro Leu Met Gln Thr Thr Pro
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Gln Gly Pro Pro Gly Asp Thr Val Leu Trp
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Gln Gly Pro Pro Gly Asp Ile Val Leu Ala
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Gln Gly Pro Pro Gly Ser Tyr Asp Tyr Ser
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Gln Gly Pro Pro Gly Asp Gly Gly Ser Val
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Gln Gly Pro Leu Ser Gly Gln Ser Thr Pro
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Gln Gly Pro Pro Gly Asp Trp Leu Gln Val
1 5 10
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<212> PRT
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Gln Gly Pro Pro Leu Met Ser Phe Gln Ser
1 5 10
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Gln Gly Pro Pro Leu Met Ser Thr Gln Ser
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Gln Gly Pro Pro Leu Met Ser Leu Gln Val
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Gln Gly Pro Pro Leu Met Gly Leu Gln Val
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Gln Gly Pro Leu Ser Gly Trp Leu Gln Val
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Gln Gly Pro Pro Leu Met Ser Val Leu Ala
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Gln Gly Pro Pro Gly Ser Trp Ser Ser Val
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Gln Gly Pro Pro Leu Gly Ser Met Gly Pro
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Gln Gly Pro Pro Leu Ser Trp Leu Gln Val
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<212> PRT
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Gln Gly Pro Pro Leu Ser Trp Leu Gln Ser
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Gln Gly Pro Pro Gly Gln Trp Ser Gln Val
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Gln Gly Pro Pro Met Met Ala Gly Leu Ser
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Gln Gly Pro Pro Leu Ser Trp Gln Gln Ser
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Gln Gly Pro Pro Gly Met Trp Ser Gln Ser
1 5 10
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<213> Artificial Sequence
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<400> 36
Gln Gly Pro Pro Leu Gln Trp Arg Gln Ser
1 5 10
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<211> 10
<212> PRT
<213> Artificial Sequence
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<400> 37
Gln Gly Pro Pro Leu Met Gly Thr Gln Ser
1 5 10
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<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 38
Gln Gly Pro Pro Leu Met Gln Leu Gln Val
1 5 10
<210> 39
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 39
Gln Gly Pro Pro Leu Ser Trp Ser Gln Val
1 5 10
<210> 40
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 40
Gln Gly Pro Pro Met Ser Trp Ser Gln Ser
1 5 10
<210> 41
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 41
Gln Gly Pro Pro Leu Met Asn Leu Gln Val
1 5 10
<210> 42
<211> 10
<212> PRT
<213> Artificial Sequence
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<400> 42
Gln Gly Pro Pro Met Ser Ala Tyr Gln Val
1 5 10
<210> 43
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<212> PRT
<213> Artificial Sequence
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<400> 43
Gln Gly Pro Pro Met Gln Gly Gly Leu Ser
1 5 10
<210> 44
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 44
Gln Gly Pro Pro Leu Met Ser Leu Ala Val
1 5 10
<210> 45
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<212> PRT
<213> Artificial Sequence
<220>
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<400> 45
Gln Gly Pro Pro Leu Met Ser Leu Thr Val
1 5 10
<210> 46
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 46
Gln Gly Pro Leu Ser Gly Trp Ala Gln Val
1 5 10
<210> 47
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 47
Gln Gly Pro Leu Ser Gln Ser Ser Gln Val
1 5 10
<210> 48
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 48
Gln Gly Pro Leu Ser Ser Gln Ser Gln Val
1 5 10
<210> 49
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 49
Gln Gly Pro Leu Gly Gln Gln Gly Gln Val
1 5 10
<210> 50
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 50
Gln Gly Pro Pro Leu Gln Trp Phe Gln Val
1 5 10
<210> 51
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 51
Gln Gly Pro Pro Leu Gln Trp Thr Gln Val
1 5 10
<210> 52
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 52
Gln Gly Pro Pro Leu Met Ala Leu Ser Val
1 5 10
<210> 53
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 53
Gln Gly Pro Pro Leu Met Trp Ser Gln Val
1 5 10
<210> 54
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 54
Gln Gly Pro Pro Gly Gln Trp Gly Gln Val
1 5 10
<210> 55
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 55
Gln Gly Pro Pro Gly Ser Trp Ser Gln Val
1 5 10
<210> 56
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 56
Gln Gly Pro Pro Leu Met Ser Ser Gln Ser
1 5 10
<210> 57
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 57
Gln Gly Pro Pro Leu Met Gly Leu Ser Val
1 5 10
<210> 58
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 58
Gln Gly Pro Pro Leu Met Thr Leu Gln Val
1 5 10
<210> 59
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 59
Gln Gly Pro Pro Gly Gln Trp Tyr Gln Ser
1 5 10
<210> 60
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 60
Gln Gly Pro Pro Leu Gln Trp Met Gln Ala
1 5 10
<210> 61
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 61
Gln Gly Pro Pro Leu Gln Trp Met Gln Val
1 5 10
<210> 62
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 62
Gln Gly Pro Pro Leu Met Ser Thr Gln Val
1 5 10
<210> 63
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 63
Gln Gly Pro Pro Leu Met Ser Leu Ser Val
1 5 10
<210> 64
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 64
Gln Gly Pro Pro Leu Met Ser Leu Gln Ser
1 5 10
<210> 65
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 65
Gln Gly Pro Pro Leu Met Ser Leu Gln Ala
1 5 10
<210> 66
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 66
Gln Gly Pro Pro Leu Met Ser Val Gln Ser
1 5 10
<210> 67
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
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<400> 67
Gln Gly Pro Pro Leu Met Ser Ala Gln Ser
1 5 10
<210> 68
<211> 10
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<220>
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<400> 68
Gln Gly Pro Pro Leu Met Ser Gly Gln Ser
1 5 10
<210> 69
<211> 10
<212> PRT
<213> Artificial Sequence
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<400> 69
Gln Gly Pro Pro Leu Met Ser Gly Gln Val
1 5 10
<210> 70
<211> 69
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 70
Gln Gly Pro Pro Leu Met Ala Thr Gln Ser Cys Cys Phe Ala Tyr Ile
1 5 10 15
Ala Arg Pro Leu Pro Arg Ala His Ile Lys Glu Tyr Phe Tyr Thr Ser
20 25 30
Gly Lys Cys Ser Asn Pro Ala Val Val Phe Val Thr Arg Lys Asn Arg
35 40 45
Gln Val Cys Ala Asn Pro Glu Lys Lys Trp Val Arg Glu Tyr Ile Asn
50 55 60
Ser Leu Glu Met Ser
65
<210> 71
<211> 69
<212> PRT
<213> Artificial Sequence
<220>
<223> synthetic
<400> 71
Gln Gly Pro Pro Gly Asp Ile Val Leu Ala Cys Cys Phe Ala Tyr Ile
1 5 10 15
Ala Arg Pro Leu Pro Arg Ala His Ile Lys Glu Tyr Phe Tyr Thr Ser
20 25 30
Gly Lys Cys Ser Asn Pro Ala Val Val Phe Val Thr Arg Lys Asn Arg
35 40 45
Gln Val Cys Ala Asn Pro Glu Lys Lys Trp Val Arg Glu Tyr Ile Asn
50 55 60
Ser Leu Glu Met Ser
65
<210> 72
<211> 69
<212> PRT
<213> Artificial Sequence
<220>
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<400> 72
Gln Gly Pro Pro Leu Met Ser Leu Gln Val Cys Cys Phe Ala Tyr Ile
1 5 10 15
Ala Arg Pro Leu Pro Arg Ala His Ile Lys Glu Tyr Phe Tyr Thr Ser
20 25 30
Gly Lys Cys Ser Asn Pro Ala Val Val Phe Val Thr Arg Lys Asn Arg
35 40 45
Gln Val Cys Ala Asn Pro Glu Lys Lys Trp Val Arg Glu Tyr Ile Asn
50 55 60
Ser Leu Glu Met Ser
65
Claims (20)
1.一种治疗癌症的方法,所述方法包含向对象施用CCR5抑制剂,其中所述CCR5抑制剂包含N-末端部分和C-末端部分,其中所述N-末端部分包含特征序列QGP[P或L],且所述C-末端部分的氨基酸序列与SEQ ID NO:1至少70%相同。
2.根据权利要求1所述的方法,其中所述CCR5抑制剂抑制HIV进入细胞,且相较于CCR1和CCR3,所述CCR5抑制剂是CCR5选择性的。
3.根据权利要求2所述的方法,其中所述CCR5抑制剂仅抑制CCR5细胞内信号传导通路的亚组。
4.根据权利要求3所述的方法,其中所述CCR5抑制剂抑制或减少CCR5的炎性作用,例如,当在钙流信号传导测定中以300nM的浓度测试时,导致信号传导应答为PSC-RANTES引发的最大应答(Emax)的30%或更低。
5.根据权利要求1所述的方法,其中所述特征序列为QGP[P或L][L或G或S或M][M或D或S或Q或G]。
6.根据权利要求1所述的方法,其中所述特征序列为QGP[P或L][L或G或S或M][M或D或S或Q或G]XX[Q或G或L或A或T或S]X,其中X表示任何天然的或修饰的氨基酸。
7.根据权利要求1所述的方法,其中所述特征序列为QGP[P或L]LM或QGPPG[D或S]。
8.根据权利要求1所述的方法,其中所述特征序列为QGPPLM或QGPPGD。
9.根据权利要求1所述的方法,其中所述特征序列为QGP[P或L][L或M][M或Q][A或W或G或Q或N]X[Q或G或L][S或V或T或G],其中X表示任何天然的或修饰的氨基酸。
10.根据权利要求1所述的方法,其中所述特征序列为QGPPLM[A或W][L或T或M][Q或G][S或V或T或G]。
11.根据权利要求1所述的方法,其中所述特征序列为QGPP[G或L][M或Q]XX[Q或S][S或V],其中X表示任何天然的或修饰的氨基酸。
12.根据权利要求1所述的方法,其中所述特征序列选自QGPPLMALQS(SEQ ID NO:2)、QGPPLMWMQV(SEQ ID NO:3)、QGPPLMWLQV(SEQ ID NO:4)、QGPPLMWTQS(SEQ ID NO:5)、QGPPLMWLQT(SEQ ID NO:6)、QGPPLMWTQV(SEQ ID NO:7)、QGPPLMWMQS(SEQ ID NO:8)、QGPPLMATQS(SEQ ID NO:9)、QGPPLMWLQS(SEQ ID NO:10)、QGPPLMALQV(SEQ ID NO:11)、QGPPLMWLGG(SEQ ID NO:12)、QGPPLMWRGS(SEQ ID NO:13)、QGPLLMWLQV(SEQ ID NO:14)、QGPPLMQTTP(SEQ ID NO:15)、QGPPLSWLQV(SEQ ID NO:30)、QGPPLSWLQS(SEQ ID NO:31)、QGPPGQWSQV(SEQ ID NO:32)、QGPPMMAGLS(SEQ ID NO:33)、QGPPLSWQQS(SEQ ID NO:34)、QGPPGMWSQS(SEQ ID NO:35)、QGPPLQWRQS(SEQ ID NO:36)、QGPPLMGTQS(SEQ ID NO:37)、QGPPLMQLQV(SEQ ID NO:38)、QGPPLSWSQV(SEQ ID NO:39)、QGPPMSWSQS(SEQ ID NO:40)、QGPPLMNLQV(SEQ ID NO:41)、QGPPMSAYQV(SEQ ID NO:42)和QGPPMQGGLS(SEQ ID NO:43)。
13.根据权利要求1所述的方法,其中所述特征序列选自QGPPLMALQS(SEQ ID NO:2)、QGPPLMWMQV(SEQ ID NO:3)、QGPPLMWLQV(SEQ ID NO:4)、QGPPLMWTQS(SEQ ID NO:5)、QGPPLMWLQT(SEQ ID NO:6)、QGPPLMWTQV(SEQ ID NO:7)、QGPPLMWMQS(SEQ ID NO:8)、QGPPLMATQS(SEQ ID NO:9)、QGPPLMWLQS(SEQ ID NO:10)、QGPPLMALQV(SEQ ID NO:11)、QGPPLMWLGG(SEQ ID NO:12)、QGPPLMWRGS(SEQ ID NO:13)、QGPLLMWLQV(SEQ ID NO:14)和QGPPLMQTTP(SEQ ID NO:15)。
14.根据权利要求1所述的方法,其中所述特征序列为QGPPLMATQS(SEQ ID NO:9)。
15.根据权利要求14所述的方法,其中所述特征序列位于最N末端。
16.根据权利要求15所述的方法,所述所述C末端部分与SEQ ID NO:1相同。
17.根据权利要求1所述的方法,其中所述CCR5抑制剂包含SEQ ID NO:70的氨基酸序列。
18.根据权利要求1所述的方法,其中所述癌症是结直肠癌、乳腺癌、肺癌、前列腺癌、卵巢癌、胰腺癌、食管癌、胃癌、肝癌或白血病。
19.根据权利要求18所述的方法,其中所述癌症为转移性的。
20.根据权利要求18所述的方法,其中所述癌症是化疗或放疗难治性的和/或对化疗或放疗具有抗性的。
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