CN117946213A - 治疗癌症的肽 - Google Patents
治疗癌症的肽 Download PDFInfo
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- CN117946213A CN117946213A CN202410129031.0A CN202410129031A CN117946213A CN 117946213 A CN117946213 A CN 117946213A CN 202410129031 A CN202410129031 A CN 202410129031A CN 117946213 A CN117946213 A CN 117946213A
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Abstract
本申请涉及治疗癌症的肽。本发明涉及癌症治疗或预防领域。特定言之,本发明提供来自SLIT2蛋白质的肽片段,及其在抑制癌症生长、侵入及转移中的应用。
Description
本申请是申请日为2018年4月27日、申请号为“201880028245.1”、名称为“治疗癌症的肽”的发明专利申请的分案申请。
技术领域
本发明涉及癌症治疗或预防。特定言之,本发明提供来自SLIT2蛋白质的肽片段,及其在抑制癌症生长、癌症侵入及癌转移中的应用。
背景技术
近年来,抗癌肽获得更高关注。然而,大部分公知抗癌药物生物活性较低且毒性较高。因此,需要开发具有高生物活性及低毒性的抗癌生物活性肽。
发明内容
本发明提供一种包含如本文所描述的氨基酸序列的肽。某些实施例包括包含FHIVELLA或FHAVELLA氨基酸序列的肽。某些其他实施例包括如本文所描述的环肽、聚乙二醇化肽及茀基甲氧基羰基-肽。
本发明提供一种医药组合物,其包含如本文所描述的肽。
本发明提供一种用于抑制癌症生长、癌症侵入及/或癌转移的方法,其包含投与有效量的如本文所描述的肽。
本发明提供一种用于预防、治疗或减缓癌症的方法,其包含投与有效量的如本文所描述的肽。
附图说明
图1显示茀基甲氧基羰基(Fmoc)-LT1-3(LT1-3)的丙胺酸取代对细胞增殖的影响。
图2显示Fmoc-LT-A3(LT-A3)的碱基取代对细胞增殖的影响。
图3显示CL1-5细胞中Fmoc-LT-肽(LT-肽)对生长抑制的剂量影响。
图4显示各种肺癌细胞株中Fmoc-LT1-3及Fmoc-LT-A3的生长抑制活性。
图5(A)至5(C)显示Fmoc-LT1-3(A)、Fmoc-LT-A3(B)及Fmoc-LT-A3-PEG3(C)对侵入抑制的剂量影响。
图6显示经不同量的LT1-3肽治疗的小鼠在第18天的早期肿瘤形成速率。
图7显示异种移植模型中Fmoc-LT1-3对肿瘤生长的影响。
图8显示经不同量的LT1-3肽治疗的肿瘤的尺寸。
图9显示经不同量的Fmoc-LT1-3治疗的动物的相对器官重量。
图10显示Fmoc-LT1-3对经由尾部血管注射的CL1-5细胞的肺脏癌转移的影响。
图11显示对照组、CDDP、LT1-3、CDDP+LT1-3在维持疗法中的存活比例及CDDP+LT1-3在组合疗法中的存活比例。
图12显示LT-1、LT-3、LT-4、LT-5对CL1-5细胞的侵入抑制的影响。
图13显示CL1-5细胞中LT1-3肽对细胞侵入抑制的影响。
图14显示CL1-5细胞中LT-A3肽对细胞侵入抑制的影响。
图15显示CL1-5细胞中C-肽的N端或C端修饰对细胞侵入的影响。
图16显示CL1-5细胞中LT-A3-PEG肽对细胞侵入的影响。
图17显示CL1-5细胞中LT1-3-PEG对细胞侵入的影响。
图18显示A549细胞中LT1-3-PEG对细胞侵入的影响。
图19显示H1299细胞中LT1-3-PEG对细胞侵入的影响。
图20(A)及20(B)显示CL1-5细胞中肽的N端或C端修饰对细胞增殖的影响;(A),PEG-LT1-3、PEG-LT-A3及LT-A3-PEG;(B),LT1-3及LT1-3-PEG。
图21显示LT1-3-PEG对各种肺癌细胞株的增殖的影响。
图22显示LT1-3未抑制Beas2B、HUVEC及MRC5正常细胞株的生长。
图23显示LT1-3-PEG对MCF-7、T-47D、MDA-MB-453及MDA231乳癌细胞的增殖的影响。
图24显示PKA抑制剂(H89)提高了CL1-5细胞上LT1-3肽的生长抑制活性。
图25显示JNK抑制物(Sp600125)提高了CL1-5细胞上LT1-3肽的生长抑制活性。
图26显示PKACA的基因表达阻断提高了CL1-5细胞上LT1-3-PEG参与的生长抑制活性。
图27显示JNK1的基因表达阻断提高了CL1-5细胞上LT1-3-PEG参与的生长抑制活性。
具体实施方式
应理解,本文所描述的各种实施例及实例仅旨在提供说明且不用于限制申请专利范围的范畴。
冠词“一种(a/an)”在本文中用于指代一种或多于一种(即至少一种)所述冠词的语法对象。
氨基酸的缩写在本发明全文中使用,且遵循本领域中已知的标准命名法。举例而言,如本领域普通技术人员将理解,丙胺酸为Ala或A;精胺酸为Arg或R;天冬酰胺为Asn或N;天冬胺酸为Asp或D;半胱胺酸为Cys或C;麸胺酸为Glu或E;麸酰胺酸为Gln或Q;甘胺酸为Gly或G;组胺酸为His或H;异白胺酸为Ile或I;白胺酸为Leu或L;离胺酸为Lys或K;甲硫胺酸为Met或M;苯丙胺酸为Phe或F;脯胺酸为Pro或P;丝胺酸为Ser或S;苏胺酸为Thr或T;色胺酸为Trp或W;酪胺酸为Tyr或Y;且缬胺酸为Val或V。
具有疏水性侧链的氨基酸包括以下的非限制性实例:丙胺酸(A)、异白胺酸(I)、白胺酸(L)、甲硫胺酸(M)、苯丙胺酸(F)、色胺酸(W)、酪胺酸(Y)及缬胺酸(V)。具有亲水性侧链的氨基酸包括以下的非限制性实例:甘胺酸(G)、天冬酰胺(N)、麸酰胺酸(Q)、丝胺酸(S)、苏胺酸(T)及半胱胺酸(C)。具有碱性侧链的氨基酸包括以下的非限制性实例:组胺酸(H)、离胺酸(K)及精胺酸(R)。具有酸性侧链的氨基酸包括以下的非限制性实例:天冬胺酸(D)及麸胺酸(E)。在典型生理学条件下,具有带正电侧链的氨基酸包括以下的非限制性实例:精胺酸(R)、组胺酸(H)及离胺酸(K)。在典型生理学条件下,具有带负电侧链的氨基酸包括以下的非限制性实例:天冬胺酸(D)及麸胺酸(E)。具有两极不带电侧链的氨基酸包括以下的非限制性实例:丝胺酸(S)、苏胺酸(T)、天冬酰胺(N)及麸酰胺酸(Q)。
非天然氨基酸包括(但不限于)氮杂环丁烷羧酸、2-胺基己二酸、3-胺基己二酸、β-丙胺酸、萘基丙胺酸(“naph”)、胺丙酸、2-胺基丁酸、4-胺基丁酸、6-胺基己酸、2-胺基庚酸、2-胺基异丁酸、3-胺基异丁酸、2-胺基庚二酸、第三丁基甘胺酸(“tBuG”)、2,4-二胺基异丁酸、锁链赖胺酸(desmosine)、2,2'-二胺基庚二酸、2,3-二胺基丙酸、N-乙基甘胺酸、N-乙基天冬酰胺、高脯胺酸(“hPro”或“homoP”)、羟基离胺酸、别-羟基离胺酸、3-羟基脯胺酸(“3Hyp”)、4-羟基脯胺酸(“4Hyp”)、异锁链赖胺酸(isodesmosine)、别-异白胺酸、N-甲基丙胺酸(“MeAla”或“Nime”)、包括N-甲基甘胺酸的N-烷基甘胺酸(“NAG”)、N-甲基异白胺酸、包括N-甲基戊基甘胺酸的N-烷基戊基甘胺酸(“NAPG”)。N-甲基缬胺酸、萘基丙胺酸、正缬胺酸(“Norval”)、正白胺酸(“Norleu”)、辛基甘胺酸(“OctG”)、鸟胺酸(“Orn”)、戊基甘胺酸(“pG”或“PGly”)、六氢烟生佥酸、硫代脯胺酸(“ThioP”或“tPro”)、高离胺酸(“hLys”)及高精胺酸(“hArg”)。
如本文所使用,“野生型”(wt)是指一个物种中聚核苷酸、多肽或蛋白质的天然形式(包括序列)的术语。野生型形式与基因突变引起的聚核苷酸、多肽或蛋白质的突变形式不同。
如本文所使用,术语“氨基酸”是指天然氨基酸、非天然氨基酸及氨基酸类似物,除非另有指示,否则若其结构容许立体异构形式,则所有氨基酸呈其D及L立体异构体形式。
如本文所使用,术语“肽”或“寡肽”是指由氨基酸组成的有机化合物,其可在环化的前排列成直链(由羧基与相邻氨基酸残基的胺基之间的肽键连接在一起),或呈环状形式或呈限定(例如,“巨环”)形式。
如本文所使用,术语“医药学上可接受的盐”是可调配成用于医药用途的化合物的盐,其包括(但不限于)金属盐(例如,钠、钾、镁、钙等)及氨盐或有机胺盐。
如本文中可互换地所用,术语“个人”、“个体”、“主体”及“患者”是指哺乳动物,其包括(但不限于)鼠(大鼠、小鼠)、非人类灵长类、人类、犬科动物、猫科动物、有蹄动物(例如,马科动物、牛科动物、绵羊、猪科动物、山羊)等。
如本文所使用,术语“预防性”治疗是出于降低产生病变风险的目的,向未显示疾病征象或仅呈现早期疾病征象的个体进行投与的治疗。本发明的化合物或组合物可作为预防性治疗提供以减小产生病变的可能性或以使病变(若患有)的严重性降至最低。
如本文所使用,术语“治疗(treatment/treating)”及类似者涵盖对哺乳动物,尤其人类的疾病的任何治疗,且包括:(a)防止疾病出现于易患有疾病但尚未诊断患有所述疾病的个体中;(b)抑制疾病,即遏制其发展;及(c)缓解疾病,即促使疾病消退。
如本文所使用,术语“治疗有效量”或“灵验量”是指当投与哺乳动物或其他个体用于治疗疾病时,足以实现对所述疾病的所述治疗的本发明肽的量。
本发明意外地发现SLIT2蛋白质的片段对抑制肿瘤生长及侵入具有有利影响。特定言之,本发明发现一种来自SLIT2由91个氨基酸组成的片段(ASAIYSVETINDGNFHIVELLALDQSLSLSVDGGNPKIITNLSKQSTLNFDSPLYVGGMPGKS NVASLRQAPGQNGTSFHGCIRNLYINSE)(SEQ IDNO:1),其具有同时抑制肿瘤生长及侵入的作用。本发明意外地发现,以下SEQ ID NO:1中五种交迭的肽序列对肿瘤生长及/或侵入有效。
LT-1:ASAIYSVETINDGNFHIVELLA(SEQ ID NO:2)
LT-2:FHIVELLALDQSLSLSVDGGNPKIIT(SEQ ID NO:3)
LT-3:KIITNLSKQSTLNFDSPLYVGG(SEQ ID NO:4)
LT-4:GGMPGKSNVASLRQAPGQNGTSF(SEQ ID NO:5)
LT-5:LRQAPGQNGTSFHGCIRNLYINSE(SEQ ID NO:6)
LT-1对生长及侵入活动具有抑制性作用,而LT-3、LT-4及LT-5仅对细胞侵入具有抑制性作用。LT-2的N端序列含有LT1-3序列(SEQ ID NO:4),且因此LT-2极可能对生长及侵入活动具有抑制性作用。
因此,本发明提供一种包含如SEQ ID NO:1中所示的氨基酸序列的肽,或其片段。在一些实施例中,肽的片段包含如SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5或SEQ ID NO:6中所示的氨基酸序列。
本发明亦意外地发现,10氨基酸片段LT1-1(ASAIYSVETI(SEQ IDNO:7))、10氨基酸片段LT1-2(ETINDGNFHI(SEQ ID NO:8))及8氨基酸片段LT1-3(FHIVELLA(SEQ ID NO:9))此三种片段可在22氨基酸片段LT-1内加以识别,且LT1-3同时对抑制肿瘤生长及侵入具有优异效果。
在一个实施例中,本发明提供一种肽,其包含下式I,
X1-X2-X3-X4-X5-X6-X7-X8(I)
其中X1选自具有疏水性侧链的氨基酸;X2选自具有碱性侧链的氨基酸、具有酸性侧链的氨基酸或具有疏水性侧链的氨基酸;X3选自具有疏水性侧链的氨基酸;X4选自具有疏水性侧链的氨基酸;X5选自具有碱性侧链的氨基酸、具有酸性侧链的氨基酸或具有疏水性侧链的氨基酸;X6选自具有疏水性侧链的氨基酸;X7选自具有疏水性侧链的氨基酸或具有亲水性侧链的氨基酸;且X8选自具有疏水性侧链的氨基酸或具有亲水性侧链的氨基酸;
或经修饰的肽或其盐。
在一些实施例中,X1选自F、A、Y及W;X2选自H、K、R、A及E;X3选自I或A;X4选自V及A;X5选自E、D、H、Orn、A及H;X6选自L及A;X7选自L及S且X8选自A及S;或经修饰的肽或其盐。
在一些实施例中,所述肽包含FHIVELLA(LT1-3)(SEQ ID NO:9)、FHAVELLA(LT-A3)(SEQ ID NO:10)、FKAVELLA(LT-K2)(SEQ ID NO:11)、FRAVELLA(LT-R2)(SEQ ID NO:12)、FHAVDLLA(LT-D5)(SEQ ID NO:13)、FHAVHLLA(LT-H5)(SEQ ID NO:14)、FHAVOLLA(LT-Orn5)(SEQ ID NO:15)、AHAVELLA(LT-A13)(SEQ ID NO:16)、FHAAELLA(LT-A34)(SEQ ID NO:17)、FHAVEALA(LT-A36)(SEQ ID NO:18)、FHAAEALA(LT-A346)(SEQ ID NO:19)、FAIVALLA(LT-A25)(LT-A2)(SEQ ID NO:20)、FEAVHLLA(LT-E2H5)(SEQ ID NO:21)、YHAVELLA(LT-Y1)(SEQID NO:22)、WHAVELLA(LT-W1)(SEQ ID NO:23)、FHAVELSA(LT-S7)(SEQ ID NO:24)、FHAVELLS(LT-S8)(SEQ ID NO:25)、DGNFHIVELLA(LT-11AA)(SEQ ID NO:26)、AHIVELLA(LT-A1)(SEQ ID NO:27)、FAIVELLA(LT-A2)(SEQ ID NO:28)、FHIAELLA(LT-A4)(SEQ ID NO:29)、FHIVALLA(LT-A5)(SEQ ID NO:30)、FHIVEALA(LT-A6)(SEQ ID NO:31)、FHIVELAA(LT-A7)(SEQ ID NO:32)、或包含以下氨基酸序列的肽:所述序列在阐述于SEQ ID NO:9至SEQID NO:32中任一者中的氨基酸序列中具有一种或数种氨基酸取代、缺失及/或添加且其活性等于或高于阐述于SEQ ID NO:9至SEQ ID NO:32中任一者中的氨基酸序列的活性;或经修饰的肽或其盐。
在另一实施例中,本发明的肽为FHAVELLA(SEQ ID NO:10);或经修饰的肽或其盐。
本发明的肽包括包含以下氨基酸序列的肽:所述序列在阐述于式(I)中的氨基酸序列中具有一种或数种氨基酸取代、缺失及/或添加(此后亦称为“经修饰的肽”)。本领域的一般技术人员广泛熟知的事实为:由在特定氨基酸序列中具有一种或数种氨基酸取代、缺失及/或添加的氨基酸序列组成的肽可维持初始肽的生物活性。
在本上下文中,在一种或数种氨基酸经其他氨基酸取代的情况下,氨基酸侧链的特性较佳在取代前后得以保留。氨基酸侧链的特性包括疏水性氨基酸(A、I、L、M、F、P、W、Y、V)、亲水性氨基酸(R、D、N、C、E、Q、G、H、K、S、T)、具有脂肪族侧链的氨基酸(G、A、V、L、I、P)、具有含羟基的侧链的氨基酸(S、T、Y)、具有含硫原子的侧链的氨基酸(C、M)、具有含羧酸或酰胺的侧链的氨基酸(D、N、E、Q)、具有含碱基的侧链的氨基酸(R、K、H)、具有含芳族的侧链的氨基酸(H、F、Y、W)(括号中的各字母代表氨基酸的单字母符号)。
此外,经修饰的肽与初始肽之间的相同性较佳为60%或更多、更佳为75%或更多、甚至更佳为85%或更多、尤其较佳为95%或更多、且最佳为98%或更多。
本发明的肽可经修饰以改良溶解性或稳定性。在一些实施例中,经修饰的肽为环肽、聚乙二醇化肽或茀基甲氧基羰基-肽。举例而言,可以任意添加一系列极性残基或PEG(聚乙二醇)至本发明的肽以改良其溶解性。PEG可添加至本发明的肽的C端或N端。在一个实施例中,PEG添加至本发明的肽的N端或C端。在一些实施例中,经修饰的肽为PEG-肽,其中PEG结合至肽的N端或C端,所述肽包含选自由SEQ ID NO:9至SEQ ID NO:32组成的群的氨基酸序列。在一个实施例中,PEG-肽为PEG-LT1-3或PEG-LT-A3(亦即,PEG结合至肽的C端或N端,所述肽包含选自由SEQ ID NO:9或SEQ ID NO:10组成的群的氨基酸序列)。
在一个实施例中,茀基甲氧基羰基(Fmoc)添加至本发明的肽以改良稳定性。在一些实施例中,经修饰的肽为Fmoc-肽,其中Fmoc结合至肽的N端或C端,所述肽包含选自由SEQID NO:9至SEQ ID NO:32组成的群的氨基酸序列。在一个实施例中,Fmoc-肽为Fmoc-LT1-3或Fmoc-LT-A3(亦即,Fmoc结合至肽的N端,所述肽包含选自由SEQ ID NO:9或SEQ ID NO:10组成的群的氨基酸序列。
可使用任何本领域中已知的用于制造多肽的方法制造这些肽,包括(例如)合成及重组方法。因为其尺寸相对较小,本发明的肽可根据公知技术在溶液中或在固态载体上直接合成。各种自动合成器可商购且可根据已知方案使用。举例而言,在一些实施例中,可使用合成化学技术合成这些肽,诸如固相合成、梅里菲尔德型固相合成(Merrifield-typesolid-phase synthesis)、t-Boc固相合成、Fmoc固相合成、BOP固相合成及溶液相合成。在其他实施例中,可根据本领域中的技术人员熟习的重组技术制造肽,举例而言,通过在细胞或无细胞系统中以对肽进行编码的核苷酸来表达所述肽。这些肽可并入本领域中的技术人员所知的各种修饰形及保护基中的任一者。
在一个实施例中,本发明经修饰的肽呈环状形式。在一个实施例中,本发明经修饰的肽为环状,其通过在肽的N端添加一个或多于一个亲水性氨基酸、视情况一个或多于一个疏水性氨基酸而形成。在一个实施例中,环肽包含两个亲水性氨基酸及一个疏水性氨基酸,这些氨基酸结合至本发明的肽的N端。
在一个实施例中,本发明的肽为式I的肽的环状形式。在另一实施例中,本发明提供具有如下式II的环肽,
Xa1-Xa2-Xa3-X1-X2-X3-X4-X5-X6-X7-X8(II)
其中
Xa1结合至X8形成头-尾环化,且Xa1为D;Xa2为G;Xa3为N;且X1、X2、X3、X4、X5、X6、X7及X8各自为本文所定义的氨基酸。
本发明的具有环状部分的肽化合物是指由氨基酸及/或氨基酸类似物的酰胺键或酯键形成的化合物且具有环状部分,所述部分产生自共价键参与的环化,诸如酰胺键或碳-碳键形成反应。
本发明具有环状部分的经修饰的肽化合物并非特定局限于只要所述肽在环状位置发生环化即可。转译后环化位置须为环化单元,所述单元形成保证膜渗透性与代谢稳定性(类药性)相容的官能基。任何此种环化方法均可在无特定限制的情况下使用。此类方法的实例包括自羧酸形成酰胺键,及使用过渡金属作为催化剂形成胺键及碳-碳键,诸如铃木反应(Suzuki reaction)、赫克反应(Heck reaction)及抗发炎反应(Sonogashirareaction)。因此,本发明的肽化合物含有至少一组能够进行此种键生成反应的官能基。
本发明的肽化合物中的环状部分较佳为(例如)转译合成后由化学反应产生的环化所形成的环状部分。再者,环状部分较佳为转译后甚至可在不影响诸如RNA或DNA的核苷酸的反应条件下形成的环状部分。
在另一实施例中,本发明的环肽包含氨基酸序列DGNFHIVELLA(SEQ ID NO:26),其中D结合至A形成头-尾环化(环状-LT-11AA)。
本发明的肽同时对肿瘤生长及肿瘤侵入展现出抑制性,且因此可用于治疗癌症。
在另一实施例中,本发明提供一种医药组合物,其包含本文所描述的肽。在一个实施例中,所述组合物包含第二抗癌剂。举例而言,第二抗癌剂包括(但不限于)埃罗梯尼(erlotinib)、阿法替尼(afatinib)、吉非替尼(gefitinib)、贝伐单抗(bevacizumab)、雷莫芦单抗(ramucirumab)、拉帕替尼(lapatinib)、顺铂、太平洋紫杉醇、甲胺喋呤、环磷酰胺、异磷酰胺、氮芥苯丁酸、双氯乙基亚硝脲、卡铂(carboplatin)、长春新碱、长春花碱、噻替派(thiotepa)、洛莫司汀、司莫斯汀(semustine)、5-氟尿嘧啶、皮质类固醇、钙调神经磷酸酶抑制剂、NSAID、5-脂肪加氧酶抑制剂及阿糖胞苷。
与用于医疗或预防治疗的医药组合物相关的一些实施例提供特定针对经黏膜(经口、经鼻、吸入、经肠、经阴道、经气管等)、非经肠、外部或局部投与中任一者的调配物。在一些实施例中,适当地非经肠投与这些医药组合物,例如经静脉、皮下、皮内或肌内投与。本发明的医药组合物可根据公知方法调配(例如,Remington's Pharmaceutical Science,最新版本,Mark Publishing Company,Easton,U.S.A.),且亦可含有医药学上可接受的载剂及添加剂。实例包括(但不限于)界面活性剂、赋形剂、着色剂、调味剂、防腐剂、稳定剂、缓冲剂、悬浮剂、等张剂、固着剂、崩解剂、润滑剂、流动促进剂及矫正剂,且可适当地使用其他常用载剂。载剂的特定实例包括轻质无水硅酸、乳糖、结晶纤维素、甘露糖醇、淀粉、羧甲基纤维素钙、羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯缩醛二乙胺基乙酸酯、聚乙烯吡咯啶酮、明胶、中链三酸甘油酯、聚氧乙烯硬化蓖麻油60、蔗糖、羧基甲基纤维素、玉米淀粉、无机盐及此类物。
在另一实施例中,本发明提供一种用于预防、治疗或改善癌症的方法,其包含向个体投与有效量的本文所描述的肽。
在另一实施例中,本发明提供一种用于抑制癌症生长、癌症侵入及/或癌转移的方法,其包含向个体投与有效量的本文所描述的肽。
在一个实施例中,本发明的方法进一步包含投与如本文所描述的第二抗癌剂的步骤。在另一实施例中,本发明的肽及第二抗癌剂并行投与或分开投与。
举例而言,能够由本发明的肽、组合物及方法治疗的癌症包括(但不限于)由以下组成的群:神精母细胞瘤;胆管癌;肺癌;非小细胞肺癌;肝细胞癌;头颈鳞状细胞癌;鳞状细胞子宫颈癌;淋巴瘤;鼻咽癌;胃癌;大肠癌;子宫颈癌;胆囊癌;前列腺癌;乳癌;睾丸生殖细胞肿瘤;大肠直肠癌;神经胶质瘤;甲状腺癌;基底细胞癌;胃肠基质癌;肝胚细胞瘤;子宫内膜癌;卵巢癌;胰腺癌;肾细胞癌、卡波西式肉瘤(Kaposi's sarcoma)、慢性白血病、肉瘤、直肠癌、喉癌、黑色素瘤、大肠癌、膀胱癌、肥胖细胞瘤、乳房癌、乳腺癌、咽腔鳞状细胞癌、睾丸癌、胃肠癌、或胃癌及尿路上皮细胞癌。
由本文所描述的方法治疗的个体涵盖哺乳类个体,包括人类个体及非人类(动物)个体,诸如犬、猫、兔、山羊、马、猪、牛等。如本文所使用的术语“并行投与”意指在十分相近的时间内投与两种化合物以取得组合(免疫性)效果。因此,并行投与可以顺序投与或同步投与方式进行(例如,以共同或相同载剂进行同步投与)。
在一些实施例中,所揭示的肽及组合物可通过任何合适的投与途径进行投与,其包括(但不限于)注射(皮下、腹膜内、静脉内、脊髓、肌内、脑室内及脊柱注射)、鼻内、经口、经皮、非经肠、吸入、经鼻咽或经黏膜吸收。投与涵盖提供至少一种调配成医药组合物的如本文描述的肽。医药学上可接受的载剂为本领域的技术人员所熟知的。决定针对给定治疗的特定医药调配物及治疗有效量及用剂规范为处于本领域的技术人员所考虑的能力范围内,例如患者年龄、体重、性别、族群、器官(例如肝及肾)功能、所需治疗的程度、疾病阶段及严重性及相关症状、及患者对治疗的容忍度。
在有关治疗应用的实施例中,可在已患有所关注的病症的个体上进行投与。处于疾病潜伏期或急性发病期的个体可通过本文所描述的方法治疗,如适当地基于特定疾病/病症、患者及组合进行单独治疗或与其他治疗组合进行。本领域中的技术人员应能够决定组合治疗是否合适的时间。在治疗方法及使用中,本文所描述的肽及组合物可以足以治疗、或至少部分抑制症状及/或并发症的量投与至个体。足以实现此目的的量通常称为“治疗有效剂量”。对此用途有效的量将部分取决于肽、组合物、投与方式、待治疗症状的阶段及严重性、患者的年龄、体重及大体健康状况、及开处方的医师的判断。
无需进一步详细描述,咸信本领域的技术人员可基于先前描述最大程度地利用本发明。因此,以下实例应理解为仅为说明性的且无论如何不限制本发明的范畴。
实例
实例1制备LT-肽.
二甲亚砜(DMSO;>99.9%)及γ-环糊精(γ-CD;2.5mM于RPMI-1640中(无血清))用作溶剂以溶解LT-肽。LT肽溶解于DMSO或γ-CD中,最终达2.5mM浓度,且涡旋流动30min。使用RPMI培养基进一步稀释肽溶液至1mM、0.5mM及50μM。LT1-3-PEG肽可直接溶解于RPMI-1640中。在显微镜下观察肽溶液以检测其溶解性。
实例2细胞增殖分析
以下描述的肽经Fmoc修饰且溶解于DMSO及γ-CD中,且随后用于细胞增殖分析。在含有10% FBS的RPMI培养基中培养CL1-5细胞达80%汇流。在分离后,将3×104个细胞接种于12孔盘上。培育16h后,在治疗前采收细胞(标记为0h),或用LT肽治疗24h(标记为24h),且计数活细胞数目。通过以下方程计算相关细胞数目的倍数变化或细胞生长的百分比增长(%):(细胞数目24h-细胞数目0h)/(对照组细胞数目24h-对照组细胞数目0h)。
结果显示,Fmoc-LT-A3具有最佳生长抑制能力。F-moc-LT-A1、LT-A2、LT-A4、LT-A6及LT-A7的抑制活性亦优于F-moc-LT1-3肽(图1)。对LT-A3肽的进一步修饰显示出低于Fmoc-LT-A3肽的生长抑制活性(图2)。剂量影响实验亦显示Fmoc-LT-A3具有最佳生长抑制能力(图3)。吾人亦测定Fmoc-LT1-3及Fmoc-LT-A3在不同肺癌细胞株中对生长抑制的影响。结果显示Fmoc-LT1-3及Fmoc-LT-A3大大地抑制了CL1-5、H1355及H460肺癌细胞株,部分抑制了H1299细胞株,且对A549细胞株无影响(图4)。Fmoc-LT1-3与Fmoc-A3之间的生长抑制趋势相似,暗示了此两种肽特定地在生长抑制中起作用。
实例3细胞侵入分析.
在细胞侵入分析中使用Fmoc-LT1-3。24孔经修饰的具有聚碳酸酯膜的Boyden腔室(8-μm孔径)用于体外侵入分析。所述膜涂布有18μg Matrigel(Becton Dickinson,稀释于RPMI-1640中)。将具有各种浓度的肽的RPMI培养基中的CL1-5细胞(3×104个细胞/孔)接种于上腔室中。RPMI-1640培养基单独用于下腔室中。在培育24h后,细胞经冰冻100%甲醇固定且经10%吉姆萨染液(Giemsa)染色。在染色后,用棉拭子移除位于膜上侧的细胞。在光学显微镜下计数附着于聚碳酸酯膜的下表面的受侵入细胞的数目。所有实验均重复进行三次。如图5A及图5B中显示,Fmoc-LT1-3及Fmoc-LT-A3均抑制细胞侵入,然而,Fmoc-LT1-3的侵入抑制能力优于Fmoc-LT-A3。有趣的是,Fmoc-LT-A3的C端聚乙二醇化大大地提升了侵入抑制活性(图5C)。
实例4异种移植动物模型中Fmoc-LT1-3对肿瘤生长的影响
将六周龄免疫缺陷BALB/CAnN.Cg-Foxn1nu/CrlBltw小鼠安置于单独的通风腔室(individual ventilated chambers,IVC)中。使总共2×106个CL1-5肺癌细胞于100μL PBS中与100μL的10×Matrigel混合。肺癌细胞/Matrigel混合物经皮下注射至小鼠的下背部。三天后,每天用0、10、20、或30nmol的Fmoc-LT-1-3对小鼠进行皮下治疗。自第3天至第17天,Fmoc-LT-1-3肽溶解于100% DMSO中且在PBS中稀释至所需浓度。在第18天,吾人观察到80%对照组动物、40%10nmol组动物、20%20nmol组动物及40%30nmol组动物产生肿瘤。在10nmol与20nmol之间,无肿瘤动物的百分比随着Fmoc-LT1-3的量的提高而提高。然而,30nmol组未展现无肿瘤动物的百分比的进一步提高(图6)。此现象可源于Fmoc-LT1-3在较高浓度下的较低溶解性。因此,吾人决定用γ-CD溶剂替换DMSO溶剂,且将肽稀释至所需浓度以在第18天或其后进行注射。定期量测肿瘤体积。结果显示,20nmol Fomc-LT1-3对抑制肿瘤生长具有最佳效果(图7)。尽管如图6所示,在第18天10nmol及30nmol Fmoc-LT1-3/DMSO具有相似的初始肿瘤生长速率,但在用γ-CD替换溶剂之后,30nmol Fmoc-LT1-3/γ-CD治疗组明显抑制了肿瘤生长(图7)。在第39天,动物死去。称量、固定肿瘤及器官且将其嵌入石蜡中。对嵌入的组织进行分段且用苏木精-伊红染色用于组织学分析。如图8中所示,在与囊泡对照组比较时,20nmol及30nmol Fmoc-LT-1-3明显抑制了肿瘤重量。图9显示,治疗组与对照组之间的相对器官重量无明显差异。在用Fmoc-LT1-3治疗时,组是学分析未揭示动物中的明显毒性。
实例5Fmoc-LT1-3肽对肺癌的癌转移的影响
将五周龄免疫缺陷BALB/CAnN.Cg-Foxn1nu/CrlBltw小鼠安置于IVC中。用200μMFmoc-LT1-3预治疗CL1-5细胞达24h,且随后培养于含有Fmoc-LT1-3肽的新鲜培养基中达6h,之后采收细胞。CL1-5细胞经分离、离心且再悬浮于含200μM Fmoc-LT1-3肽的PBS中以用于注射。在尾部血管注射前三十分钟,亦用20nmol Fmoc-LT1-3对小鼠进行皮下治疗。将总计1×106个CL1-5细胞经静脉注射至小鼠中。在尾部血管注射后第二天,每天将20nmolFmoc-LT1-3/0.5% DMSO或Fmoc-LT1-3/γ-CD皮下注射至小鼠中。至第56天,动物死去,且针对癌转移形成检测所有器官。在解剖显微镜下计数肺表面上的转移性结节。固定器官且将其嵌入石蜡中。对嵌入的组织进行分段且用苏木精-伊红染色用于组织学分析。如图10中所示,Fmoc-LT1-3明显抑制了经由尾部血管注射的两种溶剂中的CL1-5细胞的癌转移。
实例6Fmoc-LT1-3肽及顺铂的疗法
CL1-5细胞经洗涤、分离且再悬浮于PBS中。随后,将含有2×106个细胞于80μL PBS中的单细胞悬浮液与20μL 10×Matrigel(Corning,5117012)混合。将细胞悬浮液皮下注射至免疫缺陷BALB/CAnN.Cg-Foxn1nu/CrlBltw小鼠的上背部中。使肿瘤生长10天,在此期间,90%小鼠产生肿瘤。携带肿瘤的小鼠分为五组(n=8/组)。在以下五组中,平均肿瘤体积为120-140mm3:对照组、Fmoc-LT1-3、顺铂、维持治疗及组合治疗。在第13天,每天用20nmolFmoc-LT1-3/γ-CD对Fmoc-LT1-3组中的小鼠在下背部进行皮下注射。每周向顺铂组中的小鼠腹膜内注射(IP)投与4mg/kg顺铂,总共4次。维持治疗中的小鼠接受4次顺铂的IP,且在第三次IP注射顺铂时每天注射20nmol Fmoc-LT1-3/γ-CD。对组合治疗组中的小鼠一周四次地投与顺铂的IP,且每天投与20nmol Fmoc-LT1-3/γ-CD。在各治疗的过程期间,每3天量测肿瘤体积。记录小鼠的死亡率,包括肿瘤体积超过1500mm3的小鼠。存活率的百分比记录于图11中,且各组的中位生存期计算于表1中。结果显示,囊泡对照组的中位生存期为27.5天,仅有顺铂及仅有Fmoc-LT1-3的组将中位生存期延长至37.5天,使用顺铂及Fmoc-LT1-3的组合治疗将中位生存期进一步延长至47.5天,且维持治疗组亦将中位生存期延长至44天。有趣的是,Fmoc-LT1-3似乎缓解顺铂引发的毒性,正如吾人所观测,在仅使用顺铂的组中,小鼠在注射顺铂后死去,小鼠在维持组之前两个周期中死去,但未在组合治疗组中死去(图11)。此外,组合治疗中的小鼠比仅使用顺铂的组中的小鼠更活跃且更健康。因此,Fmoc-LT1-3不仅抑制肿瘤生长及癌转移,而且降低顺铂的毒性,且显著提升使用顺铂的组合治疗中的动物存活时间。
表1.Fmoc-LT1-3肽在与顺铂的组合治疗中及在维持疗法中延长动物存活时间.
实例7LT内的片段(SEQ ID NO:1)的细胞增殖及侵入分析
根据实例2及实例3中所描述的方法,对在0μM、12.5μM、25μM及50μM的浓度下的肽片段LT-1、LT-2、LT-3、LT-4及LT-5进行细胞增殖分析及侵入分析。LT-1对生长及侵入活动具有抑制性作用,而LT-3、LT-4及LT-5仅对细胞侵入具有抑制性作用。由于肽合成期间的环化作用,未获得用于最终分析的全长LT-2肽。然而,LT-2的N端序列含有LT1-3的序列,且因此极有可能LT-2对生长及侵入活动具有抑制性作用(参见图12及如下表格)。
表2.LT-1、LT-3、LT-4、LT-5在CL1-5细胞的生长及侵入抑制中的作用.
生长抑制 | 侵入抑制 | |
LT-1 | 是 | 是 |
LT-3 | 否 | 是 |
LT-4 | 否 | 是 |
LT-5 | 否 | 是 |
实例8CL1-5肺癌细胞中LT-肽对细胞侵入的影响
LT1-3及LT-A3具有疏水性。LT-A3的生长抑制活性优于LT1-3(图1),而LT1-3的侵入抑制活性优于LT-A3(图13及图14)。为了提高肽溶解性,在LT1-3及LT-A3的N端或C端进行PEG修饰。结果显示,LT-1-3及LT-A3肽(PEG-1-3&PEG-A3)的N端上的PEG3修饰在CL1-5细胞上不具有侵入抑制活性,而LT-A3(A3-PEG)的C端PEG3修饰具有良好抑制活性(图15)。LT-A3-PEG对肺癌细胞的侵入抑制的剂量影响显示,相较于LT-A3(图14),LT-A3-PEG大大地提升了肽的侵入抑制活性(图16)。相较于LT1-3(图13),C端经PEG3修饰的LT-1-3(LT1-3-PEG)亦提升了侵入抑制活性(图17)。
实例9A549及H1299肺癌细胞中LT-1-3-PEG对细胞侵入的影响
重要的是要检测LT-肽是否抑制除CL1-5外的肺癌细胞的发展。结果显示,LT1-3-PEG亦有效抑制A549及H1299细胞的侵入(图18及图19)。LT1-3-PEG亦抑制H460及H1355肺癌细胞的侵入,且当前正在研究LT1-3-PEG对此等两种细胞株的剂量影响。
实例10CL1-5细胞中PEG修饰的LT-肽对细胞增殖的影响
尽管LT-A3在CL1-5细胞中具有优异生长抑制活性,LT-A3上的N端或C端PEG3修饰(PEG-A3&A3-PEG)及LT1-3上的N端PEG3修饰(PEG-1-3)不具有生长抑制活性(图20A)。幸运的是,C端经PEG3修饰的LT1-3(LT1-3-PEG)保持了生长抑制活性(图20B)。
实例11各种肺癌细胞株中LT1-3-PEG对细胞增殖的影响
检测各种细胞株中LT1-3-PEG对细胞增殖的剂量影响。结果显示,LT1-3-PEG有效抑制了CL1-5、A549、H460及H1355增殖但未抑制H1299增殖(图21)。
实例12LT-肽对正常细胞类型的影响
重要的是要研究LT-肽如何影响正常细胞株。吾人用LT-肽治疗SV40转化的人类支气管上皮细胞Beas2B、人类胚胎肺脏成纤维细胞MRC5及HUVEC,且进行细胞增殖分析。吾人的初始结果显示LT-肽未抑制此等正常细胞的生长(图22)。实例13LT1-3-PEG对乳癌细胞增殖的影响
LT1-3-PEG亦抑制MCF-7、T-47D、MDA-MB-231及MDA-MB-453乳癌细胞株的增殖(图23)。
实例14阻断PKA及JNK活性提升了LT-肽参与的生长抑制
PKA抑制剂(H89)及JNK抑制剂(SP600125)提高了CL1-5肺癌细胞中LT1-3及LT1-3-PEG参与的生长抑制(图24及图25)。为了证实此类观察,在CL1-5中用siRNA干扰PKA及JNK1的催化子单元,且随后对这些细胞进行LT-肽治疗。结果证明PKA及JNK的活性降低提升了对LT-1-3-肽参与的生长的抑制性效果(图26及图27)。
Claims (12)
1.一种肽,其为DGNFHIVELLA(LT-11AA)(SEQ ID NO:26);或经修饰的肽或其盐,其中所述经修饰的肽为环肽、聚乙二醇化(PEG)-肽或茀基甲氧基羰基(Fmoc)-肽。
2.如权利要求1的肽,其中所述经修饰的肽具有改良的稳定性或溶解性。
3.如权利要求1或2的肽,其中所述经修饰的肽为Fmoc-肽,其中Fmoc结合至SEQ ID NO:26的肽的N端或C端。
4.如权利要求1或2的肽,其中所述经修饰的肽为PEG-肽,其中PEG结合至SEQ ID NO:26的肽的N端或C端。
5.如权利要求1的肽,其中所述经修饰的肽为环肽,其中D以头尾环化形式键结至A。
6.一种医药组合物,其包含如权利要求1至5中任一项的肽及医药学上可接受的载剂。
7.如权利要求6的医药组合物,其进一步包含第二抗癌剂。
8.如权利要求7的医药组合物,其中所述第二抗癌剂为埃罗梯尼(erlotinib)、阿法替尼(afatinib)、吉非替尼(gefitinib)、贝伐单抗(bevacizumab)、雷莫芦单抗(ramucirumab)、拉帕替尼(lapatinib)、顺铂(cisplatin)、太平洋紫杉醇(paclitaxel)、甲胺喋呤(methotrexate)、环磷酰胺(cyclophosphamide)、异磷酰胺(ifosfamide)、氮芥苯丁酸(chlorambucil)、双氯乙基亚硝脲(carmustine)、卡铂(carboplatin)、长春新碱、长春花碱、噻替派(thiotepa)、洛莫司汀(lomustine)、司莫斯汀(semustine)、5-氟尿嘧啶、皮质类固醇、钙调神经磷酸酶(calcineurin)抑制剂、NSAID、5-脂肪加氧酶抑制剂或阿糖胞苷(cytarabine)。
9.一种如权利要求1至5中任一项的肽的用途,其用于制备预防、治疗及/或改善癌症或抑制癌症生长、侵入及/或转移的药剂。
10.如权利要求9的用途,其中所述药剂进一步包含第二抗癌剂或可与第二抗癌剂共投与。
11.如权利要求10的用途,其中所述第二抗癌剂为埃罗梯尼、阿法替尼、吉非替尼、贝伐单抗、雷莫芦单抗、拉帕替尼、顺铂、太平洋紫杉醇、甲胺喋呤、环磷酰胺、异磷酰胺、氮芥苯丁酸、双氯乙基亚硝脲、卡铂、长春新碱、长春花碱、噻替派、洛莫司汀、司莫斯汀、5-氟尿嘧啶、皮质类固醇、钙调神经磷酸酶抑制剂、NSAID、5-脂肪加氧酶抑制剂或阿糖胞苷。
12.如权利要求10的用途,其中所述药剂用于组合疗法或维持疗法。
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