CN105378084B - 用于治疗癌症的方法和组合物 - Google Patents
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Abstract
本发明涉及Myc显性负突变体,称为Omomyc,其用于医药以及用于预防和/或治疗癌症。本发明还涉及包含Omomyc的融合蛋白及其药物组合物以及它们在医药中的用途,特别是用于治疗癌症的用途。
Description
技术领域
本发明涉及癌症领域,且更具体地,涉及使用Omomyc多肽用于治疗癌症的方法和组合物以及涉及包含Omomyc和一种或更多种抗癌药物的组合物及它们用于治疗癌症的用途。
背景技术
理想的癌症药物应持续地靶向对于肿瘤的维持是必要的,但对于任何正常组织的维持和功能是非必要的非冗余功能。因此,最常见的逻辑是靶向在癌症中特异性突变的基因产物,其依据是或许这些突变体分子对于正常组织不太关键,但将是癌症的可能“驱动者(driver)”。由于这些原因,许多注意力都集中在为特定癌症类型中的复发性损害进行目录分类(cataloguing)。不幸的是,这种方法存在数个问题。首先,大多数人实体癌经过基因组不稳定性的事件并表现出可掩盖“驱动者”突变以及其伴随效应物途径的突变噪音。其次,癌症是包括通过多个演变瓶颈(evolutionary bottleneck)的转变之过程的最终结果。每个瓶颈可能需要特定类型的突变,从那以后其功能对于肿瘤维持是非必要的,因此,其在肿瘤演变中的该点之后不是良好的治疗靶标。
Myc是参与生长控制和癌症的碱性螺旋-环-螺旋亮氨酸拉链(b-HLH-LZ)蛋白质,其在网络中与结构上相关的蛋白质Max、Mad和Mnt一起起作用。Myc/Max二聚体激活基因转录并诱导细胞增殖或凋亡。Mad/Max和Mnt/Max复合物充当阻抑物并引起细胞生长停滞和分化。所有二聚体均识别相同的DNA共有位点(CACGTG E-框)。
在正常细胞中Myc受到严格地调控,在其中其增殖水平较高,而非增殖水平较低。异常高的和/或失调的Myc活性与大多数癌症因果相关并且常与攻击性的、低分化的以及血管生成的肿瘤有关。Myc表达的失调是由于通过基因扩增的过表达、转录调控的丧失、受损的降解或提高的稳定性。这导致了异常的增殖、提高的存活、代谢的改变、血管生成和炎症,所有这些都代表癌症的主要特点。多项研究证实了Myc在支配肿瘤发生的细胞内和细胞外方面的关键作用,表明靶向其功能将具有治疗价值。
已知通过BET溴结构域(bromodomain)抑制剂下调myc导致多种肿瘤类型的退化(Delmore,J.E.等,2011,Cell,146:904-917)。虽然这种方法显示了良好的潜力,但是它显示出一些局限性,例如毒性和许多脱靶效应。
许多破坏Myc/Max相互作用的小分子已经在细胞中显示出低特异性(Prochownik,E.V.和Vogt,P.K.,2010,Genes Cancer 1,650-659)。
然而,Myc抑制剂在临床上还不可用,并且其设计提出了多种注意事项:第一,Myc是一种核转录因子,因此其比膜或细胞质分子更难到达;第二,Myc不具有可被靶向的酶促“活性位点”;第三,Myc家族包括3种不同的蛋白质,c-Myc、N-Myc和L-Myc,在一定的条件下,它们是功能冗余的,所以需要同时抑制它们全部。此外,担心Myc抑制通过抑制正常组织的增殖将会诱发严重的副作用。由于所有这些原因,使得Myc抑制剂药物具有挑战性。
Omomyc是包含Myc的b-HLH-LZ结构域且在Myc的亮氨酸拉链中携带4个氨基酸替换的显性负MYC突变体(dominant-negative MYC mutant)(Soucek,L.等,1998,Oncogene 17,2463-2472;Soucek,L.等(2002),Cancer Res 62:3507-3510)。氨基酸替换E61T、E68I、R74Q和R75N赋予了蛋白质改变的二聚化特异性,这保留了与其天然伴侣Max结合的能力以及与野生型c-Myc、N-Myc和L-Myc形成同源二聚体和异源二聚体的能力。
由于这些特性,在体外和体内两种情况下,通过使Myc与其DNA识别结合位点(E框)结合的能力失效,Omomyc能够防止Myc依赖性基因反式激活功能(Savino,M.等,2011,PLoSOne 6,e22284;Soucek,L.等(2004),CellDeath Differ 11,1038-1045)。与此同时,Omomyc以依赖Myc表达水平的方式强烈地加强了Myc诱导的凋亡,并因此增强了Myc的反式阻抑活性。因此,Omomyc阻止Myc与启动子E-框结合以及靶基因的反式激活,同时保留了对启动子的Miz-1依赖性结合以及反式阻抑。在Omomyc存在下,引导Myc相互作用组(interactome)来进行阻抑且其活性由原致癌活性转变为肿瘤抑制活性。
施用多西环素后,TRE-Omomyc;CMVrtTA小鼠(其中Omomyc表达受四环素响应启动子元件控制并且广泛表达的rtTA反式激活因子由CMV启动子驱动)在大多数组织中表现出高的Omomyc表达(Soucek等,2008,Nature,455:679-683)。将这些小鼠与已很好建立的肺肿瘤发生的LSL-KrasG12D鼠模型进行杂交。Omomyc表达仅3天就足以引起肿瘤的明显收缩,并且一周就使得动物基本上没有了肿瘤。重要的是,虽然在治疗过程中其他分裂组织(例如皮肤、睾丸、肠)显示出显著降低的增殖速率,并表现出一定程度的萎缩,但没有小鼠显示出明显的痛苦或疾病迹象。此外,由Omomyc表达造成的Myc抑制的副作用是完全可逆的并且治疗中止后便会消失。
迄今为止,尽管事实上已证明Omomyc的表达是有效的体内Myc抑制策略,但是其仅使用基因治疗方法被单独地应用。事实上,认为Omomyc是过大的肽,不适于递送至所期望的细胞区室(Montagne M.等,PLoS One.2012;7:e32172.doi:10.1371/journal.pone.0032172),Savino M.等,PLoS One.2011;6:e22284.doi:10.1371/journal.pone.0022284)和Genes Dev.,2011,25:895-7.doi:10.1101/gad.2053311)。
此外,因为Omomyc固有的物理化学性质(例如,使用Kyte和Doolittle亲水性图预测的疏水性,Kyte J.,Doolittle R.F.(1982)J.Mol.Biol.157:105-132),所以预测Omomyc表现出差的跨越生理屏障的能力。另外,尽管在Omomyc的碱性区域内存在多个精氨酸残基,然而预测肽的自发细胞穿透能力的最新算法没有预测出Omomyc拥有这种特性(Gautam等,Journal of Translational Medicine 2013,11:74)。
因此,基于b-HLH-LZ结构域能够跨真核细胞的细胞膜转导并抑制Myc依赖性基因反式激活而提供用于治疗癌症的治疗方法将是有利的。
发明内容
在第一个方面,本发明涉及SEQ ID NO:1的多肽或其功能等同变体,其用于医药(medicine)以及用于预防和/或治疗癌症。
在另一个方面,本发明涉及融合蛋白,其包含:
(i)SEQ ID NO:1的多肽或其功能等同变体,和
(ii)细胞穿透肽序列(cell-penetrating peptide)和/或核定位信号(nuclearlocalization signal)。
在另一个方面,本发明涉及药物组合物,其包含根据本发明的融合蛋白以及涉及所述融合蛋白在医药中的用途,特别是用于治疗癌症的用途。
在另一个方面,本发明涉及组合物,其同时或单独包含:
(i)SEQ ID NO:1的多肽、其功能等同变体或根据本发明的融合蛋白,和
(ii)抗肿瘤剂。
在另一个方面,本发明涉及药物组合物,其包含本发明的组合物以及涉及本发明的组合物在医药中的用途,特别是用于治疗癌症的用途。
附图说明
图1.(A)在37℃下,用Omomyc-FITC孵育A549细胞2小时的荧光成像,示出了Omomyc-FITC定位于细胞核和细胞质中。(B)核的Hoescht染色。(C)相差(phase contrast)。
图2.对用10μM的Omomyc或10μM的Max*孵育的细胞进行计数并用膜联蛋白V和PI染色。(A)PBS、Omomyc或Max处理的A549的总细胞数目。(B)用PI染色的死亡细胞的百分比。(C)(非染色的)活细胞的百分比。(D)膜联蛋白V阳性细胞的百分比。
图3.(A)在20℃下记录的c-Myc*、Max*和Omomyc纯化的蛋白质(32μM)的圆二色(CD)谱,表明与Myc*相比,Omomyc具有更类似于Max*的折叠结构。(mdeg,毫度)(B)通过圆二色性以1℃/分钟研究c-Myc*、Max*和Omomyc纯化的蛋白质的热变性表明与Max*相比,Omomyc具有更高热稳定性的折叠结构。(°m,在222nm的特定波长下的毫度)。
图4.在37℃下用Omomyc或Max*以不同的肽浓度(5μM、10μM和25μM)孵育2小时后,对来自用4%PFA固定的A549细胞之共焦显微术图像的荧光进行定量(每个图像计数30至80个细胞)。AU,任意单位。
图5.在37℃下用Omomyc或Max*(20μM)孵育20分钟后,对来自A549活细胞的共聚焦显微术图像的荧光进行定量。AU,任意单位。
图6.用25μM Omomyc或Max*肽处理A549和H1650肺腺癌细胞指定时间的结晶紫染色。
图7.通过结晶紫染色对用25μM Omomyc或Max*肽处理A549和H1650肺腺癌细胞指定时间的增殖抑制进行定量。
图8.通过结晶紫染色对A549细胞对Omomyc和Max*的剂量响应进行定量。
图9.以25μM用Omomyc或Max*肽处理的U87神经胶质瘤细胞之增殖的定量。
图10.(A)在鼻内施用荧光肽Omomyc(37.5mg/kg的单剂量)后10分钟,未处理的(左)和经处理的(右)的动物的肺。(B)在鼻内施用荧光肽Omomyc(37.5mg/kg的单剂量)后10分钟,未处理的(左)和经处理的(右)动物的脑。
图11.通过鼻内施用PBS或Omomyc治疗肺腺癌。(A)肿瘤的增殖速率。(B)细胞密度。
图12.在通过鼻内施用PBS或Omomyc治疗肺腺癌后,肿瘤区域%(%tumor area)的测量。
具体实施方式
本发明的作者已出人意料地发现,Omomyc能够有效地跨细胞膜转导并移位(translocate)至细胞核,在细胞核中它发挥其肿瘤抑制作用。因此,Omomyc是真正的蛋白质转导结构域(Protein Transduction Domain,PTD)。因此,首次Omomyc本身可用作抗Myc药物而不需要使用将多肽递送至细胞之细胞质的载体,或不需要使用将编码Omomy的核酸递送至细胞的基因治疗方法。这使得能够使用Omomyc多肽以用于治疗与失调的细胞增殖有关的疾病(例如癌症)。本发明的作者意外地发现,与Max(Max*)的bHLHZ结构域相比,Omomyc具有以下几个优点:
●在不同的细胞类型和不同的浓度下,与Max*相比,Omomyc显示出更好的细胞穿透能力(实施例6)
●与Max*相比,Omomyc具有更高的热稳定性,这对于药物设计而言是明显的优势(实施例5)
●与Max*相比,Omomyc在防止细胞生长(实施例8)和增加癌细胞的死亡(实施例4)两方面均更有效。
此外,Omomyc能够跨过血脑屏障(实施例9和图10B)并在体内发挥其治疗作用(实施例10)。
使用Omomyc的治疗方法
本发明基于具有SEQ ID NO:1的序列的多肽(其对应于Omomyc)或其功能等同变体之用途,提供了用于治疗癌症的方法。
在第一方面,本发明涉及SEQ ID NO:1的多肽或其功能等同变体,其用于医药。
在另一方面,本发明涉及SEQ ID NO:1的多肽或其功能等同变体,其用于预防和/或治疗癌症。
在另一方面,本发明还涉及用于预防和/或治疗癌症的方法,其包括向有此需要的对象施用治疗有效量的SEQ ID NO:1的多肽或其功能等同变体。
在另一方面,本发明还涉及SEQ ID NO:1的多肽或其功能等同变体,其用于制备用于预防和/或治疗癌症的药物。
序列SEQ ID NO:1的多肽对应于Omomyc蛋白质序列。如本文所使用的术语“Omomyc”指的是由携带E61T、E68I、R74Q和R75N突变的Myc之bHLHZip结构域的突变形式组成的多肽(其中给出了所述突变位点相对于Myc区的序列的编号,Myc区对应于2012年6月27日发布的NCBI数据库中根据登录号NP_002458所定义之多肽的365至454位氨基酸)。在下面示出了NCBI数据库中根据登录号NP_002458提供的c-Myc序列,其中,衍生出Omomyc的区域用下划线示出:
在下面示出了编码Omomyc的多核苷酸(SEQ ID NO:3)和对应的多肽序列(SEQ IDNO:1),其中下划线和粗体三联体对应于相对于Myc而突变的那些位置:
Omomyc还包含具有序列RQRRNELKRSF(SEQ ID NO:49)的c-Myc的M2结构域(参见Dang和Lee,Mol.Cell.Biol.,1988,8:4048-4054)(以上的双下划线部分)且其对应于核定位信号。
Omomyc的特征在于它显示出与所有三种致癌Myc蛋白质(c-Myc、N-Myc和L-Myc)提高的二聚化能力。Omomyc可衍生自本领域已知的任何Myc蛋白质的bHLHZip结构域,条件是保留导致肿瘤抑制物作用的突变。因此,可在本发明中使用的Omomyc可衍生自任何哺乳动物物种,包括但不限于家养动物和农场动物(牛、马、猪、绵羊、山羊、狗、猫或啮齿类动物)、灵长类动物和人。优选地,Omomyc蛋白衍生自人Myc蛋白(2012年6月27日发布的登录号NP_002458)。
如本文所使用的术语“Myc”指的是一个转录因子家族,其包括c-Myc、N-Myc和L-Myc。Myc蛋白通过结合在共有序列CACGTG(增强子框序列或E-框和募集组蛋白乙酰基转移酶或HAT)上激活许多基因的表达。然而,Myc也可充当转录阻抑物。通过结合Miz-1转录因子并置换p300辅激活蛋白,其抑制Miz-1靶基因的表达。Myc还具有直接控制DNA复制的作用。
Myc b-HLH-LZ或Myc碱性区螺旋-环-螺旋亮氨酸拉链结构域指的是决定Myc与Max蛋白二聚化并与Myc靶基因结合的区域。这个区域对应于人Myc的365至454位氨基酸,其特征在于由环连接的两个α螺旋(Nair,S.K.和Burley,S.K.,2003,Cell,112:193-205)。
当提及Omomyc时,术语“功能等同变体”指的是相对于SEQ ID NO:1的多肽由缺失、插入或添加一个或更多个氨基酸而产生的任何多肽或由SEQ ID NO:1的多肽的化学修饰产生的任何多肽,并且其基本上保留了Omomyc多肽的肿瘤抑制活性。本领域技术人员将理解,保留Omomyc的肿瘤抑制物活性需要一旦在细胞核中出现Myc,变体可与Myc二聚化且抑制其活性,即需要其能够跨细胞膜移位并且需要其能够跨核被膜移位。
Omomyc的合适功能等同变体包括基本上由SEQ ID NO:1的多肽组成的多肽。在这个情况下,“基本上由......组成”意指所指定分子将不包含会改变Omomyc活性的任何其他序列。
靶向肽的合适功能变体是相对于SEQ ID NO:1的肽显示出一定程度同一性(约大于25%的氨基酸序列同一性)的那些,例如25%、40%、60%、70%、80%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%。使用本领域技术人员广泛已知的计算机算法和方法来确定两个多肽之间同一性的程度。优选通过使用如先前所描述的BLASTP算法来确定两个氨基酸序列之间的同一性[BLAST Manual,Altschul,S.等,NCBI NLM NIH Bethesda,Md.20894,Altschul,S.等,J.Mol.Biol.1990;215:403-410]。在一个优选的实施方案中,通过SEQ ID NO:1的多肽的整个长度或通过变体的整个长度或这二者来确定序列同一性。
Omomyc多肽的功能等同变体还可包括翻译后修饰,例如糖基化、乙酰化、异戊二烯化、肉豆蔻酰化、蛋白水解加工等。
或者,靶向肽的合适功能变体是其中Omomyc多肽内的一个或更多个位置包含为在上述Omomyc蛋白中存在的氨基酸保守替换之氨基酸的那些功能变体。“保守的氨基酸替换”是由用另一个具有相似结构和/或化学性质的氨基酸替代一个氨基酸造成的。例如,下面的6组各自包含彼此为保守替换的氨基酸:1)丙氨酸(A)、丝氨酸(S)、苏氨酸(T);2)天冬氨酸(D)、谷氨酸(E);3)天冬酰胺(N)、谷氨酰胺(Q);4)精氨酸(R)、赖氨酸(K);5)异亮氨酸(I)、亮氨酸(L)、甲硫氨酸(M)、缬氨酸(V);和6)苯丙氨酸(F)、酪氨酸(Y)、色氨酸(W)。对这样保守氨基酸替换的选择在本领域普通技术人员的能力范围内并且例如由Dordo等(J.Mol.Biol,1999年,217;721-739)和Taylor等(J.Theor.Biol.,1986,119:205-218)进行了描述。
应理解的是,Omomyc的功能等同变体包含对应于在衍生自人c-Myc的Omomyc中发现的突变E61T、E68I、R74Q和R75N之位置上的突变。可通过对不同Myc序列的多重序列比对来确定以及通过对对应于衍生自人c-Myc的Omomyc的序列内61、68、74和75位的那些位置的比对来鉴定在功能等同变体中所述突变发生的位置。
多重序列比对是成对比对的扩展以一次并入超过两个序列。多重比对方法在给定的查询集(query set)中比对所有的序列。一种优选的多重序列比对程序(及其算法)是ClustalW、Clusal2W或ClustalW XXL(参见Thompson等(1994)Nucleic Acids Res 22:4673-4680)。如本文所述,一旦对来自不同生物体的c-Myc序列和变体序列进行比较(比对),技术人员可容易地鉴定对应位置的每个序列内的位置并在Omomyc变体中引入这样的突变,其对应于在衍生自人c-Myc的Omomyc中发现的E61T、E68I、R74Q和R75N突变。
用于确定多肽是否可被认为是Omomyc的功能等同变体之合适的测定包括但不限于:
-测量多肽与Max和Myc形成二聚体复合物之能力的测定,例如,如在Soucek等(Oncogene,1998,17:2463-2472)中描述的基于报道基因的表达的测定以及PLA(蛋白质连接测定)或免疫共沉淀。
-测量多肽与DNA内Myc/Max识别位点(CACGTG位点)结合之能力的测定,例如在Soucek等(同上)中描述的电泳迁移率变动测定(electrophoretic mobility shiftassay,EMSA)。
-测量阻抑Myc诱导的反式激活之能力的测定,例如由Soucek等(同上)描述的,在对Myc/Max特异性的DNA结合位点的控制下,基于报道基因表达的测定。
-如由Soucek等(同上)描述的基于多肽抑制表达myc癌基因的细胞生长之能力的测定。
-测量多肽增强myc诱导的凋亡之能力的测定,例如由Soucek等(Oncogene,1998:17,2463-2472)描述的测定。此外,可使用本领域通常已知的用于评估细胞中凋亡的任何测定,例如Hoechst染色、碘化丙啶(PI)或膜联蛋白V染色、台盼蓝、DNA梯度/断裂和TUNEL。
在一个优选的实施方案中,如果多肽在上述一个或更多个测定法中显示出至少10%、20%、30%、40%、50%、60%、70%、80%、90%或100%的天然Omomyc的活性,则认为所述多肽是Omomyc的功能等同变体。
此外,在变体与所述细胞接触后,Omomyc的功能等同变体也能够转导细胞。应理解的是,Omomyc的功能等同变体包含在天然Omomyc中发现的蛋白质转导结构域或另一种功能性蛋白质转导结构域。
在本说明书中使用的术语“细胞穿透肽序列”可与“CPP”、“蛋白质转导结构域”或“PTD”互换使用。其指的是指导蛋白质转运至细胞内部的长度可变的肽链。进入细胞的递送过程通常通过胞吞作用发生,但是也可通过直接的膜移位方式将肽内在化到细胞中。CPP通常具有氨基酸组分,其包含高相对丰度的带正电荷氨基酸(例如赖氨酸或精氨酸),或者具有包含交替方式的极性/带电荷氨基酸和非极性疏水氨基酸的序列。可用于本发明的CPP的实例包括但不限于:在果蝇触角足(Drosophila antennapedia)蛋白中发现的CPP(RQIKIWFQNRRMKWKK,SEQ ID NO:4),在单纯疱疹病毒(HSV-1)VP22DNA结合蛋白中发现的CPP,(DAATATRGRSAASRPTERPRAPARSASRPRRPVE,SEQ ID NO:5),Bac-7的CPP(RRIRPRPPRLPRPRPRPLPFPRPG;SEQ ID NO:6),由49至57位氨基酸(RKKRRQRRR,SEQ ID NO:7),48至60位氨基酸(GRKKRRQRRRTPQ,SEQ ID NO:8)、47至57位氨基酸(YGRKKRRQRRR,SEQID NO:9)组成的HIV-1 TAT蛋白的CPP;S413-PV肽的CPP(ALWKTLLKKVLKAPKKKRKV;SEQ IDNO:10),穿膜肽(penetratin)的CPP(RQIKWFQNRRMKWKK;SEQ ID NO:11),SynB1的CPP(RGGRLSYSRRRFSTSTGR;SEQ ID NO:12),SynB3的CPP(RRLSYSRRRF;SEQ ID NO:13),PTD-4的CPP(PIRRRKKLRRLK;SEQ ID NO:14),PTD-5的CPP(RRQRRTSKLMKR;SEQ ID NO:15),FHVCoat-(35-49)的CPP(RRRRNRTRRNRRRVR;SEQ ID NO:16),BMV Gag-(7-25)的CPP(KMTRAQRRAAARRNRWTAR;SEQ ID NO:17),HTLV-II Rex-(4-16)的CPP(TRRQRTRRARRNR;SEQID NO:18),D-Tat的CPP(GRKKRRQRRRPPQ;SEQ ID NO:19),R9-Tat的CPP(GRRRRRRRRRPPQ;SEQ ID NO:20),MAP的CPP(KLALKLALKLALALKLA;SEQ ID NO:21),SBP的CPP(MGLGLHLLVLAAALQGAWSQPKKKRKV;SEQ ID NO:22),FBP的CPP(GALFLGWLGAAGSTMGAWSQPKKKRKV;SEQ ID NO:23),MPG的CPP(ac-GALFLGFLGAAGSTMGAWSQPKKKRKV-cya;SEQ ID NO:24),MPG(ENLS)的CPP(ac-GALFLGFLGAAGSTMGAWSQPKSKRKV-cya;SEQ ID NO:25),Pep-1的CPP(ac-KETWWETWWTEWSQPKKKRKV-cya;SEQ ID NO:26),Pep-2的CPP(ac-KETWFETWFTEWSQPKKKRKV-cya;SEQ ID NO:27),具有结构RN(其中,N是4至17)的聚精氨酸序列,GRKKRRQRRR序列(SEQID NO:28),RRRRRRLR序列(SEQ ID NO:29),RRQRRTS KLMKR序列(SEQ ID NO:30);转运蛋白(transportan)GWTLNSAGYLLGKINLKALAALAKKIL(SEQ ID NO:31);KALAWEAKLAKALAKALAKHLAKALAKALKCEA(SEQ ID NO:32);RQIKIWFQNRRMKWKK(SEQ ID NO:33),YGRKKRRQRRR序列(SEQID NO:34);RKKRRQRR序列(SEQ ID NO:35);YARAAARQARA序列(SEQ ID NO:36);THRLPRRRRRR序列(SEQ ID NO:37);GGRRARRRRRR序列(SEQ ID NO:38)。
用于确定多肽是否保留了Omomyc的细胞膜移位能力之合适的测定,包括但不限于,测量多肽在培养物中转导细胞之能力的测定,例如本发明的实施例3中所示的测定。这种测定基于使多肽与培养细胞接触并检测细胞内定位的多肽的存在。在一个优选的实施方案中,通过荧光显微术来进行本发明多肽的检测。
在一个优选的实施方案中,如果多肽能够像天然Omomyc的至少10%、20%、30%、40%、50%、60%、70%、80%、90%或100%一样有效地转导靶细胞,那么认为所述多肽是OmOmyc的功能等同变体。
此外,在将变体与细胞接触后,Omomyc的功能等同变体也能够到达经转导之所述细胞的核。应理解的是,Omomyc的功能等同变体包含于天然Omomyc中发现的NLS或另外的功能性NLS。
如本文所使用的术语“核定位信号”指的是约的4至20个氨基酸残基长度的氨基酸序列,其用于指导蛋白质到细胞核。通常,核定位序列富含碱性氨基酸且示例性序列是本领域公知的(Gorlich D.(1998)EMBO 5.17:2721-7)。在一些实施方案中,NLS选自:SV40大T抗原NLS(PKKKRKV,SEQ ID NO:39);核质蛋白NLS(KRPAATKKAGQ AKKKK,SEQ ID NO:40);CBP80NLS(RRRHSDENDGGQPHKRRK,SEQ ID NO:41);HIV-I Rev蛋白NLS(RQARRNRRRWE,SEQ ID NO:42);HTLV-I Rev(MPKTRRRPRRSQRKRPPT,SEQ ID NO:43);hnRNP A NLS(NQSSNFGPMKGGNFGGRSSGPYGGGGQYFKPRNQGGY,SEQ ID NO:44);rpL23a NLS(VHSHKKKKIRTSPTFTTPKTLRLRRQPKYPRKSAPRRNKLDHY,SEQ ID NO:45)。在本发明的一个实施方案中,核定位信号包含基序K(K/R)X(K/R)(SEQ ID NO:46)。
按照跨细胞膜移位的能力,用于确定多肽是否是Omomyc的功能等同变体的合适测定包括用对多肽特异性的试剂和用特异性标记细胞核的染料(例如DAPI或Hoechst染料)进行双标记。在本发明的实施例6中示出了这样的测定。在一个优选的实施方案中,通过共聚焦显微术或荧光显微术来检测本发明的多肽。
在一个优选的实施方案中,如果多肽能够像天然Omomyc的至少10%、20%、30%、40%、50%、60%、70%、80%、90%或100%一样有效地移位至靶肿瘤细胞的细胞核,那么认为所述多肽是Omomyc的功能等同变体。
合适的功能等同变体包括如下定义的多肽Omomyc*TAT和Omomyc*LZArg:
根据本发明,在用于预防或治疗对象之癌症的方法中使用Omomyc多肽或其功能等同变体。应理解的是,根据本发明的预防或治疗方法包括直接使用Omomyc多肽或其功能等同变体。因此,根据本发明的预防或治疗方法不包括施用编码Omomyc或其功能等同变体的核酸。
“预防”应理解为在疾病的初始或早期阶段,施用根据本发明第一方面的SEQ IDNO:1的多肽或其功能等同变体,或含有其的药物,或者还可防止疾病发生。
术语“治疗”用于指明在临床体征出现之前或之后,施用根据本发明第一方面的SEQ ID NO:1的多肽或其功能等同变体或含有其的药物以控制疾病的进展。疾病进展的控制应理解为有益的或期望的临床结果,包括但不限于症状的减少、疾病持续时间的减少、病理状况的稳定(特别是避免其他损伤)、延缓疾病的进展、改善病理状况以及(部分和完全)缓解。疾病进展的控制还包括与如果没有施加治疗的预期存活相比,存活的延长。
术语“癌症”指的是具有以下特征的疾病:不受控制的细胞分裂(或存活的提高或凋亡抗性)、所述细胞侵入其他周边组织(侵袭)的能力或通过淋巴管和血管扩散到细胞通常不定位之身体的其他区域(转移)。根据肿瘤是否可通过侵袭和转移而扩散,将其分为良性的或恶性的:良性肿瘤是不能通过侵袭或转移而扩散的肿瘤,即,它们只在局部生长;而恶性肿瘤是能够通过侵袭和转移而扩散的肿瘤。根据本发明的方法可用于治疗局部肿瘤和恶性肿瘤。如本文所使用的术语癌症包括但不限于以下类型的癌症:乳腺癌;胆道癌;膀胱癌;脑癌,包括胶质母细胞瘤和成神经管细胞瘤;宫颈癌;绒膜癌;结肠癌;子宫内膜癌;食道癌;胃癌;血液瘤,包括急性淋巴细胞白血病和髓性白血病;T细胞急性淋巴细胞白血病/淋巴瘤;多毛细胞白血病;慢性髓性白血病、多发性骨髓瘤;AIDS相关的白血病和成体T细胞白血病/淋巴瘤;上皮内瘤,包括鲍恩病(Bowen′s disease)和佩吉特病(Paget′s disease);肝癌;肺癌;淋巴瘤,包括何杰金病(Hodglun′s disease)和淋巴细胞性淋巴瘤;神经母细胞瘤;口腔癌,包括鳞状细胞癌;卵巢癌,包括由上皮细胞、基质细胞、生殖细胞和间充质细胞产生的那些;胰腺癌;前列腺癌;直肠癌;肉瘤,包括平滑肌肉瘤、横纹肌肉瘤、脂肉瘤、纤维肉瘤和骨肉瘤;皮肤癌(slun caner),包括黑素瘤、梅克尔细胞癌(Merkel cellcarcinoma)、卡波西肉瘤、基底细胞癌和鳞状细胞癌;睾丸癌,包括生殖肿瘤,例如精原细胞瘤、非精原细胞瘤(畸胎瘤、绒膜癌)、基质瘤和生殖细胞肿瘤;甲状腺癌,包括甲状腺腺癌和髓样癌;以及肾癌,包括腺癌和维尔姆斯瘤(Wilms tumor)。其他癌症对本领域普通技术人员来说是已知的。在一个优选的实施方案中,治疗的癌症是肺癌,优选肺腺癌,更优选KRas驱动的肺腺癌。
本发明的作者还观察到无论癌症是否显示出Myc蛋白之提高的表达或活性,Omomyc或其功能等同变体都能够降低细胞增殖。
本文使用的“对象”包括具有癌症或表现出癌症症状,或处于发生癌症或表现出癌症症状风险的任何动物。合适的对象(患者)包括实验室动物(例如小鼠、大鼠、兔或豚鼠)、农场动物和家养动物或宠物(例如猫或狗)。包括非人灵长类动物,优选人患者。
在根据本发明的方法中使用的Omomyc或其功能等同变体之合适的剂量将取决于不同的因素,例如待治疗的癌症类型、疾病的严重程度和进程、施用组合物是用于预防目的还是治疗目的、先前的疗法,患者的临床病史和对肽或多肽的响应以及主治医师的判断。
在一次或在一系列治疗中向患者适当地施用一定量的SEQ ID NO:1的多肽或其功能等同变体。根据疾病的类型和严重程度,合适的剂量水平通常为每天每kg患者体重约0.01至500mg(可以以单剂量或多剂量施用)。优选地,剂量水平为每天约0.1mg/kg至约250mg/kg;更优选地为每天约0.5mg/kg至约100mg/kg。合适的剂量水平可为每天约0.01mg/kg至250mg/kg,每天约0.05mg/kg至100mg/kg或每天约0.1mg/kg至50mg/kg。在此范围内,剂量可为每天0.05mg/kg至0.5mg/kg、0.5mg/kg至5mg/kg或5mg/kg至50mg/kg。对于经口施用,优选以片剂的形式提供组合物,其含有1.0毫克至1000毫克的活性成分,特别是1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0和1000.0毫克的活性成分以用于向待治疗的患者进行剂量的症状调节。可按照每天1至4次,优选每天一次或两次的方案施用化合物。
可通过任何类型的合适途径施用SEQ ID NO:1的多肽或其功能等同变体的多肽,所述途径例如通过经口途径、表面途径、通过吸入或肠胃外途径,以使得包括用于配制所需剂型的必需可药用赋形剂。所述药物组合物的优选施用途径是静脉内途径。在另一个实施方案中,施用途径是鼻内途径。
在一个实施方案中,Omomyc或其功能等同变体与载体一起制备,其将保护所述多肽免于从体内被迅速地除去,例如控释制剂,包括植入体和微囊化的施用系统。可使用可生物降解的生物相容性聚合物,例如乙烯乙酸乙烯酯、聚酐类、聚乙醇酸、胶原蛋白、聚原酸酯类和聚乳酸。本领域技术人员清楚制备所述制剂的方法。材料也可在Alza Corporation和Nova Pharmaceuticals,Inc.商购获得。
尽管事实上Omomyc和其功能等同变体能够跨生物膜移位,可以以纳米颗粒配制Omomyc或其任何的功能等同变体。所述纳米颗粒可有助于保存生物流体中多肽的完整性直到其到达靶器官。此外,也可修饰纳米颗粒以使得其包含将纳米颗粒靶向目的器官的部分。以这种方式,Omomyc或其功能等同变体将被递送至靶器官的附近,从而促进Omomyc进入需要其生物活性的细胞内部。
因此,在另一个实施方案中,提供形成纳米颗粒的一部分的Omomyc或其任何的功能等同变体。
如本文所使用的术语“纳米颗粒”指的是具有1nm至1,000nm尺寸的任何材料。在一些实施方案中,纳米颗粒的尺寸为2nm至200nm,优选为2nm至150nm,甚至更优选为2nm至100nm。可在本发明中使用的纳米颗粒包括这样的纳米级材料,例如基于脂质的纳米颗粒、超顺磁性纳米颗粒、纳米壳、半导体纳米晶体、量子点、基于聚合物的纳米颗粒、基于硅的纳米颗粒、基于二氧化硅的纳米颗粒、基于金属的纳米颗粒、富勒烯和纳米管。
通过添加配体可实现靶向递送,而不影响纳米颗粒递送其多肽有效载荷(payload)的能力。可以设想,这使得能够递送至特定的细胞、组织和器官。基于配体的递送系统的靶向特异性基于配体受体在不同的细胞类型上的分布。靶向配体可以非共价地或共价地与纳米颗粒缔合,并且可通过如本文所讨论的多种方法与纳米颗粒缀合。
可用于靶向纳米颗粒的蛋白质或肽的实例包括转铁蛋白(transferin)、乳铁蛋白(lactoferrin)、TGF-β、神经生长因子、白蛋白、HIV Tat肽、RGD肽和胰岛素以及其他。
应理解的是,Omomyc或其功能等同变体的制剂在纳米颗粒中不不旨在或不完全旨在促进Omomyc进入细胞内部,而且是保护Omomyc免于降解和/或促进纳米颗粒靶向目的器官。
Omomyc缀合物和包含Omomyc的融合蛋白
本发明还提供了缀合物,其包含含有SEQ ID NO:1的多肽或其功能等同变体的第一区域和含有促进细胞摄取所述多肽的化学部分的第二区域。用于增强细胞摄取的部分的实例包括但不限于:疏水基团(例如,脂质或脂肪酸)、蛋白质转导结构域和某些金属螯合物。
在Omomyc分子中存在另外的化学部分导致缀合物相对于未修饰的Omomyc显示出提高的跨生物膜移位的能力,从而导致提高的肿瘤抑制物活性。
因此,在另一个方面,本发明涉及缀合物,其包含:
(i)SEQ ID NO:1的多肽或其功能等同变体,和
(ii)促进细胞摄取所述多肽的化学部分。
如本文所使用的术语“缀合物”指的是两个或更多个共价连接在一起的化合物,以使得每个化合物的功能均被保留在缀合物中。
在一些优选的实施方案中,根据本发明的缀合物包含至少1个、至少2个、至少3个、至少4个、至少5个、至少6个、至少7个、至少8个、至少9个、至少10个或更多个化学部分,所述化学部分促进细胞摄取多肽或其功能等同变体。
在一个实施方案中,促进细胞摄取多肽的化学部分是脂质或脂肪酸。
脂肪酸通常是包含在链的末端具有酸性部分(例如,羧酸)之碳链的分子。脂肪酸的碳链可以是任何长度,然而,优选的是碳链的长度为至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或更多个碳原子以及来源于其中的任何范围。在某些实施方案中,在脂肪酸链部分的碳链的长度为4至18个碳原子。在某些实施方案中,脂肪酸碳链可包含奇数个碳原子数,然而,在某些实施方案中,可优选在链中有偶数个碳原子。将在其碳链中仅包含单键的脂肪酸称为饱和的,而将在其链中包含至少一个双键的脂肪酸称为不饱和的。脂肪酸可以是支链的,但在本发明的一些优选实施方案中,脂肪酸是无支链的。特定的脂肪酸包括但不限于:亚油酸、油酸、棕榈酸、亚麻酸、硬脂酸、月桂酸、肉豆蔻酸、花生酸(arachidic acid)、棕榈油酸、花生四烯酸。
在一个优选的实施方案中,促进细胞摄取多肽的化学部分是细胞穿透肽序列,在这种情况下,缀合物是包含Omomyc或其功能等同变体和细胞穿透肽序列的融合蛋白。
术语“融合蛋白”涉及通过基因技术产生的蛋白质,其由衍生自不同蛋白质的两个或更多个功能结构域组成。可通过常规方法获得融合蛋白,例如可通过在合适的细胞中表达编码所述融合蛋白的核苷酸序列的基因。应理解的是,细胞穿透肽指的是与形成SEQ IDNO:1的多肽或其功能等同变体的一部分的细胞穿透肽不同的细胞穿透肽。
术语“SEQ ID NO:1的多肽”、“SEQ ID NO:1的多肽的功能等同变体”和“细胞穿透肽”已经在本发明的医药用途的上下文中详细地进行了描述,并且同样适用于融合蛋白的情况。
在一个优选的实施方案中,所述细胞穿透肽不是内源性Omomyc细胞穿透肽。
在一个实施方案中,细胞穿透肽序列融合在SEQ ID NO:1的多肽的N末端或其功能等同变体的N末端。在另一个实施方案中,细胞穿透肽融合在SEQ ID NO:1的多肽的C末端或其功能等同变体的C末端。
在一些优选的实施方案中,除了在SEQ ID NO:1的多肽或其功能等同变体的多肽中发现的自身细胞穿透肽之外,根据本发明的融合蛋白还包含至少1个、至少2个、至少3个、至少4个、至少5个、至少6个、至少7个、至少8个、至少9个、至少10个或更多个另外的细胞穿透肽。
在另一个优选的实施方案中,本发明的缀合物或融合蛋白包含SEQ ID NO:1的多肽或其功能等同变体且还包含N末端或C末端核定位信号。术语“核定位信号(NLS)”已经在本发明的治疗用途的上下文中进行了描述,并同样适用于本发明的融合蛋白。应理解,另外的NLS指的是与在Omomyc或其功能等同变体中发现的内源性NLS不同的NLS。另外的NLS与在Omomyc或其功能等同变体中发现的内源性NLS可以相同或不同。
在一个实施方案中,NLS是一种在Myc序列中内源性出现的NLS,例如M1肽(PAAKRVKLD,SEQ ID NO:50)或M2肽(RQRRNELKRSF,SEQ ID NO:49)(参见Dang和Lee,同上)。
在一些优选的实施方案中,除了在SEQ ID NO:1的多肽或其功能等同变体中发现的内源性NLS之外,根据本发明的缀合物或融合蛋白还包含至少1个、至少2个、至少3个、至少4个、至少5个、至少6个、至少7个、至少8个、至少9个、至少10个NLS。
技术人员应理解,可以期望的是,融合蛋白还包含与SEQ ID NO:1的多肽或其功能等同变体、细胞穿透肽序列和/或NLS连接的一个或更多个柔性肽。因此,在一个具体的实施方案中,本发明的多肽直接与细胞穿透肽序列连接。在另一个具体的实施方案中,本发明的多肽通过柔性肽与细胞穿透肽序列连接。在一个具体的实施方案中,本发明的多肽与细胞穿透肽序列和NLS直接连接。在另一个具体的实施方案中,本发明的多肽通过第一柔性肽接头与细胞穿透肽序列连接并通过第二柔性肽接头与NLS连接。
如本文所使用的术语“柔性肽”、“间隔肽”或“接头肽”指的是将两个蛋白质或部分共价地结合但不是任意多肽一部分的肽,使得一个肽相对于另一个运动而不会对蛋白质或部分的功能造成相当不利的作用。因此,柔性接头不影响Omomyc序列的肿瘤抑制物活性、细胞穿透肽的细胞穿透活性或NLS的核定位能力。
柔性肽包含至少1个氨基酸、至少2个氨基酸、至少3个氨基酸、至少4个氨基酸、至少5个氨基酸、至少6个氨基酸、至少7个氨基酸、至少8个氨基酸、至少9个氨基酸、至少10个氨基酸、至少12个氨基酸、至少14个氨基酸、至少16个氨基酸、至少18个氨基酸、至少20个氨基酸、至少25个氨基酸、至少30个氨基酸、至少35个氨基酸、至少40个氨基酸、至少45个氨基酸、至少50个氨基酸、至少60个氨基酸、至少70个氨基酸、至少80个氨基酸、至少90个氨基酸或约100个氨基酸。在一些实施方案中,柔性肽将允许一个蛋白质相对于另一个蛋白质运动以提高蛋白质的溶解度和/或提高其活性。合适的接头区包括聚甘氨酸区,甘氨酸、脯氨酸和丙氨酸残基之组合的GPRRRR序列(SEQ ID NO:51)。
在一些实施方案中,本发明的融合蛋白可包含另外的化学部分,尤其包括:荧光基团、生物素、聚乙二醇(PEG)、氨基酸类似物、非天然氨基酸、磷酸基团、糖基、放射性同位素标记和药物分子。在另一些实施方案中,异源多肽可包含一个或更多个化学反应性基团,尤其包括酮、醛、Cys残基和Lys残基。
在一个具体的实施方案中,本发明的缀合物或融合蛋白包含与缀合物或者所述融合蛋白或其变体的C-末端或N-末端结构域结合的标签。所述标签通常是可用于分离或纯化所述融合蛋白的肽或氨基酸序列。因此,所述标签能够与一个或更多个配体结合,例如,亲和基质(例如具有高亲和力的色谱法支持物或珠)的一个或更多个配体。所述标签的一个实例是组氨酸标签(His-标签或HT),例如,包含6个组氨酸残基的标签(His 6或H6),其可以高亲和力与镍(Ni2+)柱或钴(Co2+)柱结合。His标签具有在变性条件下可使其配体与大多数蛋白质结合并破坏大多数蛋白质-蛋白质相互作用的期望特征。因此,它可用于在破坏诱饵(bait)参与的蛋白质-蛋白质相互作用之后,除去用H6标记的诱饵蛋白质。
用于分离或纯化融合蛋白的另外的说明性非限制性实例包括:Arg-标签、FLAG-标签(DYKDDDDK;SEQ ID NO:52)、Strep-标签(WSHPQFEK,SEQ ID NO:53)、能够被抗体识别的表位(例如c-myc-标签(被抗c-myc抗体识别))、HA标签(YPYDVPDYA,SEQ ID NO:54)、V5标签(GKPIPNPLLGLDST,SEQ ID NO:55)、SBP-标签、S-标签、钙调蛋白结合肽、纤维素结合结构域、壳多糖结合结构域、谷胱甘肽S-转移酶-标签、麦芽糖结合蛋白、NusA、TrxA、DsbA、Avi-标签等(Terpe K.,Appl.Microbiol.Biotechnol.2003,60:523-525),氨基酸序列例如AHGHRP(SEQ ID NO:56)或PIHDHDHPHLVIHSGMTCXXC(SEQ ID NO:57)、β半乳糖苷酶等。
如果需要的话,标签可用于分离或纯化所述融合蛋白。
在另一方面,本发明涉及根据本发明的缀合物或融合蛋白,其用于医药。
在另一方面,本发明涉及根据本发明的缀合物或融合蛋白,其用于预防和/或治疗癌症。
在另一方面,本发明涉及根据本发明的缀合物或融合蛋白用于制备用于预防和/或治疗癌症之药物的用途。
在另一方面,本发明涉及治疗和/或预防对象中的癌症的方法,其包括向所述对象施用根据本发明的缀合物或融合蛋白。
在一个优选的实施方案中,待预防或治疗的癌症是Myc诱发的癌症。在另一个优选的实施方案中,待预防或治疗的癌症是与KRAS基因中的突变有关的癌症。在一个实施方案中,KRAS基因中的突变是在12位的甘氨酸、在13位的甘氨酸或在61位的谷氨酰胺的突变。在一个更优选的实施方案中,突变是选自以下的突变:G12S突变、G12V突变、G13D突变、G12C突变、G12R突变、G12F突变、G12I突变、G13C突变、G13R突变或Q61L突变。
在先前已经定义了术语“药物”、“预防”、“治疗”、“癌症”和“Myc诱发的癌症”且同样适用于本发明的这一方面。
抗肿瘤组合物
当提供作为开启与其他抗肿瘤药物一起配制Omomyc之可能性的多肽时,意外地发现Omomyc多肽能够跨生物膜移位并发挥其肿瘤抑制物活性。因此,在另一个方面,本发明还提供了组合物,其同时或单独包含选自以下的第一组分:
(i)Omomyc,
(ii)其功能等同变体,
(iii)根据本发明的缀合物或融合蛋白
以及,作为第二组分的抗肿瘤化合物。
根据本发明的组合物的第一组分包括根据SEQ ID NO:1的多肽、其功能等同变体或根据本发明的融合蛋白。合适的多肽、SEQ ID NO:1的多肽的功能等同变体和融合蛋白已经在以上根据本发明的治疗方法的上下文中进行了描述且同样适用于根据本发明的组合物。
如本文所使用的“抗肿瘤剂”应理解为治疗肿瘤或预防其形成的所述生物或化学化合物。在一个优选的实施方案中,所述抗肿瘤剂选自细胞毒剂、抗血管生成剂、抗转移剂和抗增殖剂。
如本发明中所使用的术语“细胞毒剂”涉及能够促进细胞死亡并具有用于减少生长、停止生长或破坏细胞(特别是迅速增殖的细胞,且更特别地为肿瘤细胞)的试剂。可通过任何机制引起细胞死亡,例如凋亡(但并不限于此原因)、通过代谢抑制、干扰细胞骨架的组织或DNA的化学修饰。术语细胞毒剂包括任何化学治疗剂,其包括小的有机分子、肽、寡核苷酸等;毒素;酶;细胞因子;放射性同位素或放射治疗剂。
“化学治疗剂”应理解为化学化合物,例如但不限于:蒽环类抗生素例如多柔比星(doxorubicin)和柔红霉素(daunorubicin)、紫杉烷类例如TaxolTM和多西他赛、长春花生物碱类例如长春新碱和长春花碱、5-氟尿嘧啶(5-FU)、亚叶酸、伊立替康、伊达比星、丝裂霉素C、奥沙利铂、雷替曲塞、他莫西芬、顺铂、卡铂、甲氨蝶呤、放线菌素D、米托蒽醌、博来霉素或光辉霉素。
“毒素”应理解为与根据本发明第一方面的多肽或根据本发明第二方面的融合蛋白缀合而形成免疫毒素的毒剂。确定的毒素与所述多肽或与所述融合蛋白的缀合降低了前者的毒性,使其能够用作治疗剂,因为否则其毒性太大。毒素与根据本发明第一方面的多肽或根据本发明第二方面的融合蛋白之间的结合是经化学方法进行的,保护了其生物活性。它们的分离一般发生在靶细胞的溶酶体中,以使得所提及的化学结合仅在由溶酶体提供的封闭酸性细胞环境中才被破坏。在本发明的上下文中可用的毒素是植物毒素、细菌毒素、真菌或动物来源的毒素及其片段,例如但不限制于:蓖麻毒蛋白A链、皂甙、白喉A链(diphtheria A-chain)、白喉毒素的活性非结合片段、铜绿假单胞菌(Pseudomonasaeruginosa)外毒素A链、相思豆毒蛋白A链、塑莲根毒蛋白(modecin)A链、α-帚曲霉素(α-sarcin)、油桐(Leurites fordii)A-蛋白、香石竹毒蛋白、垂序商陆(Phytolacaamericana)(PAPI、PAPII和PAP-S)蛋白、苦瓜(Momordica charantia)抑制剂、麻风树毒蛋白(curcine)、巴豆毒蛋白、肥皂草(Saponaria officinalis)抑制剂、白树毒蛋白(gelonin)、mitogelin、局限曲霉素、酚霉素、伊诺霉素和单端孢菌毒素。
在本发明的上下文中,“酶”应理解为毒素或药物激活酶,例如但不限于:激活依托泊苷和多柔比星的碱性磷酸酶;激活氮芥的羧肽酶G2;激活多柔比星、紫杉醇和丝裂霉素的β-内酰胺酶。
“细胞因子”应理解为不同尺寸和分子量的肽,为了调节免疫应答的目的,其综合免疫系统的细胞,且它们可以是激素、生长因子、坏死因子等。它们可以是天然来源或来自重组细胞培养物以及天然序列细胞因子的生物活性等同物。它们与抗体的缀合产生免疫细胞因子。在本发明中可用的细胞细胞因子是但不限于:TNF因子α、INF-γ、GM-GSF因子或IL-2。
“放射性同位素”应理解为放射性同位素,例如但不限于:131I、90Y、177Lu、188Re、67Cu、211At、213Bi、125I、111In。
“抗血管生成剂”应理解为抑制或降低新血管的形成(即,血管生成)的化学或生物物质。
可与根据本发明第一方面的多肽或与根据本发明第二方面的融合蛋白缀合的抗血管生成剂包括但不限于选自以下的抗血管生成剂:紫杉醇、2-甲氧基雌二醇、普啉司他(prinomastat)、巴马司他、BAY 12-9566、羧胺三唑、CC-1088、右美沙芬乙酸、二甲基夹氧杂蒽酮乙酸(dimethylxanthenone acetic acid)、内皮抑制素、IM-862、马马司他、青霉胺、PTK787/ZK 222584、RPI.4610、乳酸角鲨胺(squalamine lactate)、SU5416、沙立度胺、考布他汀、他莫昔芬、COL-3、新伐司他(neovastat)、BMS-275291、SU6668、抗VEGF抗体、Medi-522(Vitaxin II)、CAI、白细胞介素12、IM862、阿米洛利、制管张素(angiostatin)、Kl-3制管张素、Kl-5制管张素、卡托普利、DL-α-二氟甲基鸟氨酸、DL-α-二氟甲基鸟氨酸HCl、内皮抑制素、烟曲霉素、除莠霉素A、4-羟基苯基视黄酰胺、胡桃醌、层粘连蛋白、层粘连蛋白六肽、层粘连蛋白五肽、熏草菌素A、甲羟孕酮、米诺环素、胎盘核糖核酸酶抑制剂、苏拉明、血小板反应蛋白、针对促血管生成因子的抗体(例如,Avastin、Erbitux、Vectibix、Herceptin);促血管生成生长因子的低分子量酪氨酸激酶抑制剂(例如Tarceva、Nexavar、Sutent、Iressa);mTOR抑制剂(例如Torisel);干扰素α、β和γ、IL-12、基质金属蛋白酶抑制剂(例如,COL3、马马司他、巴马司他);ZD6474、SUl1248、vitaxin;PDGFR抑制剂(例如Gleevec);NM3和2-ME2;环肽类,例如西仑吉肽(cilengitide)。
“抗转移剂”应理解为这样的化学或生物物质,其从根本上抑制或降低引起癌症的细胞通过淋巴流或血流的转移(即距离传播(distance propagation))以及在所述转移的目标位点中的新肿瘤生长。
“抗增殖剂”应理解为能够防止或抑制肿瘤的形成或生长的化学或生物物质。抗增殖剂包括但不限于:(i)抗代谢物,例如叶酸抗代谢物(氨蝶呤、二甲叶酸、甲氨蝶呤、依达曲沙、曲麦克特、诺拉曲塞、洛美曲索、培美曲塞、雷替曲塞、吡曲克辛、蝶罗呤、亚叶酸、10-炔丙基-5,8-二脱氮叶酸酯(PDDF、CB3717))、嘌呤类似物(克拉屈滨、氯法拉滨、氟达拉滨、巯基嘌呤、喷司他丁、硫鸟嘌呤)和嘧啶类似物(卡培他滨、阿糖胞苷或ara-C、地西他滨、氟尿嘧啶、5-氟尿嘧啶、脱氧氟尿苷、氟尿苷和吉西他滨)(ii)天然产物,例如抗肿瘤抗生素和有丝分裂抑制剂,例如长春花生物碱类例如长春地辛、长春新碱、长春花碱、长春瑞滨;紫杉烷类例如紫杉醇(TaxolTM)、多西他赛(TaxotereTM);秋水仙碱(NSC 757)、硫代秋水仙碱(NSC361792)、秋水仙碱衍生物(例如,NSC 33410)以及别秋水仙碱(NSC 406042);软海绵素B(NSC 609395);多拉司他汀10(dolastatin 10)(NSC 376128);美登素(NSC 153858);根霉素(NSC 332598);埃博霉素A;埃博霉素B;盘皮海绵内酯;雌莫司汀;诺考达唑;(iii)激素及其拮抗物,例如他莫昔芬、托瑞米芬、阿那曲唑、阿佐昔芬、拉索昔芬、雷洛昔芬、萘福昔定、氟维司群、氨鲁米特、睾内酯、阿他美坦、依西美坦、法倔唑、福美司坦、来曲唑、戈舍瑞林、亮丙瑞林(leuprorelin)或醋酸亮丙瑞林(leuprolide)、布舍瑞林、组氨瑞林、甲地孕酮和氟甲睾酮;(iv)生物试剂,例如病毒载体、干扰素α和白细胞介素;(v)基于铂的化合物,例如卡铂、顺铂[顺-二氯二氨铂(CDDP)]、奥沙利铂、异丙铂、奈达铂、三铂(triplatin)四硝酸酯、四铂(tetraplatin)、赛特铂(JM216)、JM118[顺式-二氯化氨(II)]、JM149[顺式-二氯化氨(环己胺)反-二羟基铂(IV)]、JM335[反式-二氯化氨二羟基铂(IV)]、反铂、ZD0473、顺式、反式、顺式-Pt(NH3)(C6H11NH2)(OOCC3H7)2Cl、丙二酸-1,2-环己二胺铂(II)、5-磺基水杨酸-反式-(1,2环己二胺)铂(II)(SSP)、聚-[(反式-1,2-环己二胺)铂]-羧基直链淀粉(POLY-PLAT)和4-羟基-磺酰基乙酸苯酯(反式-1,2-环己二胺)铂(II)(SAP)等以及(vi)DNA烷基化药物例如氮芥、亚硝基脲、乙烯亚胺衍生物、烷基磺酸盐/酯和三氮烯,包括但不限于:环磷酰胺(CytoxanTM)、白消安、英丙舒凡、哌泊舒凡、哌泊溴烷、美法仑(L-苯丙氨氮芥)、苯丁酸氮芥、二氯甲基二乙胺或氮芥、乌拉莫司汀或尿嘧啶氮芥、新恩比兴(novembichin)、苯芥胆甾醇(phenesterine)、曲磷铵(trofosfamide)、异环磷酰胺、卡莫司汀(BCNU)、洛莫司汀(CCNU)、氯脲霉素、福莫司汀、尼莫司汀、雷莫司汀、司莫司汀(甲基CCNU)、链脲霉素(streptozocin)、噻替派、三乙撑蜜胺、三亚乙基硫代磷酰胺、甲基苄肼(procarbazine)、六甲蜜胺、达卡巴嗪、米托唑胺和替莫唑胺。
药物组合物
本发明还提供了包含本发明缀合物和融合蛋白或根据本发明组合物的药物组合物。因此,在另一方面,本发明提供了药物组合物(本发明的第一药物组合物),其包含药学活性量的根据本发明的缀合物或融合蛋白和药学活性载体。在另一方面,本发明提供了药物组合物(根据本发明的第二药物组合物),其包含药学活性量的根据本发明的组合物和药学活性载体。
如在本发明中使用的表述“药物组合物”涉及已适于向细胞分裂不受控制(例如癌症)的细胞、细胞组、器官、组织或动物施用预定剂量的一种或几种治疗可用之试剂的制剂。
本发明的第一药物组合物包含药物有效量的根据本发明的缀合物或融合蛋白。用于根据本发明药物组合物之合适的缀合物和融合蛋白包括以上根据在本发明的Omomyc缀合物和融合蛋白的段落提及的任何融合蛋白。
本发明的第二药物组合物包含药物有效量的根据本发明的组合物和药学活性载体。本发明的第二药物组合物包含根据本发明的SEQ ID NO:1的多肽、其功能等同变体或融合蛋白。用于根据本发明第二药物组合物之合适的SEQ ID NO:1的多肽的功能等同变体或合适的融合蛋白如以上根据本发明的治疗用途或根据本发明的融合蛋白分别限定。
本文所使用的表述“药物有效量”应理解为能够提供治疗作用的量,并且其可由本领域技术人员通过通常使用的手段来确定。Omomyc多肽或其功能等同变体或融合蛋白或可与根据本发明的药物组合物组合的抗肿瘤化合物的量将根据施用的对象和具体方式而变化。本领域技术人员将理解,剂量也可按照Goldman和Goldman的The PharmacologicalBasis of Therapeutics,第九版(1996),附录II,第1707-1711页以及按照Goldman和Goldman的The Pharmacological Basis of Therapeutics,第十版(2001),附录II,第475-493页的指导来确定。
药物组合物中有效成分或成分的适当剂量将取决于待治疗的癌症的类型、疾病的严重程度和进程、施用该组合物是用于预防目的还是治疗目的、先前的疗法、患者的临床病史和对肽或多肽的响应以及主治医生的判断。在一次或在一系列治疗中向患者适当地施用一定量的SEQ ID NO:1的多肽、其功能等同变体、融合蛋白。根据疾病的类型和严重程度,合适的剂量水平一般为每天每kg患者体重约0.01mg至500mg,这可以以单剂量或多剂量施用。优选地,剂量水平为每天约0.1mg/kg至约250mg/kg;更优选地为每天约0.5mg/kg至约100mg/kg。合适的剂量水平可为每天约0.01mg/kg至250mg/kg,每天约0.05mg/kg至100mg/kg,或每天约0.1mg/kg至50mg/kg。在此范围内,剂量可为每天0.05mg/kg至0.5mg/kg、0.5mg/kg至5mg/kg或5mg/kg至50mg/kg。对于经口施用,优选以片剂形式提供组合物,其包含1.0至1000毫克的活性成分,特别是1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0和1000.0毫克的活性成分以用于待治疗的患者进行剂量的症状调整。可以按照每天1至4次的方案,优选每天一次或两次施用化合物。
在根据本发明的第二药物组合物的情况下,其含有选自根据本发明的SEQ ID NO:1的多肽、其功能等同变体和融合蛋白的第一组分和为抗肿瘤剂的第二组分,所述组合物可呈现为单一制剂(例如,包含定量的各种组分的片剂或胶囊剂),或者,在另一方面,可呈现为单独的制剂,其将在后面组合用于共同、顺序或分开施用。本发明的组合物还包括作为成套试剂盒(kit-of-parts)的制剂,其中分别配制组分,但包装在相同的容器中。本领域技术人员将理解,在根据本发明的第二药物组合物的情况下,不同组分的配制可以是类似的,换言之,类似的配制(以片剂或丸剂)使得其通过相同的途径施用。在本发明的不同组分单独配制的情况下,两种组分可呈现在泡罩(blister)中。每个泡罩包含必须在当天被消耗的药物。如果药物必须每天施用几次,对应于每次施用的药物可被放置在泡罩的不同部分中,优选在泡罩的每个部分记录药物应该被施用的一天中的时间。或者,本发明的组合物的组分可有差别地进行配制以使得有差别地施用不同的组分。因此,有可能将第一组分配制成片剂或胶囊剂以用于其经口施用和将第二组分配制用于其静脉内施用,或反之亦然。本领域技术人员可通过根据在每种特定情况下所使用的抗肿瘤剂以及所期望的指示来调整用于根据本发明的第二药物组合物中组合物部分的组分之间的比。因此,本发明设想了这样的组合物,其中所述两种组分的量之间的比可以为50∶1至1∶50,特别是20∶1至1∶20,1∶10至10∶1或5∶1至1∶5。
本发明第一和第二药物组合物还可包含一个或几个另外的化合物以用于病理的预防和/或治疗,在其中有不受控制的细胞分裂(例如癌症)。所述另外的化合物(例如抗肿瘤剂)可作为独立实体形成药物组合物的一部分。
本发明的第一和第二药物组合物还含有一种或几种另外的可药用赋形剂。“可药用赋形剂”应理解为无治疗活性物质,认为用于并入活性成分,且从药理学/毒理学的观点上可被患者接受,从有关组分、制剂、稳定性、患者的接受和生物利用度的物理/化学的观点上可被制备其的药物化学家接受。
可药用赋形剂的数目和性质取决于所期望的剂型。可药用赋形剂是本领域技术人员已知的(Faulíy Trillo C.(1993)“Tratado de Farmacia Galénica”,Luzán 5,S.A.Ediciones,Madrid)。可通过现有技术中已知的常规方法来制备所述组合物(“Remington:The Science and Practice of Pharmacy”,第20版(2003)Genaro A.R.,编辑,Lippincott Williams&Wilkins,Philadelphia,US)。
可通过任何类型的合适途径施用本发明的第一和第二药物组合物,例如通过经口途径、表面途径,通过吸入或肠胃外途径以使得包含用于配制期望剂型所必需的可药用赋形剂。所述药物组合物的优选的施用途径是静脉内途径。
“经口途径”应理解为在吞咽后药物组合物被并入生物体中。在一个具体的实施方案中,本发明的药物组合物可以是适合其通过经口途径施用的剂型,无论是固体或液体。适于其通过经口途径施用的剂型可以是片剂、胶囊剂、糖浆剂或溶液剂,并且可包含本领域已知的任何常规的赋形剂,例如粘合剂,例如糖浆、阿拉伯胶、明胶、山梨醇或聚乙烯吡咯烷酮;填充剂,例如乳糖、糖、玉米淀粉、磷酸钙、山梨醇或甘氨酸;用于压缩的润滑剂,例如硬脂酸镁;崩解剂,例如淀粉、聚乙烯吡咯烷酮、淀粉的乙醇酸钠或微晶纤维素;或可药用润湿剂例如十二烷基硫酸钠。可通过混合、填充或压缩的常规方法来制备固体经口组合物。重复的混合操作可用于将活性剂完全散布在那些使用大量填充剂的组合物中。所述操作是本领域中常规的。可例如通过湿法或干法制粒的手段制备片剂,并根据在常见的药学实践中已知的方法(特别是用肠溶衣)任选地对其进行包衣。
另一方面,“表面途径”应理解为通过非全身途径的施用,且包括将本发明的药物组合物外部施加到表皮上、口腔中以及将所述组合物滴注到耳朵、眼睛和鼻子中,并且其中药物组合物不显著地进入血流。“全身途径”应理解为通过经口途径、静脉内途径、腹膜内途径和肌内途径的施用。用于治疗或预防作用所需的抗体的量将根据所选择的抗体、将治疗的疾病的性质和严重程度以及患者而自然地变化。
“吸入”应理解为通过鼻内途径和通过经口吸入施用。适于所述施用的剂型(例如气雾剂或计量吸入器(meter dosed inhaler)的制剂)可通过常规技术制备。在一个实施方案中,施用途径是鼻内途径。
如本文所使用的术语“肠胃外”包括通过静脉内途径、腹膜内途径、肌内途径或皮下途径的施用。通常优选肠胃外施用的皮下、肌内和静脉内剂型。
在一个实施方案中,本发明的第一和第二药物组合物可适于其肠胃外施用,例如适当剂量单位形式的无菌溶液、悬浮液或冻干产品。适于其可注射使用的药物组合物包括无菌水溶液(当它们可溶于水时),或者用于临时制备无菌注射溶液或分散体的分散体和无菌粉末。对于其通过静脉内途径的施用,一些合适的载体包括用磷酸盐(PBS)缓冲的盐水溶液。在所有的情况下,组合物必须是无菌的,并且必须是达到易于注射能力之程度的流体。在制备和储存条件下,它必须是稳定的,并且必须防止微生物(例如细菌和真菌)的污染作用。所述载体可以是溶剂或含有例如水、乙醇、可药用多元醇(例如甘油、丙二醇、液体聚乙二醇及其合适混合物)的分散介质。例如,通过使用包衣(例如卵磷脂),在分散体的情况下通过保持所需的颗粒大小以及通过使用表面活性剂来维持适当的流动性。可通过多种抗细菌剂和抗真菌剂(例如,对羟基苯甲酸酯类、氯丁醇、苯酚、抗坏血酸、硫柳汞等)来实现预防微生物的作用。在大多数情况下,优选在组合物中包含等渗剂,例如糖类;多元醇例如甘露醇、山梨醇;或氯化钠。可通过包含延迟吸收的试剂(例如,单硬脂酸铝和明胶)使可注射组合物的吸收延长。
根据需要,可通过将所需量的活性化合物与一种上述成分或其组合并入到合适的溶剂中来制备可注射的无菌溶液,随后通过使用无菌膜进行过滤灭菌。一般地,通过将活性化合物并入到含有基础分散介质和前面列出的所需的其余成分的无菌载剂中来制备分散体。在用于制备可注射无菌溶液的无菌粉末情况下,优选的制备方法是真空干燥和冻干,这产生具有活性成分加上来自其先前过滤的无菌溶液之任何所需的另外成分的粉末。
可通过脉冲输注适当地施用本发明的药物组合物,例如,用降低剂量的组合物。优选地,通过注射施用所述剂量,更优选地静脉内或皮下注射,部分取决于施用是急性的或长期的。
在一个实施方案中,与保护所述多肽免于从体内迅速消除的载体(例如控释制剂,包括植入物和微囊化施用系统)一起制备本发明的第一或第二药物组合物。可使用生物可降解的生物相容性聚合物,例如乙烯乙酸乙烯酯、聚酐类、聚乙醇酸、胶原蛋白、聚原酸酯和聚乳酸。本领域技术人员清楚用于制备所述制剂的方法。该材料也可在Alza Corporation和Nova Pharmaceuticals,Inc.商购获得。
持续释放的组合物也包括悬浮在可保持悬浮液中的晶体的合适制剂中之抗体晶体的制剂。当通过皮下或腹膜内途径注射这些制剂时可产生持续释放的作用。其他组合物还包括在脂质体中捕获的抗体。包含这种抗体的脂质体是通过已知的方法制备的,例如Epstein等,Proc.Natl.Acad.Sci.USA,(1985)82:3688-3692;Hwang等,Proc.Natl.Acad.Sci.USA,(1980)77:4030-4034;EP 52,322;EP 36,676;EP 88,046;EP143,949。
尽管事实上Omomyc和包含Omomyc的缀合物和融合蛋白能够跨生物膜移位,本领域技术人员应理解,也可方便地配制在纳米颗粒中包含Omomyc的缀合物或融合蛋白。纳米颗粒可有助于保持生物流体中多肽的完整性直到其到达靶器官。此外,在包含抗肿瘤剂的组合物的情况下,组合物的封装可减少由抗肿瘤剂所引起的继发效应(secondary effect)。最后,也可以修饰纳米颗粒以使其包含使得所述纳米颗粒靶向目的器官的部分。
因此,在另一个实施方案中,本发明的药物组合物包含形成纳米颗粒的一部分之根据本发明的缀合物、融合蛋白和组合物。
可在本发明的上下文中使用的合适的纳米颗粒包括这样的纳米级材料,例如基于脂质的纳米颗粒、超顺磁性纳米颗粒、纳米壳、半导体纳米晶体、量子点、基于聚合物的纳米颗粒、基于硅的纳米颗粒、基于二氧化硅的纳米颗粒、基于金属的纳米颗粒、富勒烯和纳米管。
可通过添加配体来实现靶向递送而不影响纳米颗粒递送其多肽有效载荷的能力。可以设想,这将能够使得递送到特定的细胞、组织和器官。基于配体的递送系统的靶向特异性基于配体受体在不同类型细胞上的分布。靶向配体可非共价地或共价地与纳米颗粒缔合,并且可如本文所讨论的通过多种方法与纳米颗粒缀合。
可用于靶向纳米颗粒的蛋白质或肽的实例包括转铁蛋白、乳铁蛋白、TGF-β、神经生长因子、白蛋白、HIV Tat肽、RGD肽和胰岛素以及其他。
本发明的第一和第二药物组合物可与可药用载体一起配制。在一个优选的实施方案中,载体不允许将融合蛋白或组合物直接递送到细胞的细胞质,即载体不能够与所述靶细胞的质膜融合。本文所使用的“载体”意指用于提高药物组合物内活性成分的递送和效力的任何物质。可药用载体的实例包括一种或更多种的水、盐水、磷酸盐缓冲盐水、葡萄糖、甘油、乙醇等以及其组合。在许多情况下,优选在组合物中包含等渗剂例如糖类,多元醇例如甘露醇、山梨醇或氯化钠。可药用载体还可包含少量的辅助物质,例如润湿剂或乳化剂、防腐剂或缓冲剂,这增强了形成药物组合物一部分的融合蛋白或组合物的保质期或效力。适当的载体的实例是文献中公知的(参见例如Remington′s Pharmaceutical Sciences,第19版,Mack Publishing Company,Easton,PA,1995年)。载体的非限制性实例是一系列的糖,例如乳糖、葡聚糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇和麦芽糖醇;一系列的淀粉,例如玉米淀粉、小麦淀粉、大米淀粉和马铃薯淀粉;一系列的纤维素,例如纤维素、甲基纤维素、羧甲基纤维素钠和羟丙甲基纤维素;一系列的填料,例如明胶和聚乙烯吡咯烷酮。在一些情况下,可添加崩解剂,例如交联聚乙烯吡咯烷酮、琼脂、藻酸或藻酸钠。
本发明的第一和第二药物组合物适合用于施用到任何类型的哺乳动物(优选人类)中。
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本发明通过以下实施例详述如下,这些实施例仅是说明性的且决不限制本发明的范围。
实施例
材料和方法
实施例1
在丰富培养基(rich medium)或M9基本培养基中Omomyc构建体的表达
对于在丰富培养基中产生Omomyc,在1L含有氨苄青霉素与BL21-AITM One的2YT培养基中接种转化有Omomyc-pET-3a构建体的化学感受态大肠杆菌(Escherichiacoli)(Life technologies),在250rpm搅拌下,于37℃培养直到OD600达到0.8。用10mL的阿拉伯糖溶液诱导蛋白质表达,于37℃孵育12小时。或者,对于在M9基本培养基中产生Omomyc,将转化有Omomyc-pET3a构建体的大肠杆菌接种于1L含有氯霉素和氨苄青霉素与BL21-CodonPlus(Strategene)的M9基本培养基中并在250rpm的搅拌下,于37℃培养直到OD600达到0.8。用1mL的IPTG 1000X溶液诱导蛋白质表达。在250rpm搅拌下,将细胞培养物于37℃下孵育12小时。
在4℃下,使用250mL瓶在SLA-1500转子中将细菌培养物以10,000rpm离心5分钟。依次离心培养物以合并每瓶1L当量的培养物。
为了验证蛋白质的成功表达,收集来自培养物的1mL等分试样并测量其OD600。将800μL的所述等分试样以16,060×g旋转1分钟并弃去上清液。将沉淀物悬浮于一定体积的相当于(0.1×OD600值)μL的IB Laemmli缓冲液中,以确保在每个样品中有等量的溶解的细胞提取物并有助于在蛋白表达之前和之后的细胞之间进行比较。然后通过涡旋将样品混合,以最大功率超声5秒,在液氮中冷冻,最后,沸腾2分钟(重复3次),之后上样到变性16.5%的丙烯酰胺SDS-PAGE凝胶上。电泳,随后进行考马斯蓝染色或Western印迹。优化IBLaemmli缓冲液以允许增溶包含体(inclusion body)并确保充足的迁移和蛋白质分离以便显现Omomyc的表达。
实施例2
Omomyc b-HLH-LZ的纯化
通过涡旋将细胞沉淀物悬浮于每克沉淀物3mL的裂解缓冲液中。每克培养物沉淀物添加150μL的Triton溶液。通过使用超声均质器以功率15在冰上超声6×15秒来降低悬浮液的粘度。
然后,添加100μL/g当量的牛胰DNA酶I的培养物沉淀物,接着在50rpm搅拌下于37℃孵育60分钟。在4℃下,将样品以12,000×g(在Sorvall RC 5B Plus之SS34转子中为13,000rpm,使用35mL离心瓶)离心20分钟以沉淀包含体以及高分子量复合物(例如细胞壁、核糖体和未降解的基因组DNA)。在离心后,弃去构成上清液的脂质、可溶性蛋白质、氨基酸、糖类和核酸。
通过涡旋用15mL的Bullcracker缓冲液A部分溶解沉淀的包含体。这种酸性的高离子强度和变性缓冲液使得Omomyc构建体从包含体完全溶解,并使得通过离心除去高分子量的复合物和残余的DNA。
用Bullcracker B部分以1∶1稀释包含体溶液,之后,在4℃下,将样品以30,000×g(在Sorvall RC 5B Plus之SS34转子中为19,000rpm)离心30分钟。
通过阳离子交换色谱法在5个于FPLC系统上串联安装的5mL阳离子交换柱(来自GEHealthcare的HiTrapTM SP Sepharose HP柱或等同物)上纯化上清液。首先,用2柱体积(CV)的FPLC缓冲液B以5mL/分钟的流量洗涤柱。然后,用5CV(125mL)的FPLC缓冲液A以2.5mL/分钟的流量平衡柱。以2.5mL/分钟上样上清液(每次上样相当于最大9g的培养物沉淀物)。上样上清液后,立即用75mL(3CV)的U8缓冲液以2.5mL/分钟的流量洗涤柱。用1CV的缓冲液A洗涤。然后,向柱添加3CV的10%缓冲液B。在2.5mL级分中用在50mL(0.5%/mL)中的10%-35%梯度的缓冲液B以2.5mL/分钟完成Omomyc洗脱。在这些条件下,用90%纯度的~1.5M氯化钠(即~30%v/v的梯度)洗脱Omomyc。
将含有纯构建体的级分合并,并且在5个来自GE Healthcare的连续HiTrapTM脱盐柱(或等同物)上进行脱盐,用脱盐的TFA缓冲液以3.0mL/分钟的流量平衡所述脱盐柱。注射合并的级分(每次注射的最大体积为7.5mL)并洗脱随后用OD280检测器。注射后在首个15mL内洗脱的蛋白质。丢弃之后示出低OD280值和高导电性的级分。此方法允许98%-99%脱盐蛋白质之~95%的回收率。
可通过在Ultra离心过滤器-3K(MilliporeTM)或等同物中离心,或通过冻干来浓缩纯化的蛋白质。对于使用Ultra的浓缩,按照制造商的指示进行。或者,对于冻干,向脱盐级分添加50%v/v的乙腈,在液氮中冷冻并冻干。可将所得到的泡沫状冻干的蛋白质称重并在含有0.05%v/v TFA的50%v/v的乙腈中重新溶解至100μL/mg,每个微量离心管等分1至10mg,并再次冻干。
在丰富培养基中培养物的产量约为25mg/L和在M9基本培养基中培养物的产量为15mg/L。
实施例3
将Omomyc转导进入A549细胞
本发明的作者旨在证明用Omomyc处理的细胞示出即使在这么短的时间之后,Omomyc已经到达了细胞核。
如实施例1和2所示进行Omomyc的表达和纯化。
在含有5%CO2的潮湿气氛中,于37℃在补充有10%胎牛血清的Dulbecco改良的Eagle培养基(DMEM)中维持A549细胞(ATCC)。对于荧光显微术,将20,000个A549细胞接种于0.5英寸玻璃盖玻片上并培养16小时。添加补充有Omomyc肽(35μM)的新鲜培养基并在37℃孵育2个小时。将细胞用PBS洗涤3次并固定在3%多聚甲醛中,并在显微镜下观察。
图1显示了Omomyc可以作为蛋白质转导结构域发挥作用,跨细胞膜转导并移位到细胞核。
实施例4
Omomyc减少了存活的A549细胞的数目并诱导凋亡
在24孔板中用10μM Max*或Omomyc将A549细胞孵育72小时。如在Montagne M等(Montagne M.等,2012.PLoS One,7(2):e32172)中描述得到Max*。收获细胞并根据制造商的方案(凋亡试剂盒A10788,Life technologies)用膜联蛋白V和PI染色细胞并使用基于图像的流式细胞仪对荧光进行定量。
在这项研究中,本发明的作者表明,在减少存活的A549细胞的数目方面,Omomyc比Max的bHLHZ结构域更有效(图2A和C)。相一致地,用Omomyc肽处理后的死亡/凋亡细胞的百分比高于用Max*肽的处理(图2B和D)。
实施例5
Omomyc 比c-Myc*更加折叠且在溶液中比Max*和c-Myc*更热稳定
在多肽被配制成药物组合物的那些情况下,热稳定的多肽是有利的。因此,确定了Omomyc和Max*的比较热稳定性。
如实施例1中所述的表达Omomyc基因并且如上述实施例2进行纯化。如在BeaulieuM.E等,2013(Methods Mol Biol,1012:7-20)中详细描述的进行Max*的纯化。简言之,用含有Max*插入物的pET-3a表达载体转化BL21-DE3-pLys细菌,并且如上所述进行培养。用IPTG(0.6mM)进行孵育4小时,之后收获细胞。在用裂解缓冲液裂解并以30,000×g离心后,如上所述用阳离子交换色谱法纯化溶解的蛋白质提取物并脱盐。将纯化并冻干的蛋白质重悬于50mM KH2PO4、50mM KCl、5mM DTT中(使用1N KOH或1N HCl调节pH)。
使用32μM的蛋白质浓度,按照在Beaulieu M.E.等,2012(J Mol Recognit,25(7):414-26)中所述进行圆二色性测量。在20℃下记录CD谱,并以1℃/分钟进行热变性(图3A和3B),在222nm波长处进行监测以测量蛋白质的螺旋含量(反映折叠,结构化状态)。
实施例6
Omomyc比Max*更有效地穿透细胞的核
简言之,通过工程化的C端半胱氨酸残基用荧光素马来酰亚胺(FITC)标记经纯化的Omomyc和Max*肽。在纯化和通过质谱法评估每个蛋白质分子的单个荧光标记的存在之后,向在含有0.5%血清的RPMI中培养的A549细胞(K-Ras突变体肺腺癌)添加不同浓度的蛋白质(5μM、10μM或25μM)并于37℃孵育2小时,之后用PBS洗涤三次并在4%PFA中固定10分钟,用1.5μg/mL的Hoechst染色10分钟,并封片在显微载片上。共焦显微术图像示出在5μM、10μM和25μM浓度时,Omomyc比Max*更有效地穿透A549细胞的核(数据未示出)。使用ImageJ对核荧光强度进行定量,每个图像计数30至80个细胞。图4示出了在A549固定细胞中观察到的Omomyc和Max*的细胞穿透的定量。
在活细胞中确认了在20μM的浓度孵育20分钟后,Omomyc比Max*更好的细胞穿透能力(以避免潜在的固定假象)。简言之,将FITC标记的Omomyc和Max*添加至在含有0.5%血清的RPMI中的A549培养细胞,在37℃下孵育20分钟,之后在PBS中洗涤三次并用含Hoechst的封片介质封片。共焦显微术图像示出在20μM时Omomyc比Max*更有效地穿透A549活细胞的核(数据未示出)。使用ImageJ对核荧光强度进行定量,每个图像计数30至80个细胞。图5示出了在A549活细胞中观察到的Omomyc和Max*的细胞穿透的定量。
实施例7
通过ATP依赖性过程发生Omomyc进入
示出Max*通过ATP依赖性过程穿透细胞,这可降低温度至4℃来阻止。Omomyc的细胞穿透能力涉及类似的机制。将A549细胞用20μM FITC-标记的肽于4℃孵育2小时并用4%PFA固定,之后用PBS洗涤三次并使用含Hoechst的封片介质在显微载玻片上封片。共聚焦显微术图像显示降低温度至4℃可阻止Omomyc进入。
实施例8
Omomyc比Max*更有效地减少了细胞的总数目
简言之,在含有5%血清的RPMI中用25μM的Omomyc或Max*肽孵育A549和H1650肺腺癌细胞并用4%PFA以指定的时间(2天或4天)固定,随后进行结晶紫染色(在25%甲醇中0.5%结晶紫,10分钟),并用水洗涤至少三次。Omomyc和Max*二者都阻止细胞的生长,但在这种情况下,Omomyc更有效(图6)。将结晶紫染色的细胞溶解于10%的乙酸中并将得到的溶液在H2Odd中以1∶4稀释,并通过测量在OD595的吸光度进行定量。通过结晶紫对增殖的抑制的定量示出在25μM浓度下使用6天时,Omomyc比Max*明显更有效地减少H1650细胞(EGFR突变体肺腺癌细胞)的增殖(图7)。
为了计算Omomyc和Max的IC50,如上所述在含有5%血清的培养基中用指定的肽浓度处理A549细胞并用结晶紫染色。如上所述进行定量。图8示出了A549细胞对Omomyc与Max*的剂量响应,示出Omomyc比Max*具有较低的IC50(即,与Max*相比,Omomyc需要较低的剂量以将细胞的数目减少至一半)。具体而言,对于Omomyc,IC50为1.2μM,而对于Max*,IC50为2.6μM。
在U87神经胶质瘤细胞中测定了Omomyc对细胞增殖的作用。在含有5%血清的DMEM中用Omomyc或Max*肽(25μM的终浓度)将U87神经胶质瘤细胞孵育48小时。将细胞用胰蛋白酶消化并用Tali细胞计数器(Life Technologies Inc.)计数。图9示出了Omomyc比Max*更有效地降低了U87神经胶质瘤细胞的增殖。
实施例9
鼻内施用后Omomyc有效地到达肺和脑组织
通过鼻内施用以37.5mg/kg单剂量的Omomyc处理动物或不处理(用PBS处理)。鼻内施用后10分钟,检测荧光肽。经处理的动物的肺由于Omomyc定位出现荧光(图10A)。这证明可通过鼻内滴注向动物施用Omomyc肽且其有效地到达肺。在前面的图中所描述的相同的动物的脑也出现荧光(图10B)。很明显,荧光Omomyc肽可通过血-脑屏障(BBB)并到达脑。
实施例10
Omomyc肽在体内具有治疗效果
作为鼻内施用的肽,Omomyc在KRas驱动的肺腺癌小鼠模型中减少了增殖。本发明者利用了KRas驱动的肿瘤发生小鼠模型(LSLKRasG12D模型)。简言之,用AdenoCre病毒滴注8周大的小鼠以诱导在肺中特异性的KRas-G12D突变体蛋白质的表达。当小鼠发生了肺腺癌(感染后18周)时,每天用Omomyc肽(在35μL体积中15mg/kg)鼻内处理动物,持续3天。Omomyc降低了肿瘤的增殖速率(Ki67染色;图11A)且降低了细胞的密度(图11B)。
在处理1周后,Omomyc肽还降低了体内的肿瘤负荷。使用如先前所描述的相同的小鼠模型和实验条件,每天用15mg/kg肽处理动物,持续1周。使用ImageJ测量肿瘤区域(tumorarea)%。图12示出了在KRas驱动的肺腺癌小鼠模型中Omomyc降低了肿瘤负荷。
Claims (19)
1.SEQ ID NO:1的多肽的功能等同变体用于制备药物的用途,其中所述功能等同变体由在SEQ ID NO:1的N末端插入甲硫氨酸而产生,并且配制所述功能等同变体以用于施用。
2.SEQ ID NO:I的多肽的功能等同变体用于制备用于预防和/或治疗癌症之药物的用途,其中所述功能等同变体由在SEQ ID NO:1的N末端插入甲硫氨酸而产生,并且配制所述功能等同变体以用于施用。
3.缀合物,其包含:
(i)SEQ ID NO:1的多肽或其功能等同变体,所述功能等同变体由在SEQ ID NO:1的N末端插入甲硫氨酸而产生,和
(ii)促进细胞摄取所述多肽或其功能等同变体的化学部分。
4.根据权利要求3所述的缀合物,其中所述促进细胞摄取所述多肽或其功能等同变体的化学部分是细胞穿透肽,并且其中所述细胞穿透肽与所述多肽或其功能等同变体形成融合蛋白。
5.根据权利要求4所述的缀合物,其中所述细胞穿透肽序列选自GRKKRRQRRR(SEQ IDNO:28)和RRRRRRLR(SEQ ID NO:29)。
6.根据权利要求3至5中任一项所述的缀合物,其还包含核定位信号。
7.根据权利要求6所述的缀合物,其中所述核定位信号选自PKKKRKV(SEQ ID NO:39)、PAAKRVKLD(SEQ ID NO:50)和KRPAATKKAGQAKKKK(SEQ ID NO:40)。
8.根据权利要求3至5中任一项所述的缀合物,其中所述缀合物选自SEQ ID NO:47和SEQ ID NO:48。
9.药物组合物,其包含可药用赋形剂和药学活性量的根据权利要求3至8中任一项所述的缀合物。
10.根据权利要求3至8中任一项所述的缀合物用于制备药物的用途。
11.根据权利要求3至8中任一项所述的缀合物用于制备用于预防和/或治疗癌症之药物的用途。
12.根据权利要求10或11中任一项所述的用途,其中配制所述缀合物以用于施用。
13.组合物,其同时或单独包含:
(i)SEQ ID NO:1的多肽的功能等同变体或根据权利要求3至8中任一项所述的缀合物,所述功能等同变体由在SEQ ID NO:1的N末端插入甲硫氨酸而产生,和
(ii)抗肿瘤剂。
14.根据权利要求13所述的组合物,其中所述抗肿瘤剂选自细胞毒剂、抗血管生成剂和抗转移剂。
15.根据权利要求13或14中任一项所述的组合物,其中所述缀合物选自SEQ ID NO:47和SEQ ID NO:48。
16.药物组合物,其包含可药用赋形剂和药学活性量的根据权利要求13至15中任一项所述的组合物。
17.根据权利要求13至15中任一项所述的组合物用于制备药物的用途。
18.根据权利要求13至15中任一项所述的组合物用于制备用于预防和/或治疗癌症之药物的用途。
19.根据权利要求17或18所述的用途,其中配制所述SEQ ID NO:1的多肽、其功能等同变体或缀合物以用于施用。
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EP2801370A1 (en) | 2013-05-07 | 2014-11-12 | Fundació Privada Institut d'Investigació Oncològica de Vall Hebron | Methods and compositions for the treatment of cancer |
US10654894B2 (en) * | 2016-02-03 | 2020-05-19 | Keenesaw State University Research And Service Foundation, Inc. | Methods for delivering cargo into a cell by using signal molecules as cell penetration agents |
WO2017190061A1 (en) * | 2016-04-29 | 2017-11-02 | The University Of Chicago | Synthetic dna binding domain peptides and uses thereof |
EP3269734A1 (en) * | 2016-07-15 | 2018-01-17 | Fundació Privada Institut d'Investigació Oncològica de Vall-Hebron | Methods and compositions for the treatment of cancer |
CN106591335A (zh) * | 2016-11-08 | 2017-04-26 | 安徽省农业科学院水稻研究所 | 一种密码子植物化改造的LbCpf1基因及其应用 |
EP3678679A1 (en) * | 2017-09-08 | 2020-07-15 | IDP Discovery Pharma, S.L. | New treatments of multiple myeloma |
WO2019108134A1 (en) * | 2017-11-29 | 2019-06-06 | Agency For Science, Technology And Research | Chimeric molecule for targeting c-myc in cells |
KR20200143416A (ko) * | 2018-04-09 | 2020-12-23 | 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 | 엑소좀을 사용하는 종양 유전자의 치료학적 표적화 |
US20220088221A1 (en) * | 2019-01-12 | 2022-03-24 | The Methodist Hospital | Self-assembled peptide nanoparticle and use thereof |
CA3133155A1 (en) * | 2019-03-19 | 2020-09-24 | Fundacio Privada Institut D'investigacio Oncologica De Vall Hebron | Combination therapy for the treatment for cancer |
TWI829893B (zh) * | 2019-03-19 | 2024-01-21 | 瓦爾希伯倫私人腫瘤研究基金會 | 診斷肺癌的方法 |
KR102221227B1 (ko) | 2019-05-07 | 2021-03-03 | 김영화 | 공급자 연동과 다국어 지원 기능을 구비한 쇼핑몰 플랫폼 제공 장치 및 그 방법 |
US20220307013A1 (en) * | 2019-08-30 | 2022-09-29 | The Regents Of The University Of California | Gene fragment overexpression screening methodologies, and uses thereof |
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