CN110790829B - pHLIP胞外段作为抗原制备的抗体在制备抗肿瘤药物中的应用 - Google Patents
pHLIP胞外段作为抗原制备的抗体在制备抗肿瘤药物中的应用 Download PDFInfo
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Abstract
本发明公开了pHLIP胞外段作为抗原制备的抗体在制备抗肿瘤药物中的应用。本发明研究发现，改进型低pH插入肽的胞外段可以作为抗原制备抗体，该抗体可以用于肿瘤治疗。
Description
本申请是以下专利申请的分案申请：申请号“2018114594499”，申请日“2018.11.30”，发明名称“一种改进型低pH插入肽”。
技术领域
本发明属于生物医学领域，涉及pHLIP胞外段作为抗原制备的抗体在制备抗肿瘤药物中的应用。
背景技术
在过去的10年里，化学疗法在肿瘤治疗中具有非常重要的作用，同时也受到人们的广泛关注。但是传统抗肿瘤药物仍然具有很多局限性,例如它们无法区分正常组织与肿瘤组织，使得治疗效率非常低，更甚者还会引起致命的不良反应。因此，提高选择性成为抗肿瘤药物研发的关键。靶向药物递送系统，能够将抗肿瘤药物特异性地传递到肿瘤组织，并且能够降低正常组织对抗肿瘤药物的摄取，可以降低其不良反应、提高临床治疗效果。目前靶向药物递送系统种类繁多，有些已用于临床治疗中。然而，在正常组织中也有相同的受体表达，它们同样能识别该靶向配体，只是识别水平较低，这使得其靶向效率及治疗效果受到明显的限制。
肿瘤组织与正常组织最大的区别在于，前者细胞外环境偏酸性。近年来，以肿瘤组织的酸性微环境为靶点的抗肿瘤药物得到较快发展。由于肿瘤细胞对葡萄糖的高摄取，在无氧条件下葡萄糖被酵解成乳酸，形成酸性环境；另一方面，肿瘤的异常血管引起肿瘤供氧不足、肿瘤细胞转化的生长失控引起缺氧和代谢失常增加了无氧代谢；肿瘤细胞自身通过上调低氧诱导因子以适应低氧环境和相应糖酵解产生乳酸后的酸性环境，最终导致肿瘤组织微环境的pH值为5.7-7.0，明显低于正常组织的pH 7.4。酸性微环境是提高抗肿瘤药物选择性的一个非常有效的靶点。
来源于细菌视紫红质的跨膜螺旋蛋白C的低pH插入肽(pHLIP，pH low insertionpeptide)正是由于其在酸性微环境中的特殊性质成了近年来的研究热点。pHLIP是一种水溶性的多肽，能够插入细胞双层脂膜形成稳定的跨膜α螺旋。肽折叠和膜插入是由中性或碱性(pH>7.4)pH下降至弱酸性(pH＝7.0-6.5或者更低)驱动的。pHLIP具有三种主要形态：在中性pH下无结构溶于水的形态I，在中性pH下无结构且结合到细胞膜表面上的状态II，在酸性pH下插入并以α螺旋穿过细胞膜的状态III。因为容易凝集产生的溶解性差是膜肽的性质，pHLIP作为膜肽也有凝集的趋势，尤其是在高浓度和/或低pH的条件下，在中性pH的水溶液中，pHLIP单体存在的浓度小于30μg/ml，在低pH条件下，状态II和状态III的pHLIP肽全部以单体形式存在。许多研究显示，由于结构上的改变导致的肽溶解性的降低会导致肽与膜的结合能力以及整个肽的构象发生改变。在血液中肽的稳定性是非常重要的性质，因为血液中的蛋白酶能在数分钟内降解L型氨基酸构成的肽。尽管D型氨基酸构成的多肽相对稳定的多，但是由于它们可变的手性，并不适合用于与特异性受体结合。因为pHLIP和脂质双分子层之间不存在特异性的相互作用，所以人们并不意外由L型或D型构成的pHLIP具有相同的生物物理学和肿瘤定位的特性，越来越多的证据表明，pHLIP定位并不需要任何特异性分子结合事件的发生。仅有一个显著的区别在于，D-pHLIP形成跨膜的左手螺旋，而L-pHLIP形成跨膜的右手螺旋。与穿透细胞的肽相比，pHLIP在插入细胞膜之后停留在细胞膜中，一端进入细胞质，另一端进入细胞外空间。因此，肽具有双重传递能力:一种能力是它能将货物分子系到细胞表面，另一种能力是它能将不能穿膜的货物分子注射或释放到细胞质中。为了实现第一种能力，可将货物分子连接到pHLIP的N端，这样的货物分子具有宽泛的极性和大小，一个应用的实例如将成像探针递送到酸性组织并将其稳定的系于细胞膜表面。为了实现第二种能力，可将货物分子通过一个可以在细胞质内被剪切的键连接到pHLIP的C端，这样的可以被剪切的键入二硫键，一个应用的实例是将抗肿瘤药物递送到肿瘤组织并将其导入肿瘤细胞质内发挥作用，如荧光染料、环肽、极性毒素和肽核酸等。
随着对pHLIP研究的不断深入，发现野生型pHLIP的应用受到一些关键因素的限制，如体内清除慢、羧基端所带电荷对膜插入过程的影响。学者们尝试通过对pHLIP氨基酸序列进行调整，设计具有更好性能的pHLIP衍生物。目前pHLIP序列调节方式主要包括：①切除或反转野生型pHLIP序列的膜插入末端；②用谷氨酸残基、带正电的赖氨酸残基或质子化的非标准氨基酸残基(γ-羧基酸、α-氨基乙二酸)替换跨膜区部分或全部天冬氨酸。经序列调节产生的pHLIP衍生物，如pHLIP变体3(切除膜插入末端)，可减少pHLIP所带电荷，加快pHLIP进入细胞膜形成跨膜螺旋的过程，提高其肿瘤靶向性。pHLIP变体7，在保持良好靶向性的同时加快在血液中的消除速度，有利于实现药物的体内递送。可以借鉴当前pHLIP的序列调节方法发展更为先进的pHLIP衍生物。
发明内容
本发明的目的之一在于提供一种改进型低pH插入肽及其制备方法。
本发的目的之二在于提供包含上述改进型低pH插入肽的组合物，所述组合物用于疾病的治疗、诊断或标识。
本发明的目的之三在于提供由上述改进型低pH插入肽为抗原制备的抗体。
本发明的目的之四在于提供前面所述的抗体在制备抗肿瘤药物中的应用。
为了完成上述目的，本发明采取了如下技术方案：
本发明提供了一种改进型低pH插入肽，所述改进型低pH插入肽的序列含有如下序列：WT低pH插入肽或其变体的胞外段重复一次、重复两次或重复两次以上获得的多肽序列。
优选地，WT低pH插入肽的变体包括Var1-Var16。
WT低pH插入肽或其变体的序列如下：
WT:ACEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT(SEQ ID NO.2)；
Var1:ACEDQNPYWARYADWLFTTPLLLLDLALLVDG(SEQ ID NO.3)；
Var2:ACEDQNPYWRAYADLFTPLTLLDLLALWDG(SEQ ID NO.4)；
Var3:ACDDQNPWRAYLDLLFPTDTLLLDLLW(SEQ ID NO.5)；
Var4:ACEEQNPWRAYLELLFPTETLLLELLW(SEQ ID NO.6)；
Var5:ACDDQNPWARYLDWLFPTDTLLLDL(SEQ ID NO.7)；
Var6:CDNNNPWRAYLDLLFPTDTLLLDW(SEQ ID NO.8)；
Var7:ACEEQNPWARYLEWLFPTETLLLEL(SEQ ID NO.9)；
Var8:CEEQQPWAQYLELLFPTETLLLEW(SEQ ID NO.10)；
Var9:CEEQQPWRAYLELLFPTETLLLEW(SEQ ID NO.11)；
Var10:ACEDQNPWARYADWLFPTTLLLLD(SEQ ID NO.12)；
Var11:ACEEQNPWARYAEWLFPTTLLLLE(SEQ ID NO.13)；
Var12:ACEDQNPWARYADLLFPTTLAW(SEQ ID NO.14)；
Var13:ACEEQNPWARYAELLFPTTLAW(SEQ ID NO.15)；
Var14:TEDADVLLALDLLLLPTTFLWDAYRAWYPNQECA(SEQ ID NO.16)；
Var15:CDDDDDNPNYWARYANWLFTTPLLLLNGALLVEAEET(SEQ ID NO.17)；
Var16:CDDDDDNPNYWARYAPWLFTTPLLLLPGALLVEAEET(SEQ ID NO.18)；
上述序列中划横线的部分即为低pH插入肽的胞外段序列。Var1-Var 16都是WT的变体。
将序列为SEQ ID NO.2-18的低pH插入肽的胞外段重复一次、重复两次或重复两次以上获得的多肽序列包括：
(胞外段)n+Linker+SEQ ID NO.2-18，其中，n＝1、2、3、4...........。
可用于本发明的Linker序列可以是(GGGS)m，其中m＝1、2、3、4............。
在本发明的具体实施例中，所述改进型低pH插入肽的序列是将序列为SEQ IDNO.9的Var7的胞外段重复一次获得的序列，序列为：
ACEEQNPGGGSACEEQNPWARYLEWLFPTETLLLEL(SEQ ID NO.1)。
在本发明的具体实施例中，虽然是以Var7为例，证明了低pH插入肽的胞外段重复一次后获得的序列相比原序列具有更有益的效果，但是本领域技术人员根据本发明的研究成果会直接的毫无意义的推断出对于WT的其他变体，其胞外段重复一次后获得的序列相比原序列同样可以具有更有益的效果，因为本发明的实验结果表明了低pH插入肽的胞外段的优势的共性，所以以上WT、以及包括Var1-Var 16在内的WT的变体经过改进后的低pH插入肽均包含在本发明的保护范围之内。
本发明提供了一种组合物，所述组合物包括前面所述的改进型低pH插入肽。
进一步，所述组合物还包括功能体，所述功能体包括治疗剂、诊断剂、标识分子。
所述功能体与前面所述的改进型低pH插入肽可以在N端连接也可以在C端连接。具体来说，如治疗剂通过细胞表面上的分子发挥治疗作用，则该治疗剂需连接在低pH插入肽的N端，如治疗剂通过细胞内部的分子发挥治疗作用，则该治疗剂需连接在低pH插入肽的C端；诊断剂用于显示疾病病理状态的存在，可将诊断剂可以连接在N端使其在细胞表面上显示，也可以连接在C端使其在细胞质内显示；标识分子用于使细胞膜表面不包含该标识分子的细胞增加该标识分子的表达，因此一般来说，标识分子连接于低pH插入肽的N端。
进一步，所述治疗剂包括但不限于抗体药物、小分子药物、抗生素、多肽、肽核酸、纳米粒、脂质体。
抗体药物可以是针对任何肿瘤分子的抗体药物，只要其能治疗该肿瘤即可。抗体药物包括：分子靶向单抗药物、靶向抗体偶联药物、双特异性抗体药物、靶向免疫检验点药物等。这样的抗体药物的实例包括但不限于：利妥昔单抗、曲妥珠单抗、吉妥单抗、阿仑单抗、替伊莫单抗、托西莫单抗、贝伐珠单抗、西妥昔单抗、帕尼单抗、奥法木单抗、地诺单抗、伊匹木单抗、本妥昔单抗、帕妥珠单抗、ado-曲妥珠单抗、阿托珠单抗、雷莫芦单抗、派姆单抗、博纳吐单抗、纳武单抗、达雷木单抗、地努图希单抗、耐昔妥珠单抗、埃罗妥珠单抗、阿特朱单抗、阿维单抗、狄诺塞麦、吉姆单抗、Necitumumab、Atezolizumab。
进一步，所述抗生素包括抗肿瘤抗生素，是由微生物代谢产生的具有抗肿瘤活性的化学物质。可用于本发明的抗肿瘤抗生素包括C1027、丝裂霉素、阿霉素、CC-1065、adozelesin、ducarmycins、gilvusmycin、四环素类、肉桂酰胺、MMI-166、batimastat、绿茶多酚、丹酚酸A、C3368-A、C3368-B、大黄素、三环吡喃酮类、gel danamycin、17AAG、紫杉酸、epothilone A、epothilone B、卡里奇霉素、力达霉素。
进一步，所述小分子药物通常是信号传导抑制剂，它能够特异性地阻断肿瘤生长、增殖过程中所必需的信号传导通路，从而达到治疗的目的，小分子药物的实例包括但不限于：伊马替尼、尼罗替尼、达沙替尼、依维莫司、厄洛替尼、舒尼替尼、依鲁替尼、索拉非尼、克唑替尼、帕唑帕尼、吉非替尼、卡非佐米、托法替尼、阿西替尼、瑞戈非尼、威罗非尼、西罗莫司、泊那替尼、乐伐替尼、奥拉帕尼、阿柏西普、色瑞替尼、罗米地辛、艾乐替尼、贝利司他、博舒替尼、凡德他尼、卡博替尼、帕比司他、阿法替尼、帕利夫明、曲美替尼、达拉非尼、坦西莫司、拉帕替尼、伏立诺他、Venetoclax、格列卫、易瑞沙。
进一步，所述多肽的实例包括但不限于毒素、环肽、微管抑制因子、蛋白酶激活受体。毒素的实例如鹅膏蕈碱，环肽的实例如鬼笔环肽，微管抑制因子实例如单甲基艾瑞他汀E(MMAE)，蛋白酶激活受体实例如P1AP。
进一步，所述肽核酸包括anti-miR(反义核酸)寡核苷酸肽。
进一步，纳米粒包括壳聚糖靶向纳米粒、长循环纳米粒、聚乳酸纳米粒、固体脂质纳米粒、金纳米粒、载多柔比星介孔硅纳米粒、超顺磁性氧化铁纳米粒。
进一步，所述脂质体包括磷脂、胆固醇。
本发明所述的磷脂包括但不限于，大豆磷脂(SPC)、聚乙二醇1000维生素E琥珀酸酯(TPGS)、二肉豆蔻酰卵磷脂(DMPC)、二月桂酰卵磷脂(DLPC)、二硬酯酰卵磷脂(DPPC)，二棕榈酰卵磷脂(DPPC)、二硬脂酰卵磷脂(DSPC)、1-肉豆蔻酰-2-棕榈酰卵磷脂(MPPC)、1-棕榈酰-2-肉豆蔻酰卵磷脂(PMPC)、1-棕榈酰-2-硬脂酰卵磷脂(PSPC)、1-硬脂酰-2-棕榈酰卵磷脂(SPPC)、蛋黄卵磷脂(EPC)、氢化豆磷脂(HSPC)、二油酰基卵磷脂(DOPC)、二油酰磷脂酰乙醇胺(DOPE)、二月桂酰磷脂酰甘油(DLPG)、二棕榈脂酰甘油(DPPG)、二硬脂酰磷脂酰甘油(DSPG)、二油酰磷脂酰甘油(DOPG)、二肉豆蔻酰磷脂酸(DMPA)、二棕榈酰磷脂酸(DPPA)、二肉豆蔻酰磷脂酰乙醇胺(DMPE)、二棕榈酰磷脂酰乙醇胺(DPPE)、二肉豆蔻酰磷脂酰丝氨酸(DMPS)、二棕榈酰磷脂酰二丝氨酸(DPPS)、脑磷脂酰丝氨酸(PS)、脑神经鞘磷脂(BSP)、二棕榈酰神经鞘磷脂(DPSP)、二硬脂酰神经鞘磷脂(DSSP)、二硬脂酰磷脂酰乙醇胺(DSPE)中的任一种或任几种的混合，其中优选的为：大豆卵磷脂(SPC)、二硬脂酰磷脂酰乙醇胺(DSPE)或二油酰磷脂酰乙醇胺(DOPE)。
进一步，所述诊断剂包括荧光染料。荧光染料包括但不限于Alexa750、Alexa546、Alexa647、Cy5.5、DyLight 680、DyLight 680 4*PEG-conjugate(DyP680)、
680RD(IR680)、
800CW(IR800)、吲哚花青绿ICG、PE、Percy-Cy5.5、FITC、APC、Cy7、FITC、GFP、Alexa Fluar488、Bidipy、Fluo-3、Propidium Iodide(PI)、PerCP、PE-Cy5、PE-TesesRed、7-AAD、PE-Cy7、PE-Alexa Flour750、Alexa Fluor660、Alexa Fluor700、APC-Cy7、APC-Alexa Flour750、Hoechsr33342-Blue、DAPI、Hoechsr33342-Red、arific Blue、CascadeBlue、Alexa Flour 405、Parific orange。
进一步，所述标识分子包括肿瘤表面抗原或其功能结构域，肿瘤表面抗原泛指在肿瘤发生、发展过程中在细胞表面新出现或过度表达的抗原物质。
肿瘤表面抗原的实例包括但不限于ER、PR、P53、EGFR、IGFR、Her2、CD20、CD25、CD117、CD34、CD138、CD33、VEGFR、BCMA、Mesothelin、CEA、PSCA、MUC1、EpCAM、S100、CD22、CD19、CD70、CD30、ALK、RANK、GPC2、GPC3、Her3、EGFRvIII、GD2、PD-L1、PD-L2。
本发明还提供了一种新抗原，所述新抗原序列包括前面所述的改进型低pH插入肽的胞外段序列或其变体序列。
在本发明的具体实施方案中，所述新抗原序列如SEQ ID NO.19所示。
本发明的新抗原具有以下功能：(1)抗原性；(2)与载体蛋白连接后作为免疫原刺激动物产生特异性的抗体。
本发明的新抗原的制备方法可用化学合成法：利用多肽自动合成仪，通过固相法合成抗原。
本发明还提供了一种核酸分子，所述核酸分子编码前面所述的新抗原。
本发明还提供了一种重组载体，所述重组载体由空载体和插入该空载体的目的基因组成，所述目的基因为前面所述的核酸分子。
在本发明中，所述“空载体”(或称“载体”)可选用本领域己知的各种载体，如市售的各种质粒、粘粒、噬菌体及反转录病毒等。所述空载体可以包括多种常用的检测标记(例如荧光标记、抗生素标记等报告基因)和酶切位点。重组载体构建可采用空载体本身多克隆位点的各种核酸内切酶进行酶切获得线性质粒，与采用相同核酸内切酶切割的基因片段连接，获得重组质粒。
本发明还提供了一种重组宿主细胞，所述重组宿主细胞含有前面所述的重组载体。
可以通过本领域常规的方法将所述重组载体转化、转导或者转染到宿主细胞中，如氯化钙法化学转化、高压电击转化，优选电击转化；所述宿主细胞可以为原核细胞或真核细胞，优选为大肠杆菌、枯草杆菌、酵母(如毕赤酵母)或各种动植物细胞，更优选所述宿主细胞为本领域常用的基因工程菌，如大肠杆菌、枯草芽孢杆菌或毕赤酵母。
可以使用本领域常用的方法从重组宿主细胞中分离和纯化本发明的新抗原。例如，离心分离培养基和重组宿主细胞，高压匀浆破碎细胞、离心过滤去除细胞碎片，亲和层析纯化新抗原。对于分离纯化所得的新抗原的产物，可以使用本领域常用的方法进行纯度鉴定。例如，考马斯亮蓝法、凯氏定氮法、双缩脲法、lowry法、紫外吸收法、亲和层析、抗原抗体法、电泳分析(例如十二烷基磺酸钠聚丙烯酰胺凝胶电泳)、沉降分析、扩散分析、恒溶度法、蛋白质谱等。
本发明还提供了一种融合蛋白，所述融合蛋白包括前面所述的新抗原以及与所述新抗原连接的蛋白或多肽。
进一步，所述融合蛋白包括前面所述的新抗原以及与所述新抗原偶联的载体蛋白。
可用于本发明的载体蛋白包括但不限于KLH(钥孔血蓝蛋白)、牛血清白蛋白(BSA)、卵清蛋白OVA等。由于KLH(钥孔血蓝蛋白)免疫原性强，结合位点多，免疫效果较好，并且与免疫动物亲缘关系较远，用其作为载体蛋白不易引起交叉反应，因此是优选的。
本发明的融合蛋白具有免疫原性和特异性，是一种免疫原，可用来免疫动物从而制备特异性的针对前面所述的新抗原的抗体。
本发明还提供了一种新抗体，所述新抗体是以前面所述的新抗原或以前面所述的融合蛋白制备而成。
优选地，本发明的上述新抗体是单克隆抗体。
本发明还提供了一种药物组合，所述药物组合包括前面所述的新抗体。
进一步，所述药物组合还包括前面所述的改进型低pH插入肽。
在本发明的具体实施方案中，所述新抗体与所述改进型低pH插入肽独立存在，不相互连接，同时施用发挥作用时，所述抗体结合所述改进型低pH插入肽的胞外段。
本发明的单克隆抗体可以使用本领域的常规技术制备而成，现有技术中常用的制备抗体的方法包括：
(1)基于小鼠/兔子的杂交瘤技术。
基本步骤：动物免疫、细胞融合、杂交瘤细胞的筛选与单抗检测、杂交瘤细胞的克隆化、单抗的鉴定及制备等。
(2)基于噬菌体抗体展示库的抗体筛选技术。
基本步骤：①从外周血或脾、淋巴结等组织中分离B淋巴细胞，提取mRNA并反转录为cDNA；②应用抗体轻链和重链引物，根据建库的需要通过PCR技术扩增不同的Ig基因片段；③构建噬菌体载体；④表达载体转化细菌，构建全套抗体库。通过多轮的抗原亲和吸附-洗脱-扩增，最终筛选出抗原特异的抗体克隆。
(3)基于单克隆抗体库的筛选技术。
本发明前面所述的低pH插入肽，可以使用本领域的常规技术制备而成，这样的合成技术包括：固相合成、液相合成。
固相合成的原理在于：将氨基酸的羧基末端通过适当连接分子固定在不溶性树脂上，然后在此树脂上经过脱去氨基保护基依次缩合氨基酸，延长肽链、直到得到所需多肽。最后用适当试剂除去侧链保护基并从树脂上裂解产物。与液相相比，多肽固相合成优点在于：(1)每步反应只需简单的过滤和洗涤树脂，便可达到纯化目的，克服了经典液相合成法中的每一步产物都需要纯化的困难，操作省时，省力；(2)可溶性试剂可以过量以使反应完全和获得高产率，过量试剂可简单的用溶剂冲洗，过滤清除；(3)所有的反应都可以在一个容器中进行，因此避免了反应中间体转移的手续和损失；(4)如果选择适当的连接分子和裂解条件，高分子树脂可再生重复利用。
固相合成多肽的策略包括Boc固相法、Fmoc固相法。在本发明的具体实施方式中，本发明使用了Fmoc固相法。
本发明提供了前面所述的改进型低pH插入肽在制备前面所述的新抗原中的应用。
本发明提供了前面所述的改进型低pH插入肽在制备前面所述的融合蛋白中的应用。
本发明提供了前面所述的改进型低pH插入肽在制备前面所述的组合物或新抗体中的应用。具体来说：
本发明提供了前面所述的改进型低pH插入肽在制备肿瘤药物靶向递送系统中的应用。将前面所述的肿瘤治疗剂与低pH插入肽连接，依赖低pH插入肽对微酸环境的靶向性，将肿瘤治疗剂靶向递送到肿瘤组织并对其进行特异性杀伤。
本发明提供了前面所述的改进型低pH插入肽在制备肿瘤诊断工具中的应用。将用于前面所述的肿瘤诊断剂与低pH插入肽连接，依赖低pH插入肽对微酸环境的靶向性，使肿瘤诊断试剂靶向递送到肿瘤组织并标记肿瘤组织的存在，以此来判断受试者是否患有肿瘤。
本发明提供了前面所述的改进型低pH插入肽在制备肿瘤标识系统中的应用。将前面所述的肿瘤表面抗原与低pH插入肽连接，依赖低pH插入肽对微酸环境的靶向性，使肿瘤表面抗原靶向递送并停留在肿瘤细胞表面，使肿瘤细胞被肿瘤表面抗原标识，有利于针对该特定抗原的肿瘤药物能够对该肿瘤发挥杀伤作用。以HER2为例，曲妥珠单抗仅对HER2阳性乳腺癌患者具有治疗作用，通过将低pH插入肽连接的HER2靶向定位于HER2阴性乳腺癌患者的乳腺癌细胞表面，使得曲妥珠单抗对HER2阴性乳腺癌患者也能发挥治疗作用，扩大了曲妥珠单抗的适用范围。
本发明还提供了前面所述的改进型低pH插入肽在制备CAR-T序列中的应用。以本发明的改进型低pH插入肽作为抗原筛选获得的抗体可以作为全新的Scfv序列设计CAR-T序列。
本发明还提供了前面所述的新抗原在制备前面所述的融合蛋白，或前面所述的新抗体中的应用。
本发明还提供了前面所述的新抗体在制备抗肿瘤药物中的应用。
本发明还提供了前面所述的新抗体在制备CAR-T序列中的应用。
本发明还提供了前面所述的新抗体在制备前面所述的组合物中的应用。
本发明还提供了前面所述的新抗体在制备前面所述的药物组合中的应用。
文中术语“CAR-T”，全称是Chimeric Antigen Receptor T-Cell Immunotherapy，嵌合抗原受体T细胞免疫疗法。根据肿瘤微环境这一特性，科学家优化了一系列的CART序列，使其在不同的pH值情况下和抗原的亲和力有完全不同的亲和力，从而在不同pH值情况下激活。
文中术语“靶向抗体偶联药物”，或称免疫偶联物(immunoconjugate)。免疫偶联物分子由单抗与“弹头”药物两部分构成。可用作“弹头”的物质主要有三类，即放射性核素、药物和毒素；与单抗连接分别构成放射免疫偶联物、化学免疫偶联物和免疫毒素。
文中术语“双特异性抗体药物”是指能同时与两个抗原表位结合的抗体，双抗可以分为两种，即T细胞募集型，包含肿瘤细胞靶点-T细胞募集位点，这占双抗的大部分比例，其中，T细胞募集位点指CD3(T细胞)，CD16靶点(NK细胞)，而靶点通常位于肿瘤细胞；另外，双抗也可能结合双靶点位点(如VEGF-PDGF、VEGF-Ang2)，抑制2条信号通路，从而减少耐药产生的可能性。
文中术语“肽核酸”(peptidenucleicacid，PNA)是一种人工合成的DNA或RNA类似的物，其骨架由重复排列的N-2(氨乙基)-甘氨酸(N(2-aminoethyl)glycine)单位构成，碱基和骨架间以亚甲羰键相连。由于其没有如DNA或RNA上的磷酸基团，因此显电中性，与DNA和RNA间无电性排斥，碱基配对特异性强，在结合DNA和RNA时可形成稳定的复合物，热稳定性高，加之PNA也不易被蛋白酶或者核酸酶水解，因此，PNA在生物学研究和临床医学领域有着广阔的应用前景。
文中术语“单克隆抗体”单克隆抗体是由单一B细胞克隆产生的高度均一、仅针对某一特定抗原表位的抗体，称为单克隆抗体。
本发明中的多肽序列均是按照从N端到C端的顺序列出。
本发明的优点和有益效果：
本发明在已知的低pH插入肽的基础上进行了序列上的改进，改进后的多肽在酸性的肿瘤组织微环境中具有更强的选择性，且在体内维持时间更长。
附图说明
图1显示低pH插入肽var7在细胞上定位的荧光图；
图2显示改进型低pH插入肽p-var7在细胞上定位的荧光图；
图3显示利用活体成像技术研究低pH插入肽在动物体内定位的图，其中，A：24h；B：48h；C：72h；D：72h，解剖小鼠获得的肿瘤组织；
图4显示1G12对肿瘤生长影响的曲线图；
图5显示1G12对肿瘤重量影响的统计图；
图6显示1G12对小鼠体重影响的统计图；
图7显示肝脏病理染色图；
图8显示肾脏病理染色图；
图9显示肺脏病理染色图；
图10显示大肠病理染色图；
图11显示脾脏病理染色图。
具体实施方式
通过参阅下述实施例可以更容易地了解本发明的内容，这些实施例只是为进一步说明本发明，并不意味着限定本发明的范围。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1改进型低pH插入肽的合成
根据SEQ ID NO.9和SEQ ID NO.1的序列从羧基端向氨基端依次合成。
(1)第一个氨基酸与树脂的连接
将2-Chlorotrtyl Chloride Resin树脂l g置于干燥洁净的肽合成柱中，加入8mlDCM，溶胀5min，真空吸弃溶剂。分别取2mmol Fmoc氨基酸和5mmol DIEA，溶于8ml DCM，并加入于树脂中，室温轻轻摇动反应60min。真空吸弃溶剂。用10ml DMF洗涤树脂2次，每次2min。加入10ml DCM/甲醇/DIEA(80：15：5)，轻轻摇动反应10min，真空吸弃溶剂。重复一次。用10ml DMF洗涤树脂3次，每次2min。真空吸弃溶剂，N2吹干。
(2)第一个氨基酸与树脂的偶联率测定
精确称取2mg干燥的Fmoc氨基酸一树脂置于比色杯中，加入3ml 20％哌啶/DMF，轻轻摇动反应10min，用20％哌啶/DMF作为空自对照调零，紫外分光光度计测定样品的290nm光吸收值。重复测定2次，取平均值。偶联率通过以下公式计算：
偶联率(mmol/g)＝(Abs样品)/(样品重量mg*1.75)
(3)Fmoc基团的脱保护
向树脂中加入l 0ml脱保护(DEBLOCK)试剂，混匀，室温轻轻摇动反应5min。弃溶剂，用10ml DMF洗涤树脂3次，每次2min。用6ml异丙醇洗涤树脂3次，每次5min。用6ml己烷洗涤树脂3次，每次5min。真空吸弃溶剂。取少量树脂样品，用茚三酮显色法(Kaiser法)快速测定树脂上的游离氨基含量：将树脂2ml用乙醇洗涤3次，分别加入2滴5％茚三酮、80％苯酚和KCN(2ml 0.001M KCN：98ml哌啶)，充分混匀，120℃加热4～6min。判断Fmoc基团的去保护反应程度。
(4)第二个氨基酸的偶联反应
第二个氨基酸的连接采用原位活化法，取2mmol的Fmoc氨基酸、4.0mmol的TBTU和4.0mmol的HOBT，加入最少量的DMF溶解后加入5mmol的DIEA，充分混匀后，加于脱Fmoc基团的树脂中。室温轻轻摇动反应60min。真空吸弃溶剂。用5ml甲醇洗涤树脂3次，每次5min。用10ml DMF洗涤树脂3次，每次2min。真空吸弃溶剂。取少量树脂样品进行茚三酮显色分析。测定偶联率。
(5)肽链的延伸反应
用10ml DEBLOCK试剂脱去上一个氨基酸N端的Fmoc保护基团，10ml DMF洗涤树脂3次，真空吸弃溶剂。取少量树脂样品进行茚三酮显色分析。按照(3)方法偶联下一个氨基酸。重复进行Fmoc保护基团脱保护和氨基酸偶联反应，直至偶联得到所需多肽链。
(6)肽链N端标记Alexa647
合成好全部氨基酸序列的树脂，脱去氨基酸N端的Fmoc保护基团，用10ml异丙醇洗涤树脂3次，每次5min。取1.38g Alexa647，1.6g TBTU53和0.76ml DIEA，混合后加于肽一树脂中，室温轻轻摇动反应60min。真空吸弃溶剂。用5ml甲醇洗涤树脂3次，每次5min。用10mlDMF洗涤树脂3次，每次2min。真空吸弃溶剂。
(7)肽链的侧链去保护及从树脂上的切割
将已合成好全部氨基酸序列的树脂，用10ml DMF洗涤后再用6ml异丙醇洗涤树脂3次，每次5min。用6ml己烷洗涤树脂3次，每次5min。真空吸弃溶剂后N2吹干，放入裂解容器中。1g树脂加入25ml切割试剂，室温切割反应2h，不时摇动混匀，反应后的混合液经玻璃滤器过滤树脂，收集切割反应混合液，用TFA洗涤树脂3次。将反应混合液转移于一圆底烧瓶中，用等体积预冷的乙醚洗涤4次，收集沉淀。干燥后即得到合成多肽粗品。
(8)合成多肽的脱盐
将多肽粗品加蒸馏水溶解。称取Amersham G-25凝胶15g，溶胀后装柱，装好后的柱子先用50ml蒸馏水平衡，平衡好后，每次上样3-5ml，用蒸馏水进行洗脱，紫外分光光度仪检测220nm处紫外吸收，按峰收集多肽。
(9)HPLC纯化多肽
使用Waters公司的Waters Delta Prep 4000制备型HPLC高效色谱仪分离纯化多肽。色谱柱为径向加压色谱柱(25×100，15μm，DELTA PAKC18填料)，洗脱系统为：A液：5％乙腈溶液(含0.1％TFA)；B液：95％乙腈溶液(含0.08％TFA)。手动进样，每次进样1ml，流速4ml/min，线性梯度，45min内，B液从5％升到50％，然后5min内升到95％B液做最后洗脱。215nrn处检测紫外吸收，按峰收集组分，用于质谱检测。将分子量检测正确的组分收集，真空冻干，成为需要的纯品，备用。
实施例2低pH插入肽在体外培养的肿瘤细胞上的定位
1、细胞系
人结直肠癌细胞系SW480(购买于ADCC)。
2、试剂
RPMI 1640培养基(solarbio)，胎牛血清(元亨金马公司)，PBS(pH＝7.4)(Gibco)，盐酸，alexa647标记的var7(var7为标准var7，序列为:Ala-Cys-Glu-Glu-Gln-Asn-Pro-Trp-Ala-Arg-Tyr-Leu-Glu-Trp-Leu-Phe-Pro-Thr-Glu-Thr-Leu-Leu-Leu-Glu-Leu(SEQID NO.9))和alexa647标记的p-var7(p-var7为var7的胞外段重复一次的加长版var7，序列为：Ala-Cys-Glu-Glu-Gln-Asn-Pro-Gly-Gly-Gly-Ser-Ala-Cys-Glu-Glu-Gln-Asn-Pro-Trp-Ala-Arg-Tyr-Leu-Glu-Trp-Leu-Phe-Pro-Thr-Glu-Thr-Leu-Leu-Leu-Glu-Leu(SEQID NO.1))，alexa647连接在上述两个多肽的N端第2位的Cys上。
3、仪器
超净台(RONGFENG)，二氧化碳孵箱(Thermo)，离心机(Thermo)，激光共聚焦细胞培养皿(20mm)(Corning)，电子pH计(赛多利斯)，光学显微镜(Olympus)，激光共聚焦显微镜(Nikon)。
4、实验方法
(1)收集处于对数期的SW480细胞，弃去培养液，用生理盐水洗两次，加入适量0.25％胰酶消化至细胞不贴壁，加入适量培养液终止消化，移入10ml试管中，1000rpm离心5min，吸去上清，加入1ml含10％胎牛血清的RPMI 1640培养基重悬混匀细胞。从中吸取10μl细胞悬液加入细胞计数板中计数后，取一定量的细胞悬液加入激光共聚焦细胞培养皿中，后用完全培养基调整至5*105，1ml细胞的体系，放入细胞孵箱培养过夜。
(2)使用1mol/L的盐酸与pH＝7.4的PBS缓冲液制备培养液。将盐酸逐滴加入PBS缓冲液中，最终滴定缓冲液的pH值至6.3。将合成的肽((p-var7和var7)分别加入pH为6.3以及7.4的PBS缓冲液中充分混匀，按比例稀释至肽终浓度为2.5μmol/L，即为含肽PBS培养液。
(3)待培养过夜后的SW480细胞贴壁，吸去培养基上清，用pH＝7.4的PBS缓冲液洗涤两次。
(4)将细胞培养皿中的PBS缓冲液吸去，向两个皿中分别加入1ml先前配置好的pH＝6.3以及7.4的PBS与肽的混合培养缓冲液，并在另外对照组培养皿中加入1ml不含肽的pH＝7.4的PBS培养基，均放入37℃细胞孵箱中孵育1小时。
(5)孵育结束后吸去含肽PBS培养液上清，用各自组不同pH值的不含肽PBS缓冲液冲洗三遍，后加入pH＝7.4的PBS缓冲液。
(6)将制备好的细胞培养皿放置在激光共聚焦显微镜下(647mm激发波长)观察细胞膜表面荧光表达情况。
3、实验结果：
结果如图1和图2所示，var7和p-var7在酸性溶液环境中均能有效插入人结肠癌细胞SW480表面，但在中性溶液环境中p-var7的膜插入能力丧失(图2)，而var7保留了该能力(图2)，显示p-var7在酸性的肿瘤组织微环境中具有更强的选择性。
实施例3低pH插入肽在动物体内的定位
1、实验步骤：
小鼠结肠癌细胞CT26皮下接种Balb/c小鼠，肿瘤长到约1cm，静脉分别注射生理盐水(N.S.)，alexa647标记的p-var7，alexa647标记的var7，剂量60μΜ/100μL N.S.，24，48，72小时活体成像(用Cy5.5的波长进行激发)，仰卧位照相。处死小鼠取肿瘤成像。
2、实验结果
结果如图3结果显示，var7和p-var7均能够标记上肿瘤，但p-var7的标记能力更强，且随着时间推移，var7的荧光强度衰变更显著，到72小时时，肿瘤组织仅可见少量标记，相反，p-var7在72小时时仍可见较强的荧光标记。该实验证明了p-var7能够在体内靶向到肿瘤组织，且维持较长时间。A图中黑色箭头代表的是肿瘤组织。
实施例4以p-var7胞外段作为抗原制备而成的抗体的抑瘤效果评价
实验材料：MC38细胞，购自ATCC；p-var7多肽(分子量为4095Da)，委托北京华大蛋白质研发中心有限公司合成，溶于PBS，浓度为40μM；p-var7的胞外段(Ala-Cys-Glu-Glu-Gln-Asn-Pro-Gly-Gly-Gly-Ser-Ala-Cys-Glu-Glu-Gln-Asn-Pro，SEQ ID NO.19)连接KLH(北京金斯瑞生物科技有限公司合成)；6-8周龄雌性C57/BL6鼠购自维通利华。
1、抗体制备：
(1)步骤：用KLH连接的p-var7的胞外段免疫Balb/c鼠，制备杂交瘤，获得2株单抗，ELISA检测抗体与抗原的特异结合以及抗体亚型。
(2)结果：
结果显示，命名为1G12和1G1的单抗能与抗原特异结合，其中1G12亲和力较高，1G1亲和力较低，OD值分别为1.4423、0.4924，且这2株均为IgG1亚型，制备的抗体浓度约为0.7mg/ml。
2、抗体抑瘤效果评价
(1)建立小鼠结肠癌MC38移植瘤模型：MC38接种于C57/BL6鼠，待肿瘤直径长至1cm时，无菌剥离肿瘤，剪碎，匀浆，滤网，制成单细胞悬液，在1640完全培养基中培养扩增，将细胞注射于C57/BL6鼠侧腹部皮下，2x106个细胞/只，待肿瘤直径长至0.8-1cm，剔除过大和过小的肿瘤，将肿瘤大小基本一致的小鼠分组。共分4组：p-var7单独注射组，10只；p-var7联合1G12注射组，10只；p-var7联合1G1注射组，10只；生理盐水N.S注射组，10只。每隔3天测量肿瘤大小。
(2)给药方法：p-var7给药：每次每只静脉注射40μM/100μl(约为16μg，参考之前活体成像的实验结果，相同剂量的注射能够观察到荧光在肿瘤部位的聚集，但到第三天时基本消退)，从分组完成后当天开始注射，一天注射一次，每隔2天注射一次；抗体给药：腹腔注射，剂量5mg/kg(抗体和p-var7的摩尔比约为1:5)，注射频率与p-var7相同，注射时间在p-var7给药后6-12小时，直至结束。
(3)结果：
结果如图4和图5所示，1G12能够显著抑制肿瘤生长，2周时抑制率为50％，1G1没有明显的抑瘤效果；治疗过程中小鼠体质状况良好，未出现活动下降、腹泻、体重降低等症状，图6显示小鼠体重不变；病理结果显示，治疗组小鼠肝肾肺脾肠的器官未出现器质性改变(图7-11)。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。
序列表
<110> 北京泽勤生物医药有限公司
<120> pHLIP胞外段作为抗原制备的抗体在制备抗肿瘤药物中的应用
<150> 2017113770766
<151> 2017-12-19
<160> 19
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Claims (6)
1.一种抗原表位肽，其特征在于，所述抗原表位肽序列如SEQ ID NO.19所示。
2.一种核酸分子，其特征在于，所述核酸分子编码权利要求1所述的抗原表位肽。
3.一种重组载体，其特征在于，所述重组载体由空载体和插入该空载体的目的基因组成，所述目的基因为权利要求2所述的核酸分子。
4.一种重组宿主细胞，其特征在于，所述重组宿主细胞含有权利要求3所述的重组载体或权利要求2所述的核酸分子。
5.一种融合蛋白，其特征在于，所述融合蛋白包括权利要求1所述的抗原表位肽以及与所述抗原表位肽偶联的载体蛋白。
6.根据权利要求5所述的融合蛋白，其特征在于，所述载体蛋白包括KLH、BSA或OVA。
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| CN109517073A (zh) * | 2018-11-30 | 2019-03-26 | 北京泽勤生物医药有限公司 | 一种靶向治疗肿瘤的融合肽及其应用 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1259524A (zh) * | 1999-11-12 | 2000-07-12 | 清华大学 | 用表位多肽诱导/制备表位特异性的单克隆抗体的方法 |
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-
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1259524A (zh) * | 1999-11-12 | 2000-07-12 | 清华大学 | 用表位多肽诱导/制备表位特异性的单克隆抗体的方法 |
Non-Patent Citations (6)
| Title |
|---|
| Comparative study of tumor targeting and biodistribution of pH low insertionpeptodes (pHLIP peptides) conjugated with different fluorescent dyes;Adochite Ramona-Cosmina等;《Molecular Imaging And Biology》;20161031;第18卷(第5期);1-5 * |
| Domain structure of growth signalobodies critically affects the outcome of antibody library selection;Rie Yoshida等;《The Journal of Biochemistry》;20150630;第157卷(第6期);497-506 * |
| Family of ph low insertion peptides for tumor targeting;Weerakkody Dhammika等;《Proceedings of The National Academy of Sciences of The United States of America》;20130325;第110卷(第15期);5834-5839 * |
| pH-responsive pHLIP (pH low insertion peptide) nanoclusters of superparamagnetic iron oxide nanoparticles as a tumor-selective MRI contrast agent：pumbed, pH (low) insertion peptides tumor;Yushuang Wei等;《Acta Biomaterialia》;20170630;第55卷;194-203 * |
| Targeting diseased tissues by pHLIP insertion at low cell surface pH;Andreev Oleg A等;《Frontiers In Physiology》;20140313;第5卷;1-7 * |
| 低pH插入肽研究情况;贾学丽等;《药学学报》;20180306;第53卷(第3期);375-382 * |
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