CN117069838B - Aoh1160和抗体联合治疗癌症的用途 - Google Patents
Aoh1160和抗体联合治疗癌症的用途 Download PDFInfo
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Abstract
本发明涉及AOH1160和抗体联合治疗癌症的用途。本发明针对HOXD9设计并合成了免疫原,将该免疫原免疫小鼠后,通过杂交瘤技术制备并筛选获得了特异性针对该免疫原的单克隆抗体H4G8,该抗体具有较好的特异性和亲和活性,并且具有剂量依赖性的抑制癌细胞的克隆形成及迁徙,特别是将其与化合物AOH1160一起联用后,能够有效的抑制小鼠体内癌细胞的成瘤,效果较好。
Description
技术领域
本申请涉及生物领域,具体的涉及AOH1160和抗体联合治疗癌症的用途。
背景技术
化学治疗是晚期 NSCLC 的标准治疗方式之一, 但近年来传统细胞毒性药物的疗效已经到达平台。 随着肺癌驱动基因的发现和相应靶向药物的研究和应用, 肺癌的治疗已经走上了以基因为导向的个体化治疗之路。
癌症治疗的最终挑战是选择性杀死癌细胞,同时保留正常组织。许多传统的化疗药物利用了对DNA修复机制的内在依赖性并通过它们的DNA破坏特性使复制压力超载来诱导细胞死亡。虽然最初有效,但这些DNA损伤剂会引起严重的副作用,并经常诱导耐药性,这两者都限制了其在临床上的长期使用。此外,导致耐药性的机制大多不清楚。最近,许多针对特定致癌信号成分(包括细胞周期检查点)的治疗药物已经进入临床。然一般来说,与早期化疗药物如顺铂相比,其副作用较轻,但这些靶向治疗的成功受到耐药性快速发展的限制。就单靶点药物而言, 只对携有特定基因型的 NSCLC 患者具有卓越疗效, 但对于多数患者来说疗效较差。 而且, 耐药问题也是该类药物临床应用中不可忽视的问题。 另外,NSCLC 是具有高度异质性的恶性肿瘤, 其活化的肿瘤信号通路纷繁复杂, 且纵横交错。因此, 针对多个基因或针对某一信号通路的多个分子的多靶点抑制剂 (如索拉菲尼、 舒尼替尼、 凡德他尼、 阿西替尼等) 可能为 NSCLC 的治疗带来新的思路。
通过靶基因内突变的积累或替代生存途径的激活。防止这种获得性耐药性的一个有希望的策略是靶向“中枢”蛋白,其功能是广泛和必要的细胞过程的中心,这种获得性耐药性是癌症的适应性和异质性本质所固有的。关键是针对关键过程,如DNA复制或修复过程,而不会在非恶性细胞中引起不可接受的副作用。最近对PCNA的研究为这一有希望的策略提供了概念证明。PCNA是在所有真核细胞中发现的进化上保守的蛋白质。形成环绕DNA的同三聚体环结构,PCNA作为一个中心“枢纽”,为十几种蛋白质提供锚定处,主要通过其跨氨基酸M121至Y133的结构域间连接环。与该环相互作用的蛋白质包括p21 (CDKN1A),DNA聚合酶δ (Pol δ) ,活瓣核酸内切酶1(EN1),DNA甲基转移酶(MeCTr),和DNA连接酶1 (LIGI) ,它们通过其PIP-box结构域与PCNA相互作用。除了将这些蛋白质募集到染色质上,PCNA还为这些蛋白质提供了一个滑动的“工作平台”,以调节DNA复制、细胞周期进程和DNA损伤反应。由于PCNA在细胞生长、存活和诱变中的基本作用,近年来已经进行了许多治疗性抑制PCNA的尝试,并取得了有希望的结果,证明了PCNA作为癌症治疗的治疗靶点的潜力。
肿瘤细胞特异表达ca-PCNA,小分子化合物AOH1160及其类似物也被开发用于靶向caPCNA蛋白-蛋白相互作用区。AOH1160 (CAS号:2089314-57-6)是一种有效的小分子增殖细胞核抗原 (PCNA) 抑制剂,干扰 DNA 复制,阻断同源重组介导的 DNA 修复,导致细胞周期停滞并诱导细胞凋亡。AOH1160与部分由L126-Y133区域描绘的PCNA表面口袋结合,干扰DNA复制并阻断HR介导的DNA修复,导致细胞周期停滞、未修复DNA损伤的累积和对顺铂治疗的敏感性增强,AOH1160能显著抑制肿瘤生长。但是目前采用该抑制剂的联合用药研究还不够多有待于进一步的提供改进的方案。
发明内容
研究发现,HOXD9 可与肺癌细胞的PCNA 的启动子直接结合,通过调控 PCNA 转录改变PCNA表达,促进癌细胞的增殖和迁徙,而抑制HOXD9,则可以抑制肺癌细胞的增殖,促进凋亡。
通过筛选鉴定,获得高活性位点和高免疫原性表位的免疫原序列为WNPVHAAGANAVPAAVYHHHHHHPYVHPQAPVAA。
将该免疫原免疫小鼠后,通过杂交瘤技术制备并筛选获得了特异性针对该免疫原的单克隆抗体H4G8,该抗体具有较好的特异性和亲和活性,并且具有剂量依赖性的抑制癌细胞的克隆形成及迁徙,特别是将其与化合物AOH1160一起联用后,能够有效的抑制小鼠体内癌细胞的成瘤,效果较好。
本发明一方面,提供了一种特异性针对HOXD9的单克隆抗体,具体的,所述抗体的其重链可变区序列如SEQ ID No:1所示,其轻链可变区序列如SEQ ID No:2所示。
进一步的,本发明的单克隆抗体还含有保守性的突变或者取代,但是仍保持单抗活性。
进一步的抗体的氨基酸序列的变化涵盖于本发明中,条件是氨基酸序列的变化保持至少75%,更优选至少80%、90%、95%和最优选99%。包括其间的某些百分比,例如75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%和99%序列同一性。尤其,包括保守性氨基酸置换。保守性置换是在与侧链相关的氨基酸家族中发生的置换。遗传编码的氨基酸通常分为以下家族:(1)酸性氨基酸为天冬氨酸、谷氨酸;(2)碱性氨基酸为赖氨酸、精氨酸、组氨酸;(3)非极性氨基酸为丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸,和(4)不带电的极性氨基酸为甘氨酸、天冬酰胺、谷氨酰胺、半胱氨酸、丝氨酸、苏氨酸、酪氨酸。亲水性氨基酸包括:精氨酸、天冬酰胺、天冬氨酸、谷氨酰胺、谷氨酸、组氨酸、赖氨酸、丝氨酸和苏氨酸。疏水性氨基酸包括丙氨酸、半胱氨酸、异亮氨酸、亮氨酸、甲硫氨酸、苯丙氨酸、脯氨酸、色氨酸、酪氨酸和缬氨酸。其它氨基酸家族包括(i)为脂肪族羟基家族的丝氨酸和苏氨酸;(ii)为含有酰胺的家族的天冬酰胺和谷氨酰胺;(iii)为脂肪族的丙氨酸、缬氨酸、亮氨酸和异亮氨酸;和(iv)为芳香族的苯丙氨酸、色氨酸和酪氨酸。例如,有理由期望用异亮氨酸或缬氨酸单独置换亮氨酸,用谷氨酸单独置换天冬氨酸,用丝氨酸单独置换苏氨酸,或用结构相关的氨基酸对氨基酸进行相似置换对所得分子的结合或性质无较大影响,特别是如果置换不牵涉骨架位点内的氨基酸时。通过检测多肽衍生物的特异性活性可易于确定氨基酸变化是否产生功能性肽。本文对检测进行了详细描述。本领域的普通技术人员可易于制备抗体或免疫球蛋白分子的片段或类似物。片段或类似物的优选氨基端和羧基端出现在功能结构域边界附近。可通过比较核苷酸和/或氨基酸序列数据和公共或私有序列数据库鉴定结构和功能结构域。优选地,使用计算机化比较法鉴定其它已知结构和/或功能的蛋白质中出现的序列基序或预测蛋白质构象结构域。鉴定折叠成已知三维结构的蛋白质序列的方法已知。因此,前述实例证明本领域的技术人员可根据本发明识别可能用于限定结构和功能结构域的序列基序和结构构象。
进一步的,本发明提供一种治疗肺癌的药物组合物,其特征在于含有特异性针对HOXD9的单克隆抗体以及药学上可接受的载体,所述抗体的其重链可变区序列如SEQ IDNo:1所示,其轻链可变区序列如SEQ ID No:2所示。
本发明的抗体及其衍生物、片段、类似物及其同源物可并入可包含药学上可接受的载体的药物组合物中。如本文所使用的术语“药学上可接受的载体”旨在包括任何及所有与药物施用相容的溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗和吸收延迟试剂等。这种载体或稀释剂的优选实例包括但不限于水、盐水、林格氏溶液、葡萄糖溶液和5%人血清白蛋白。也可使用脂质体和非水媒介物,例如不挥发性油。本领域中众所周知这种介质和试剂用于药物活性物质的用途。包括任何常规介质或试剂与活性在组合物中的用途,除非其与活性化合物不相容。补充活性化合物也可并入组合物中。
将本发明的药物组合物配制为与其预期施用途径相容。施用途径的实例包括肠胃外,例如静脉内、皮内、皮下、口腔(例如,吸入)、经皮(即,局部)、跨粘膜和直肠施用。用于肠胃外、皮内或皮下应用的溶液或悬浮液可包括以下组分:无菌稀释剂,例如注射用水、盐溶液、不挥发性油、聚乙二醇、丙三醇、丙二醇或其它合成溶剂;抗菌剂,例如苯甲醇或尼泊金甲酯;抗氧化剂,例如抗坏血酸或亚硫酸氢钠;螯合剂,例如乙二胺四乙酸(EDTA);缓冲液,例如醋酸盐、柠檬酸盐或磷酸盐和用于调节张力的试剂,例如氯化钠或葡萄糖。可用酸或碱,例如盐酸或氢氧化钠调节pH。可将肠胃外制剂装入用玻璃或塑料制成的安瓿、一次性注射器或多剂量瓶内。
适于注射用的药物组合物包括无菌水溶液(水溶性)或分散剂和用于临时制备无菌可注射溶液或分散剂的无菌粉剂。对于静脉内施用,适合的载体包括生理盐水、抑菌水、或磷酸盐缓冲盐水(PBS)。在所有情况下,组合物可为无菌并且应为易于注射程度的流动性。它可在生产和储存条件下稳定并且必须保存免受微生物,例如细菌和真菌的污染作用。载体可为含有(例如)水、乙醇、多元醇(例如,丙三醇、丙二醇和液体聚乙二醇等)的溶剂或分散介质及其混合物。例如,可通过使用包衣(例如卵磷脂),通过在分散情况下保持所需粒径和通过使用表面活性剂保持适当的流动性。可通过各种抗菌剂和抗真菌剂,例如尼泊金、氯丁醇、苯酚、抗坏血酸、硫柳汞等实现微生物作用的预防。在许多情况下,在组合物中可优选包括等渗剂,例如糖、多元醇(例如甘露醇、山梨糖醇)、氯化钠。可通过将延迟吸收的试剂(例如单硬脂酸铅和明胶)包括在组合物内引起可注射组合物的延长吸收。
本发明的组合物也可制备缓释制剂。缓释制剂的适合实例包括含有抗体的固体疏水性聚合物的半透性基质,所述基质呈成形物品形式,例如薄膜或微胶囊。缓释基质的实例包括聚酯、水凝胶(例如,聚(2-羟乙基-甲基丙烯酸酯)或聚(乙烯醇))、聚交酯、L-谷氨酸和γ乙基L-谷氨酸的共聚物、不可降解的乙烯-乙酸乙烯酯、可降解的乳酸-乙TM醇酸共聚物(例如LUP ON DEPOT (由乳酸-乙醇酸共聚物和醋酸亮丙瑞林组成的可注射微球))和聚-D-(-)-3-羟基丁酸。虽然聚合物,例如乙烯-乙酸乙烯酯和乳酸-乙醇酸使得能够释放分子100天以上,但是某些水凝胶释放蛋白质的时间段更短。
本发明抗体的治疗有效量通常涉及达到治疗目标所需的量。如上所述,这可能是抗体及其在某些情况下干扰靶标作用的靶抗原之间的结合相互作用。而且,需要施用的量还取决于施用的抗体从施用的受试者自由体积损耗的速率。就非限制性实例而言,本发明抗体或抗体片段的治疗有效剂量的常见范围为约0.1mg/kg体重至约50mg/kg体重。例如,常见剂量频率范围为每日一次至每周一次。
进一步的,本发明提供一种治疗肺癌的药物组合物,其特征在于含有特异性针对HOXD9的单克隆抗体以及以及AOH1160和药学上可接受的载体,所述抗体的其重链可变区序列如SEQ ID No:1所示,其轻链可变区序列如SEQ ID No:2所示。本发明抗体或抗体片段的治疗有效剂量的常见范围为约0.1mg/kg体重至约50mg/kg体重。例如,常见剂量频率范围为每日一次至每周一次。本发明AOH1160的治疗有效剂量的常见范围为约0.1mg/kg体重至约50mg/kg体重。例如,常见剂量频率范围为每日一次至每周一次。
具体的,本发明还提供了特异性针对HOXD9的单克隆抗体和AOH1160在制备用于治疗肺癌的药物组合物中的用途。
附图说明
图1为H4G8单克隆抗体效价结果图。
图2为Western blot检测结果图,泳道1是小鼠Sp2/0细胞,泳道2是人NCI-H2170细胞。
图3为单抗对NCI-H2170细胞克隆形成的影响图。
图4为单抗对NCI-H2170细胞侵袭能力的影响图。
具体实施方式
本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。以下实施案例中的方法、设备、材料,如果未进行特别说明,均为本领域常规方法、设备和材料,均可由市场购得。
实施例1 HOXD9单克隆抗体的制备
将过筛选鉴定,获得的高活性位点和高免疫原性表位的免疫原序列WNPVHAAGANAVPAAVYHHHHHHPYVHPQAPVAA进行人工合成,并将其偶联至KLH上。
将前述合成免疫原按照100μg·只-1的剂量与弗氏完全佐剂1∶1乳化,背部多点皮下注射6周龄BALB/c雌鼠2只。2周后,用弗氏不完全佐剂与免疫原1∶1乳化,按照80 μg·只-1剂量连续免疫小鼠2次,间隔2周免疫1次。第3次免疫后3d,对免疫小鼠进行尾静脉采血,选取血清抗体效价高的2号小鼠(1:30000)进行冲击免疫1次。
使用DEME培养基(含10%胎牛血清)提前1周在37℃、5%CO2培养箱中培养小鼠骨髓瘤细胞Sp2/0。在无菌条件下取免疫后小鼠的脾脏并制备成悬液。将Sp2/0骨髓瘤细胞与脾细胞按1︰9进行混合,使两种细胞在PEG1500的作用下进行融合。融合后的细胞使用20%胎牛血清-HAT-DMEM培养基悬浮,然后以每孔100μL的量均匀铺于含有饲养层细胞的96孔板中,在37℃、5%CO2培养箱中培养7d后,用10%胎牛血清-HT-DMEM培养基进行细胞换液,两周后用间接ELISA方法对分泌特异性抗体的细胞进行检测。以细胞培养上清作为一抗,GAM-IgG-HRP作为二抗,检测阳性克隆共计87株。对筛选的阳性细胞采用有限稀释法进行4次克隆化,直至细胞孔中的培养上清阳性率达100%,获得一株稳定性最好,阳性反应最强的杂交瘤细胞H4G8。
取BALB/c小鼠腹腔注射弗氏不完全佐剂,每只500μL,7d后腹腔注射杂交瘤细胞1×107,待小鼠腹部明显膨大以后抽取腹水,10000r/min离心15min,取上清。使用辛酸-硫酸铵法以及亲和层析法对其进行纯化,随后进行PBS透析,获得高纯度的单克隆抗体,采用SDS-PAGE鉴定获得了较为纯净的二个条带。采用BCA鉴定蛋白的浓度为2.3mg/mL。
实施例2 H4G8单克隆抗体效价测定
以每孔1.25 μg·mL-1 免疫原多肽包被于96孔酶标板,采用间接ELISA法测定单克隆抗体效价,将H4G8单克隆抗体分别进行倍比稀释,作为一抗进行孵育。酶标仪测定各孔OD450nm值,阴性对照OD450nm<0.2时试验成立,待检抗体OD450nm/阴性对照OD450 nm(S/N)≥2.1的最大稀释倍数作为抗体效价。
如图1所示,经间接ELISA检测H4G8单克隆抗体效价,结果显示 H4G8单克隆抗体效价为1:64000。
实施例3 单克隆抗体特异性鉴定
小鼠Sp2/0细胞和人NCI-H2170细胞(购买自上海宾穗生物科技有限公司)分别提取总蛋白,进行SDS-PAGE电泳,湿转至PVDF膜,5%脱脂奶室温封闭1 h;H4G8单克隆抗体(1:1000稀释)为一抗,4℃孵育12h;HRP标记的山羊抗鼠IgG(1∶:5000稀释)为二抗室温孵育1h,显色并分析试验结果。
从图2的经Western blot检测结果显示,H4G8单克隆抗体值能与人NCI-H2170细胞中的HOXD9蛋白发生特异性反应,不能与Sp2/0细胞发生反应,表现出较好的特异性。
实施例4 单克隆抗体亲和力鉴定及序列将定
将实施例1中的抗原肽用碳酸氢盐缓冲液稀释至质量浓度为1µg/mL,ELISA板包被,4℃过夜。洗板1次后加入封闭液,37℃放置2h。洗板5次,加入纯化的单克隆抗体(0.5mg/mL),从1∶1000开始进行倍比稀释,稀释12个梯度,PBS缓冲液为空白,设置重复对照,37℃孵育30min。洗板5次,加入HRP-羊抗鼠二抗,37℃孵育30min。洗板5次,最后加入TMB底物显色剂,37℃反应10min,加入终止液终止反应,最后用酶标仪双波长(450nm/630nm)进行检测。结果显示,H4G8单克隆抗体相对亲和力为(3.52±0.14)×10-10mol/L,亲和活性较好。
将杂交瘤细胞委托艾柏森生物进行轻重链序列鉴定,经测序分析,或者其重链可变区序列如SEQ ID No:1所示,其轻链可变区序列如SEQ ID No:2所示。
实施例5 H4G8单克隆抗体活性鉴定
NCI-H2170细胞,购买自上海宾穗生物科技有限公司。
克隆形成实验:使用6孔板每孔接种200个H2170肺癌细胞并置于培养箱中培养14d,其中使用的培养基为添加10%胎牛血清和1%双抗的RPMI1640培养基,其中,H4G8单克隆抗体的添加终浓度分别为500μg/mL,200μg/mL,100μg/mL,10μg/mL,不加抗体的空白对照。弃去培养基后将细胞用PBS清洗3次,用4%多聚甲醛固定15min,然后用结晶紫染色20min,PBS清洗3次后进行拍照与计数。结果如图3所示。
从图3可以看出,本发明的H4G8单克隆抗体具有剂量依赖性的抑制NCI-H2170肺癌细胞克隆形成,与对照相比,高浓度的500μg/mL时,克隆形成最少,抑制率接近90%。
(2)细胞侵袭实验:将transwell小室置于24孔板中,向小室上层内加入100μL按1:10的比例用1%双抗的RPMI1640培养基稀释的基质胶,待其凝固后向小室上层接种100μL用添加单抗和10%胎牛血清和1%双抗的RPMI1640培养基重悬的肺癌细胞(其中,H4G8单克隆抗体的添加终浓度分别为500μg/mL,200μg/mL,100μg/mL,10μg/mL,不加抗体的空白对照,细胞密度为2×103个/mL),并向小室下层内加入600μL添加10%胎牛血清和1%双抗的RPMI1640培养基。培养48h后用4%多聚甲醛固定15min,用结晶紫染色20min后拍照,计数小室下层肺癌细胞。结果如图4所示。
从图4可以看出,本发明的单克隆抗体也能够显著的抑制癌细胞的侵袭,并且随着单抗浓度的升高,抑制活性也是逐渐增强,与对照相比,差异及其显著(P<0.01)。
实施例6 H4G8单克隆抗体联合AOH1160的小鼠成瘤抑制实验
取3周龄雌性小鼠,实验前进行为期7天的适应性饲养,饲养环境湿度控制在50%-60%,温度控制在24℃±1℃,维持12小时明/暗循环。实验过程中小鼠可自由获取SPF级小鼠饲料及饮水。小鼠随机分为4组,每组10只。将107个NCI-H2170肺癌细胞注射入小鼠右侧腋窝皮下。随后每组按照如下条件进行治疗给药:抗体实验组:皮下注射H4G8单克隆抗体100mg/kg/5天(200μL);AOH1160实验组:皮下注射AOH1160 20mg/kg/3天(200μL);抗体联合AOH1160实验组:皮下注射H4G8单克隆抗体100mg/kg/5天同时皮下注射AOH1160 20mg/kg/3天(共200μL));对照组:皮下注射生理盐水(200μL)。给药3周后,再饲养5d,处死小鼠,切除皮下瘤。计算肿瘤体积公式为:体积=(长×宽2)/2。结果如表1所示。
表1 各治疗组对肿瘤体积的影响
从表1的结果可以看出,采用本发明的单克隆抗体和AOH116均可以显著的抑制肺癌细胞的肿瘤生长,二者与对照组相比均差异及其显著(*P<0.01)。而单抗和AOH1160联合使用后,更是显著的降低肿瘤体积与对照组相比均差异及其显著(*P<0.01),分析其协同作用原理是AOH116可以直接靶向caPCNA蛋白,而抗体可以通过靶向HOXD9的活性后进一步的影响PCNA的活性,从而起到协同降低PCNA活性的效果。
当对本发明的实施方式进行实施或试验时,可以使用与本说明书中记载的方法和材料类似或等同的任选的方法和材料,本说明书中记载了优选的方法、装置、材料。然而,在记载本发明的材料与方法之前,应当理解为,可以按照常规的实验方法以及最优化的目的来改变本说明书中记载的特定的大小、形状、尺寸、材料、方法、手段等,因此本发明不限于这些。并且应当理解为,本说明书中使用的专业术语仅用于说明特定的类型或实施方式,并不用于限制本发明的范围,本发明的范围仅受添附的权利要求的范围的限制。
Claims (6)
1.特异性针对人HOXD9 的单克隆抗体,其特征在于所述抗体的重链可变氨基酸序列如SEQ ID NO:1所示,轻链可变氨基酸序列如SEQ ID NO:2所示。
2.一种用于治疗肺癌的药物组合物,所述药物组合物包含权利要求1所述的抗体和药学上可接受的载体。
3.一种用于治疗肺癌的药物组合物,所述药物组合物包含权利要求1所述的抗体和AOH1160以及药学上可接受的载体。
4.特异性针对人HOXD9 的单克隆抗体和AOH1160在制备用于治疗肺癌的药物组合物中的用途,其中所述抗体的重链可变氨基酸序列如SEQ ID NO:1所示,轻链可变氨基酸序列如SEQ ID NO:2所示。
5.如权利要求4所述的用途,其特征在于所述的药物组合物还含有药学上可接受的载体。
6.如权利要求5所述的用途,其特征在于所述的药物组合物是注射剂型。
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