CN116655795B - 抗体及干细胞在治疗胰腺癌中的用途 - Google Patents
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Abstract
本发明涉及抗体及干细胞在治疗胰腺癌中的用途。本发明提供以EGFR作为免疫原制备并获得了特异性的单克隆抗体E‑4E5，该单克隆抗体具有剂量依赖性的抑制胰腺癌细胞的增殖，同时单独或者联合干细胞培养物使用后能够有效的促进胰腺癌细胞的凋亡，具有较好的医药应用前景。
Description
技术领域
本申请涉及生物领域，具体的涉及一种抗体及干细胞在治疗胰腺癌中的用途。
背景技术
胰腺癌（cancer of pancreas,pancreatic cancer）是消化道常见的恶性肿瘤之一，多发生于胰头部。腹痛及无痛性黄疸为胰头癌的常见症状。糖尿病患者长期大量吸烟，高脂肪高动物蛋白饮食者，发病率相对增高，本病多发于中老年人，男性患者远较绝经前的妇女多，绝经后妇女发病率与男性相仿。发病原因尚不清楚，发现些环境因素与胰腺癌的发生有关。已定的首要危险因素为吸烟，糖尿病胆石病饮酒(包括啤酒)以及慢性胰腺炎等进食高脂肪高蛋白饮食和精制的面粉食品，胃切除术也是发生胰腺癌的危险因素，其死亡率极高。
目前胰腺癌的化疗药物首选吉西他滨（GEM），与5-氟尿嘧啶（5-FU）标准疗法相比，其在提高胰腺癌患者生活质量和延长生存期方面均占优势，中位生存期为5-6个月，而1年生存率低于20%。放射治疗可以帮助改善临床症状，控制局部复发，较单纯化疗可提高10%-15%的生存期。但是目前治疗胰腺癌的三大方式都未能取得令人满意的效果。随着肿瘤靶向治疗的不断发展，分子靶向药物在治疗胰腺癌方面提供了新的可能。EGFR属于ErbB家族的酪氨酸酶激酶跨膜受体。EGFR是一种转导细胞外信号进入细胞内的细胞表面分子，在细胞的生长、分裂、修复和功能分化中起重要作用。当EGFR与配体结合后，发生二聚体化，激发胞质区中的酪氨酸残基磷酸化，从而活化了受体中酪氨酸激酶，使酪氨酸激酶作用靶蛋白的结合位点充分暴露，多条下游信号传导途径被激活，最终导致细胞增殖、入侵和转移。目前EGFR抑制剂主要包括：EGFR单克隆抗体、酪氨酸激酶抑制剂以及表皮生长因子受体2（Her-2）抑制剂3大类。
EGFR单克隆抗体西妥昔单抗是一种EGFR单克隆抗体，它竞争性结合EGFR的胞外部分，减少受体和配体的连接，抑制细胞磷酸化，导致EGFR介导的信号传导通路被阻断，从而促进肿瘤细胞的凋亡。2009年中国抗癌协会公布了C225在头颈部鳞状细胞癌（SCCHN）、转移性结肠直肠癌（mCRC）、非小细胞肺癌（NSCLC）和乳腺癌（BC）等实体肿瘤治疗中表现出了很好的效果。目前C225已被批准用于mCRC的治疗。过一项C225和GEM联合放射治疗34例EGFR阳性局部晚期胰腺癌患者的前瞻性临床试验。C225第1天初始剂量为400mg/m2，随后每周维持剂量为250mg/（m2·周）；GEM维持剂量为300mg/（m2·周）；放疗剂量为50.4Gy/周；研究时间从2008年11月至2012年1月，其中10例患者（29.4%）由于在预处理阶段出现转移性疾病而被剔除试验，3例患者拒绝放、化疗，21例患者（61.7%）完成联合治疗方案。结果显示：24%的患者部分缓解（partialresponse，PR），52%的患者表现出疾病稳定（stabledisease，SD），1年生存率和2年生存率分别为66%和28%，中位生存期（MST）为15.3个月，其中3例患者（14.3%）出现1级皮疹。C225和GEM联合放射治疗晚期胰腺癌耐受性良好，改善了胰腺癌患者的中位生存时间，提高了患者的生活质量，有望在临床上广泛的应用。但是目前可供选择的单克隆抗体的种类还有待进一步的开发和拓展。
干细胞定向分化移植在晚期胰腺肿瘤的应用已取得一定成果。NK4为肝细胞生长因子受体拮抗剂,常被作为候选靶向治疗。将带有NK4腺病毒转染的BMSCs植入大鼠胰腺癌模型体内,不仅对胰腺癌细胞有明显趋向性,而且强烈抑制胰腺癌细胞的增殖和迁移。这些研究结果表明,BMSCs可以作为胰腺癌靶向基因治疗的载体。有学者还发现与健康对照组相比胰腺癌患者高水平表达IL-6、IL-8、IL-10、TNF-α、IL-23浓度。在胰腺癌患者,IL-6、IL-8、IL-10水平,和IL-23表达与外周血骨髓间充质细胞和胚胎样干细胞水平密切相关,因此BMSCs移植可能改变胰腺癌临床症状。此外,研究发现,转染肿瘤坏死因子相关的凋亡诱导配体的BMSCs也显著抑制胰腺癌细胞的生长。采用局部放疗联合自体干细胞移植支持下的大剂量化疗治疗手术无法切除的胰腺癌,取得了较好的疗效。术后应用干细胞移植进行治疗,将给患者带来希望。
但是目前，干细胞治疗胰腺癌的药物还不够多，提供的可选择形式也不够丰富，有待进一步的开发应用。
发明内容
本发明一方面，针对胰腺癌的治疗靶点EGFR，开发了特异性的单克隆抗体E-4E5。
所述抗体具有较好的特异性和亲和力，其通过测序，鉴定得到该单抗的轻链可变区序列如SEQ ID NO：1所示，重链可变区序列如SEQ ID NO：2所示。
如本文所讨论，认为抗体或免疫球蛋白分子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。
更进一步的，本发明还提供了一种药物组合物，所述药物组合物含有本发明制备的单克隆抗体E-4E5以及药学上可接受的载体。
更进一步的，本发明还公开了单克隆抗体E-4E5在制备用于治疗胰腺癌的药物组合物中的用途。
具体的，所述的药物组合物含有药学上可接受的载体。
更进一步的，本发明还公开了单克隆抗体E-4E5在制备用于促进胰腺癌细胞凋亡的药物组合物中的用途。
进一步的，所述的组合物中的药学上可接受的载体包括，但不限于，离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人类血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和的植物脂肪酸的偏甘油酯混合物、水、盐或电解质类，如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧化丙烯-嵌段聚合物、聚乙二醇和羊毛脂。本发明的组合物可以口服、肠胃外给药，通过吸入喷雾、局部地、经直肠地、经鼻地或通过植入池给药。
任何形式的具有细胞毒性或细胞抑制性作用的部分均可结合到本发明抗体上，以形成本发明的细胞毒性结合物并抑制或杀伤特异性NK受体表达的细胞，包括发射性同位素、毒性蛋白、毒性小分子，例如药剂、毒素、免疫调节剂、激素、激素拮抗剂、酶、寡核苷酸、酶抑制剂、治疗放射性核素、血管形成抑制剂、化学治疗剂、长春碱、氨茴环霉素、表叶毒素(epidophyllotoxin)、紫杉烷、抗代谢物、烷化剂、抗生素、COX-2抑制剂、SN-38、抗有丝分裂物、抗血管形成和凋亡剂、尤其是阿霉素、氨甲蝶呤、红豆杉醇、CPT-11、喜树碱(camptothecans)、氮芥、吉西他滨、烷基磺酸盐、亚硝基脲、三氮烯、叶酸类似物、嘧啶类似物、嘌呤类似物、铂配位化合物、假单胞外毒素、蓖麻毒、相思豆毒蛋白、5-氟尿嘧啶核苷、核糖核酸酶(RNase)、脱氧核糖核酸酶I、葡萄球菌肠毒素-A，美洲商陆抗病毒蛋白、白树素、白喉毒素、假单胞菌外毒素、和假单胞菌内毒素以及其他物质。
进一步的，本发明还提供了人骨髓间质干细胞的培养上清用于促进胰腺癌凋亡中的用途。
具体的，所述的培养上清是将hMSCs进入对数生长期后弃去含15%FBS的L-DMEM培养基，PBS洗涤2次，更换培养基为只含1%ITS的L-DMEM，继续培养72h后收集培养上清，离心取上清，冷冻干燥后-70℃保存获得。
更进一步的，本发明还提供了人骨髓间质干细胞的培养上清联合单克隆抗体E-4E5在制备促进胰腺癌细胞凋亡的药物组合物中的用途。
有益效果
本发明提供以EGFR作为免疫原制备并获得了特异性的单克隆抗体E-4E5，该单克隆抗体具有剂量依赖性的抑制胰腺癌细胞的增殖，同时单独或者联合干细胞培养物使用后能够有效的促进胰腺癌细胞的凋亡，具有较好的医药应用前景。
附图说明
图1 E-4E5单克隆抗体Western blot鉴定特异性
图2 E-4E5单克隆抗体细胞学功效验证结果图
实施方式
下面将参照附图更详细地描述本发明的具体实施例。虽然附图中显示了 本发明的具体实施例，然而应当理解，可以以各种形式实现本发明而不应被 这里阐述的实施例所限制。相反，提供这些实施例是为了能够更透彻地理解 本发明，并且能够将本发明的范围完整的传达给本领域的技术人员。
尽管本文使用了特定的术语，但它们仅用于一般性和描述性的意义，而 不是为了限制的目的。除非另有定义，否则本文使用的所有技术和科学术语 具有与本公开描述的主题所属领域的普通技术人员通常理解的相同的含义。
实施例1 EGFR单克隆抗体的开发
将EGFRvIII重组蛋白（目录号:HY-P70189，MCE）作为免疫原与弗氏佐剂混合，皮下注射6周龄雌性BALB/c小鼠（60μg/只），每2周免疫1次，免疫4次后，采血，分离血清,检测效价最高的1号小鼠进行细胞融合。取小鼠脾脏，制备成单细胞悬液，与骨髓瘤细胞等比例混匀，在融合池中电融合，加入HAT-DMEM培养基，将细胞均匀铺到96孔板中培养10d后筛选检测。ELISA筛选效价高的融合细胞上清，共获得了52株阳性细胞株。将阳性反应最高的1株细胞进行亚克隆4倍稀释融合细胞悬液，均匀加入到96孔板中，10d后挑出阳性单克隆细胞，扩大培养定株。最终获取1株亚克隆细胞的上清能够结合EGFR的细胞，克隆号命名为E-4E5。
将1×107筛选后的亚克隆细胞腹腔注射BALB/c小鼠，13d左右取小鼠腹水，用0.2μm滤器过滤，用结合缓冲液按照1:1比例稀释腹水。将腹水采用柱纯化，并且纯化的抗体加入浓缩柱中，以5000rpm/min的转速离心15min，加入PBS置换获得浓缩后的单抗。采用BCA法检测抗体的浓度为10mg/mL备用。
实施例2 E-4E5单克隆抗体效价、亲和力测定
以重组蛋白EGFRvIII包板，包板浓度为5μg/mL，每孔100μL，同时设空白孔和阴性对照孔，4℃过夜。用1‰PBST液洗板后，每孔加入单克隆抗体E-4E5，按1∶1000倍比稀释，每孔100μL，振荡摇匀后，37℃置1h，洗板，加入HRP标记的羊抗鼠抗体（1∶3000稀释，每孔100μL），37℃孵育40min后用1‰PBST洗板，再以TMB显色系统显色，用酶标仪于450nm处测定各孔光密度值［D（450）］。
抗体的亲和力测定采用间接ELISA法。以获得的重组蛋白EGFRvIII包板，包板浓度分别为1、0.5、0.25、0.125μg/mL，同时设空白孔和阴性对照孔，4℃过夜。1‰PBST液洗板后用1%BSA封闭，37℃1h。洗板后每孔加入单克隆抗体E-4E5（1μg/mL），振荡摇匀后37℃置1h，洗板后加入HRP标记的羊抗鼠抗体（1：3000稀释，每孔100μL），37℃孵育40min后，用1‰PBST洗板，利用TMB显色系统显色后，用酶标仪于450nm处测定各孔光密度值［D（450）］。然后根据公式Kd=（n－1）/2（n［Ab'］－［Ab］）（式中：n=［Ab］/［Ab'］；［Ab］或［Ab'］代表间接ELISA法中达到最大光密度值一半时的抗体浓度）计算获得单抗相对亲和力。结果如表1所示。
表1 单克隆抗体E-4E5的亲和力及效价测定结果
| 抗体名称 | 效价 | 亲和力（L/mol） |
| E-4E5 | 1：2048000 | （2.52±0.08）×109 |
从表1可以看出，本发明的单克隆抗体具有较好的亲和力以及效价。
通过测序，鉴定得到该单抗的轻链可变区序列如SEQ ID NO：1所示，重链可变区序列如SEQ ID NO：2所示。
实施例3 E-4E5单克隆抗体特异性鉴定
将人胰腺癌细胞 SW1990裂解液、变性的EGFRvIII重组蛋白样品以及BSA进行SDS-PAGE蛋白电泳；电泳结束后，进行湿法转膜。封闭液室温封闭2h；用单克隆抗体作为一抗，4℃孵育过夜；PBST洗液洗膜3次，PBS洗液洗膜1次；加二抗1:5000稀释后室温孵育40min，孵育过程中轻微振荡；用PBST洗液洗膜3次，PBS洗液洗膜1次，用红外成像系统扫描。结果见图1。
从图1的结果表明，泳道1和泳道2对应的人胰腺癌细胞 SW1990裂解液、变性的EGFRvIII重组蛋白样品均能够与单克隆抗体E-4E5形成特异性的条带。而泳道3的BSA蛋白不能和抗体形成特异性的条带，这说明本发明的单克隆抗体E-4E5能够特异性的与癌细胞中的EGFR结合，也能够与重组EGFR蛋白结合，表现了较好的特异性。
实施例4 E-4E5单克隆抗体细胞学功效验证
将购买的冻存的原代人胰腺癌细胞SW1990置于37℃水浴中快速溶解，在超净台内将溶化的细胞液转移至离心管中，1000r/min离心5min，弃上清液，加入DMEM培养液1ml，吹散打匀，转至含有10%小牛血清DMEM培养液，37℃、5%CO2、饱和湿度条件下培养，24h后观察细胞并更换培养液。人胰腺癌细胞SW1990为贴壁生长细胞，换液时间为3d，传代时间为4d。取处于对数生长期的细胞，采用胰蛋白酶消化，将DMEM培养基细胞悬液浓度调整为5×105个/ml；采用96孔板，每孔加细胞悬液100μl，每孔细胞数约为5000个；5%CO2、37℃培养箱孵育细胞贴壁后，分别加入10、50、100、200μg/ml浓度的E-4E5单克隆抗体，每个浓度组设5个复孔；继续孵育，于48h后吸去培养液，每孔加100μl含MTT的DMEM培养基，继续培养4h；吸去含MTT的DMEM培养基，加入DMSO 150μl/每孔，摇床低速振荡10min，充分溶解结晶物；采用酶联免疫检测仪测量490nm波长处各孔吸光度值。同时设置调零孔，即空白对照组。采用MTT法检测不同浓度、不同作用时间E-4E5单克隆抗体对胰腺癌细胞增殖SW1990的影响，计算细胞抑制率，细胞抑制率=(1－实验组平均吸光度值)/空白对照组平均吸光度值×100%。以同浓度的西妥昔单抗作为对照。结果如图2所示。
从图2可以看出，本发明的E-4E5单克隆抗体具有剂量依赖性的抑制人胰腺癌细胞SW1990的增殖，在同浓度下，本发明的抗体具有相对于对照西妥昔单抗更好的抑制细胞增殖的活性。在浓度为100μg/ml E-4E5单克隆抗体处理时，吸光度值只有0.06±0.02，与空白对照组的1.5相比，差异极其显著。
实施例5 E-4E5单克隆抗体联合干细胞的功效实验
取培养的第三代hMSCs进入对数生长期后弃去含15%FBS的L-DMEM培养基，PBS洗涤2次，更换培养基为只含1%ITS的L-DMEM，继续培养72h后收集培养上清，离心取上清，冷冻干燥后-70℃保存备用。
胰腺癌细胞SW1990细胞系采用含10%FBS及1%双抗的RPMI-1640培养液培养，置37℃、5%二氧化碳，饱和湿度的培养箱中培养，2d换液一次，待细胞生长约90%融合后，用0.25%胰蛋白酶消化，按104/ml密度传代培养。SW1990贴壁生长约90%融合后，用0.25%胰蛋白酶消化收获，按2×105/ml密度、每孔1.5ml接种于6孔板。待细胞贴壁后，加入实验试剂：
实验一：hMSCs培养上清冻干粉RPMI-1640溶解液0.5ml/孔，终浓度为100μg/ml；
实验二：hMSCs培养上清冻干粉RPMI-1640溶解液0.5ml/孔，终浓度为300μg/ml；
实验三：E-4E5单克隆抗体，终浓度为100μg/ml；
实验四：西妥昔单克隆抗体，终浓度为100μg/ml；
实验五：hMSCs培养上清冻干粉RPMI-1640溶解液0.5ml/孔，终浓度为100μg/ml，同时添加E-4E5单克隆抗体，终浓度为100μg/ml；
实验六：hMSCs培养上清冻干粉RPMI-1640溶解液0.5ml/孔，终浓度为100μg/ml，同时添加西妥昔单克隆抗体，终浓度为100μg/ml；
对照组为无血清L-DMEM 0.5ml/孔。继续培养24h后，用0.25%胰蛋白酶（不含EDTA）消化收获SW1990，2000r/min离心5min，PBS洗涤、离心两次。将细胞移入流式管，调整每管细胞数量为5×105，结合缓冲液重悬至500µl。对照组细胞取4管，分别为AnnexinV-FITC及PI双标、AnnexinV-FITC单标、PI单标、无标记组；实验组为AnnexinV-FITC和PI双标。根据分组情况加入AnnexinV-FITC 5µl和（或）PI5µl。轻柔混匀，室温、避光孵育15min后流式细胞仪检测凋亡率，结果如表2所示。
表2
| 组别 | 凋亡率 |
| 对照组 | 0.0945±0.0003 |
| 实验组一 | 0.1568±0.0018* |
| 实验组二 | 0.1983±0.0021* |
| 实验组三 | 0.3517±0.0057* |
| 实验组四 | 0.2981±0.0031* |
| 实验组五 | 0.4686±0.0062*# |
| 实验组六 | 0.3948±0.0059*# |
*表示与空白对照组相比，差异显著（P<0.01）;#表示与与实验组一相比，差异显著（P<0.01）
从表2可以看出，hMSCs培养上清冻干粉作用24h后，实验组凋亡率与对照组相比，实验组细胞凋亡率随着浓度升高而升高，组间差异有显著性意义（P<0.05）。并且，单抗组比干细胞组的凋亡率更高，具有更好的促进细胞凋亡效果，而将单抗与干细胞一起使用后，能够显著的提高癌细胞的凋亡率，具有较好的应用价值。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中的知识说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等同物界定。
Claims (6)
1.一种特异性靶向EGFR的单克隆抗体，其特征在于，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。
2.编码如权利要求1所述的单克隆抗体的核苷酸。
3.一种表达载体，包括编码如权利要求2所述单克隆抗体的核苷酸。
4.一种宿主细胞，其包含权利要求3所述的表达载体。
5.如权利要求1所述的单克隆抗体在制备抑制胰腺癌细胞增殖的产品中的应用。
6.骨髓间充质干细胞培养物和权利要求1所述的单克隆抗体在制备促进胰腺癌细胞凋亡的药物组合物中的用途；其中，骨髓间充质干细胞培养物是取培养的第三代hMSCs进入对数生长期后弃去含15%FBS的L-DMEM培养基，PBS洗涤2次，更换培养基为只含1%ITS的L-DMEM，继续培养72h后收集培养上清，离心取上清，冷冻干燥后制得。
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| CN106800599A (zh) * | 2016-12-05 | 2017-06-06 | 中国人民解放军第二军医大学 | 抗人EGFR和Notch多特异性抗体、其制备方法及用途 |
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| CN106800599A (zh) * | 2016-12-05 | 2017-06-06 | 中国人民解放军第二军医大学 | 抗人EGFR和Notch多特异性抗体、其制备方法及用途 |
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