CN114316018A - 一种fgf21蛋白类似物及其应用 - Google Patents
一种fgf21蛋白类似物及其应用 Download PDFInfo
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- CN114316018A CN114316018A CN202111423760.XA CN202111423760A CN114316018A CN 114316018 A CN114316018 A CN 114316018A CN 202111423760 A CN202111423760 A CN 202111423760A CN 114316018 A CN114316018 A CN 114316018A
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Abstract
本发明属于医药技术领域,涉及一种FGF21蛋白类似物及其应用,该FGF21蛋白类似物的氨基酸序列如SEQ ID NO.1‑3中任一所示,能够用于制备预防、缓解和/或治疗前列腺癌的药物。本发明发现FGF21基因的新功能,能够显著降低肿瘤病灶的大小,因而可作为各种剂型药物的有效成分,对于前列腺癌的治疗具有极其重大的意义;通过口服或注射FGF21蛋白类似物,可缓解前列腺癌的发生和发展,抑制前列腺癌的生成和转移。
Description
技术领域
本发明属于医药技术领域,涉及一种FGF21(人成纤维细胞生长因子21) 蛋白类似物及其应用,用于制备预防、缓解和/或治疗前列腺癌的药物。
背景技术
2012年我国肿瘤登记地区前列腺癌发病率为9.92/10万,列男性恶性肿瘤发病率的第6位。发病年龄在55岁前处于较低水平,55岁后逐渐升高,发病率随着年龄的增长而增长,高峰年龄是70-80岁。家族遗传型前列腺癌患者发病年龄稍早,年龄≤55岁的患者占43%。目前,前列腺癌的治疗主要以外科根治手术为主,化疗、放疗、中医药治疗及生物治疗作为其辅助性治疗手段。首次诊断的病人中大约有三分之二接受了根治术,其中超过一半的患者出现复发或远处转移。对晚期癌肿或有广泛转移的癌肿,不能进行根治性手术,内科综合治疗常成为主要治疗手段,在可手术的患者中,前列腺癌术后仍有较高的复发率。而常用的治疗药物通常为广谱类化学药物,具有较多的副作用。因此,开发一种安全的、同时具有抑制肿瘤生长和复发且器官保护效应的、无相关明显副作用的、安全的治疗前列腺癌药物是目前研发的理想目标。
近年来,大量临床调查结果显示前列腺癌癌的发生发展与代谢异常存在十分紧密的联系。大量研究发现代谢通路包括糖酵解、三羧酸循环、脂肪酸代谢、谷氨酰胺代谢等在肿瘤细胞中均发生了重编程变化,肿瘤细胞可通过对各种代谢途径间的协调,提供增殖所必须的脂肪酸、核苷酸等,从而使生物大分子的合成过程更适合于肿瘤细胞的快速增殖。尤其需要指出的是,代谢异常并不仅仅是肿瘤发生发展的结果,还可能直接参与肿瘤的始发过程。目前,从代谢的角度开发抗肿瘤药物,已在诸多的肿瘤中获得了成功的应用,比如,最近的研究发现某些编码代谢酶类的基因本身就是癌基因,如延胡索酸羧化酶的突变与肾癌的发生、发展;琥珀酸羧化酶的突变与嗜铬细胞瘤的发生、发展;异柠檬酸脱氢酶的突变产生代谢物小分子2HG抑制HNF4α的表达从而诱导胆管癌等。基于以上分析表明靶向肿瘤细胞代谢可能是杀死肿瘤细胞的有效途径之一。然而,目前开发的药物都是一些小分子抑制剂,靶向性较弱,副作用较多,而生物蛋白类药物吸收快,靶向性强。因此,针对前列腺癌开发新型靶向生物蛋白类制剂是目前肿瘤研究的热点。
发明内容
本发明经过大量的研究发现,作为参与糖脂代谢网络多个环节的重要成员的FGF21可以显著抑制前列腺癌的发生发展以及转移。基于此,本发明提供了一种FGF21蛋白类似物及其在制备预防、缓解和/或治疗前列腺癌的药物方面的新用途。
按照本发明的计算方案,所述FGF21蛋白类似物的氨基酸序列如SEQ ID NO.1-3中任一所示。
本发明的第二方面提供了上述FGF21蛋白类似物在制备预防、缓解和/或治疗前列腺癌的药物中的应用。
进一步的,所述FGF21蛋白类似物的有效剂量为0.1-10mg/kg。
本发明的第三方面提供了一种预防、缓解和/或治疗前列腺癌的药物,以上述FGF21蛋白类似物为有效成分。
进一步的,还包括药学上可接受的修饰、载剂或辅料。
进一步的,所述药物的给药途径包括口服、腹腔注射、皮下注射、静脉注射或肌肉注射。
本发明的第四方面提供了编码上述FGF21蛋白类似物的基因,其序列如 SEQ IDNO.4-6中任一所示。
本发明的第五方面提供了上述基因作为药物靶标在筛选具有治疗前列腺癌的药物中的应用。
本发明的第六方面提供了携带上述基因的载体和/或微生物细胞。
本发明的技术方案相比现有技术具有以下优点:
(1)本发明发现FGF21基因的新功能,能够显著降低肿瘤病灶的大小,因而可作为各种剂型药物的有效成分,对于前列腺癌的治疗具有极其重大的意义。
(2)本发明通过口服或注射FGF21蛋白类似物,可缓解前列腺癌的发生和发展,抑制前列腺癌的生成和转移。
附图说明
图1为FGF21蛋白类似物对人前列腺癌移植瘤体积的影响图。
图2为FGF21蛋白类似物对人前列腺癌移植瘤质量的影响图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实验动物及饲养:裸鼠购于江苏集萃药康生物科技有限公司。饲养于江南大无锡医学院动物中心,每12小时交替照明,温度20±2℃。
细胞培养:前列腺癌细胞系DU145由中国科学院生物化学与细胞生物学研究所提供;
DMEM、0.05%Trypsin,购于博士德公司;胎牛血清购于四季青公司。其他药品为国产分析纯。前列腺癌细胞系贴壁生长于含10%胎牛血清的DMEM培养液中,于37℃,5%CO2湿化培养箱中培养,隔天传代一次。
实施例1 FGF21在制备药物中的应用
FGF21蛋白通过培养微生物细胞制备获得,制备方法已公开于授权专利号为ZL202110269910X的专利申请中。
具体如下:
(1)FGF21-1、FGF21-2和FGF21-3表达载体的构建
根据计算机模拟替换及大肠杆菌密码子偏好性,设计出3种新型FGF21基因,其核苷酸序列分别如序列表中FGF21-1(SEQ ID NO.4)、FGF21-2(SEQ ID NO.5)、FGF21-3(SEQID NO.6)所示。将这3种基因送至上海捷瑞生物公司合成,同时在各基因两端设计NdeI与BamHI两酶切位点。将3种合成的含有各自目的基因片段的载体和pET30a(+)分别用NdeI与BamHI双酶切,酶切完毕后,胶回收各自需要的目标片段。使用T4DNA连接酶将3种目的片段分别与原核表达载体pET30a(+)连接,连接反应体系为10μL,混匀,4℃连接过夜,然后各自转化至大肠杆菌DH5α中。挑取阳性克隆,经过酶切鉴定后,即分别构建得到4种重组质粒pET30a-FGF21-1、pET30a-FGF21-2和pET30a-FGF21-3。
(2)蛋白的表达及纯化
将含有正确序列的重组质粒pET30a-FGF21-1、pET30a-FGF21-2和 pET30a-FGF21-3转化至表达菌株Rosseta(DE3)感受态细胞中。转化后的单菌落分别接种至20mL含Kan(50μg/mL)的LB培养基中,37℃培养8h,以体积比为 1:100接种于另一20mL含Kan(50μg/mL)的LB培养基中,37℃培养,当A600 在0.35左右时,加入IPTG至终浓度为0.25mmol/L进行诱导,诱导温度为30℃, 5h后收获菌体,用Lysisbuffer(20mmol/LTris,150mmol/LNaCl,pH8.0)重悬菌体,破碎菌体后离心,分别取上清和沉淀进行12wt%SDS-PAGE电泳分析。结果显示FGF21-1、FGF21-2和FGF21-3蛋白在大肠杆菌中表达量显著增加,目标蛋白大部分以包涵体形式存在。
收集大量诱导后的菌体,向菌体中加入溶菌酶(1mg/mL),冰上放置30min,超声波细胞破碎菌体细胞(工作1s,间隔1s,4min/次,共3次循环)。菌体破碎彻底后,利用QuixStand预处理系统(750kD超滤中空纤维柱)处理细胞破碎液,富集包涵体,弃去膜透过端液体。当总体积约为60mL时,加入 100mLwashbuffer(20mmol/LTris,2mol/LUrea,150mmol/LNaCl,pH8.0)洗涤包涵体。当溶液体积为50mL,再向其中加入洗涤液100mL,重复上述操作4次。洗涤完毕后,当溶液体积为50mL,关闭透过端,向洗涤后的包涵体中加入150mL 的变性液(20mmol/LTris,10mol/LUrea,150mmol/LNaCl,pH8.0),循环变性 2小时。打开透过端,膜透过端收集液即为mFGF21变性液。用5KD中空纤维柱对变性后的mFGF21进行浓缩,至体积80mL后进行复性,将装有复性液(20mmol/LTris,50mmol/LNaCl,pH8.0)的容器用胶皮管与中空纤维柱的储液器连接。储液器密封后,透过端流出液体后,由于储存器中产生负压,使复性液以一定的速度滴加至变性液中,缓慢匀速复性。当加入复性液体积为变性液6 倍时,即复性完毕,8000rpm/min,4℃离心20min,收集上清。复性上清液经AKTApurifier100系统,与5倍柱体积IEXbufferA(20mmol/LTris、10mmol/LNaCl, pH8.0)平衡好的CaptoQ柱(装于XK16/20空柱,柱高10cm,流速300cm/h)完全结合后,用3-4倍柱体积IEXbufferA冲洗;当紫外曲线达到稳定的基线时,利用IEXbufferA和IEXbufferB(20mmol/LTris,1mol/LNaCl,pH8.0)混合液洗脱,15wt%和100wt%IEXbufferB液冲洗杂蛋白,18.5wt%-19wt%IEXbufferB液洗脱目标蛋白,收集各洗脱峰,并进行15wt%SDSPAGE电泳分析,结果显示纯化后蛋白纯度在95%以上。
将微生物细胞制备的获得FGF21蛋白与药学上可接受的修饰、载剂或辅料共同用于制备药物,所述药学上可接受的修饰、载剂或辅料可以为PEG修饰、 FC修饰、赋形剂、佐剂和/或稀释剂等。
实施例2 FGF21对人前列腺癌移植瘤生长速度的影响
按照实施例1的方法制备氨基酸序列如SEQ ID NO.1所示的FGF21蛋白。
将人前列腺癌细胞DU145细胞按照1×106个细胞/只接种6周龄的雄性裸鼠的皮下,待肿瘤长至200mm3随机分为四组,①生理盐水组:注射等体积生理盐水;②低剂量组:注射1mg/kg FGF21;③中剂量组:注射5mg/kg FGF21;④高剂量组:注射10mg/kgFGF21。每天注射一次,连续注射15天。每天监测肿瘤体积,三周后处死小鼠,称量肿瘤重量。结果显示:三种不同剂量的FGF21均能抑制移植瘤体积和最终肿瘤重量,且呈现剂量依赖性。高剂量FGF21 (10mg/kg)注射后,可完全抑制肿瘤生长,使肿瘤维持在700mm3,最终体积仅为对照组的21.5%,同样肿瘤质量也下降了约67%,注射1mg/kg和5mg/kg 分别能使肿瘤质量下降50%和55%(如图1、2所示)。
对SEQ ID NO.2~3所示的FGF21蛋白的在治疗前列腺癌方面的效果进行了研究,结果显示,如SEQ ID NO.2~3任一所示的FGF21蛋白与SEQ ID NO.1所示的FGF21蛋白具有相当的效果。
显然,上述实施例仅仅是为清楚地说明所作的举例,并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
SEQUENCE LISTING
<110> 江南大学
<120> 一种FGF21蛋白类似物及其应用
<130> 12
<160> 6
<170> PatentIn version 3.3
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cgtttcctgc cgttgccggg tctgccgccg gctctgccgg agccgcctgg catcctggca 1200
ccgcaaccgt tagaaaccga cagcatggat ccgtttggct tggttaccgg tttggaggct 1260
gtgcgctctc cgtccttcga aaaataa 1287
Claims (9)
1.一种FGF21蛋白类似物,其特征在于,所述FGF21蛋白类似物的氨基酸序列如SEQ IDNO.1-3中任一所示。
2.如权利要求1所述的FGF21蛋白类似物在制备预防、缓解和/或治疗前列腺癌的药物中的应用。
3.如权利要求2所述的应用,其特征在于,所述FGF21蛋白类似物的有效剂量为0.1-10mg/kg。
4.一种预防、缓解和/或治疗前列腺癌的药物,其特征在于,以权利要求1所述的FGF21蛋白类似物为有效成分。
5.如权利要求4所述的药物,其特征在于,还包括药学上可接受的修饰、载剂或辅料。
6.如权利要求4所述的药物,其特征在于,所述药物的给药途径包括口服、腹腔注射、皮下注射、静脉注射或肌肉注射。
7.编码权利要求1所述FGF21蛋白类似物的基因。
8.如权利要求7所述的基因作为药物靶标在筛选具有治疗前列腺癌的药物中的应用。
9.携带权利要求7所述基因的载体和/或微生物细胞。
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