CN105061567A - 免疫受体调节剂偶联体及其制备方法和应用、制备其的偶联前体以及合成偶联前体的化合物 - Google Patents
免疫受体调节剂偶联体及其制备方法和应用、制备其的偶联前体以及合成偶联前体的化合物 Download PDFInfo
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- CN105061567A CN105061567A CN201510253948.2A CN201510253948A CN105061567A CN 105061567 A CN105061567 A CN 105061567A CN 201510253948 A CN201510253948 A CN 201510253948A CN 105061567 A CN105061567 A CN 105061567A
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Classifications
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- C—CHEMISTRY; METALLURGY
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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Abstract
一种免疫受体调节剂偶联体,其由偶联前体和生物配体反应得到,偶联前体为9位胺甲基苄基嘌呤类生物偶联前体,生物配体选自多肽、蛋白、糖蛋白、多糖、多聚核苷及酸、灭活的细胞和灭活的微生物的一种或多种。偶联体为具有以下通式的化合物:本发明中的免疫受体调节剂偶联体可应用于免疫调节、抗体制备、抗病毒、糖尿病、肿瘤免疫调节和肿瘤生物免疫治疗。上述偶联体化合物或它们的盐可制成各种治疗药物、可与其他药物制成复方药物、或制成药学上可接受的载体的复合物或结合物。本发明还涉及用于合成上述偶联前体的化合物或它们的盐。
Description
本申请是2012年10月10日提交的申请号为201210382202.8、发明名称为“免疫受体调节剂偶联体及其制备方法和应用、制备其的偶联前体以及合成偶联前体的化合物”的申请的分案申请。
技术领域
本发明涉及一种免疫受体调节剂偶联体、该偶联体的制备以及该偶联体在抗肿瘤、抗病毒、糖尿病、抗体诱导和免疫调节中的应用。本发明尤其涉及用于制备上述免疫受体调节剂偶联体的9位胺甲基苄基嘌呤类生物偶联前体。进一步地,本发明还涉及合成上述偶联前体的化合物或其盐。
背景技术
免疫激动剂和免疫抗原(如多肽、蛋白、糖蛋白、多糖、多聚核苷酸、细胞裂解物、灭活的细胞和灭活的微生物等)的联合应用或者偶联,往往产生提高的免疫效应(WorldChinJDigestol2005September15,13(17):2078-2081;Vaccine,Volume23,Issue45,1November2005,Pages5263-5270;TheJ.Clin.Invest.2011,121(5),1782-1796)。
本发明制备了一类小分子免疫激动剂偶联前体及其和生物配体或免疫抗原合成的偶联体,并公开了所制备的偶联体在抗肿瘤、抗病毒、糖尿病、抗体诱导和免疫调节中的应用。
发明内容
本发明的目的在于,提供具有增强的免疫效应的免疫受体调节剂偶联体及其制备方法。本发明的目的在于,提供用于制备上述偶联体的偶联前体及合成这些偶联前体的化合物或它们的盐。本发明的另一目的在于,提供所制备的免疫受体调节剂偶联体在免疫调节、抗体制备、抗病毒、糖尿病、肿瘤免疫调节和肿瘤生物免疫治疗中的应用。
根据本发明的一个方面,提供一种免疫受体调节剂偶联体,所述偶联体由偶联前体和生物配体反应得到,所述偶联体为具有以下通式[Ⅰ]的化合物:
式[Ⅰ]中:R2表示所述生物配体,X1表示OH或SH,R1表示直链烷基、支链烷基、取代烷基、未取代烷基或烷氧基烷基,X2表示偶联基团;m和n均为1~10的整数;m为小分子激动剂的数目(m定义为偶联度),n为生物配体的数目
当所述偶联前体为式1的化合物时:
所述X2表示硫代羰基基团:
当所述偶联前体为式2的化合物时:
所述X2表示如下基团:
当所述偶联前体为式3的化合物时:
式3中,u为0~12的整数;
X2表示如下基团:
其中u为0~12的整数;
当所述偶联前体为式4的化合物时:
式4中,PEG表示聚乙二醇基团;
X2表示如下基团:
在上述免疫受体调节剂偶联体中,生物配体选自多肽、蛋白、糖蛋白、多糖、多聚核苷及酸、灭活的细胞和灭活的微生物的一种或多种。
在上述免疫受体调节剂偶联体中,PEG为聚乙二醇基团如二聚乙二醇基团为三聚乙二醇基团为四聚乙二醇基团为等。
当偶联前体为式3或式4的化合物时,以OCT4、SOX2、NANOG、MUC1,MG7、POSTN、Twist、Anxa1、Akt、CD47、Sp17、PSMA、M2e(单体和四聚体)、NP366-374(9肽表位)、FOXO1、PEAK1、HER2、MMP-10、PD-L1、PD-1、SGLT2等为例作为生物配体R2形成的蛋白的偶联体的典型代表结构式如下:
在式5和式6中,“或R2”表示OCT4和SOX2可以被其它抗原、蛋白或多肽取代:NANOG分别取代形成化合物5-3和6-3、MUC1分别取代形成化合物5-4和6-4,MG7分别取代形成化合物5-5和6-5、POSTN分别取代形成化合物5-6和6-6、Twist分别取代形成化合物5-7和6-7、Anxa1分别取代形成化合物5-8和6-8、Akt分别取代形成化合物5-9和6-9、CD47分别取代形成化合物5-10和6-10、Sp17分别取代形成化合物5-11和6-11、PSMA分别取代形成化合物5-12和6-12、M2e(单体和四聚体)分别取代形成化合物5-13和6-13、NP366-374(9肽表位)分别取代形成化合物5-14和6-14、SGLT2分别取代形成化合物5-15和6-15、PEAK1分别取代形成化合物5-16和6-16、HER2分别取代形成化合物5-17和6-17、MMP-10分别取代形成化合物5-18和6-18、PD-L1分别取代形成化合物5-19和6-19,PD-1分别取代形成化合物5-20和6-20。上述化合物具体如下表1和2所示:
表1式3的偶联前体与不同生物配体形成的偶联体化合物
表2式4的偶联前体与不同生物配体形成的偶联体化合物
其中OCT4、SOX2和NANOG为肿瘤干细胞抗原蛋白(中国医药导报,2011,8(8):17-20;生命科学,2004,16(3),129-134),MG7是胃癌相关抗原蛋白(中国癌症杂志,2010年第20卷第4期,312-313),MUC1为多种肿瘤相关抗原(EuropeanJournalofOrganicChemistry,2011,20(21):3685-3689),POSTN是肿瘤相关蛋白(Nature,2012,481:85-89),Twist和Akt均为肿瘤相关抗原(沈阳医学院学报,2010,第12卷,第3期,182-184),Anxa1在多种肿瘤组织中特异表达(PNAS,2011,October3,19587-19592;癌症进展,20l0年l月,第8卷,第l期,63-66),CD47在几乎每种癌细胞表面都高表达(Science:TranslationalMedicine,22December2010Vol2Issue6363ra94)。Sp17是在卵巢癌细胞异常高表达的肿瘤抗原(PloSONE,2010,5(5),e10471,1-13)。PSMA是前列腺癌的特殊标记物(Cancer,1998,82(11):2256-2261.)。M2e和NP366-374是A型流感保守蛋白的表位多肽;SGLT2是和糖排泄有关的功能蛋白(ChineseJournalofMedicinalChemistry,2011,Vol.21,No.4,p322)。PEAK1是胰腺癌早期生物标志物(CancerRes.2012May15;72(10):2554-64)。HER2是原癌基因人类表皮生长因子受体2(MEDICALJOURNALOFCASC,2002,4(1),69-70)。MMP-10是与肺癌发生与转移密切相关的蛋白(AnticancerRes.2007Jul-Aug;27(4C):2791-5.)。PD-L1和PD-1是肿瘤免疫逃逸的配体和受体(N.Engl.J.Med.,2012,Jun2.,1-11)。
当偶联前体为式1或式2的化合物时,以MUC1(表位,),MG7、M2e(单体)为例作为生物配体R2形成的多肽的偶联体的典型代表合成及其结构式如下:
在本发明的免疫受体调节剂偶联体中,可用的生物配体也并不受限于以上所列举的多肽或蛋白,其可以为表3中所示的各种肿瘤抗原。
表3可用的肿瘤抗原形式的生物配体
(表2中的各种肿瘤抗原的特性和制备、来源,可参看文献(ClinCancerRes,2009;15(17),5323-5337)
偶联前体的制备:
偶联前体化合物1的合成——合成路线如下:
其中式7的化合物的制备方法参考WO2009005687中化合物1096159-02-2P。
合成方法:将化合物7(5克)溶解于100毫升甲醇,加入0.5克活性镍,在3个大气压下,室温氢化还原24小时。过滤出催化剂镍,减压浓缩至较小体积,于-10度冷冻12小时,析出固体产品8(3克,收率60%),熔点265-267℃,质谱(ESI,M+1):345。
将化合物8(1克,2.9mmol))与2毫升二硫化碳,0.5毫升三乙胺,0.1克DMAP,(BOC)2O(640毫克)与50毫升二氯甲烷混合,室温搅拌2小时,加热回流4小时,减压浓缩,硅胶柱层析分离(5%甲醇-二氯甲烷),得化合物1(0.7克,收率65%),熔点221-223℃,质谱(ESI,M+1):373。
偶联前体化合物2的合成——合成路线如下:
合成方法:将化合物8(1克)与9(0.78克)混合溶解于30毫升DMF中,室温搅拌2小时。减压浓缩,硅胶柱层析分离(乙酸乙酯),得化合物2(1.1克,收率82%),熔点203-205℃,质谱(ESI,M+1):496。
偶联前体化合物3-1(u=2)的合成——合成路线如下:
合成方法:将化合物8(1克)与丁二酸酐(0.3克)混合溶解与DMF(50毫升),室温搅拌12小时,加入0.34克的N-羟基丁二酰亚胺,和等摩尔的DCC,室温继续搅拌12小时,得化合物3的DMF溶液。将此混合溶液减压蒸馏至干,用乙酸乙酯(50毫升)提取残余固体,提取液加入等体积乙醚,-10度冷冻12小时,析出固体3(u=2)(0.6克,收率38%),质谱(ESI,M+1):542.
偶联前体化合物4-1的合成——合成路线如下:
其中化合物11的合成参考文献:申请号为No.2011134669、公开日为2011年11月3号的PCT专利申请。
注意:1)特定选择性按比例增加,2)特定选择性按比例增加,3)按比例增加反应物:3,试剂:3,溶剂3,步骤:3,阶段:3
化合物12的合成:按照化合物8的合成方法,收率88%,质谱(ESI,M+1)329.
化合物13的合成:将化合物12(1克)溶解于二氯甲烷(50毫升)中,加入10毫升溴素,室温搅拌12小时。鼓入空气将过量溴素吹出吸收于饱和碳酸氢钠溶液。残余固体过滤,得淡黄色固体13(1克),收率85%。质谱(ESI,M+1)407.
化合物15的合成:将化合物13(0.5克)溶解于10毫升干燥的DMF中,加入14(0.24克),搅拌均匀后,与0℃下,加入DCC(0.26克),0度搅拌2小时,室温12小时。过滤出DCU,溶液减压蒸馏干,残余加入50毫升饱和碳酸氢钠溶液,于40℃搅拌4小时,冷却下用浓盐酸中和至pH4,析出固体过滤,水洗,干燥,得化合物15(0.5克,收率72%),质谱(ESI,M+1)567.
化合物16的合成:将化合物15(0.4克)溶解于甲醇20毫升,加入硫脲(1克),混合物加热回流12小时,冷却,过滤,滤液减压浓缩,残余物溶解于10毫升5%碳酸钠溶液,冷却下用浓盐酸中和至pH4,析出固体过滤,水洗,干燥,得化合物16(0.23克,收率65%),质谱(ESI,M+1)521.
偶联前体4的合成:将化合物16(0.15克)溶解于5毫升干燥的DMF中,加入N-羟基丁二酰亚胺(0.04克),搅拌均匀后,与0℃下,加入DCC(0.06克),0度搅拌2小时,室温12小时。过滤出DCU,溶液减压蒸馏干,用乙酸乙酯(10毫升)提取残余固体,提取液加入等体积乙醚,-10度冷冻12小时,析出固体4(0.05克,收率32%),质谱(ESI,M+1):618。
本发明中的免疫受体调节剂偶联体可用于恶性肿瘤的免疫治疗和免疫调节,其用药方法可为腹腔注射、皮下注射、肌肉注射和静脉注射;或者可采用将本发明中的免疫受体调节剂偶联体和免疫细胞(如树突状细胞、自然杀伤细胞NK、淋巴细胞、单核/巨噬细胞、粒细胞等)共培养后,分离免疫细胞体内回输的方法。
本发明中的免疫受体调节剂偶联体可应用于免疫调节、抗体制备、抗病毒、糖尿病、肿瘤免疫调节和肿瘤生物免疫治疗。上述偶联体化合物或它们的盐可制成适用于上述各种治疗药物、可与其他药物制成复方药物、或制成药学上可接受的载体的复合物或结合物。本发明的免疫受体调节剂偶联体或它们的盐可制成各种比例的治疗药物中。
附图说明
以下将结合附图和具体示例对本发明做进一步详细说明。附图中:
图1a是不同浓度的偶联前体3(式3表示的化合物)的紫外吸收图谱;
图1b是根据图1a中的紫外吸收数据绘制的偶联前体3的浓度-紫外吸收的线性回归曲线;
图1c是由偶联前体3形成的偶联体5(式5表示的化合物)的紫外吸收图谱;
图2是偶联体1-2的IFN-γ诱导对比图,其中T7为偶联前体1,T7-MUC1为偶联体1-2;
图3是偶联体2-1的IL-12诱导对比图,其中T7为偶联前体2,T7-M2e为偶联体2-1;
图4是偶联体5(m=5)的抑瘤效果的示意图,其中T7为偶联前体10,T7-OCT4为偶联体5(m=5),*p<0.001;
图5是偶联体6-17(m=5)的抑瘤效果的示意图,其中T7为偶联前体10,T7-HER2为偶联体6-17(m=5),*p<0.001;
图6是流感保守蛋白M2e偶联体(T7-M2e)的体内抗体诱导效果示意图(与原始抗原M2e形成对比);
图7是尿糖再吸收功能蛋白SGLT2的免疫诱导效应的示意图,其中T7-SGLT2为偶联体5-15。
具体实施方式
抗原来源说明:所有蛋白的分子量参考国际蛋白库数据(http://www.uniprot.org/uniprot/P48432)。
蛋白或者多肽来源:除了给出的特定制备方法或合成方法外,其余的多肽合成由深圳翰宇药业股份有限公司合成。
蛋白制备自以下公司购买或制备:
南京金斯瑞生物科技有限公司(http://www.genscript.com.cn/index.html);
上海近岸蛋白质科技有限公司(http://www.sinobio.net/);
北京义翘神州生物技术有限公司(http://www.sinobiological.cn/);
亚诺法生技股份有限公司(http://www.abnova.com/cn/)。
物质鉴定质谱仪型号:LDI-1700激光解吸电离飞行时间质谱,生产商:美国LinearScientific公司。
质谱确定偶联度的方法如下举例:POSTN的平均分子量为86kDa(参考文献WorldJGastroenterol,2007October21;13(39):5261-5266;http://www.sinobiological.cn/Periostin-Protein-g-465.html),质谱鉴定所得偶联产物5-6的分子量为88132,计算(88132-86000)/427=4.99︾5;(其中427为化合物3减去一个水分子以后的分子量),确定偶联了5个化合物3的单体(偶联度m=5)。
各个抗原偶联化合物的偶联度(m)除了可用蛋白质谱鉴定外,还可应用紫外光谱法确定,方法如下(以化合物5为例):
化合物3的UV单独的吸收峰在324nm。化合物5化学偶联3后的紫外吸收峰在348nm。图1a先以不同浓度的化合物3测定其紫外吸收,再将得出的数据进行线性回归,得到图1b,而化合物5的紫外吸收峰在348nm,在已知OCT4的浓度下测定化合物5的吸收度图1c,再代入线性回归方程(y=bx+a,其中y为吸收度,x为化合物3的相当浓度,b为常数,a为修正差值,即可得出化合物5的浓度,再比上OCT4的浓度,可以算出其比例大约为5:1,即偶联度m=5。
以下通过具体示例来详细说明本发明的偶联体的制备。
化合物1-1的合成:
将MG7(0.37mmol)和化合物1(0.88mmol)混合溶解于无水甲醇,加入无水三乙胺(1.12mmol),混合物于45℃反应4小时。减压蒸除溶剂,残余硅胶柱层析分离(10%甲醇-二氯甲烷),得化合物1-1(55mg,收率23%)。MS(ESI)理论值m/z969.1516,found970.1518(M+H)。
化合物1-2的合成:
参照化合物1-1的合成方法,将MUC1(表位)和化合物1以摩尔比1:1混合,加入1.5倍摩尔的三乙胺,于甲醇中反应,反应温度控制在20℃,反应12小时。后处理同上,得化合物1-2(收率20%)。MS(ESI)理论值m/z3341.72,found3342.75(M+H)。
化合物1-3的合成:
参照化合物1-1的合成方法,将M2e和化合物1以摩尔比1:1混合,加入1.5倍摩尔的三乙胺,于甲醇中反应,反应温度控制在20℃,反应12小时。后处理同上,得化合物1-3(收率25%)。MS(ESI)理论值m/z3303.32,found3304.33(M+H)。
化合物2-1的合成:
将化合物2(0.22mmol)与M2e(0.1mmol)混合于10毫升无水DMSO中,室温搅拌12小时。混合物中加入100毫升水,冷冻干燥除去溶剂,残余硅胶柱层析分离(10%甲醇-二氯甲烷),得化合物2-1(56mg,收率15%)。MS(ESI)理论值m/z3761.71,found3761.75(M+H)。
化合物5的制备:
1)OCT4的表达制备,参照文献《现代生物医学进展》(PogressinModernBiomedicineVol.10NO.09MAY.2010,1610---1612)。
2)化合物5(m=5)的合成:
将10mg的OCT4(平均分子量38216)溶解于10mL的PBS溶液。50mg化合物3(u=2)的2mL的DMSO溶液与等摩尔的NHS混合,加入等摩尔的EDC.于室温搅拌2小时,将OCT4的PBS溶液加入混合于10℃搅拌过夜。用PD-10脱盐柱分离(AmershamdisposablePD-1desaltingcolumn),将含产品偶合物5的流出液(用320nm吸收波检测)合并,冷冻干燥.用质谱确定平均分子量为40348。确定产品5包含了5个化合物3(u=2)的对应单体(即偶联度m等于5)。用同样的方法不同摩尔比的3(u=2),合成了5(m=1、2、3、4)。
化合物5-4的合成:
(1)MUC1(表位)的制备,参考以下文献方法:
[1]ProcNatlAcadSci.2011,109(1):261-266.
[2]AngewChemIntEdEngl,2010,49(21):3688–3692.
[3]AngewChemIntEdEngl,2011,50(7):1635–1639.
[4]EuropeanJournalofOrganicChemistry,2011,20(21):3685-3689.
[5]Chemistry,2011,17(23):6396-6406.
MUC1(表位)的分子量为2967(参考文献[1]中化合物11)。
(2)将偶联前体3(u=2)(10mg,0.019mmol)溶解于2毫升DMSO溶液,加入MUC1(表位)(59mg,0.02mmol),室温搅拌2小时,混合物中加入20毫升水,冷冻干燥除去溶剂,残余硅胶柱层析分离(10%甲醇-二氯甲烷),得化合物5-4(16mg,收率25%)。质谱MS(ESI):3396.6(M+H)。偶联度m=1。
化合物5-14的合成:
参照化合物5-4的合成方法,将NP366-374(ASNENMDAM)代替MUC1(表位),其余溶剂和反应物摩尔比相同,得化合物5-14,质谱MS(ESI):1424.54(M+H)。偶联度m=1。
以下偶联化合物的合成:
如果抗原是蛋白,则参照化合物5的方法合成,如果是多肽(aa数目小于50),则参照化合物5-4的合成方法(溶剂和反应物摩尔比相同,反应时间、温度、分子量、偶联度等确定以及方法步骤条件相同),得下表所示的各个偶联产物:
R2代表多肽或蛋白
偶联化合物6的制备:
SOX2的制备:参考文献JournalofHuazhongNormalUniversity(Nat.Sci.),2008,42(1),102-105。
Sp17的制备参考文献(中国病理生理杂志,2001,17(10),1019-1021)。PSMA的制备参考文献(南京医科大学学报(自然科学版),2010,30(11):1608-1611)。
化合物6(m=3)的合成:
将10mg的SOX2(平均分子量34310)溶解于10mL的PBS溶液。50mg化合物4(PEG=乙二醇基团)的2mL的DMSO溶液与等摩尔的NHS混合,加入等摩尔的EDC.于室温搅拌2小时,将SOX2的PBS溶液加入混合于10℃搅拌过夜。用PD-10脱盐柱分离(AmershamdisposablePD-1desaltingcolumn),将含产品化合物6的流出液(用320nM吸收波检测)合并,冷冻干燥.用质谱确定平均分子量为35817。确定产品6包含了3个化合物4(PEG=乙二醇基团)的对应单体(即偶联度m等于3)。用同样的方法不同摩尔比的4(PEG=乙二醇基团),合成了6(m=1,2,4)。
化合物6-3(m=4)的合成:
化合物6-3(m=4)的合成参照化合物6相同的合成方法,NANOG的分子量为34620,分析测得化合物6-3(m=4)分子量:36630.24。用同样的方法不同摩尔比的4(PEG=乙二醇基团),合成了6-3(m=1、2、3、5)。
化合物6-14的合成(通式I中的配体为NP366-374,n=3):
将化合物4(PEG=乙二醇基团)(11mg,0.02mmol)溶解于2毫升DMSO溶液,加入三聚NP366-374(59.1mg,0.02mmol),室温搅拌2小时,混合物中加入20毫升水,冷冻干燥除去溶剂,残余硅胶柱层析分离(10%甲醇-二氯甲烷),得化合物6-14(R2为三聚合NP366-374)(17mg,收率25%)。质谱MS(ESI):3460.8(M+H)。偶联度m=1.。
以下偶联化合物的合成:
如果抗原是蛋白,则参照化合物6的方法合成,如果是多肽(aa数目小于50),则参照化合物6-14的合成方法(溶剂和反应物摩尔比相同,反应时间、温度、分子量、偶联度等确定以及方法步骤条件相同),得下表所示的各个偶联产物:
R2代表多肽或蛋白
体形
(注:其中偶联体6-14对应的R2为三聚合的NP366-374。;偶联体6-5对应的R2为三聚合的MG7)
生物活性测试方法
1、免疫因子的测试方法:
方法:ELISA
试剂和条件:
人体外周血单核细胞用重力沉降法离心分离得到。离心机为Ficoll-Hypaque。将分离出的细胞悬浮在RPMI1640媒介中,添加10%的FBS、L-谷氨酸、青霉素/链霉素(RP10,Invitrogen),植于96井的试板。用本发明中的化合物在浓度0.1-10μM激发细胞,于37℃、5%的CO2环境下培养24小时。用Luminex仪(Austin,TX)测量γ-干扰素和白介素12的水平。图2和图3分别为偶联体1-2和偶联体2-1的体外免疫诱导效果,图6为偶合物化合物5的体外免疫诱导效果,图中所示的结果为三次测试的平均值。
2、抗肿瘤效应方法:
以偶联体5为例的小鼠体内抗肿瘤实验方法如下:
细胞:F9,小鼠睾丸胚胎癌细胞,1x106个每只。
动物:BALB/C雌雄各半5周。
种瘤:小鼠左/右皮下注射肿瘤细胞。
给药:腹腔注射(0.125mg/只/次,PBS溶液),分别在种瘤前一周、种瘤后当天,第7天共给药3次。
观察小鼠健康状况和肿瘤大小(目测)。14天后杀死老鼠,取血测细胞因子、取肿瘤称重、量长宽计算肿瘤体积。以化合物6-17为例的小鼠体内抗肿瘤实验方法如上,只是将细胞改为小鼠乳腺癌细胞。图3、图4为所示为抑制肿瘤效果,图5为抗体诱导作用;图6为糖尿病有关蛋白免疫诱导效应。
3、抗体诱导方法(以化合物1-3和2-1为例):
将5~6周龄的雌性BALB/c小鼠(16g左右)36只随机分在6个鼠笼中,每个笼6只小鼠,每日给予由动物中心配置的标准鼠粮,以及凉白开水。购买后,适应喂养一周,检查健康后进行正式实验,实验动物随机分成6组,分组情况如表4:
表4试验动物分组及处理
将以上各组小鼠腹腔注射200μL各组药物。第一次免疫14天后用相同的抗原加强免疫,免疫剂量不变。第一次免疫前、第二次免疫前、第二次免疫7天后从小鼠尾静脉断尾取血,将血液置于l.5mLEppendorf中,4℃放置数小时后,3000r/min离心l5分钟分离血清,免疫血清中M2e特异性的抗体采用标准ELISA的方法检测。
Claims (8)
1.一种免疫受体调节剂偶联体,其特征在于,所述偶联体为由前体化合物和生物配体组成的通式[I]的偶联体,其中:
通式[I]中:R2表示所述生物配体,X1代表OH或SH,R1表示直链的未取代的烷氧基烷基,X2表示偶联基团,m和n各自表示1至10的整数,
(1)当前体化合物为1时:
X2代表硫代羰基基团:
(2)当前体化合物为2时:
X2代表如下基团:
(3)当前体化合物为3时:
其中,u为0~12的整数;
X2表示如下基团:
其中u为0~12的整数;
(4)当前体化合物为4时:
式4中,PEG表示聚乙二醇基团;
X2表示如下基团:
2.权利要求1所述的免疫受体调节剂偶联体,其特征在于,所述偶联体为偶联体2-1、偶联体5、偶联体6、在下表中所示的偶联体5-3至5-20或偶联体6-3至6-20:
其中,“或R2”表示偶联体5中的OCT4和偶联体6中的SOX2被下表中所列的抗原、蛋白或多肽取代,m为1至6的整数,
其中偶联体6-14对应的R2为三聚合的NP366-374;偶联体6-5对应的R2为三聚合的MG7。
3.权利要求2所述的免疫受体调节剂偶联体,其特征在于,所述偶联体为偶联体2-1、偶联体5或偶联体6-17。
4.一种用于制备权利要求1-3中任一项所述的免疫受体调节剂偶联体的前体化合物,其特征在于,所述偶联体的前体化合物分别如下所示:
其中,u为0~12的整数;
5.权利要求4所述的前体化合物在制备免疫受体调节剂偶联体中的用途。
6.用于合成权利要求4的前体化合物的化合物,其特征在于,所述化合物分别如下所示:
7.权利要求1-3中任一项所述的免疫受体调节剂偶联体在制备复方药物中的用途,所述复方药物用于肿瘤免疫治疗、流感病毒治疗、免疫调节和抗体制备。
8.权利要求6所述的用途,所述复方药物包含药学上可接受的载体的复合物或结合物。
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