CN107583058A - 一种t‑2毒素‑抗体缀合物及其用途 - Google Patents
一种t‑2毒素‑抗体缀合物及其用途 Download PDFInfo
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- CN107583058A CN107583058A CN201710855581.0A CN201710855581A CN107583058A CN 107583058 A CN107583058 A CN 107583058A CN 201710855581 A CN201710855581 A CN 201710855581A CN 107583058 A CN107583058 A CN 107583058A
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Abstract
本发明公开了一种T‑2毒素‑抗体缀合物及其用途,所述T‑2毒素‑抗体缀合物由T‑2毒素依次与第一连接子共价连接,所述第一连接子与第二连接子共价连接,所述第二连接子与抗体共价连接,每分子抗体连接的T‑2毒素分子数为1~5。其中第一连接子含有3~24个碳原子,且至少含有一个羧基;第一连接子通过羧基与T‑2毒素的羟基经酯化反应以酯键共价连接;第二连接子通过酰胺键、酯键、C‑C键或C‑N键与第一连接子共价连接。上述T‑2毒素‑抗体缀合物制备工艺简单,对肿瘤细胞具有显著的抑制作用。
Description
技术领域
本发明涉及医药领域,具体涉及一种T-2毒素-抗体缀合物及其用途。
背景技术
恶性肿瘤也称为癌症,是人体细胞分裂失控,导致细胞异常增殖,侵袭邻近组织或发生转移而引发的一类疾病。根据2014年流行病学统计信息,我国恶性肿瘤发病率为235.23/10万(男性268.65/10万,女性200.21/10万),中国人口标化率(中标率)184.58/10万。城市中标发病率187.53/10万;农村地区中标发病率181.10/10万。全国恶性肿瘤死亡率为148.81/10万(男性186.37/10万,女性109.42/10万),中标率113.92/10万。城市中标死亡率109.21/10万。农村中标死亡率119.00/10万。肺癌、女性乳腺癌、胃癌、肝癌、食管癌、结直肠癌、宫颈癌是我国常见的恶性肿瘤,也是主要的肿瘤死因。城市人群癌症发病率高于农村,45岁以上人群发病率高于45以下人群。
化疗是目前常用的肿瘤治疗方法,通常与放疗和手术治疗联合使用,以提高治愈率,抑制肿瘤转移和复发。化疗药物多为细胞毒性药物如烷化剂类药物尼莫司汀、卡莫司汀、卡氮芥、3,洛莫司汀、环磷酰胺、环磷氮芥、异环磷酰胺、异磷酰胺、甘磷酰芥;抗代谢药物去氧氟鸟苷、5-氟尿嘧啶、巯嘌呤、阿糖胞苷、替加氟、吉西他滨、安西他滨;抗肿瘤抗生素,放线菌素D、阿霉素、柔红霉素、正定霉素、表柔比星、丝裂霉素、培洛霉素、平阳霉素、博莱霉素、吡柔比星;抗肿瘤植物活性成分,三尖杉酯碱、羟基喜树碱、长春瑞宾、紫杉醇、长春新碱、依托泊苷、足叶乙苷;铂类药物如卡铂、顺铂等以及米托蒽醌、丙卡巴肼等其他药物。此外,一些天然存在的毒素,如美登素、海兔毒素、T-2毒素等对肿瘤细胞也具有极强的杀伤作用。
但是,由于化疗药物的细胞毒性作用,在用于杀伤肿瘤组织的同时,也对人体正常组织产生严重的毒性作用。因此如何提高化疗药物的靶向性,降低其对非肿瘤组织的不良影响,是目前抗肿瘤药物研发的热点之一。
抗体偶联药物 (antibody-drug conjugate, ADC)是将抗体与细胞毒性药物共价连接,其中抗体往往针对肿瘤组织特异性表达的抗原而设计,由此借助抗体的靶向作用将细胞毒药物靶向肿瘤,从而减少细胞毒性药物在正常组织中的分布,进而降低化疗中常见的药物非特异性全身毒性。连接抗体和细胞毒性药物的化学分子称为连接子(Linker)。目前连接子分为可降解连接子和非降解连接子两类,前者可通过人体内特定酶的作用发生水解,从而将细胞毒性药物从ADC上释放出来。
目前国内外批准上市的ADC药物尚少,仅有用于治疗何杰金氏淋巴瘤的Adcetris(brentuximabvedotin)和用于治疗HER2阳性乳腺癌的Kadcyla (ado-trastuzumabemtansine)获准上市,其他尚有几十种ADC药物处于研发阶段。
T-2毒素是一种主要由镰刀菌属三线镰刀菌、拟枝孢镰刀菌、梨孢镰刀菌、粉红镰刀菌、禾谷镰刀菌和雪腐镰刀菌等的特定菌株所产生的单端孢霉烯族化合物中毒性较强的一种毒素。申请人及发明人在前期研究中已经发现T-2毒素对多种肿瘤具有显著的杀伤作用,在肿瘤治疗领域具有广阔的应用前景(中国专利文献CN105688185A、CN101485653A),并对其ADC药物进行了研究(中国专利文献CN103330937A)。
中国专利文献CN103330937A公开了一种单克隆抗体抗原结合片段-T-2毒素偶联物,采用的连接子为肽链、1,4-丁二醇二缩水甘油醚、N-羟基琥珀酰亚胺基-3-(2-吡基二硫)-丙酸酯中的一种,所用的抗体为抗人肝细胞癌单克隆抗体HAblS Fab片段、抗人肝癌单克隆抗体3Α5 Fab'片段、抗IV型胶原酶单抗单克隆抗体3G11 Fabi片段中的一种。但上述ADC收率极低,制备及纯化难度极大,不具备成本优势,难以实现大工业化生产。
发明内容
针对上述现有技术,本发明的目的之一是提供一种T-2毒素-抗体缀合物,为实现上述目的,本发明的技术方案为:
一种如通式Ⅰ所示的 T-2毒素-抗体缀合物, 由T-2毒素与连接子和抗体Z通过共价键连接而成,
所述连接子由第一连接子X和第二连接子Y组成,所述第一连接子X含有3~24个碳原子,且至少含有一个羧基;所述第一连接子X通过所述羧基与T-2毒素的羟基经酯化反应以酯键共价连接;所述第二连接子Y通过酰胺键、酯键、C-C键或C-N键与所述第一连接子X共价连接;所述n为1~5。
优选的,所述第一连接子X为含有3~10个碳原子的直链有机酸。
优选的,所述第一连接子X为COOH-CH2-CH2-CH2-COOH、NH4-CH2-CH2-CH2-COOH、COOH-CH2-CH2-COOH或CH2W-CH2-CH2-COOH中的一种;所述W为卤素。
优选的,所述CH2W-CH2-CH2-COOH为CH2Cl-CH2-CH2-COOH。
优选的,所述第二连接子Y选自6-马来酰亚胺基己酸、MC-Val-Cit-PAB、Fmoc-Val-Cit-PAB、MC-Val-Cit-PAB-PNP、Fmoc-Phe-Lys(Trt)-PAB-PNP中的一种。
优选的,所述抗体Z选自抗HER2单抗、抗CD19单抗、抗CD30单抗、抗EGFR单抗中的一种;所述抗体Z通过Lys残基的氨基或Cys残基的巯基与所述第二连接子Y共价连接。
在一个进一步优选的实施例中,所述第一连接子X为COOH-CH2-CH2-COOH,所述第二连接子Y为MC-Val-Cit-PAB,所述抗体Z为抗HER2单抗,所述第一连接子X通过酯键分别与T-2毒素和第二连接子Y共价连接,所述单克隆抗体Z通过Cys残基的巯基与第二连接子Y共价连接;所述n为3~4。
本发明的另一方面提供了上述T-2毒素-抗体缀合物在制备抗癌症药物中的用途。
优选的,所述癌症选自白血病、肺癌、前列腺癌、乳腺癌、肝癌、骨肉瘤、结肠癌、直肠癌、鼻咽癌和胃癌。
优选的,所述癌症选自白血病、肺癌、前列腺癌、乳腺癌和肝癌。
本发明技术方案所述的T-2毒素英文名为T-2 Toxin,CAS号为:21259-20-1,是一种活性较强的细胞毒性物质,对肿瘤细胞具有显著抑制作用。MC-Val-Cit-PAB为可降解性连接子,通常作为抗体偶联药物的连接臂,实现细胞毒性药物与抗体的偶联;6-马来酰亚胺基己酸、MC-Val-Cit-PAB、Fmoc-Val-Cit-PAB、MC-Val-Cit-PAB-PNP、Fmoc-Phe-Lys(Trt)-PAB-PNP及T-2毒素均可通过市场购得。
本发明技术方案所述的抗HER2单抗,是指能够与人表皮生长因子-2结合的单克隆抗体,由于氨基酸序列的不同及其与人表皮生长因子-2结合区域的不同存在多种不同的分子,如曲妥珠单抗、帕妥珠单抗均属于抗HER2单抗,但二者氨基酸序列不同,与人表皮生长因子-2结合的区域也不同。类似的,本发明技术方案所述的抗CD30单抗、抗EGFR单抗分别指能够与人CD30抗原或表皮生长因子受体(epidermal growth factor receptor, EGFR)结合的单克隆抗体。已上市的抗CD30单抗如brentuximab vedotin,已上市的抗EGFR单抗如西妥昔单抗、帕尼单抗、尼妥珠单抗均可从市场购得。
对于通过抗体Cys氨基酸的巯基进行共价连接的抗体偶联药物,需要对抗体上存的二硫键预先进行还原以打开二硫键或在抗体分子上进行定点突变,将暴露于抗体表面的某些氨基酸突变为Cys氨基酸,从而引入反应性Cys氨基酸,这是本领域的公知常识。
在细胞毒性药物与抗体的偶联过程中,可采用定点偶联或非定点偶联等方式进行化学连接,当采用定点偶联时,每分子抗体结合细胞毒性药物的数量即n为单一数值,且为整数,换言之定点偶联法制备的药物-抗体缀合物为单一成分;而采用非定点偶联时,每分子抗体结合细胞毒性药物的数量为不定值,换言之非定点偶联法制备的药物-抗体缀合物为混合成分,其n为均值,这是本领域的公知常识。
本发明的申请人在进行T-2毒素的抗体偶联药物研究中发现,采用现有连接子将T-2毒素与抗体偶联过程中,抗体-药物偶联物产率极低,进而导致纯化难度极大,难以适应工业化生产的要求。因此,对T-2毒素-抗体偶联方法进行改进,在研究过程中出乎预料的发现,以现有连接子的特定组合作为连接臂,用于连接T-2毒素和抗体时,抗体-药物偶联物产率可显著升高,有利于工业化生产的推广。
附图说明
图1为化合物c的HPLC色谱图
图2为化合物f的HPLC色谱图。
具体实施方式
下面结合实施例对本发明作进一步的解释。应当理解的是,以下实施例仅用于解释本发明,而不是限制本发明的保护范围。
实施例1 T-2毒素-抗HER2单抗缀合物的制备
按照如下路线制备:
(1)化合物a的合成
在室温条件下,称取1,4-丁二酸(5.0g,42.4mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(8.13g,42.4mmol)、4-二甲氨基吡啶(51.8mg,0.42mmol)溶于二氯甲烷(100ml)中,量取N,N-二异丙基乙胺(15.5ml,89mmol),加入到上述溶液中,室温下搅拌10min。称取T-2毒素(19.78g,42.4mmol)溶于二氯甲烷(50ml)中,然后逐滴加入到上述反应液中(控制滴加速度为0.5~1.0ml/min),加料完毕后,将反应置于室温条件下搅拌6h。反应结束后,向反应液中加入H2O(100ml),搅拌5min。将水层以二氯甲烷萃取(150ml×3),收集有机层,以饱和食盐水洗涤(100ml×2),然后以无水硫酸镁干燥2h。过滤,收集滤液,滤液浓缩后得到黄色油状液体,该黄色油状液体经柱层析纯化(200-300目硅胶,乙酸乙酯:正己烷=3:1作为洗提液),得到化合物a(白色固体物质)18.77g,产率78.2%。化合物a的核磁共振图谱和质谱数据如下:
1H NMR(600Hz,DMSO-d6):δ8.94 (br, 1H),5.69-5.68 (d, J=6.0Hz, 1H), 5.54-5.43(d, J=6.0Hz, 1H),5.39-5.37 (d, J=12.0Hz, 1H),5.17-5.16 (d, J=6.0Hz, 1H),4.24-4.23(m, 1H), 4.13-4.11 (m, 2H), 3.91-3.89(m, 1H), 3.19-3.18(d, J=6.0Hz,1H), 2.82-2.81 (d, J=6.0Hz, 1H), 2.63-2.60(t, J=9.0Hz, 2H), 2.51-2.48 (t, J=9.0Hz, 2H),2.39-2.34 (m, 3H),2.22-2.20(m, 1H), 2.16(s, 3H),2.07 (s, 3H),1.85-1.81 (m, 4H) , 0.91-0.88 (m, 6H),0.62 (s, 3H)
MS:567.2441(M+H)
(2)化合物b的合成
在室温条件下,称取化合物a (17.14g,30.2mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(11.58g,60.4mmol)、4-二甲氨基吡啶(185mg,1.51mmol)溶于二氯甲烷(300ml)中,量取N,N-二异丙基乙胺(15.8ml,90.6mmol),加入到上述溶液中,室温下搅拌10min。称取MC-Val-Cit-PAB连接子(36.59g,60.4mmol)溶于二甲基甲酰胺(50ml)中,然后逐滴加入到上述反应液中,加料完毕后,将反应置于室温条件下搅拌过夜。反应结束后,向圆底烧瓶中加入饱和氯化铵溶液(100ml),搅拌5min。收集有机层,将有机层以饱和食盐水洗涤(100ml×2),然后以无水硫酸镁干燥2h。过滤,收集滤液,滤液浓缩后得到浅黄色固体物质,该固体物质经柱层析纯化(200-300目硅胶,甲醇:二氯甲烷=2:1作为洗提液),得到化合物b(白色固体物质)27.9g,产率82.5%。化合物b的核磁共振图谱和质谱数据如下:
1H NMR(600Hz,DMSO-d6):δ8.17(s, 1H),8.28(s, 1H), 7.94(br, 1H), 7.52-7.48(m,2H), 7.29(s, 1H), 7.62-7.59 (dd, J1=6.0Hz,J2=12.0Hz, 2H), 7.27-7.24 (dd, J1=6.0Hz, J2=12.0Hz, 2H), 6.52-6.49 (d, J=12.0Hz, 2H), 5.94-5.93 (d, J=6.0Hz,1H), 5.67-5.65 (d, J=12.0Hz, 1H),5.47(s, 2H), 5.34-5.30 (m, 2H), 5.28-5.25(m, 2H), 4.37-4.33 (m, 2H), 4.06-4.02 (m, 2H),3.79-3.76 (t, J=9.0Hz, 2H),3.47-3.42 (m, 2H),2.97-2.96 (d, J=6.0Hz, 1H), 2.79-2.76 (d, J=6.0Hz, 1H),2.62-2.53 (m, 4H), 2.33-2.30 (m, 1H),2.25-2.19 (m, 3H),2.08-2.04 (m, 3H),2.02 (s, 3H),1.95 (s, 3H), 1.86-1.82 (m, 1H), 1.64-1.59 (m, 5H), 1.42-1.39(m, 2H), 1.24-1.21 (m, 2H), 1.04-0.99 (m, 4H),0.93-0.91(m, 6H),0.84-0.82(m,6H), 0.59 (s, 3H).
MS: 1121.4785 (M+H)
(3)化合物c的合成
取曲妥珠单抗溶于水中,配制成浓度为2 mol/ml的溶液,向上述溶液中加入三(2-羧乙基)膦盐酸盐,加入量为曲妥珠单抗摩尔量的4倍,37℃恒温搅拌30 min,反应完毕后将反应液置双蒸水中透析1h。然后向反应液中加入反应液1倍体积的二氯甲烷和反应液3倍体积的乙醇,然后加入化合物b,化合物b的加入量为曲妥珠单抗摩尔量的5倍。40℃恒温搅拌4h,反应完毕取反应液,上Sephadex G-150 柱,以含0. 1 mol /L NaCl的0. 1 mol/L、pH 7.5 的磷酸缓冲液洗脱,除去未反应的化合物b,然后上Blue-sepharose CL-6B 柱,以0. 05 mol/L,pH 7. 5磷酸缓冲液洗脱,除去未偶联的单抗,最后以含0. 1 mol/L NaCl 的0. 05 mol/L,pH 7. 5磷酸缓冲液洗脱,得纯化的化合物c,产率75.9%。采用巯基乙醇法测定抗体与T-2毒素的偶联比,结果显示其偶联比为1:3.29。
取纯化的化合物c,采用HPLC 进行疏水层析( Hydrophobic InteractionChromatography,HIC) 分析。色谱柱为TSKgel Butyl-NPR (4.6mmI.D. x 3.5cm);流动相A: 2mol/L (NH4)2SO4、50mmol/L KHPO4、pH7.5;流动相B:50mmol/L KHPO4、20mmol/L 异丙醇、pH7.5;流速: 1.0mL/min,检测波长280nm,检测温度30℃。HPLC色谱图见说明书附图1。其中峰1为抗HER2单抗的吸收峰,峰2至峰5为抗HER2单抗与T毒素缀合物的吸收峰,说明纯化的化合物c中存在少量抗HER2单抗,且抗HER2单抗与T毒素存在多种比例的缀合物。
实施例2 T-2毒素抗EGFR单抗缀合物的制备
按照如下路线制备:
(1)化合物d的制备
在室温条件下,称取T-2毒素(15.0g,32.2mmol)、叔丁醇钾(4.35g,38.64mmol)溶于二氯甲烷(200ml)中,称取4-溴丁酸(10.75g,64.4mmol)溶于二氯甲烷(20ml)中,然后逐滴加入到上述反应液中,加料完毕后,将反应置于室温条件下搅拌过夜。反应结束后,向圆底烧瓶中加入H2O(100ml),搅拌5min。将水层以二氯甲烷萃取(150ml×3),合并有机层,以饱和食盐水洗涤(100ml×2),然后以无水硫酸镁干燥2h。过滤,收集滤液,滤液浓缩后得到黄色油状液体,该黄色油状液体经柱层析纯化(200-300目硅胶,乙酸乙酯:正己烷=5:2作为洗提液),得到化合物d(白色固体物质)15.25g,产率85.7%。化合物d的核磁共振图谱和质谱数据如下:
1H NMR(600Hz,DMSO-d6):δ 7.94 (br, 1H), 5.77-5.75 (d, J=12.0Hz, 1H), 5.59-5.58 (d, J=6.0Hz, 1H), 5.42-5.41 (d, J=6.0Hz, 1H), 4.39-4.35 (m, 3H), 4.08-4.06 (m, 1H), 3.98-3.95 (m, 3H), 2.97-2.96 (d, J=6.0Hz, 1H), 2.79-2.70 (m,3H), 2.24-2.21 (m, 1H),2.12-2.08 (m, 3H), 2.07 (s, 3H), 1.98 (s, 3H), 1.91-1.88 (m, 1H), 1.66-1.63 (m, 2H), 1.58 (s, 3H) , 0.96-0.94 (m, 6H),0.54 (s,3H)
MS:553.3261 (M+H)
(2)化合物e的制备
在室温条件下,称取化合物d (13.91g,25.1mmol)、EDCI(9.62g,50.2mmol)、DMAP(153mg,1.26mmol)溶于二氯甲烷(250ml)中,量取DIEA(13.1ml,75.3mmol),加入到上述溶液中,室温下搅拌10min。称取MC-Val-Cit-PAB连接子(28.75g,50.2mmol)溶于DMF(40ml)中,然后逐滴加入到上述反应液中,加料完毕后,将反应置于室温条件下搅拌过夜。反应结束后,向圆底烧瓶中加入饱和氯化铵溶液(100ml),搅拌5min。萃取,收集有机层,将有机层以饱和食盐水洗涤(100ml×2),然后以无水硫酸镁干燥2h。过滤,收集滤液,滤液浓缩后得到浅黄色固体物质,该固体物质经柱层析纯化(200-300目硅胶,甲醇:二氯甲烷=5:3作为洗提液),得到化合物e(白色固体物质)21.58g,产率77.64%。化合物e的核磁共振图谱和质谱数据如下:
1H NMR(600Hz,DMSO-d6):δ 8.02(m, 1H), 7.93 (br, 1H), 7.52 (s, 1H), 7.48-7.46 (m, 2H), 7.03-7.01 (m, 3H), 6.87 (s, 1H), 6.76 (s, 1H), 6.72-6.70 (dd,J1=6.0Hz, J2=12.0Hz, 2H), 5.82 (d, J=12.0Hz, 1H), 5.55 (m, 1H),5.39 (s, 2H),5.28 (d, J=6.0Hz, 1H), 5.01-4.98 (m, 2H), 4.41-4.38 (m, 2H), 4.16-4.15 (d,J=6.0Hz, 1H), 4.06-4.03 (m, 2H), 3.92-3.90 (t, J=6.0Hz, 2H), 3.76-3.73 (t, J=9.0Hz, 2H), 3.34-3.31 (m, 2H), 2.84-2.83 (d, J=6.0Hz, 1H), 2.71-2.70 (d, J=6.0Hz, 1H), 2.67-2.64 (t, J=9.0Hz, 2H), 2.29-2.24 (m, 4H), 2.19-2.15 (m, 3H),2.04-2.00 (m, 5H), 1.98 (s, 3H), 1.79-1.77 (m, 1H), 1.66-1.54 (m, 7H), 1.21-1.16 (m, 4H), 0.96-0.94 (m, 2H), 0.91-0.88 (m, 6H), 0.85-0.83 (m, 6H), 0.63(s, 3H).
MS: 1106.5946 (M+H)
(3)化合物f的制备
取西妥昔单抗溶于pH7.0的磷酸盐缓冲液,浓度为2 mol/ml,向上述溶液中加入三(2-羧乙基)膦盐酸盐,加入量为西妥昔单抗摩尔量的4倍,37℃恒温搅拌20min,反应完毕后将反应液置双蒸水中透析1h。然后向反应液中加入反应液1倍体积的二氯甲烷和反应液3倍体积的乙醇,然后加入化合物e,化合物e的加入量为西妥昔单抗摩尔量的5倍。40℃恒温搅拌4h,反应完毕取反应液,上Sephadex G-150 柱,以含0. 1 mol /L NaCl的0. 1 mol/L、pH7.0 的磷酸缓冲液洗脱,除去未反应的化合物e,然后上Blue-sepharose CL-6B 柱,以0.05 mol/ L,pH 7.0磷酸缓冲液洗脱,除去未偶联的单抗,最后以含0. 1 mol/L NaCl 的0.05 mol/ L,pH 7. 0磷酸缓冲液洗脱,得纯化的化合物f,产率80.3%。采用巯基乙醇法测定抗体与T-2毒素的偶联比,结果显示其偶联比为1:3.07。
取纯化的化合物f,采用HPLC 进行疏水层析( Hydrophobic InteractionChromatography,HIC) 分析。色谱柱为TSKgel Butyl-NPR (4.6mmI.D. x 3.5cm);流动相A: 0.1 mol/L (NH4)2SO4、0.1 mol/L KHPO4、pH7.0;流动相B:0.1mol/L KHPO4、20 mmol/L异丙醇、pH7.0;流速: 1.0mL/min,检测波长284nm,检测温度30℃。HPLC色谱图见说明书附图2。其中峰1为抗EGFR单抗的吸收峰,峰2至峰4为抗EGFR单抗与T毒素缀合物的吸收峰,说明纯化的化合物f中存在少量未偶联的抗EGFR单抗,且抗EGFR单抗与T毒素存在多种比例的缀合物。
实施例3 T-2毒素-抗HER2单抗缀合物的体内药效学实验
SPF级雌性BALB/ c 小鼠,4~5周龄,参考文献方法建立高表达HER2 的自发转移性乳腺癌小鼠模型(刘卉卉,胡思怡,沈国栋,张志辉,费保珍,刘兢,胡世莲. 高表达HER2 的自发转移性乳腺癌小鼠模型的建立与应用. 中国药理学通报. 2014,30(11):1611-1616)。待肿瘤体积生长至约100 mm3时,取荷瘤小鼠30只,随机分为3组,每组10只。第一组尾静脉注射给予生理盐水;第二组尾静脉注射给予曲妥珠单抗6mg/kg;第三组尾静脉注射给予实施例1制备的T-2毒素-抗HER2单抗缀合物,剂量为6mg/kg。各组动物均为没周给药3次,连续给药4周。
给药后用游标卡尺测量肿瘤长径(L)和短径(W),计算肿瘤体积,计算公式为: 肿瘤体积= 0. 5×L×W2 。抑瘤率计算公式为:抑瘤率=(生理盐水组平均肿瘤体积-给药组平均肿瘤体积)/生理盐水组平均肿瘤体积,抑瘤率以百分数表示。以曲妥珠单抗组为例,抑瘤率=(生理盐水组平均肿瘤体积-曲妥珠单抗组平均肿瘤体积)/生理盐水组平均肿瘤体积。
实验结果见下表:
由上表可见,T-2毒素-抗HER2单抗缀合物的抑瘤率显著高于曲妥珠单抗。
Claims (10)
1.一种如通式Ⅰ所示的 T-2毒素-抗体缀合物, 由T-2毒素与连接子和抗体Z通过共价键连接而成,
其特征在于,所述连接子由第一连接子X和第二连接子Y组成,所述第一连接子X含有3~24个碳原子,且至少含有一个羧基;所述第一连接子X通过所述羧基与T-2毒素的羟基经酯化反应以酯键共价连接;所述第二连接子Y通过酰胺键、酯键、C-C键或C-N键与所述第一连接子X共价连接;所述n为1~5。
2.根据权利要求1所述的T-2毒素-抗体缀合物,其特征在于,所述第一连接子X为含有3~10个碳原子的直链有机酸。
3.根据权利要求2所述的T-2毒素-抗体缀合物,其特征在于,所述第一连接子X为COOH-CH2-CH2-CH2-COOH、NH4-CH2-CH2-CH2-COOH、COOH-CH2-CH2-COOH或CH2W-CH2-CH2-COOH中的一种;所述W为卤素。
4.根据权利要求3所述的T-2毒素-抗体缀合物,其特征在于,所述CH2W-CH2-CH2-COOH为CH2Cl-CH2-CH2-COOH。
5.根据权利要求1所述的T-2毒素-抗体缀合物,其特征在于,所述第二连接子Y选自6-马来酰亚胺基己酸、MC-Val-Cit-PAB、Fmoc-Val-Cit-PAB、MC-Val-Cit-PAB-PNP、Fmoc-Phe-Lys(Trt)-PAB-PNP中的一种。
6.根据权利要求1所述的T-2毒素-抗体缀合物,其特征在于,所述抗体Z选自抗HER2单抗、抗CD19单抗、抗CD30单抗、抗EGFR单抗中的一种;所述抗体Z通过Lys残基的氨基或Cys残基的巯基与所述第二连接子Y共价连接。
7.根据权利要求1至6任一项所述的T-2毒素-抗体缀合物,其特征在于,所述第一连接子X为COOH-CH2-CH2-COOH,所述第二连接子Y为MC-Val-Cit-PAB,所述抗体Z为抗HER2单抗,所述第一连接子X通过酯键分别与T-2毒素和第二连接子Y共价连接,所述抗体Z通过Cys残基的巯基与第二连接子Y共价连接;所述n为3~4。
8.权利要求1至7任一项所述的T-2毒素-抗体缀合物在制备抗癌症药物中的用途。
9.根据权利要求8所述的T-2毒素-抗体缀合物在制备抗肿瘤药物中的用途,其特征在于,所述癌症选自白血病、肺癌、前列腺癌、乳腺癌、肝癌、骨肉瘤、结肠癌、直肠癌、鼻咽癌和胃癌。
10.根据权利要求8所述的T-2毒素-抗体缀合物在制备抗肿瘤药物中的用途,其特征在于,所述癌症选自白血病、肺癌、前列腺癌、乳腺癌和肝癌。
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