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研究不同偶联方法制备的力达霉素(LDM)与抗IV型胶原酶单抗3G11免疫偶联物的选择性抗肿瘤作用。采用SPDP和SMBS作为偶联剂,将LDM辅基蛋白69位赖氨酸与2-亚氨基四氢噻吩修饰的单抗3G11连接,制备免疫偶联物;ELISA法测定偶联物的免疫活性,克隆形成法及人HT-1080细胞免疫缺陷小鼠移植模型观察两种偶联物的抗肿瘤作用。偶联物保留了单抗3G11对IV型胶原酶的免疫活性,3G11-SMBS-LDM对体外培养的HT-1080细胞的杀伤作用强于LDM和3G11-SPDP-LDM。动物实验显示,LDM在等摩尔剂量条件下3G11-SMBS-LDM的抑瘤率为86.1%,游离的LDM组为71.2%,3G11-SPDP-LDM组为77.1%,3G11-SMBS-LDM的抑制作用显著增强。3G11-SMBS-LDM组动物的平均生存时间延长为163.7%,3G11-SPDP-LDM组为125.3%,LDM组为71.9%,3G11-SMBS-LDM能显著延长荷瘤鼠的生存期,两个偶联物之间有显著性差异。3G11-SMBS-LDM偶联物更具有选择性抗肿瘤作用,疗效显著提高,荷瘤动物生存期延长,毒性明显降低,可能成为新的肿瘤治疗药物。
To study the selective anti-tumor effect of lidamycin (LDM) and anti-type IV collagenase monoclonal antibody 3G11 immunoconjugates prepared by different coupling methods. Using SPDP and SMBS as coupling reagents, lysine 69 of LDM cofactor protein was linked with 3G11 monoclonal antibody modified by 2-iminothiolane to prepare immunoconjugates. The immunoconjugates were assayed by ELISA, Clonal formation and human HT-1080 cell immunodeficiency mouse transplantation model observed two kinds of conjugates anti-tumor effect. The conjugate retained the immunogenicity of mAb 3G11 against type IV collagenase. The killing effect of 3G11-SMBS-LDM on HT-1080 cells cultured in vitro was stronger than that of LDM and 3G11-SPDP-LDM. Animal experiments showed that the anti-tumor rate of 3G11-SMBS-LDM was 86.1% in LDM at the same molar dose, 71.2% in the free LDM group, 77.1% in the 3G11-SPDP-LDM group and the inhibitory effect on the 3G11-SMBS-LDM Significantly enhanced. The mean survival time of 3G11-SMBS-LDM group was 163.7%, that of 3G11-SPDP-LDM group was 125.3% and that of LDM group was 71.9%. 3G11-SMBS-LDM significantly prolonged the survival of tumor- There was a significant difference between the compounds. 3G11-SMBS-LDM conjugate is more selective anti-tumor effect, significantly improved efficacy, prolonged survival of tumor-bearing animals, significantly reduced toxicity, may become a new drug for oncology.