Design, Synthesis, and Biological Evaluation of Antibody-Drug Conjugates Comprised of Potent Camptothecin Analogues
Design, Synthesis, and Biological Evaluation of Antibody-Drug Conjugates Comprised of Potent Camptothecin Analogues
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DOI：
10.1021/bc9001097
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发表时间：
2009-06-01
影响因子：
4.7
通讯作者：
Jeffrey, Scott C.
中科院分区：
文献类型：
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作者：
Burke, Patrick J.;Senter, Peter D.;Jeffrey, Scott C.
抗体-药物缀合物（ADC）是用经由基于二肽或葡糖苷酸的接头连接至单克隆抗体（mAb）的有效喜树碱类似物制备的。使用含苯胺的喜树碱类似物来提供通过氨基甲酸酯键连接的位点，其在循环中是稳定的。喜树碱类似物，7-丁基-10-氨基-喜树碱和7-丁基-9-氨基-10，11-亚甲二氧基-喜树碱，通常比喜树碱有效10-1000倍。使用含有自分解间隔区的二肽和葡糖苷酸药物接头，其在ADC内化到抗原阳性细胞系中后在溶酶体降解后释放药物。喜树碱药物接头与三种抗体缀合：嵌合BR 96、嵌合AC 10和人源化IF 6，其分别与癌上的Lewis-Y抗原、血液恶性肿瘤上的CD 30和血液恶性肿瘤和肾细胞癌上存在的CD 70结合。携带有效喜树碱类似物7-丁基-9-氨基-10，11-亚甲二氧基-喜树碱的ADC在体外对一组癌细胞系具有高度有效性和免疫特异性，并且在肾细胞癌异种移植模型中以耐受良好的剂量有效。
Antibody-drug conjugates (ADCs) were prepared with potent camptothecin analogues attached to monoclonal antibodies (mAbs) via dipeptide or glucuronide-based linkers. Aniline-containing camptothecin analogues were employed to provide a site of linker attachment via carbamate bonds that would be stable in circulation. The camptothecin analogues, 7-butyl-10-amino-camptothecin and 7-butyl-9-amino-10,11-methylenedioxy-camptothecin, are generally 10-1000 times more potent than camptothecin. Dipeptide and glucuronide drug linkers were employed containing self-immolative spacers that release drug following lysosomal degradation upon ADC internalization into antigen-positive cell lines. The camplothecin drug linkers were conjugated to three antibodies: chimeric BR96, chimeric AC10, and humanized IF6, which bind to the Lewis-Y antigen on carcinomas, CD30 on hematologic malignancies, and CD70 present on hematologic malignancies and renal cell carcinoma, respectively. ADCs bearing the potent camptothecin analogue, 7-butyl-9-anlino-10,11-methylenedioxy-camptothecin, were highly potent and immunologically specific on a panel of cancer cell lines in vitro, and efficacious at well-tolerated doses in a renal cell carcinoma xenograft model.