Design, Synthesis, and Biological Evaluation of Antibody−Drug Conjugates Comprised of Potent Camptothecin Analogues

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• 作者：Patrick J. Burke ; Peter D. Senter ; David W. Meyer ; Jamie B. Miyamoto ; Martha Anderson ; Brian E. Toki ; Govindarajan Manikumar ; Mansukh C. Wani ; David J. Kroll ; Scott C. Jeffrey
• 刊名：Bioconjugate Chemistry
• 出版年：2009
• 出版时间：June 17, 2009
• 年：2009
• 卷：20
• 期：6
• 页码：1242-1250
• 全文大小：212K
• 年卷期：v.20,no.6(June 17, 2009)
• ISSN：1520-4812

文摘

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 camptothecin drug linkers were conjugated to three antibodies: chimeric BR96, chimeric AC10, and humanized 1F6, 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-amino-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.