Synthesis and Evaluation of Hydrophilic Linkers for Antibody鈥揗aytansinoid Conjugates

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• 作者：Robert Y. Zhao ; Sharon D. Wilhelm ; Charlene Audette ; Gregory Jones ; Barbara A. Leece ; Alexandru C. Lazar ; Victor S. Goldmacher ; Rajeeva Singh ; Yelena Kovtun ; Wayne C. Widdison ; John M. Lambert ; Ravi V. J. Chari
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：May 26, 2011
• 年：2011
• 卷：54
• 期：10
• 页码：3606-3623
• 全文大小：1419K
• 年卷期：v.54,no.10(May 26, 2011)
• ISSN：1520-4804

文摘

The synthesis and biological evaluation of hydrophilic heterobifunctional cross-linkers for conjugation of antibodies with highly cytotoxic agents are described. These linkers contain either a negatively charged sulfonate group or a hydrophilic, noncharged PEG group in addition to an amine-reactive N-hydroxysuccinimide (NHS) ester and sulfhydryl reactive termini. These hydrophilic linkers enable conjugation of hydrophobic organic molecule drugs, such as a maytansinoid, at a higher drug/antibody ratio (DAR) than hydrophobic SPDB and SMCC linkers used earlier without triggering aggregation or loss of affinity of the resulting conjugate. Antibody鈥搈aytansinoid conjugates (AMCs) bearing these sulfonate- or PEG-containing hydrophilic linkers were, depending on the nature of the targeted cells, equally to more cytotoxic to antigen-positive cells and equally to less cytotoxic to antigen-negative cells than conjugates made with SPDB or SMCC linkers and thus typically displayed a wider selectivity window, particularly against multidrug resistant (MDR) cancer cell lines in vitro and tumor xenograft models in vivo.