Development of Anilino-Maytansinoid ADCs that Efficiently Release Cytotoxic Metabolites in Cancer Cells and Induce High Levels of Bystander Killing

详细信息    查看全文

• 作者：Wayne C. Widdison ; Jose F. Ponte ; Jennifer A. Coccia ; Leanne Lanieri ; Yulius Setiady ; Ling Dong ; Anna Skaletskaya ; E. Erica Hong ; Rui Wu ; Qifeng Qiu ; Rajeeva Singh ; Paulin Salomon ; Nathan Fishkin ; Luke Harris ; Erin K. Maloney ; Yelena Kovtun ; Karen Veale ; Sharon D. Wilhelm ; Charlene A. Audette ; Juliet A. Costoplus ; Ravi V. J. Chari
• 刊名：Bioconjugate Chemistry
• 出版年：2015
• 出版时间：November 18, 2015
• 年：2015
• 卷：26
• 期：11
• 页码：2261-2278
• 全文大小：787K
• ISSN：1520-4812

文摘

Antibody anilino maytansinoid conjugates (AaMCs) have been prepared in which a maytansinoid bearing an aniline group was linked through the aniline amine to a dipeptide, which in turn was covalently attached to a desired monoclonal antibody. Several such conjugates were prepared utilizing different dipeptides in the linkage including Gly-Gly, l-Val-l-Cit, and all four stereoisomers of the Ala-Ala dipeptide. The properties of AaMCs could be altered by the choice of dipeptide in the linker. Each of the AaMCs, except the AaMC bearing a d-Ala-d-Ala peptide linker, displayed more bystander killing in vitro than maytansinoid ADCs that utilize disulfide linkers. In mouse models, the anti-CanAg AaMC bearing a d-Ala-l-Ala dipeptide in the linker was shown to be more efficacious against heterogeneous HT-29 xenografts than maytansinoid ADCs that utilize disulfide linkers, while both types of the conjugates displayed similar tolerabilities.