Abstract 4532: Functional evaluation of novel Tubulysin analogs as payloads for antibody-drug conjugates
| Autor: | Xiaotao Zhuo, Sanxing Sun, Hongsheng Xie, Yang Qingliang, Xiaomai Zhou, Guo Huihui, Xing Li, Lan Qu, Shun Gai, Li Wenjun, Huang Yuanyuan, Ye Hangbo, Lin Chen, Robert Yongxin Zhao, Jia Junxiang |
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| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Cancer Research. 75:4532-4532 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2015-4532 |
| Popis: | Antibody-drug conjugates (ADCs) couple tumor cell targeting specificity of monoclonal antibodies with potency of small molecule cytotoxic payloads to overcome the limitations of antibody's moderate cytotoxicity and narrow therapeutic window /poor pharmacokinetics of chemotherapeutic agents[1]. Most of the small molecule drugs used in ADCs now target either microtubules or DNA. Since the highly cytotoxic drugs linked to antibodies may be partially released, which leads to side-effects before they are delivered into the target cancer cells [2], it is important to choose appropriate cytotoxic molecules, linkage structures and conjugation strategies, in order to achieve maximal therapeutic window. To this end, we have designed and synthesized a series of Tubulysin B analogs and then conjugated these articles to anti-Her2 antibodies using different conjugation techniques. Functional assays in vitro based on Her2+ cancer cells showed that some of these novel molecules had significantly lower cytotoxicities as free drugs due to their favorable physiochemical and biological properties, in comparisons with the maytansinoid DM1derivatives, but were more potent than DM1 conjugates in killing the target cells when linked to identical anti-Her2 antibodies. Consistently, in comparisons with T-DM1, our novel ADCs demonstrated improved efficacy as well as reduced systemic side toxicities in Her2-positive xenograft tumor models. The conjugate structures and results from functional assays at both cellular and animal model levels are detailed in the presentation. References: 1. Goldmacher, V.S. and Y.V. Kovtun, Antibody-drug conjugates: using monoclonal antibodies for delivery of cytotoxic payloads to cancer cells. 2011 2(3):. 397-416.. 2. Xie, H., et al., Pharmacokinetics and biodistribution of the antitumor immunoconjugate, cantuzumab mertansine (huC242-DM1), and its two components in mice. J Pharmacol Exp Ther, 2004. 308(3): 1073-1082. Citation Format: Junxiang Jia, Xiaomai Zhou, Yuanyuan Huang, Hongsheng Xie, Huihui Guo, Shun Gai, Lan Qu, Wenjun Li, Lin Chen, Xing Li, Sanxing Sun, Qingliang Yang, Xiaotao Zhuo, Hangbo Ye, Robert Zhao. Functional evaluation of novel Tubulysin analogs as payloads for antibody-drug conjugates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4532. doi:10.1158/1538-7445.AM2015-4532 |
| Databáze: | OpenAIRE |
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