Abstract SY28-02: Tumor targeting with antimitotic monoclonal antibody drug conjugates.

Abstract

Abstract Monoclonal antibodies (mAbs) have played a major role in cancer medicine, with active drugs such as trastuzumab, cetuximab, bevacizumab and rituximab in a wide range of therapeutic applications. The mechanism of activity of these agents involves cell signaling, effector functions through interactions with Fcγ receptor positive cells, and complement fixation. The activity of mAbs can be enhanced through the generation of antibody drug conjugates (ADCs) that are capable of delivering cytotoxic agents with some degree of selectivity to tumor cells. Early work in this field involved the use of clinically approved anticancer drugs that generally were low in potency. Consequently, the resulting ADCs had suboptimal activities. Because of this, significant attention was directed towards the identification of appropriate drugs for targeted delivery, the most successful being antimitotic drugs such as monomethyl auristatin E (MMAE), and maytansinoids. These drugs inhibit tubulin polymerization and arrest cell growth in a cell-cycle dependent manner. Successful delivery of these agents requires drug, linker, and conjugation optimization, in addition to judicious selection of an antigen target on tumor cell surfaces. Brentuximab vedotin, a conjugate comprised of the anti-CD30 mAb cAC10 conjugated with MMAE through a highly stable peptide linker, is an example of how addressing these considerations can lead to ADCs with pronounced clinical efficacy. In August 2011, brentuximab vedotin received accelerated approval by the US Food and Drug Administration for use in relapsed or refractory Hodgkin lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma, two diseases with significant unmet medical needs. An overview of how this targeted antimitotic drug was developed and how we are extending the technology will be provided. Citation Format: Peter Senter. Tumor targeting with antimitotic monoclonal antibody drug conjugates. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY28-02. doi:10.1158/1538-7445.AM2013-SY28-02