Abstract 3637: MM-302, a HER2-targeted liposomal doxorubicin, shows binding/uptake and efficacy in HER2 2+ cells and xenograft models

Abstract

Abstract Introduction: MM-302 is an ErbB2/HER2-targeted liposomal doxorubicin formulation designed to target doxorubicin to HER2-overexpressing cancer cells while limiting uptake into non-target cells. The characterization of the binding and uptake of MM-302 as a function of HER2 surface levels on various cell lines and in tumor models will help determine the minimum HER2 receptor levels required for MM-302 patient selection. Methods: Cellular models included 16+ established human tumor cell lines as well as 4T1 murine breast cancer and HeLa human cervical cancer cells engineered to overexpress HER2 from 1E05-1E06 receptors/cell. Cells were incubated with MM-302, untargeted liposomes or free doxorubicin and binding/uptake was measured by HPLC or flow cytometry. In vivo efficacy was determined in select mouse xenograft models. Tumors were mechanically and enzymatically dissociated, followed by flow cytometry to quantify the uptake of targeted and untargeted liposomes into HER2-expressing tumor cells, macrophages and other cell types. Results: Binding and uptake of MM-302 increased with rising HER2 surface levels in cells of common parental origin (4T1, HeLa), with significant uptake into cells with >2E05 HER2/cell. Further, total cell binding/uptake of MM-302 also increased with rising HER2 expression across a panel of 16+ cell lines. There was negligible uptake of untargeted liposomes under all conditions that showed no dependence on HER2 expression. Improved anti-tumor efficacy of MM-302 was observed in BT474-M3 and NCI-N87 mouse xenograft models relative to untargeted liposomal doxorubicin and free doxorubicin. Further, using disaggregated tumors, the relationship between HER2 expression and MM-302 uptake was confirmed in vivo in both models. Conclusions: Our studies identified a HER2 threshold for uptake of MM-302 of approximately 2E05 receptors/cell, and suggest a role for MM-302 not only in HER2 3+ cancers, but also in HER2 2+ cancers as well. The ability to treat HER2 2+ tumors offers an exciting opportunity to serve a major unmet clinical need. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3637. doi:10.1158/1538-7445.AM2011-3637