Abstract 3912: MM-310, a novel EphA2-targeted docetaxel nanoliposome
Authors: Kirpotin Dmitri B. , Tipparaju Suresh , Huang Zhaohua Richard , Kamoun Walid S. , Pien Christine , Kornaga Tad , Oyama Shinji , Olivier Ken , Marks James D. , Koshkaryev Alexander , Schihl Sarah S. , Fetterly Gerald , Schoeberl Birgit , Noble Charles , Hayes Mark , Drummond Daryl C. 
Published: July 2016

Abstract
Taxanes are widely used to treat solid tumors either in the curative or palliative setting, in first or later lines of therapy. Analysis of docetaxel dose-response relationship strongly suggests that a higher dose would lead to high response, however will also lead to higher toxicity. This is likely related to the lack of organ and cellular specificity of docetaxel leading to high exposures in normal tissues and the relatively short circulation half-life which indirectly requires higher doses. With the goal of addressing the pharmacokinetic limitations of free docetaxel and the lack of cellular specificity, we developed a novel docetaxel-based nanoliposome (MM-310), targeted against Ephrin receptor A2 (EphA2) which is overexpressed in a wide range of tumors. MM-310 provides sustained release of docetaxel following accumulation in solid tumors. Preclinical models have demonstrated that MM-310 leverages tumor-specific accumulation through the enhanced permeability and retention effect, and cellular specificity through active targeting of EphA2 with specific scFv antibody fragments conjugated to the surface of the liposomes.
Pharmacokinetic and biodistribution studies were performed in mice and rats to compare MM-310 to free docetaxel. Chronic tolerability studies were performed in rodent and non-rodent models with focus on overall animal health, as well as hematologic toxicities. Several cell-derived models of breast, lung and prostate xenografts were used to evaluate the differences betweenf MM-310 and free docetaxel.
MM-310 had a significantly longer half-life than free docetaxel with prolonged exposure at the tumor site. In chronic tolerability studies, MM-310 was found to be 6-7 times better tolerated than free docetaxel with a maximum tolerated dose of at least 120 mpk, compared to 20 mpk for free docetaxel and no detectable hematological toxicity. At equitoxic dosing, MM-310 50 mpk showed greater activity than docetaxel 10 mpk in several breast, lung and prostate xenograft models.
In conclusion, we developed a novel EphA2 targeted docetaxel nanoliposome with prolonged circulation time and slow and sustained drug release kinetics, to enable organ and cellular targeting. MM-310 was able to overcome hematologic toxicities observed upon treatment with free docetaxel in rodent and non-rodent models. MM-310 was also able to induce tumor regression or control tumor growth in several cell derived xenograft models, and was found to be more active than free docetaxel in most models.
Citation Format: Dmitri B. Kirpotin, Suresh Tipparaju, Zhaohua Richard Huang, Walid S. Kamoun, Christine Pien, Tad Kornaga, Shinji Oyama, Ken Olivier, James D. Marks, Alexander Koshkaryev, Sarah S. Schihl, Gerald Fetterly, Birgit Schoeberl, Charles Noble, Mark Hayes, Daryl C. Drummond. MM-310, a novel EphA2-targeted docetaxel nanoliposome. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3912.