Trop-2, also known as TACSTD2, EGP-1, GA733-1 and M1S1, is frequently expressed on a variety of human carcinomas and its expression is often associated with poor prognosis of the diseases. However, it is also present on the epithelium of several normal tissues. A comprehensively designed Trop-2-targeting ADC, balancing both efficacy and toxicity, is therefore necessary to achieve clinical utility. To this end, we developed a cleavable Trop-2-ADC (RN927C) using a site-specific transglutaminase-mediated conjugation method and a proprietary MTI (microtubule inhibitor) linker-payload, PF-06380101. Robust in vitro cytotoxicity of RN927C was observed on a panel of Trop-2 expressing tumor cell lines, with IC50 generally in the subnanomolar range. As expected for an MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple cell line and patient-derived xenograft tumor models including pancreatic, lung, ovarian and triple negative breast tumor types. Single dose administration of RN927C at 0.75 - 3 mg/kg was generally sufficient to induce sustained regression of Trop-2 expressing tumors and showed superior efficacy over standard treatment with paclitaxel or gemcitabine. Administration of RN927C in non-human primate toxicity studies resulted in target mediated effects in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues with minimal, non-dose limiting off-target toxicities. Based on the combined efficacy and safety results, RN927C is postulated to have a favorable therapeutic index for treatment of solid tumors.
- Received July 5, 2016.
- Revision received August 11, 2016.
- Accepted August 12, 2016.
- Copyright ©2016, American Association for Cancer Research.