Abstract 2640: RN927C, a potent site-specific Trop-2 antibody-drug-conjugate (ADC) for treatment of solid tumors

Human trophoblast cell surface antigen-2 (Trop-2), also known as TACSTD2, EGP-1, GA733-1 and MS1, is expressed on a variety of human carcinomas and its expression is often associated with poor prognosis of the diseases. Trop-2 is frequently detected in many tumor types at high levels, however, it is also present on the epithelium of a number of normal tissues. A comprehensively designed Trop-2-targeting ADC, balancing both efficacy and toxicity, is necessary to achieve clinical utility. We developed a site-specific cleavable Trop-2-ADC (RN927C) using a novel transglutaminase-mediated enzymatic conjugation method and a proprietary MTI (microtubule inhibitor) linker-payload. Our site-specific conjugation technology enables a precise drug-loading ratio of two and thus a better control of desired potency. Robust in vitro cytotoxicity of RN927C was observed selectively on multiple Trop-2 expressing tumor cell lines, with IC50 generally in the sub-nM range. Upon binding to surface Trop-2, RN927C internalized quickly and trafficked to the lysosomal compartment, as visualized by the co-localization of RN927C with lysosomal marker LAMP-2. As expected for a 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 tumor models including pancreatic, NSCLC, and ovarian cell line and patient-derived xenograft models. Single dose administration of RN927C at 1.5 mg/kg was generally sufficient to induce sustained regression of Trop-2 expressing tumors and showed superior efficacy over standard treatment with paclitaxol or Gemcitabine. Furthermore, addition of RN927C to Gemcitiabine greatly enhanced its in vivo efficacy. RN927C was well-tolerated in non-human primates upon repeat dosing at 6mg/kg q2w, with non-severe toxicity observed primarily in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues. Importantly, only minimal off-target hematological toxicity was observed in monkeys. Based on the combined efficacy and safety results, RN927C is expected to have a favorable therapeutic index and clinical development is currently underway. Citation Format: Shu-Hui Liu, Pavel Strop, Thomas-Toan Tran, Magdalena Dorywalska, Katherine Delaria, Wei-Hsien Ho, Russell Dushin, Jaume Pons, Arvind Rajpal, Dave Shelton. RN927C, a potent site-specific Trop-2 antibody-drug-conjugate (ADC) for treatment of solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2640. doi:10.1158/1538-7445.AM2014-2640