Abstract
Abstract
Introduction:
Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer which carries an extremely poor prognosis. Up to 35% of USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels and and additional 45% of USC express HER2/Neu at moderate (2+) or low (1+) levels. For tumors with moderate/low HER2/neu expression, there is no sufficient targeted therapy. SYD985 (Synthon Biopharmaceuticals BV, Nijmegen, The Netherlands) is a novel HER2-targeting antibody-drug conjugate (ADC) composed of the mAb trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin). The objective of this study was to explore the anti-tumor activity of SYD985 and to compare it to trastuzumab emtansine (T-DM1) in USC in in vitro and in vivo studies.
Methods:
Nine primary USC cell lines were evaluated for HER2/neu surface expression by IHC and flow cytometry and gene amplification using FISH assays. The cytotoxicity of SYD985 and T-DM1 was evaluated using cell lines with differential HER2/Neu expression (i.e., 1+, 2+, and 3+). Proliferation and viability experiments were performed using propidium iodide-based, flow cytometry assays. In vivo activity of SYD985 in mouse xenograft models is ongoing.
Results:
SYD985 was 55 to 115 times more potent when compared to T-DM1 in primary USC cell lines with 1+ and 2+ HER2/neu expression. Specifically, in the HER2/neu 1+ the IC50's for SYD985 and T-DM1 were 0.065 μg/mL and 3.58 μg/mL, respectively (p = 0.004). In the HER2/neu 2+ cell lines the IC50's of SYD985 and T-DM1 were 0.016 μg/mL and 1.82 μg/mL, respectively (p = 0.005). In the HER2/neu 3+ cell lines a statistical trend was noted when comparing the cytotoxicity of SYD985 with T-DM1; the IC50's were 0.011 μg/mL and 0.035 μg/mL, respectively (p = 0.06).
Conclusions:
SYD985 is a novel ADC endowed with remarkable activity against not only USC with strong (3+) HER2/neu overexpression but also (as previously shown for SYD985 in breast cancer) versus USC with low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is significantly more potent than T-DM1 in comparative in vitro experiments. Currently, in vivo experiments in USC xenografts not responsive to T-DM1 are ongoing. This is a significant discovery as we do not currently have an adequate targeted therapy to HER2/neu 1+ and 2+ expressing tumors. Thus, clinical studies with SYD985 in patients with biologically aggressive endometrial cancer (e.g., USC) resistant to standard salvage chemotherapy are warranted.
Citation Format: Jonathan D. Black, Salvatore Lopez, Emiliano Cocco, Stefania Bellone, Elena Bonazzoli, Carlton Schwab, Diana English, Peter Goedings, Patrick Beusker, Miranda van der Lee, Marco Timmers, Wim Dokter, Thomas Rutherfor, Peter Schwartz, Alessandro Santin. SYD985, a novel HER2-targeting antibody-drug conjugate, shows strong antitumor activity in primary USC cell lines with low (1+) and moderate (2+) HER2/Neu expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2461. doi:10.1158/1538-7445.AM2015-2461
