T‐DM1, a novel antibody–drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo

Abstract

Amplification of c-erbB2 has been reported in over 30% of uterine serous carcinoma (USC) and found to confer poor survival because of high proliferation and increased resistance to therapy. In this study, we evaluated for the first time Trastuzumab emtansine (T-DM1), a novel antibody–drug conjugate, against multiple epidermal growth factor receptor-2 (HER2)-positive USC cells in vitro followed by developing a supportive in vivo model. Fifteen primary USC cell lines were assessed by immunohistochemistry (IHC) and flow cytometry for HER2 protein expression. C-erbB2 gene amplification was evaluated using fluorescent in situ hybridization. Sensitivity to T-DM1 and trastuzumab (T)-induced antibody-dependent cell-mediated cytotoxicity was evaluated in 5-h chromium release assays. T-DM1 and T cytostatic and apoptotic activities were evaluated using flow-cytometry-based proliferation assays. In vivo activity of T-DM1 versus T in USC xenografts in SCID mice was also evaluated. High levels of HER2 protein overexpression and HER2 gene amplification were detected in 33% of USC cell lines. T-DM1 was considerably more effective than trastuzumab in inhibiting cell proliferation and in causing apoptosis (P = 0.004) of USC showing HER2 overexpression. Importantly, T-DM1 was highly active at reducing tumor formation in vivo in USC xenografts overexpressing HER2 (P = 0.04) and mice treated with TDM-1 had significantly longer survival when compared to T-treated mice and control mice (P ≤ 0.0001). T-DM1 shows promising antitumor effect in HER2-positive USC cell lines and USC xenografts and its activity is significantly higher when compared to T. T-DM1 may represent a novel treatment option for HER2-positive USC patients with disease refractory to trastuzumab and traditional chemotherapy.

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody–Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression

“…More importantly, these results strongly support the view that novel HER2/neu-targeted agents effective in the treatment of PI3K-mutated/trastuzumab-resistant USC (i.e., T-DM1 and/or afatinib; refs. [25][26][27] or SYD985 (this article), might represent more effective treatment strategies against this subset of biologically aggressive endometrial cancers. Antitumor activity of SYD985 compared with T-DM1 and ADC isotype control in USC xenograft tumor models including ARK-2 (HER2/neu 3þ; A), ARK-7 (HER2/neu 2þ; B), and ARK-11 (HER2/neu 1þ; C).…”

Superior in vitro and in vivo activity of trastuzumab-emtansine (T-DM1) in comparison to trastuzumab, pertuzumab and their combination in epithelial ovarian carcinoma with high HER2/neu expression

“…R, T and P were used at a concentration of 20μg/ml. T+P was used at a concentration of 10 μg/ml of each drug and T-DM1 was used at a concentration of 2μg/ml [18]. Three days after drug treatment, cells were harvested in their entirety, centrifuged and stained with propidium iodide (2μl of 500 μg/ml stock solution in PBS).…”

“…Once the tumor volume was approximately 0.2 cm 3 , the mice were randomized into treatment groups (ie, 5 to 6 per group); those treated with R (15mg/kg), T (15 mg/kg), P (15 mg/kg), T+P (7.5 mg/kg+ 7.5 mg/kg) and T-DM1 (15 mg/kg). Drug dosages were chosen according to previous studies conducted on different xenograft models [18, 19]. All treatment drugs were given as intravenous (IV) weekly injections for three to five times to different groups of mice based on prior literature [18].…”

“…Drug dosages were chosen according to previous studies conducted on different xenograft models [18, 19]. All treatment drugs were given as intravenous (IV) weekly injections for three to five times to different groups of mice based on prior literature [18]. In some experiments mice were euthanized one week after the last injection (i.e., day 22) for necropsy studies while in other experiments mice were observed for overall survival as the primary outcome measure.…”

Targeted Therapy in the Treatment of Uterine Serous Carcinoma

“…The drug-antibody conjugate, trastuzumab ematansine (T-DM1), has shown promise in preclinical studies with improved responses seen in HER2/neu amplified USC xenografts when compared with trastuzumab alone (p < 0.0001) [8]. The improved efficacy seen in xenografts may have important implications for ongoing trials and future drug design.…”