SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression
Menée sur des lignées cellulaires de carcinome séreux de l'utérus HER2+ et à l'aide xénogreffes, cette étude met en évidence l'activité antitumorale d'un composé appelé SYD985, un conjugué combinant le trastuzumab et un agent alkylant (duocarmycin)
Uterine serous carcinoma (USC) is an aggressive form of endometrial cancer. Up to 35% of USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels by immunohistochemistry while an additional 40 to 50% express HER2/neu at moderate (2+) or low (1+) levels. We investigated the efficacy of SYD985, (Synthon-Biopharmaceuticals), a novel HER2-targeting antibody-drug conjugate (ADC) composed of the monoclonal antibody (mAb) trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in USC. We also compared the anti-tumor activity of SYD985 in head-to-head experiments to trastuzumab emtansine (T-DM1), a FDA-approved ADC, against multiple primary USC cell lines expressing different levels of HER2/neu in in vitro and in vivo experiments. Using antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing assays as well as propidium iodide-based flow cytometry assays and multiple in vivo USC mouse xenograft models, we demonstrate for the first time that SYD985 is a novel ADC with remarkable activity against USC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is 10 to 70 fold more potent than T-DM1 in comparative experiments and unlike T-DM1, it is active against USC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in patients harboring chemotherapy-resistant USC with low, moderate and high HER2 expression are warranted.
http://mct.aacrjournals.org/content/early/2016/06/02/1535-7163.MCT-16-0163.abstract