SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression

Background: Epithelial ovarian cancer (EOC) is an aggressive and heterogeneous disease. <. 10% of EOC demonstrate HER2/neu 3. + receptor over-expression. However, moderate to low (i.e., 2. + and 1. +) HER2/neu expression is reported in up to 50% of EOC. The objective of this study was to compare the anti-tumor activity of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1) in EOC models with differential HER2/neu expression. Methods: The cytotoxicity of SYD985 and T-DM1 was evaluated using ten primary EOC cell lines with 0/1. +, 2. +, and 3. + HER2/neu expression in antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments. Finally, the in vivo activity of SYD985 and T-DM1 was also studied in ovarian cancer xenografts. Results: SYD985 and T-DM1 induced similar ADCC in the presence of peripheral blood lymphocytes (PBL) against EOC cell lines with differential HER2/neu expression. In contrast, SYD985 was 3 to 42 fold more cytotoxic in the absence of PBL when compared to T-DM1 (p <. 0.0001). Unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1. + tumor cells when admixed with HER2/neu 3. + EOC cells. In vivo studies confirmed that SYD985 is significantly more active than T-DM1 against HER2/neu 3. + EOC xenografts. Conclusions: SYD985 is a novel ADC with remarkable activity against EOC with strong (3. +) as well as moderate to low (i.e., 2. + and 1. +) HER2/neu expression. SYD985 is more potent than T-DM1 in comparative experiments and unlike T-DM1, it is active against EOC demonstrating moderate/low or heterogeneous HER2/neu expression.