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

Abstract

<b>Purpose:</b> Carcinosarcomas (CS) are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression. We compared the efficacy of SYD985 (Synthon Biopharmaceuticals BV), a novel HER2-targeting antibody-drug conjugate (ADC), to trastuzumab emtansine (T-DM1, Genentech-Roche) against primary uterine and ovarian CS.<b>Experimental Design:</b> Eight primary CS cell lines were evaluated for HER2/neu surface expression by IHC and gene amplification by FISH assays. The <i>in vitro</i> experiments included cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing. <i>In vivo</i> activity was studied in mouse xenograft and patient-derived xenograft (PDX) models.<b>Results:</b> SYD985 and T-DM1 induced similar levels of ADCC against CS cell lines with low and high HER2/neu expression when challanged in the presence of effector cells. In contrast, SYD985 was 7- to 54-fold more potent than T-DM1 in the absence of effector cells. SYD985, unlike T-DM1, was active against CS demonstrating low or heterogeneous HER2/neu expression. Specifically, the mean IC₅₀ values were 0.060 μg/mL and 3.221 μg/mL (<i>P</i> < 0.0001) against HER2/neu 0/1+ cell lines and 0.013 μg/mL and 0.096 μg/mL (<i>P</i> < 0.0001) against HER2/neu 3+ cell lines for SYD985 versus T-DM1, respectively. Importantly, unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ tumor cells admixed with HER2/neu 3+ cells. <i>In vivo</i> studies confirmed that SYD985 is more active than T-DM1 in CS and highly effective against HER2/neu expressing xenografts and PDX.<b>Conclusions:</b> SYD985 may represent a novel and highly effective ADC against HER2-expressing CS. Clinical studies with SYD985 in patients harboring chemotherapy-resistant CS with low/moderate and high HER2 expression are warranted. <i>Clin Cancer Res; 23(19); 5836-45. ©2017 AACR</i>.