SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody-Drug Conjugate, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/Neu Expression

Purpose: 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. <p>Experimental Design: Eight primary CS cell lines were evaluated for HER2/neu surface expression by IHC and gene amplification by FISH assays. The in vitro experiments included cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing. In vivo activity was studied in mouse xenograft and patient-derived-xenograft (PDX) models.</p> <p>Results: 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's were 0.060 µg/mL and 3.221 µg/mL (p<0.0001) against HER2/neu 0/1+ cell lines and 0.013 µg/mL and 0.096 µg/mL (p<0.0001) against HER2/neu 3+ cell lines for SYD985 vs 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. In vivo studies confirmed that SYD985 is more active than T-DM1 in CS and highly effective against HER2/neu expressing xenografts and PDX.</p> <p>Conclusions: 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.

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