Syd985, a novel duocarmycin-based her2-targeting antibody-drug conjugate, shows antitumor activity in uterine serous carcinoma with her2/neu expression

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Abstract

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 IHC 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 mAb trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in USC. We also compared the antitumor 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 activity against USC with strong (3+)aswell 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.

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Black, J., Menderes, G., Bellone, S., Schwab, C. L., Bonazzoli, E., Ferrari, F., … Santin, A. D. (2016). Syd985, a novel duocarmycin-based her2-targeting antibody-drug conjugate, shows antitumor activity in uterine serous carcinoma with her2/neu expression. Molecular Cancer Therapeutics, 15(8), 1900–1909. https://doi.org/10.1158/1535-7163.MCT-16-0163

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