Abstract 47: SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows antitumor activity in uterine and ovarian carcinosarcoma with HER2/neu expression
Authors: Menderes Gulden , Bonazzoli Elena , Bellone Stefania , Black Jonathan , Altwerger Gary , Masserdotti Alice , Pettinella Francesca , Zammataro Luca , Buza Natalia , Hui Pei , Ratner Elena , Litkouhi Babak , Silasi Dan-Arin , Azodi Masoud , Schwartz Peter , Santin Alessandro D. 
Published: July 2017

Introduction: Carcinosarcoma (CS) is a rare and highly aggressive gynecologic malignancy. The amplification of HER2/neu has been reported to occur in 25%-56% of uterine and ovarian CSs with significant heterogeneity of the expression within epithelial and in-between epithelial and mesenchymal components. The reported high incidence makes HER2/neu an attractive target for new molecularly targeted therapies. We investigated the efficacy of SYD985, (Synthon-Biopharmaceuticals), a novel HER2-targeting antibody-drug conjugate (ADC) composed of a monoclonal antibody (mAb) similar to trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in uterine and ovarian carcinosarcoma. We also compared the anti-tumor activity of SYD985 to trastuzumab emtansine (T-DM1), a FDA-approved ADC, against multiple primary CS cell lines expressing different levels of HER2/neu in in vitro and in vivo experiments.

Methods: Eight primary CS cell lines were evaluated for HER2/neu surface expression by IHC and gene amplification using FISH assays. The cytotoxicity of SYD985 and T-DM1 was evaluated using these eight CS primary cell lines with differential HER2/neu expression (i.e., 0, 1+, and 3+). Antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability and bystander killing experiments were performed using Cr51-release assays, propidium iodide-based and flow cytometry assays, respectively. SYD985 and T-DM1 in vivo activity was also studied in mouse xenograft models.

Results: Similar ADCC were induced by SYD985 and T-DM1 when effector cells were present against CS cell lines with different HER2/neu expression. In contrast, SYD985 was significantly more cytotoxic compared to T-DM1 in the absence of the effector cells. SYD985 is 7 to 54 fold more potent than T-DM1 in comparative experiments and unlike T-DM1, it is active against CS demonstrating moderate/low or heterogeneous HER2/neu expression. Specifically, in HER2/neu 0/1+ cell lines the mean IC50’s were 0.060 µg/mL and 3.221 µg/mL for SYD985 vs T-DM1 (p&lt;0.0001) and in HER2/neu 3+ cell lines 0.013 µg/mL and 0.096 µg/mL, (p&lt;0.0001), respectively, (p&lt;0.0001). Unlike T-DM1,

SYD985 induced efficient bystander killing of HER2/neu 0/1+ EOC cells admixed with HER2/neu 3+ cells. In vivo studies confirmed that SYD985 is more active than T-DM1 in CS and effective against HER2/neu 3+ xenografts.

Conclusions: We demonstrate for the first time that SYD985 is a novel ADC with remarkable activity against CS not only with strong (3+) but also with low (0/1+) HER2/neu expression . Clinical studies with SYD985 in patients harboring chemotherapy-resistant uterine and ovarian CS with low, moderate and high HER2 expression are warranted.

Citation Format: Gulden Menderes, Elena Bonazzoli, Stefania Bellone, Jonathan Black, Gary Altwerger, Alice Masserdotti, Francesca Pettinella, Luca Zammataro, Natalia Buza, Pei Hui, Elena Ratner, Babak Litkouhi, Dan-Arin Silasi, Masoud Azodi, Peter Schwartz, Alessandro D. Santin. SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows antitumor activity in uterine and ovarian carcinosarcoma with HER2/neu expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 47. doi:10.1158/1538-7445.AM2017-47