Abstract 5360: The preclinical profile of the duocarmycin-based HER2-targeting ADC SYD985 predicts for clinical benefit in low HER2-expressing breast cancers

Abstract

Abstract SYD985 is a HER2-targeting ADC based on trastuzumab and vc-seco-DUBA, Synthon's proprietary cleavable linker-duocarmycin payload. Vc-seco-DUBA was coupled to cysteines after partial reduction on the interchain disulfides of trastuzumab. SYD985 was obtained after purification by Hydrophobic Interaction Chromatography to yield a well-defined ADC consisting of predominantly DAR 2 and DAR 4 species. To evaluate the therapeutic potential of this new ADC, and to prepare clinical development, mechanistic in vitro studies and in vivo PDX studies were conducted to compare SYD985 head-to-head to T-DM1 (Kadcyla®), another trastuzumab-based ADC with a toxin of the maytansinoid class in combination with a non-cleavable linker. SYD985 and T-DM1 had similar binding-affinities to HER2 and showed similar internalization. In vitro cytotoxicity assays showed similar potencies and efficacies in HER2 3+ cell lines, but in cell lines with low HER2 expression, SYD985 was 3 to 50-fold more potent than T-DM1. In contrast to T-DM1, SYD985 efficiently induced bystander killing in vitro of HER2 negative (HER2 0) cells when mixed with HER2 3+, 2+, or 1+ cells. SYD985 efficiently killed HER2 0 cells, even in the presence of only 20% of HER2 3+ cells. At pH conditions relevant for tumors, cathepsin B cleavage studies showed efficient release of the active toxin from SYD985 but not from T-DM1. These in vitro data suggest that SYD985 might be a more potent ADC in HER2 expressing tumors in vivo, allowing the treatment of tumor tissues with low or heterogeneous membrane expression of HER2. In line with this, in vivo anti-tumor studies in breast cancer PDX models showed that SYD985 is very active in HER2 3+, 2+, and 1+ models whereas T-DM1 only showed significant anti-tumor activity in HER2 3+ breast cancer PDX models. We conclude that the properties of SYD985 may enable expansion of the target population to patients who have low HER2 expressing breast cancer, a patient population with unmet high medical need. Early phase clinical evaluation with SYD985 is ongoing. Citation Format: Willem Dokter, Miranda van der Lee, Patrick Groothuis, Ruud Ubink, Monique van der Vleuten, Tanja van Achterberg, Eline Loosveld, Desirée Damming, Myrthe Rouwette, David Egging, Diels van den Dobbelsteen, Patrick Beusker, peter goedings, Gijs Verheijden, Jacques Lemmens, Marco Timmers. The preclinical profile of the duocarmycin-based HER2-targeting ADC SYD985 predicts for clinical benefit in low HER2-expressing breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5360. doi:10.1158/1538-7445.AM2015-5360