Abstract 2652: In vitro and in vivo antitumor activity of SYD985, a novel HER2-targeting ADC: a comparison with T-DM1
Authors: Dokter Willem H.A. , Lee Miranda van der , Groothuis Patrick , Achterberg Tanja van , Loosveld Eline , Jacobs Daniëlle , Vleuten Monique van der , Beusker Patrick H. , Hooftman Leon , Goedings Peter , Verheijden Gijs , Timmers Marco 
Published: May 2015

Abstract
SYD985 is a HER2-targeting ADC based on trastuzumab and Synthon's proprietary cleavable linker-duocarmycin payload. The preclinical profile, including mechanism of action studies, PK, efficacy, and safety studies are described in the accompanying abstract.
We have further compared SYD985 to T-DM1 (Kadcyla) and have focused on the in vitro and in vivo efficacies of both of these HER2-targeting ADCs. SYD985 and T-DM1 were compared head-to-head in a panel of 10 cell lines expressing different levels of HER2, including levels characterized as HER2 0, 1+, 2+, or 3+. SYD985 was 3 to 5 times more potent in one HER2 2+ and two HER2 3+ cell lines, while similar potencies were obtained on two other HER2 3+ cell lines. In cell lines with lower HER2 membrane expression (HER2 1+), SYD985 was a factor 7 to 300-fold more potent. These data show that the difference in potencies between SYD985 and T-DM1 becomes more pronounced at lower HER2 expression levels. Subsequently, we next studied how the in vitro data correlate with in vivo anti-tumor activities. In a xenograft with a breast BT-474 cell line (IHC HER2 3+) both SYD985 and T-DM1 dose-dependently reduced tumor growth after single dose (SD) i.v. administration. SYD985 was approximately 5-fold more potent than T-DM1 (tumor stasis at 1 mg/kg vs 5 mg/kg respectively). Subsequently, both ADCs were evaluated (SD i.v.) in a series of patient-derived xenografts (PDX) using HER2 FISH negative tumors from breast cancer patients. We have tested both ADCs in two models classified as Triple Negative Breast Cancer (TNBC; ER negative/PR negative/HER2 negative) with IHC HER2 1+ staining, two TNBC models with IHC HER2 2+ staining, and two Hormone Positive tumor models with IHC HER2 2+ staining. One model (TNBC IHC HER2 2+) did not respond to either SYD985 or T-DM1. In the other five models, SYD985 was more active than T-DM1. Corroborating with the in vitro data, the improved anti-tumor activity of SYD985 versus T-DM1 is most prominent in the PDX models with lowest HER2 expression. In the two TNBC IHC HER2 1+ models, SYD985 induced CR at 1-3 mg/kg, whereas T-DM1 was inactive at all dosages tested, up to 30 mg/kg. We conclude that
i) SYD985 is more potent than T-DM1, both in vitro and in vivo in all responsive models;
ii) In these studies, the potency advantage of SYD985 over T-DM1 is enhanced even further in the tumor cell lines and PDX models with low HER2 expression (i.e. IHC HER2 1+);
iii) The preclinical profile of SYD985 enables extending the target population of BC patients that may respond to this treatment modality to include IHC HER2 1+ and 2+ / FISH negative patients. Early phase clinical trials with SYD985 in patients with this tumor profile, besides refractory BC patients who are IHC HER2 3+ or FISH positive, appear justified and warranted.
Citation Format: Willem H.A. Dokter, Miranda van der Lee, Patrick Groothuis, Tanja van Achterberg, Eline Loosveld, Daniëlle Jacobs, Monique van der Vleuten, Patrick H. Beusker, Leon Hooftman, Peter Goedings, Gijs Verheijden, Marco Timmers. In vitro and in vivo antitumor activity of SYD985, a novel HER2-targeting ADC: a comparison with T-DM1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2652. doi:10.1158/1538-7445.AM2014-2652