The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers

Abstract

SYD985 is a HER2-targeting ADC based on trastuzumab and vc-seco-DUBA, a cleavable linker-duocarmycin payload. To evaluate the therapeutic potential of this new ADC, 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. 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 in HER2 negative (HER2 0) cells mixed with HER2 3+, 2+, or 1+ cell lines. At pH conditions relevant for tumors, cathepsin-B cleavage studies showed efficient release of the active toxin by SYD985 but not by T-DM1. These in vitro data suggest that SYD985 might be a more potent ADC in HER2 expressing tumors in vivo, especially in low HER2-expressing and/or in heterogeneous tumors. 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. These properties of SYD985 may enable expansion of the target population to patients who have low HER2 expressing breast cancer, a patient population with still unmet high medical need.