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

Abstract

<div>Abstract<p>SYD985 is a HER2-targeting antibody–drug conjugate (ADC) based on trastuzumab and vc-<i>seco</i>-DUBA, a cleavable linker-duocarmycin payload. To evaluate the therapeutic potential of this new ADC, mechanistic <i>in vitro</i> studies and <i>in vivo</i> patient-derived xenograft (PDX) studies were conducted to compare SYD985 head-to-head with T-DM1 (Kadcyla), another trastuzumab-based ADC. SYD985 and T-DM1 had similar binding affinities to HER2 and showed similar internalization. <i>In vitro</i> 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 with T-DM1, SYD985 efficiently induced bystander killing <i>in vitro</i> 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 <i>in vitro</i> data suggest that SYD985 might be a more potent ADC in HER2-expressing tumors <i>in vivo</i>, especially in low HER2-expressing and/or in heterogeneous tumors. In line with this, <i>in vivo</i> antitumor 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 antitumor 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. <i>Mol Cancer Ther; 14(3); 692–703. ©2015 AACR</i>.</p></div>