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 antibody-drug conjugate (ADC) based on trastuzumab and vc-seco-DUBA, a cleavable linkerduocarmycin payload. To evaluate the therapeutic potential of this new ADC, mechanistic in vitro studies and in vivo patientderived 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. In vitro cytotoxicity assays showed similar potencies and efficacies in HER2 3þ 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 in vitro in HER2-negative (HER2 0) cells mixed with HER2 3þ, 2þ, or 1þ 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 antitumor studies in breast cancer PDX models showed that SYD985 is very active in HER2 3þ, 2þ, and 1þ models, whereas T-DM1 only showed significant antitumor activity in HER2 3þ 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. Mol Cancer Ther; 14(3); 692-703. Ó2015 AACR.

A New Class of Antibody–Drug Conjugates with Potent DNA Alkylating Activity

“…an anti-CD70 ADC of a duocarmycin carbamate prodrug failed to achieve any objective responses in a phase I clinical study (31), whereas an ADC with a new duocarmycin prodrug design has recently entered clinical evaluation (32).…”

SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody–Drug Conjugate, Shows Antitumor Activity in Uterine Serous Carcinoma with HER2/Neu Expression

“…SYD985 was prepared as described previously (16)(17)(18). Briefly, vc-seco-DUBA was coupled to a cysteine residue of trastuzumab after partial reduction of the inter-chain disulfides.…”

“…Briefly, vc-seco-DUBA was coupled to a cysteine residue of trastuzumab after partial reduction of the inter-chain disulfides. SYD985 was further purified to deliver a well-defined ADC predominantly consisting of species with a drug to antibody ratio (DAR) of 2 and 4, yielding a mean DAR of 2.8 (16)(17)(18).…”

“…SYD985 (Synthon Biopharmaceuticals BV) is a novel HER2-targeting ADC based on the "cleavable" linker-duocarmycin payload, valine-citrulline-seco DUocarmycin hydroxyBenzamide Azaindole (vc-seco-DUBA), conjugated to trastuzumab showing impressive preclinical results in breast cancer (16)(17)(18) and encouraging clinical activity in phase I clinical trials (data not shown). The toxic payload in SYD985 (i.e., DUBA) alkylates DNA resulting in DNA damage, mitochondrial stress, impaired DNA transcription, apoptosis, and ultimately cell death in both dividing and nondividing cells (16)(17)(18).…”

“…The toxic payload in SYD985 (i.e., DUBA) alkylates DNA resulting in DNA damage, mitochondrial stress, impaired DNA transcription, apoptosis, and ultimately cell death in both dividing and nondividing cells (16)(17)(18). Importantly, cysteine proteases such as cathepsin B present in endosomes and lysosomes are released by human tumors and have been shown to cause both linker cleavage in SYD985 and release of the membrane-permeable active toxin.…”