Abstract
SYD985 is a HER2-targeting antibody-drug conjugate (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 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. 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 with 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 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.
Highlights
After many years of investigation, antibody–drug conjugates (ADC) find their way to clinical practice [1]
SYD985 was further purified by hydrophobic interaction chromatography to deliver a well-defined ADC consisting of predominantly species with a drug to antibody ratio (DAR) of 2 and 4, yielding a mean DAR of 2.8
Binding and internalization of SYD985 and T-DM1 Binding capacity and percentage of internalization of SYD985 and T-DM1 were determined in time using flow-cytometric analyses in cell lines SK-BR-3, SK-OV-3, and MDA-MB-175-VII, which are classified as HER2 3þ, 2þ, and 1þ, respectively
Summary
After many years of investigation, antibody–drug conjugates (ADC) find their way to clinical practice [1]. The introduction of T-DM1 has added great value to the therapeutic armamentarium for patients with HER2-positive metastatic breast cancer; the patient population that might benefit from a HER2-targeting ADC could be expanded by a more effective HER2-targeting ADC. T-DM1 is approved for the treatment of HER2-positive metastatic breast cancers, defined as IHC-HER2 3þ or FISH-positive/IHC-HER2 2þ. According to these criteria, approximately 20% to 25% of all metastatic breast cancer patients are currently eligible for T-DM1 therapy [9, 10]. A HER2-targeting drug that has a clinical benefit in patients whose tumor is FISH-negative but has detectable IHC HER2 expression (2þ and 1þ) would at least double that population [10, 11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
