Breast Cancer Breakthroughs: Novel ADC DHES0815A In Focus
National Breast Cancer Awareness Month
This October, we recognize National Breast Cancer Awareness Month, a time to highlight advancements in breast cancer research and raise awareness about the disease. In 2024, over 360,000 individuals are expected to be diagnosed with breast cancer. Thanks to significant progress in research, improvements in early detection methods, and the development of new treatment options, survival rates are steadily rising. When detected early at its localized stage, breast cancer has a 5-year relative survival rate of 99%.
Among breast cancer subtypes, approximately 1 in 5 cases are classified as human epidermal growth factor receptor 2 (HER2)-positive. These cancers tend to be more aggressive, with a higher risk of recurrence and poorer overall survival outcomes. Fortunately, recent advancements in targeted therapies, particularly antibody-drug conjugates (ADCs), are showing promise in combating HER2-positive (HER2+) breast cancer.
Evaluation of a Novel Antibody-Drug Conjugate in HER2-positive Metastatic Breast Cancer
A recent publication by Lewis and colleagues describes a novel antibody-drug conjugate (ADC), DHES0815A, targeting HER2+ metastatic breast cancer (BC) and outlines preclinical characterization and phase 1 trial results. ADCs work by enabling selective delivery of cytotoxic agents to tumor cells, minimizing damage to healthy tissue.
DHES0815A targets a unique HER2 epitope not addressed by currently approved ADCs like trastuzumab and pertuzumab, which are typically used in combination with microtubule inhibitors (i.e., taxanes) to treat HER2+ breast cancer. The antibody component of DHES0815A, designated as MHES0488A, is engineered for enhanced conjugation, allowing for the attachment of cytotoxic agents. The payload of DHES0815A focuses on pyrrolobenzodiazepine (PBD) dimers, which function as DNA-damaging agents—offering a different mechanism from the microtubule inhibitors traditionally used. This opens up the potential for DHES0815A to be used in combination with existing HER2-targeted therapies.
Pre-clinical Evaluation
In preclinical testing, in vitro cell killing assays demonstrated selective activity of DHES0815A in HER2+ BC cell line SK-BR-3. No activity was observed with controls, including Lifeline® Cell Technology’s normal human mammary epithelial cells and the HER2-negative (HER2-) BC cell line MCF7. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity.
In vivo studies further supported these findings with DHES0815A demonstrating dose-dependent tumor growth inhibition in both HER2-positive and HER2-low models. It was also well-tolerated in cynomolgus monkey safety studies, highlighting its potential for clinical application.
Phase I Clinical Trial
In a phase 1 dose-escalation trial, 14 patients with advanced or metastatic HER2-positive breast cancer received DHES0815A at doses ranging from 0.6 to 6 mg/kg. Out of the 14 evaluable patients, one achieved a complete response after six treatment cycles, while two experienced partial responses. Eight showed a confirmed best response of stable disease, two had progressive disease and one patient was not considered evaluable by the investigator during the study. One patient, who achieved a complete response, remained in the study for 32 months.
Despite early signs of anti-tumor activity, treatment-emergent adverse events (TEAEs) were observed in all patients at higher doses. No DLT (dose-limiting toxicity) criteria were met during dose escalation for any cohort and the maximum tolerated dose (MTD) endpoint was not reached. Unresolved TEAEs, including persistent, dermal, ocular, and pulmonary toxicities, eventually led to early termination of the phase 1 trial.
Though the phase 1 trial was halted early, the insights gained are invaluable for future ADC development. As noted by the authors, sharing lessons from clinical failures is important for the field. It can help guide the design of more effective and better-tolerated therapies in the future.
Lifeline® Human Mammary Cells and Media Products
Lifeline® products are trusted by scientists worldwide to advance research in mammary cell biology, cancer development, and therapeutic screening. We offer a range of mammary cells and culture media to support your research including:
- Normal Human Mammary Epithelial Cells – Female
- Normal Human Mammary Epithelial Cells — Male
- MammaryLife ™ Epithelial Medium Complete Kit
Have you used Lifeline products in your research? If so, we would love to hear from you. Your publication could be featured next on our blog!