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Breast cancer screening

Novel Antibody-Drug Conjugate to Treat HER2-positive Metastatic Breast Cancer

March 12, 2025 / by Lifeline® Cell Technology

Breast cancer is the most common cancer in women in the U.S., and HER2-positive breast cancer (HER2+ BC) accounts for 15-20% of all breast cancer diagnoses. HER2+ breast cancer is aggressive and fast-growing, historically associated with poor outcomes and higher mortality rates. The development of HER2-targeted therapies has significantly improved patient prognosis, with many experiencing good survival rates when treated appropriately.

HER2-directed antibody-drug conjugates (ADCs) are a promising new modality. Comprised of a targeting antibody, a linker, and a cytotoxic agent, ADCs can selectively target and deliver a cytotoxic payload directly into tumor cells while sparing the healthy cells around them, greatly minimizing potential side effects compared to traditional chemotherapy.

Evaluation of a HER2-Directed ADC Candidate DHES0815A

A recent study by Lewis et al. describes DHES0815A, an investigational HER2-directed ADC developed as an alternative to existing therapies. The antibody component, 7C2, binds to subdomain I of the HER2 extracellular domain, distinguishing it from trastuzumab (T-DM1, which binds subdomain IV) and pertuzumab (which binds subdomain II). The researchers selected a DNA damaging agent, a disulfide-linked PBD-monoamide, as the cytotoxic payload after extensive in vitro and in vivo testing.

In vitro Characterization of DHES0815A

DHES0815A demonstrated strong selectivity for HER2+ BC cells in vitro. In cell-killing assays, it effectively targeted HER2+ SK-BR-3 cells, inducing antibody-dependent cellular cytotoxicity (ADCC) and mediating bystander activity. No cytotoxic effects were observed in HER2-negative (HER2-) MCF7 cells.

To assess its impact on normal cells, researchers tested DHES0815A and its parent monoclonal antibody (MHES0488A) on human mammary epithelial cells, renal proximal tubule epithelial cells, umbilical vein endothelial cells, and small airway epithelial cells from LifeLine® Cell Technology. Neither the ADC nor its parent antibody affected the growth of these normal cell types.

Additionally, growth-arrested human epidermal keratinocytes (also from LifeLine®) were used to evaluate DHES0815A’s activity in proliferating vs. quiescent cells. DHES0815A reduced cell viability in non-dividing keratinocytes with minimal impact on dividing keratinocytes.

In vivo Testing of DHES0815A

The efficacy of DHES0815A was assessed using in vivo breast and gastric cancer models, including HER2-low breast patient-derived xenograft (PDX) models, and in combination with standard-of-care therapies.

In both HER2-positive (IHC 3+) breast and gastric cancer PDX models, DHES0815A demonstrated dose-dependent tumor growth inhibition. Combination studies in HER2+ MMTV-HER2 Fo5 and HCC1569 X2 models showed that DHES0815A, when combined with standard-of-care agents T-DM1 or docetaxel, resulted in enhanced antitumor activity compared to single-agent treatment.

Phase I Clinical Testing

A phase 1 dose-escalation study (NCT03451162) was initiated in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A. Fourteen patients were enrolled at doses of 0.6 to 6 mg/kg. Despite early signs of anti-tumor activity, patients at doses of 4.0 mg/kg and higher developed persistent and non-resolvable adverse events (AE). As a result, patient dosing was reduced to 2.4 mg/kg. Due to the limited responses at doses <4.0 mg/kg (1 patient at 1.2 mg/kg), it was deemed unlikely to identify a dose with both sufficient efficacy and safety to warrant additional development in the clinic, resulting in early termination of the phase 1 trial.

In ADC development, failures often outnumber successes. Yet, the reasons for discontinuing preclinical or clinical ADC programs are rarely disclosed. The authors believe that sharing these findings provides valuable insights to help guide the development of more efficacious and better-tolerated ADCs in the future.

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Negative controls are important in biomedical research. Without them, it would have been difficult for the researchers of our featured publication to confirm the selectivity and assess the off-target toxicities of their ADC candidates.

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