(174w) CD276-Targeted Dual-Payload ADC Triple Negative Breast Cancer Treatment

Breast cancer is a major cause of mortality among women worldwide. Triple-negative breast cancer (TNBC, ER^-/PR^-/HER2^-) comprises 15-20% of breast cancer. TNBC is highly aggressive, heterologous, and recurrent, with low response to chemotherapy and severe side effects. The goal of this study is to develop a novel antibody-drug conjugate (ADC) for targeted therapeutic treatment of TNBC. We first developed a new monoclonal antibody (mAb) to specifically target the glycosylated extracellular domain of CD276, a receptor overexpressed in TNBC associating with tumor proliferation and dissemination. The engineered (humanized) mAb showed high TNBC specificity in flow cytometry analysis, confocal microscope imaging, live-animal In Vivo Imaging System. We further conjugated a cytotoxic chemotherapy and an immunotherapy agent to construct a DualADC. The in vitro evaluation showed that our CD276-targeted DualADC has high cytotoxicity to multiple TNBC cell lines. Importantly, the DualADC significantly reduced TNBC tumor burden in multiple mouse models, including patient-derived xenograft (PDX) models, and upregulated tumoral immunity in immunocompetent models. All in all, we developed an innovative therapy for TNBC treatment.