CD276-DM1 Antibody drug conjugate with cmLumiOpto gene therapy to treat triple negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by resistance to chemotherapy, elevated metastatic potential, and frequent relapse. This study investigated the therapeutic impact of combining an antibody-drug conjugate (ADC) with mitochondria-targeted gene therapy. A CD276-directed monoclonal antibody conjugated to mertansine when paired with cmLumiOpto gene therapy, exhibited potent synergistic activity across three TNBC cell lines, impairing mitochondrial function and amplifying tumor-associated cytokine responses. In vivo experiments further demonstrated that the ADC/cmLumiOpto combination effectively suppressed metastasis in metastatic models and achieved high tumor growth inhibition in patient-derived xenograft mouse models. Mechanistic studies revealed that this dual approach downregulated metastatic signaling pathways, disrupted the tumor microenvironment, and triggered apoptosis. Importantly, histological assessments of normal tissues and body weight monitoring indicated negligible toxicity. Collectively, these findings highlight the therapeutic promise of CD276-targeted ADCs combined with gene therapy as a strategy for treating TNBC. Overall design: Metastasized 4t1 tumour cells were harvested from the lungs of BALB/cJ mice after three weeks of treatment with CD276-mertansine ADC in combination with cmLumiOpto gene therapy.Total RNA was extracted from the harvested tumour cells using the RNeasy Plus Mini Kit (Qiagen, Germantown, MD, USA). Bulk RNA sequencing with cDNA library construction were performed at Novogene America (Sacramento, CA, USA) using the Illumina HiSeq™ X Ten platform.