(497f) Advanced Immuno-Chemotherapy for TNBC Treatment

Triple-negative breast cancers (TNBCs) are highly aggressive and heterogenous and often relapse post standard cytotoxic chemotherapies (e.g. anthracycline-taxane). The immune checkpoint blockers (ICBs)-based immunotherapies represent a major breakthrough in cancer treatment, but most TNBC patients (up to 90%) failed to respond due to primary and acquired resistance. This study aims to develop and evaluate a novel treatment strategy, i.e. combined immune-chemotherapy, to effectively treat TNBCs. Literature reported that the transmembrane CD276 (B7-H3) is associated with angiogenesis, metastasis and immune tolerance. We detected that over 66% of TNBC patients (n>120) had high surface expression of CD276 in tissue microarray analysis, developed a murine anti-mouse CD276 monoclonal antibody (mAb), and further engineered it by constructing chimeric mAb (Ch276). Ch276 mAb was conjugated with highly potent payload (DM1, MMAF) to construct antibody-drug conjugate (ADC). Flow cytometry, confocal microscope image, and live-animal In Vivo Imaging System (IVIS) showed that our mAb and ADC had high surface binding to TNBC cells, effectively deliver drug intracellularly, and specifically target TNBC tumor. The high anti-cancer cytotoxicity was confirmed in multiple TNBC cell lines (MDA-MB-468, MDA-MB-231, 4T1). The in vivo evaluations showed that our Ch276ADC significantly reduced tumor burden in multiple TNBC cell line xenograft mouse models (immunocompromised and immunocompetent) and patient-derived xenograft (PDX) models, and remodeled tumor microenvironment (TME) by re-activating NK and CD8⁺ T cells. We further constructed ICB programmed cell death protein 1 (PD-1) ADC carrying immune boosting drug and evaluated the synergism of Ch276ADC and PD-1 mAb or ADC, which demonstrated that our Ch276 mAb overcame ICB resistance and further improved TNBC treatment efficacy. Altogether, our study indicated that combining CD276 and PD-1-targeted ADCs is a promising novel immune-chemotherapeutic strategy for TNBC treatment.