Novel antibody cocktail therapy targeting extracellular tumor-specific mutations to treat EMT6 cell line-derived triple-negative breast cancer

Treatment options for triple-negative breast cancer (TNBC) remain limited, and the highly heterogeneous nature of these tumors often contributes to therapeutic resistance. While we have previously demonstrated that antibodies targeting multiple distinct mutated cell surface proteins (MSPs) unique to a given tumor can disrupt tumor growth in mice, the feasibility of this approach in TNBC remains uncertain. Here, we used the murine EMT6 cell line to model TNBC and produced polyclonal antibodies (pAbs) targeting 12 different EMT6-specific MSPs. Of these, 9 bound to EMT6 cells in a cumulative manner without detectable non-tumor binding. Administering a cocktail of these 9 MSP-targeting pAbs to EMT6 tumor-bearing mice in combination with anti-PD-1 delayed tumor growth and improved survival. Analyses of TNBC patients in The Cancer Genome Atlas revealed that the tumors of a larger proportion of these patients harbored > 10 MSPs as compared to individuals with other breast cancer types (69% vs. 42%). Together, these results highlight the promise of using antibodies directed against MSPs expressed by TNBC tumor cells to kill tumor cells in vivo, providing a unique approach to individualized cancer patient care with the potential to achieve superior patient outcomes through the elimination of heterogeneous tumor cell populations.