Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies due to the absence of conventional surface receptors such as ER, PR, and HER2. This study introduces lipolysis-stimulated lipoprotein receptor (LSR) as a novel therapeutic target, identified through its overexpression in over 63% of TNBC patient tissues and various TNBC cell lines. We developed a monoclonal antibody (mAb) targeting the extracellular domain of LSR (Met1-Asp259) and engineered it with a human IgG1 Fc region for enhanced clinical potential. An antibody-drug conjugate (ADC) was constructed by conjugating the LSR mAb with mertansine (DM1), demonstrating potent cytotoxicity in vitro against TNBC cell lines (MDA-MB-231, MDA-MB-468, and 4T1). Anti-TNBC efficacy was assessed in two TNBC xenograft mouse models (MDA-MB-231 and 4T1) in vivo, where 24 mg/kg of LSR mAb-DM1 ADC reduced tumor burden by 85% in one model and induced tumor shrinkage while preventing regrowth in the other, with no detectable off-target or systemic toxicity. These results establish LSR as a promising TNBC target and the LSR mAb-DM1 ADC as a potential new therapy, offering a targeted approach to address the unmet needs in TNBC treatment.
