Triple-negative breast cancer (TNBC) accounts for 10% to 15% of all breast cancer cases and is associated with poor prognosis due to its aggressive nature, high metastatic potential, and lack of actionable therapeutic targets. Mucin1 (MUC1), a glycosylated heterodimeric protein, is aberrantly overexpressed in TNBC and contributes to tumor progression and therapy resistance. Following autoproteolytic cleavage, MUC1 generates 2 subunits: MUC1-N (extracellular) and MUC1-C (transmembrane). The MUC1-N subunit is shed and circulates in the blood, while the tumor-anchored MUC1-C subunit functions as an oncoprotein and has recently emerged as a promising therapeutic target.
XY017 is a monoclonal antibody that binds to the extracellular domain of MUC1-C. In this study, XY017 was characterized preclinically using flow cytometry to evaluate expression, internalization, and clonogenic survival. Cytotoxicity was assessed via half-maximal inhibitory concentration (IC50), and in vivo xenograft models were used to determine efficacy.
XY017 exhibited high affinity, binding to MUC1-C on the surface of TNBC cell lines (SUM52, MDA-MB-468, and SUM-149) and demonstrated substantial internalization. Antibody–drug conjugate optimization involved testing cleavable linker-exatecan combinations, with XYA02 selected for its favorable monomeric purity, drug-to-antibody ratio, stability, and yield. XYA02 demonstrated dose-dependent cytotoxicity in the TNBC cell lines, with IC50 values in the low nanomolar range. Treated TNBC cells (SUM149 and MDA-MB-468) showed significantly reduced colony formation compared with controls, confirming XYA02's ability to inhibit tumor cell proliferation. In vivo efficacy was assessed in TNBC xenograft models (SUM149 and MDA-MB-468), where XYA02 (administered at 5-10 mg/kg weekly for 3 weeks) demonstrated significant tumor growth inhibition. Importantly, no noticeable weight loss was observed in treated nu/nu mice. Even at doses 5 to 10 times higher (up to 100 mg/kg), XYA02 showed no adverse effect on hematological parameters, suggesting a favorable preclinical safety profile.
These findings support the clinical development of XYA02 as a therapeutic option for TNBC, with the potential to address the critical need for effective and targeted treatment options in this challenging patient population. Phase 1 clinical trials are planned to begin in mid-2026.
Source: Kharbanda S, Raina D, Ahmad R, et al. Novel MUC1-C-ADC exhibits remarkable anti-tumor potency in the treatment of triple-negative breast cancer (TNBC). Presented at: ESMO Congress 2025. October 20, 2025; Berlin, Germany. Abstract 560P.