Identification and characterization of mammaglobin-A epitope in heterogenous breast cancers for enhancing tumor-targeting therapy

Abstract

AbstractAlthough targeted therapy has been extensively investigated for breast cancers, a molecular target with broad application is currently unavailable due to the high heterogeneity of these cancers. Mammaglobin-A (Mam-A), which is overexpressed in most breast carcinomas, has been proposed as a promising target. However, the lack of specific targeting moieties due to uncertain binding epitopes hampers further translational study. Here, seven potential epitopes of Mam-A were disclosed, and a unique epitope was then identified in most types of breast cancers, despite the genotypic heterogeneity. With phage display technology, the epitope was determined to be N-terminal amino acids 42–51 of Mam-A (N42–51). Then, the N42–51 epitope-specific monoclonal antibody, mAb785, was conjugated to poly lactic-co-glycolic acid (PLGA) nanoparticles loaded with therapeutic agents, thereby enhancing the drug uptake and therapeutic efficacy in different genotypes of breast cancers. The computer simulation of the N42–51 epitope and the mAb785 structures, as well as their interactions, further revealed the specific targeting mechanism of the mAb785-conjugated nanoparticles to breast cancers.