Enhancement of tumor uptake and therapeutic efficacy of EGFR-targeted antibody cetuximab and antibody-drug conjugates by cholesterol sequestration.

摘要: Cetuximab, a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), has been intensively investigated as promising cancer treatment strategy. The specific mechanism of cetuximab endocytosis and its influence on uptake, biodistribution efficacy still remain elusive. Recently, statins have reported to synergize with EGFR-targeting agents. Our prior work established that nystatin, cholesterol-sequestering antifungal drug, facilitates via clathrin-dependent pathway. This study aimed investigate whether nystatin regulates uptake cetuximab-based antibody-drug conjugates (cetuximab-ADCs). In vitro in vivo efficacies activity cetuximab/cetuximab-ADCs were studied multiple human carcinoma cell lines xenograft models, respectively. We identified cholesterol sequestration by enhanced internalization EGFR-positive cells regulating EGFR trafficking/turnover facilitating switch from lipid rafts clathrin-mediated endocytosis. Combination selectively increased tumor tissues, translating into potentiated antitumor (A431 A549 tumors). Nystatin-enhanced further improved potency cetuximab-doxorubicin cetuximab-methotrexate cetuximab-resistant tumors. therapy plus either or cetuximab-ADC prolonged animal survival significantly suppressed growth, compared single-agent cetuximab-ADC. summary, our results identify novel whereby enhances mAb ADCs, therefore providing preclinical proof-of-concept combination can potentiate delivery these EGFR-targeted