Details

Autor(en) / Beteiligte

• Chen, Yang
• Liu, Guanghua
• Guo, Lifang
• Wang, Hui
• Fu, Yan
• Luo, Yongzhang

Titel

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

Ist Teil von

• International journal of cancer, 2015-01, Vol.136 (1), p.182-194

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2015

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Cetuximab, a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), has been intensively investigated as a promising cancer treatment strategy. The specific mechanism of cetuximab endocytosis and its influence on cetuximab uptake, biodistribution and efficacy still remain elusive. Recently, statins have been reported to synergize with EGFR‐targeting agents. Our prior work established that nystatin, a cholesterol‐sequestering antifungal drug, facilitates endocytosis via the clathrin‐dependent pathway. This study aimed to investigate whether nystatin regulates the uptake and efficacy of cetuximab and cetuximab‐based antibody–drug conjugates (cetuximab‐ADCs). In vitro and in vivo efficacies of nystatin on the uptake and activity of cetuximab/cetuximab‐ADCs were studied in multiple human carcinoma cell lines and xenograft models, respectively. We identified that cholesterol sequestration by nystatin enhanced cetuximab internalization in EGFR‐positive carcinoma cells by regulating EGFR trafficking/turnover and facilitating a switch from lipid rafts to clathrin‐mediated endocytosis. Combination treatment with cetuximab and nystatin selectively increased cetuximab uptake by tumor tissues, translating into potentiated antitumor efficacy of cetuximab in vivo (A431 and A549 tumors). Nystatin‐enhanced internalization of cetuximab further improved the uptake and potency of cetuximab‐doxorubicin and cetuximab‐methotrexate conjugates in EGFR‐positive cetuximab‐resistant tumors. Combination therapy with nystatin plus either cetuximab or cetuximab‐ADC further prolonged animal survival and significantly suppressed tumor growth, as compared with single‐agent cetuximab or cetuximab‐ADC. In summary, our results identify a novel mechanism whereby cholesterol sequestration enhances the uptake of EGFR‐targeting mAb and ADCs, therefore providing preclinical proof‐of‐concept that combination with nystatin can potentiate the delivery and efficacy of these EGFR‐targeted agents. What's New? Cetuximab is an antibody‐based therapy targeting the epidermal growth factor receptor (EGFR) shielding it from ligand binding and enhancing its internalization and degradation. The authors speculated that nystatin, a polyene antifungal drug known to facilitate endocytosis via the clathrin‐dependent pathway, would enhance cetuximab uptake and activity. They provide preclinical proof‐of‐concept that cholesterol sequestration mediated by nystatin increases the delivery efficiency and therapeutic efficacy of cetuximab and cetuximab‐drug conjugates where cetuximab is associated with chemotherapeutic drugs such as doxibubicin or methotrexate. These studies point to the combination of EGFR‐targeting antibodies and cholesterol‐sequestering agents as a promising new strategy to enhance clinical application of antibody‐based therapies.