Novel specific anti‐ESM1 antibodies overcome tumor bevacizumab resistance by suppressing angiogenesis and metastasis

Abstract

Suppressing tumors through anti‐angiogenesis has been established as an effective clinical treatment strategy. Bevacizumab, a monoclonal antibody, is commonly used in various indications. However, two major challenges limit the long‐term efficacy of bevacizumab: drug resistance and side effects. Bevacizumab resistance has been extensively studied at the molecular level, but no drug candidates have been developed for clinical use to overcome this resistance. In a previous study conducted by our team, a major finding was that high expression of ESM1 in bevacizumab‐resistant tumors is associated with an unfavorable response to treatment. In particular, an increase in ESM1 expression contributes to heightened lung metastasis and microvascular density, which ultimately decreases the tumor's sensitivity to bevacizumab. In contrast, the silencing of ESM1 results in reduced angiogenesis and suppressed tumor growth in tumors resistant to bevacizumab. We put forward the hypothesis that targeting ESM1 could serve as a therapeutic strategy in overcoming bevacizumab resistance. In this study, a variety of anti‐ESM1 antibodies with high affinity to human ESM1 were successfully prepared and characterized. Our in vivo study confirmed the establishment of a bevacizumab‐resistant human colorectal cancer model and further demonstrated that the addition of anti‐ESM1 monoclonal antibodies to bevacizumab treatment significantly improved tumor response while downregulating DLL4 and MMP9. In conclusion, our study suggests that anti‐hESM1 monoclonal antibodies have the potential to alleviate or overcome bevacizumab resistance, thereby providing new strategies and drug candidates for clinical research in the treatment of bevacizumab‐resistant colorectal cancer.