抑制肿瘤通过抗血管生成已被确立为一种有效的临床治疗策略。贝伐单抗是一种常用的单克隆抗体，应用于各种适应症。然而，两个主要挑战限制了贝伐单抗的长期疗效：药物抵抗和副作用。贝伐单抗抵抗已在分子水平上进行了广泛研究，但尚未开发出用于临床应用以克服这种抵抗的药物候选物。在我们团队以前的研究中，一个重要发现是贝伐单抗抗药性肿瘤中ESM1高表达与不利的治疗反应相关。特别是，ESM1表达的增加促进了肺转移和微血管密度的增加，最终降低了肿瘤对贝伐单抗的敏感性。相反，抑制ESM1导致了对贝伐单抗抗药性肿瘤中血管生成的降低和肿瘤生长的抑制。我们提出假设，靶向ESM1可能作为克服贝伐单抗抗药性的治疗策略。在本研究中，成功制备并鉴定了多种与人类ESM1具有高亲和力的抗ESM1单克隆抗体。我们的体内研究证实了贝伐单抗抗药性人类结直肠癌模型的建立，并进一步证明了贝伐单抗治疗中加入抗ESM1单克隆抗体明显改善了肿瘤反应，同时下调了DLL4和MMP9。总之，我们的研究表明，抗hESM1单克隆抗体具有缓解或克服贝伐单抗抗药性的潜力，为贝伐单抗抗药性结直肠癌的临床研究提供了新的策略和药物候选物。©2023 The Authors.亦由John Wiley ＆ Sons Australia有限公司代表日本癌症协会发表的Cancer Science。

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.© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.