Abstract：
Cancer is one of the top 10 fatal diseases worldwide, among which advanced metastatic carcinoma has the highest mortality rate. Sunitinib and immune checkpoint blockers are commonly used to treat metastatic renal carcinoma with limited efficacy. Therefore, there is an urgent need to develop novel targeted therapies for metastatic renal cancer. In this study, we designed an antibody fusion protein, 57103, that simultaneously targeted the cluster of differentiation 24 (CD24), interleukin 4 receptor (IL-4R), and integrin receptors αvβ3 and α5β1. In vitro assays showed that 57103 significantly suppressed the proliferation, migration, invasion, colony formation, and adhesion abilities of renal cancer cells, resulting in a comprehensive and significant antitumor effect. Furthermore, 57103 inhibited angiogenesis, promoted THP1-derived M0-type macrophage phagocytosis, and enhanced the antibody-dependent cellular cytotoxicity of peripheral blood mononuclear and NK92MI-CD16a cells. In vivo experiments revealed significant inhibition of tumor growth in ACHN cell xenograft nude mice and an MC38-hCD24 tumor-bearing mouse model. Immunohistochemical analysis showed that 57103 decreased the proliferation and induced the apoptosis of renal cancer cells, while inhibiting angiogenesis. The MC38-hPDL1 and MC38-hCD24-hPDL1 tumor-bearing mouse models further offer the possibility of combining 57103 with the PDL1 antagonist atezolizumab. In conclusion, 57103 is a potential candidate drug for the treatment of metastatic renal carcinoma or PDL1-overexpressing cancer.
摘要：
癌症是全球十大致命疾病之一，其中晚期转移癌死亡率最高。舒尼替尼和免疫检查点阻断剂通常用于治疗转移性肾癌，但疗效有限。因此,对于转移性肾癌,迫切需要开发新的靶向治疗方法.在这项研究中,我们设计了一种抗体融合蛋白，57103，同时靶向分化簇24（CD24），白细胞介素4受体（IL-4R），和整合素受体αvβ3和α5β1。体外实验表明57103显著抑制了细胞的增殖,迁移,入侵,菌落形成,和肾癌细胞的粘附能力，产生了全面而显著的抗肿瘤作用。此外，57103抑制血管生成，促进THP1来源的M0型巨噬细胞吞噬，并增强了外周血单核细胞和NK92MI-CD16a细胞的抗体依赖性细胞毒性。体内实验表明，在ACHN细胞异种移植裸鼠和MC38-hCD24荷瘤小鼠模型中，肿瘤生长受到显着抑制。免疫组织化学分析显示57103降低了肾癌细胞的增殖，并诱导了细胞凋亡。同时抑制血管生成。MC38-hPDL1和MC38-hCD24-hPDL1荷瘤小鼠模型进一步提供了将57103与PDL1拮抗剂阿特珠单抗组合的可能性。总之,57103是治疗转移性肾癌或PDL1过表达癌症的潜在候选药物。
