新型人源化单克隆抗体候选药物艾克舒的抗肿瘤血管形成机制研究

Monoclonal antibody-based cancer therapy has become one of the most successful strategies to treat many types of tumors and an important direction for drug research and development. To overcome tumor resistance to single-target blockage by antibody, the continuous development of novel antibody medicines against alternative cancer targets and pathways is necessary to ensure a diversified therapeutic selection for prolonged clinical efficacy against cancer. We have developed and patented a novel humanized antibody drug candidate against the new target AGR2 named agtuzumab that effectively reduces tumor cell growth and migration in vitro. Agtuzumab also suppresses xenograft tumor formation and blocks tumor angiogenesis in an animal model as well as in cell-based angiogenesis assays. The striking effect of blocking tumor angiogenesis by agtuzumab is unexpected since AGR2 has not been previously linked to blood vessel formation. Taken together, we propose that AGR2 is an new member participating in cancer angiogenesis network and agtuzumab interferes with tumor angiogenesis by blocking AGR2 signal. In this proposal, we will investigate how AGR2 and its blockage by agtuzumab may alter the expression and modification of the key members of known angiogenesis signaling networks， including cell surface acceptor, cytolasmic signaling intermediates and downstream common effectors these results will connect AGR2 to the existing angiogenesis network . This project will accelerate the pre-clinical study of the novel drug candidate agtuzumab, confirm AGR2 as a novel drug target and reveal for the first time how AGR2 functions to participate tumor angiogenesis.

单克隆抗体抗肿瘤药物是肿瘤治疗的有效手段和发展方向。研发具有新靶点、新机制的单克隆抗体药物是保障抗体药物对肿瘤治疗长期有效的关键。艾克舒（agtuzumab）是我们自主研发的专利人源化单克隆抗体候选药物。艾克舒通过阻断AGR2抑制肿瘤细胞增殖和迁移，有效抑制小鼠移植瘤及其的血管形成。但目前没有AGR2直接参与血管形成的报道。根据体内外血管形成结果，我们提出艾克舒干扰肿瘤微环境中AGR2参与的血管形成的假说。本项目通过艾克舒对AGR2功能的干扰，研究AGR2参与肿瘤微环境血管生成的机制。通过研究已知的肿瘤血管形成信号网络中主要蛋白对AGR2及艾克舒的干扰反应，揭示艾克舒阻断AGR2信号对肿瘤血管形成信号网络的影响和机制。研究结果可以推动艾克舒的临床前研究、揭示AGR2作为新的抗癌药物靶点的原理、填补AGR2信号在肿瘤血管形成中作用的研究的空白，有着重要的社会和学术价值。

单克隆抗体抗肿瘤药物是肿瘤治疗的有效手段和发展方向。研发具有新靶点、新机制的单克隆抗体药物是保障抗体药物对肿瘤治疗长期有效的关键。艾克舒（agtuzumab）是我们自主研发的专利人源化单克隆抗体候选药物。本研究项目历时4年，通过分子水平、细胞水平、整体动物水平等多种实验研究，不但详细揭示了单克隆抗体候选药物艾克舒的抑制血管形成机制，还说明了艾克舒如何通过阻断AGR2功能抑制总体肿瘤组织发生发展过程，包括艾克舒抑制AGR2诱导的成纤维细胞在肿瘤微环境组织形成过程中迁徙增生形成肿瘤组织构架支撑作用的原理， 提出了艾克舒靶标AGR2对实体肿瘤微环境的产生和发展中新的作用机制，充实了艾克舒干扰肿瘤微环境中AGR2参与的血管和肿瘤stroma形成的假说。同时，我们完成了艾克舒的表达优化并构建了CHO表达细胞株（见专利），推动艾克舒（18A4HU）抗体获得多国专利批准，完成了除毒理和中试生产以外的大部分临床前实验，为完成临床报批创造了条件。本课题的研究揭示了艾克舒的阻断靶标AGR2信号通过直接结合关键细胞信号，打破肿瘤发生部位正常细胞信号网络平衡的影响和机制。研究结果推动了艾克舒的临床前研究、揭示AGR2作为新的抗肿瘤药物靶点的原理并补充AGR2信号途径在实体肿瘤组织形成中的作用，具有重要的社会和学术价值。. 此课题支撑了我们对艾克舒候选药物及其靶标AGR2的基础和转化研究，这些研究形成了6篇SCI论文和四个国内外相关批准专利。