抗AGR2单克隆抗体抗肿瘤活性与机制研究

项目名称： 抗AGR2单克隆抗体抗肿瘤活性与机制研究

项目编号： No.81201769

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 武正华

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 本项目将研究具有自主知识产权并有治疗功能的AGR2（Anterior gradient-2）单克隆抗体18A4及其人源化抗体18A4HU的抗肿瘤活性及其机制。AGR2是一种在多种肿瘤细胞中高表达的分泌蛋白，能促进肿瘤的形成、生长与转移，并与血管生成与耐药性相关，其肿瘤靶标特征已被大量的报道，为抗体药物的研发提供了可能的新靶标。根据我们首次报道的治疗型AGR2单克隆抗体的抗肿瘤活性与相关专利，我们将着重进行2方面工作：1、研究单克隆抗体和人源化后抗体的抗肿瘤效果和有效范围；2、研究单克隆抗体的抗肿瘤作用机制，尤其是对AGR2受体和信号转导的影响。本项目将为靶向针对AGR2的新型抗肿瘤单克隆抗体药物的临床前研究奠定基础，并进一步揭示AGR2与肿瘤发生之间的关系，进而催生一系列以AGR2为靶点的新型药物。

中文关键词： Anterior gradient(AGR2)；单克隆抗体；抗肿瘤；活性；机制

英文摘要： The aim of this proposal is to study the anti-tumor effect and mechanism of the AGR2 (Anterior gradient-2) monoclonal antibody-18A4 and its humanized version 18A4HU. AGR2 protein is differentially expressed in many tumor cells and It can be both cytoplasmic and secreted. AGR2 promotes tumor formation, anchorage independent growth, migration and metastasis of tumor cells. AGR2 may also relate to the drug-resistance of tumor cells. The cancer-target features of AGR2 protein are largely validated by forced expression, siRNA and animal tumor models. Several detection and diagnostic are now on the market but no functional AGR2 blocking antibodies are reported other than 18A4 reported and patented by us earlier. Based on our early work, we propose to investigate the antitumor function of the monoclonal antibody 18A4 and its humanize version 18A4HU in the following areas: 1.The anti-tumor efficacy and effective tumor range. 2. The mechanism of anti-tumor action, especially the effects on AGR2 binding to its potential receptor and the perturbation of AGR2 signaling pathways. Our proposal will pave the foundation of further preclinical studies and reveal the underlying relationship between AGR2 and tumorigenesis. This proposal for the first time raised the question of AGR2 druggability and the effectiveness of a therap

英文关键词： AGR2；monoclonal antibody；antitumor；activity；mechanism