Chemical Synthesis of Antibody-Hapten Conjugates Capable of Recruiting the Endogenous Antibody to Magnify the Fc Effector Immunity of Antibody for Cancer Immunotherapy.
Chemical Synthesis of Antibody-Hapten Conjugates Capable of Recruiting the Endogenous Antibody to Magnify the Fc Effector Immunity of Antibody for Cancer Immunotherapy.
复制标题
DOI：
10.1021/acs.jmedchem.1c01480
复制
发表时间：
2021-12
影响因子：
7.3
通讯作者：
K. Zhou;Haofei Hong;Han Lin;Liang Gong;Dan Li;Jie Shi;Zhifang Zhou;Fei Xu;Zhimeng Wu
中科院分区：
文献类型：
--
作者：
K. Zhou;Haofei Hong;Han Lin;Liang Gong;Dan Li;Jie Shi;Zhifang Zhou;Fei Xu;Zhimeng Wu
在癌症免疫治疗中具有增强效应功能的单克隆抗体（mAb），例如补体依赖性细胞毒性（CDC）和抗体依赖性细胞介导的细胞毒性（ADCC），可以改善临床表现。在这里，我们开发了一种 mAb-半抗原缀合物策略，通过内源抗体的参与增强 mAb 效应器功能。 “现成”单克隆抗体利妥昔单抗与鼠李糖 (Rha) 半抗原进行位点特异性缀合，生成利妥昔单抗-Rha 缀合物。章鱼样缀合物可以将抗 Rha 抗体募集到癌细胞表面，并进一步形成免疫复合物，该复合物能够提供多价 Fc 结构域与免疫细胞或补体蛋白 C1q 相互作用，从而同时放大 ADCC 和 CDC。一种以 PEG2 作为连接体的最佳缀合物 R2 在异种移植模型中表现出最有效的体外癌细胞杀伤活性和显着的体内抗肿瘤功效。这是一种通用且经济有效的方法，用于生成具有改进的效应器功能的单克隆抗体，可能具有广泛的应用。
Monoclonal antibodies (mAbs) with enhanced effector functions in cancer immunotherapy, such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), could improve the clinical performance. Here, we develop an mAb-hapten conjugate strategy to augment the mAb effector functions with the engagement of endogenous antibodies. An "off-the-shelf" mAb, rituximab, is site-specifically conjugated with the rhamnose (Rha) hapten to generate rituximab-Rha conjugates. The octopus-like conjugates could recruit anti-Rha antibodies onto the cancer cell surface and further form an immune complex that is able to provide multivalent Fc domains to interact with immune cells or complement protein C1q, leading to magnified ADCC and CDC simultaneously. One optimal conjugate R2 with PEG2 as a linker exhibits the most potent in vitro cancer cell killing activity and significant in vivo antitumor efficacy in a xenograft model. This is a general and cost-effective approach to generate mAb with improved effector functions that may have broad applications.