贪婪
抗体依赖性细胞介导的细胞毒性
双特异性抗体
效应器
抗原
碎片结晶区
免疫疗法
抗体
化学
癌症研究
计算生物学
免疫学
医学
免疫系统
生物
单克隆抗体
作者
Fulai Zhou,Yinyin Ben,Hao Jiang,Song Tan,Guangmao Mu,Zhengxia Zha,Shuting Dong,Sheng Hu,Yijun Zhou,Ying Jin,Mark L. Chiu
出处
期刊:Biochemistry
[American Chemical Society]
日期:2024-03-01
标识
DOI:10.1021/acs.biochem.3c00481
摘要
Bispecific antibodies (BsAbs) are undergoing continued development for applications in oncology and autoimmune diseases. While increasing activity by having more than one targeting arm, most BsAb engineering employs single Fc engagement as monoclonal antibodies. Here, we designed a novel immunoglobulin gamma-1 (IgG1)-derived dual-Fc BsAb containing two Fc regions and two distinct asymmetric antigen binding arms comprising a Fab arm and another VHH domain. In conjunction with the knob-into-hole technology, dual-Fc BsAbs could be produced with a high yield and good stability. We explore how Fc engineering effects on dual-Fc constructs could boost the desired therapeutic efficacy. This new format enabled simultaneous bispecific binding to corresponding antigens. Furthermore, compared to the one-Fc control molecules, dual-Fc BsAbs were shown to increase the avidity-based binding to FcγRs to result in higher ADCC and ADCP activities by potent avidity via binding to two antigens and Fc receptors. Overall, this novel BsAb format with enhanced effector functionalities provides a new option for antibody-based immunotherapy.
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