posted on 2024-03-01, 13:38authored byFulai Zhou, Yinyin Ben, Hao Jiang, Siwen Tan, Guangmao Mu, Zhengxia Zha, Shuting Dong, Sheng Huang, Yijun Zhou, Ying Jin, Mark L. Chiu
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.