Fulai Zhou, Yinyin Ben, Hao Jiang, Siwen Tan, Guangmao Mu, Zhengxia Zha, Shuting Dong, Sheng Huang, Yijun Zhou, Ying Jin and Mark L. Chiu*,
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引用次数: 0
摘要
双特异性抗体(BsAbs)在肿瘤学和自身免疫疾病领域的应用正在不断发展。大多数双特异性抗体工程设计都采用单克隆抗体的单 Fc 接合方式,通过拥有一个以上的靶向臂来提高活性。在这里,我们设计了一种新型免疫球蛋白γ-1(IgG1)衍生的双 Fc BsAb,它含有两个 Fc 区和两个不同的不对称抗原结合臂,其中包括一个 Fab 臂和另一个 VHH 结构域。结合旋钮入孔技术,双 Fc BsAb 的产量高且稳定性好。我们探讨了双 Fc 构建物的 Fc 工程效应如何提高预期疗效。这种新形式可以同时与相应的抗原进行双特异性结合。此外,与单 Fc 对照分子相比,双 Fc BsAbs 通过与两种抗原和 Fc 受体的结合,提高了与 FcγRs 的亲和力,从而提高了 ADCC 和 ADCP 活性。总之,这种具有增强效应功能的新型 BsAb 形式为基于抗体的免疫疗法提供了一种新的选择。
A Novel Dual-Fc Bispecific Antibody with Enhanced Fc Effector Function
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.
期刊介绍:
Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.