Madsen Andreas V, Pedersen Lasse E, Kristensen Peter, Goletz Steffen
Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.
Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark.
Front Bioeng Biotechnol. 2024 Jan 25;12:1352014. doi: 10.3389/fbioe.2024.1352014. eCollection 2024.
Bispecific antibodies (bsAbs) have attracted significant attention due to their dual binding activity, which permits simultaneous targeting of antigens and synergistic binding effects beyond what can be obtained even with combinations of conventional monospecific antibodies. Despite the tremendous therapeutic potential, the design and construction of bsAbs are often hampered by practical issues arising from the increased structural complexity as compared to conventional monospecific antibodies. The issues are diverse in nature, spanning from decreased biophysical stability from fusion of exogenous antigen-binding domains to antibody chain mispairing leading to formation of antibody-related impurities that are very difficult to remove. The added complexity requires judicious design considerations as well as extensive molecular engineering to ensure formation of high quality bsAbs with the intended mode of action and favorable drug-like qualities. In this review, we highlight and summarize some of the key considerations in design of bsAbs as well as state-of-the-art engineering principles that can be applied in efficient construction of bsAbs with diverse molecular formats.
双特异性抗体（bsAbs）因其双重结合活性而备受关注，这种活性允许同时靶向抗原，并产生协同结合效应，这种效应甚至是传统单特异性抗体组合都无法实现的。尽管具有巨大的治疗潜力，但与传统单特异性抗体相比，bsAbs的设计和构建常常受到结构复杂性增加所带来的实际问题的阻碍。这些问题性质多样，从外源抗原结合域融合导致的生物物理稳定性下降到抗体链错配，进而形成极难去除的抗体相关杂质。额外的复杂性需要审慎的设计考量以及广泛的分子工程，以确保形成具有预期作用模式和良好类药性质的高质量bsAbs。在本综述中，我们重点介绍并总结了bsAbs设计中的一些关键考量因素，以及可应用于高效构建具有不同分子形式的bsAbs的最新工程原理。
