Bispecific therapeutics target two distinct antigens simultaneously and provide novel functionalities that are not attainable with single monospecific molecules or combinations of them. The unique potential of bispecific therapeutics is driving extensive efforts to discover synergistic dual targets, design molecular formats to integrate bispecific elements, and accelerate successful clinical translation. In particular, the past decade has witnessed a boom in the design and development of bispecific antibody formats with more than 100 collections to date. Despite the remarkable progress that has been made to expand the number of formats, qualitative fine-tuning of bispecific formats is needed to achieve optimal dual-target engagement based on understanding of the spatiotemporal interdependence of the two physically linked binding specificities and the complex target biology associated with bispecific approaches. This review provides insights into the design parameters — including affinity, valency, and geometry — that need to be considered at an early stage of development in order to take the best advantage of bispecific therapeutics.

双特异性治疗剂可同时靶向两种不同的抗原，并提供单一的单特异性分子或它们的组合无法实现的新功能。双特异性疗法的独特潜力正推动人们为发现协同的双重靶标，设计分子格式以整合双特异性成分并加速成功的临床翻译而付出的巨大努力。特别是在过去的十年中，双特异性抗体形式的设计和开发蓬勃发展，迄今已有100多个系列。尽管在扩展格式数量方面取得了显著进步，需要基于对两种物理联系的结合特异性的时空相互依赖性以及与双特异性方法相关的复杂靶生物学的理解，对双特异性形式进行定性的微调，以实现最佳的双靶结合。这篇综述提供了对设计参数的深刻见解，包括亲和力，化合价和几何形状，在开发的早期阶段就需要考虑这些参数，以便最大程度地利用双特异性疗法。