Fine-tuning bispecific therapeutics

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.