Avidity in antibody effector functions and biotherapeutic drug design

Antibody function is dependent on avidity - the accumulated strength of multiple affinity interactions between the antibody, antigen, cell surface receptors and other antibodies. In this Review, Oostindie et al. discuss the role of avidity in eliciting antibody functional responses and review the current engineering strategies for manipulating avidity interactions in antibody-based therapies. Antibodies are the cardinal effector molecules of the immune system and are being leveraged with enormous success as biotherapeutic drugs. A key part of the adaptive immune response is the production of an epitope-diverse, polyclonal antibody mixture that is capable of neutralizing invading pathogens or disease-causing molecules through binding interference and by mediating humoral and cellular effector functions. Avidity - the accumulated binding strength derived from the affinities of multiple individual non-covalent interactions - is fundamental to virtually all aspects of antibody biology, including antibody-antigen binding, clonal selection and effector functions. The manipulation of antibody avidity has since emerged as an important design principle for enhancing or engineering novel properties in antibody biotherapeutics. In this Review, we describe the multiple levels of avidity interactions that trigger the overall efficacy and control of functional responses in both natural antibody biology and their therapeutic applications. Within this framework, we comprehensively review therapeutic antibody mechanisms of action, with particular emphasis on engineered optimizations and platforms. Overall, we describe how affinity and avidity tuning of engineered antibody formats are enabling a new wave of differentiated antibody drugs with tailored properties and novel functions, promising improved treatment options for a wide variety of diseases.

Automated summary

This review discusses the role of avidity in eliciting antibody functional responses and current engineering strategies for manipulating avidity interactions in antibody-based therapies. Avidity, derived from multiple affinity interactions, is fundamental to all aspects of antibody biology and is crucial for enhancing or engineering novel properties in antibody biotherapeutics. Therapeutic antibody mechanisms of action are comprehensively reviewed with an emphasis on engineered optimizations and platforms, leading to a new wave of differentiated antibody drugs with tailored properties and promising improved treatment options for various diseases.