Molecular characterization and modeling efficient antibody effector function

ABSTRACT Antibody effector functions represent a nexus linking innate and adaptive arms of the immune system and also have direct clinical implications for antibody therapeutics and antibody-mediated pathologies. However, the potency of Ab-dependent effector responses depends on numerous antigen, antibody and effector cell properties. Variable antigen expression levels, accessibility and context on different targets influence not only Ab binding but also the ability of the effector cell to kill or engulf its target. Based on the extensive diversity of natural and engineered antibody forms and formats, both B cells and immunologists can engineer antibodies with different flexibility, affinity, and avidity to manipulate the effector response. The complexity of these interactions makes in vivo experimental testing of all combinations impractical, but the significance of these activities to antibody-based protection and pathology and the opportunity to design agents with a high probability of success once the fundamental cellular presentation mechanisms are understood makes quantitative analysis of this complex biological landscape of high significance. This proposal will elucidate our basic understanding of the cellular mechanisms that can drive advancements in the practical development of immune therapeutics and the parameters by which both B cells and effectors can drive variation in the outcome of antibody recognition. Overall, this work seeks to distill quantitative relationships between antigen, antibody, and effector biology to establish “rules” that enable the generation of antibody design criteria that encapsulate key landmarks in the antibody effector function landscape and enable robust prediction of this critical aspect of antibody activity.