An Engineering Approach for Evaluationg the Precision and Potency of Antibody Effector Function

Download or read book An Engineering Approach for Evaluationg the Precision and Potency of Antibody Effector Function written by Austin W. Boesch and published by . This book was released on 2016 with total page 324 pages. Available in PDF, EPUB and Kindle. Book excerpt: Antibodies are a growing therapeutic class addressing diverse disease states including autoimmunity, cancer and pathogenic infection. While antigen binding is commonly critical for immunoglobulin G (IgG) efficacy, in vivo studies have exposed the requirement of engaging Fc (fragment, crystallizable) receptors (FcR) on immune cells to drive effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP), to facilitate therapeutic benefit. Additional evidence supports a direct link between modulated IgG-FcR affinity and improved in vivo efficacy revealing an opportunity to develop enhanced therapeutics through a comprehensive understanding of tunable IgG-Fc features. Conveniently, antibody engineers have a diverse toolkit available through genetic, cellular, enzymatic and purification techniques to control these features, which can translate to differences in biological function in vitro and in vivo. While many structure-function relationships between IgG-Fc and FcR have been established in humans, our understanding is incomplete. Moreover, it is sparsely understood how these relationships will translate to rhesus macaque, a model organism commonly used to test potential toxicity and possible efficacy of therapeutics and vaccines prior to human trials. To address these inadequacies, we developed and leveraged high-resolution biophysical and effector function characterization assays to probe established and new human-human and rhesus-human IgG-FcR binding pairs. From these studies, we identified new IgG-Fc features, including natural and engineered amino acid sequences and glycoforms, that modulate intra and inter-species IgG-FcR interactions and developed insight towards their biological significance in vitro and possible behavior in vivo. Overall this work enriches our understanding of the individual and linked roles of the innate and adaptive arms of the human immune system, clarifies the translation between animal models and humans, and enables more cognizant development of novel therapeutic strategies and in vivo study designs.