Quantitative Systems Pharmacology of Antibody Therapeutics across Diverse Biological Contexts

ABSTRACT Antibody-based therapeutics have grown rapidly over the past two decades. However, many challenges limiting the success of this drug class persist. First, the attrition rate remains high in antibody drug development. Second, many antibody therapeutics exhibit only transient pharmacologic action. As a result, antibody therapeutics benefit only a subset of patients. A key driver of these issues is our poor understanding of antibody pharmacology in vivo across biological contexts. Our research has revealed that antibody pharmacology is highly dependent on the physical and biological contexts of the biological environments where their actions occur. Methods and tools that integrate tissue physiology, disease pathology, and immune status into the characterization of antibody pharmacology are sorely needed. Leveraging multi-dimensional spatiotemporal data, we have developed quantitative systems pharmacology (QSP) models and experimental tools that allow us to investigate many facets of antibody context-dependent pharmacology, including tissue-specific pharmacokinetics (PK) and pharmacodynamics (PD), disease pathology, antibody-mediated immune dynamics, and cell-cell interactions. Our work has yielded insights for antibody drug development and therapeutic application. In this MIRA, we propose to apply and refine these experimental and mathematical tools to continue our long-standing efforts to address critical issues surrounding antibody context-specific pharmacology. Specifically, we will continue our work in 1) measuring and modeling antibody tissue PK and target engagement in living animals; 2) modeling antibody-mediated cell-cell contact and interactions across biological contexts; and 3) determining the roles of the constant region (Fc) and effector function in soluble target neutralization. In project 1, our lab has developed a proximity-based bioluminescence resonance energy transfer (BRET) imaging approach. This BRET imaging technology can longitudinally measure antibody exposure and target engagement within tissues of living animals, elucidating the physiological and biophysical factors that govern and restrict antibody−target binding processes in vivo. In project 2, we will apply our proximity-based cell-cell imaging tools, coupled with a multidimensional QSP model for cell-cell interactions, to uncover the biophysical principles of antibody-mediated cell-cell communication. In project 3, we will investigate the multifactorial aspects of antibody pharmacology for soluble target neutralization and highlight the critical but neglected roles of Fc variants and effector function. This project could uncover overlooked mechanisms that have restricted antibody therapeutic development against soluble targets and expand the field’s design space. Overall, our research will continue to address the fundamental challenges to efficient antibody development and optimal therapeutic application through the development of experimental tools and QSP models.