Depletion and recovery of IgG following treatment with Rozanoliximab and Imlifidase in pigtail macaques

Abstract

Antibodies are central players in adaptive immunity, providing protection against a wide array of pathogens through mechanisms such as neutralization, opsonization, recruitment of effector immune cells, complement activation and engagement. However, in other contexts, these same effector functions can contribute to immunopathology, particularly when antibodies are developed against self-antigens, resulting in autoimmunity. Understanding the role antibodies play in preventing or causing disease is often supported by studies in model systems wherein manipulation of IgG levels can be used as an experimental tool. Here, we report in simian immunodeficiency virus (SIV) infected pigtail macaques (Macaca nemestrina) the capacity of two orthogonal strategies to systemically deplete IgG - treatment with a neonatal Fc receptor blocking antibody (Rozanolixizumab) that restricts IgG rescue and recycling, and administration of the IgG protease Imlifidase (IdeS) that cleaves the Fc domain. Under the conditions evaluated, we observed more rapid and effective, although not necessarily more durable, IgG depletion mediated by IdeS, reducing levels by 74.1-95.1%, compared to a lesser reduction of 31.3-66.9% with anti-FcRn treatment. We observed a similar degree of depletion, comparable kinetics of rebound among SIV antigen-specific fractions as total IgG, but differential balance among IgG subclasses following treatment in some cases. In sum, this study in a nonhuman primate model describes the efficacy and downstream impacts of new tools to modify humoral immune states providing insight into the balance between protective and pathological effects of IgG antibodies.