Evaluation of the kinetics of systemic distribution of IV injected monoclonal antibodies modified to alter host mediated Fc interaction in the rhesus macaque model

• Published in: Journal of the International AIDS Society Vol. 24; no. S1; p. 1
• Main Authors: Carias, A.M, Schneider, J, Mcraven, M, Xiao, S, Rogers, K, Arainga, M, Veazey, R, Villinger, F, Hope, T.J
• Format: Journal Article
• Language: English
• Published: International AIDS Society 01-01-2021
• Subjects: Dosage and administration; Fc receptors; Health aspects; Immune response; Injections, Intravenous; Monoclonal antibodies; Pharmacokinetics; Pharmacology, Experimental; Physiological aspects; United States
• ISSN: 1758-2652; 1758-2652
• DOI: 10.1002/jia2.25659

Background: Antibody-mediated protection against HIV/SHIV transmission has been illustrated in non-human primates (NHP) with IV injection of broadly neutralizing monoclonal antibodies (bNAbs). To gain insights into the kinetics and dynamics of BNAb distribution and localization, we utilized passively transferred fluorophore-labeled VRC01, developing a platform in the living NHP model, without affecting antibody function. After injection, we followed antibody distribution over time, providing a unique perspective to observe how bNAbs reach different anatomical sites. Using this platform, with anti-FcRn and mutated Fc-function bNAbs, we are now unraveling the mechanisms of how FcR specificity affects antibody distribution. Methods: Macaques were IV-administered fluorescently tagged, anti-FcRn, or a combination of VRC07-523-LS and/or Fc-mutated VRC07-523-LS-LALA (LALA) (mutated to disrupt FcR binding and complement) and/or VRC07-523-LS-DEL (DEL) (mutated to enhance FcgRII antibody binding and ADCC activity). Animals were necropsied between 6 hours and 1 week, tissues collected and imaged with deconvolution microscopy. Results: By analyzing those animals that received fluorescently tagged anti-FcRn, we are now able to discern the cellular locations of FcRn: on endothelial cells and select monocytes. Additionally, in columnar and brain tissues, we are able to visualize antibody distribution through the vascular system, with antibody-FcRn interactions. Lastly although studies are still ongoing, we visualize differences in VRC07-523-LS, VRC07-523-LS-LALA and VRC07-523-LS-DEL distribution amongst different tissues, across multiple time points. Conclusions: These data build on our previous data looking at the distribution and localization of fluorescently labeled anti-HIV bNAbs. However, and importantly, these studies provide novel insights into Fc receptor-associated mechanisms of antibody delivery to different organs and tissues after IV injection into multiple animals. These experiments will provide critical insights into the mechanism(s) of distribution and localization of systemic antibodies by following the time course of distribution of passively transferred antibodies in a gain or loss of function experimental fashion.