Systemic Inflammation as a Modulator of FcRn-dependent IgG Pharmacokinetics: Implications for Broadly Neutralising Antibody Efficacy in HIV Prevention

Broadly neutralising antibodies (bNAbs) represent a promising long-acting modality for HIV prevention. However, substantial interindividual pharmacokinetic variability poses a threat to real-world efficacy. This review investigates the impact of systemic inflammation, driven by the high prevalence of sexually transmitted infections (STIs), co-endemic pathogens, and metabolic activation, on bNAb persistence, particularly within the vulnerable demographic of women in sub-Saharan Africa. We aim to bridge the gap between neonatal fragment crystallisable receptor (FcRn) biology and clinical pharmacokinetic observations to identify why certain individuals clear bNAbs faster than others.

Synthesis of recent clinical trial data and cross-therapeutic PK evidence indicates that systemic inflammatory biomarkers are strong predictors of accelerated monoclonal antibody clearance. Recent evidence suggests that chronic inflammation modulates bNAb half-life through the transcriptional downregulation of the FCGRT gene, which encodes FcRn, and the competitive saturation of FcRn recycling pathways. These findings suggest that bNAbs' standard dosing does not account for the inflammatory burden that characterises many real-world populations, potentially leading to sub-therapeutic concentrations and an increased risk of breakthrough HIV infection. The host's inflammation status is a primary and currently overlooked determinant of antibody pharmacokinetics. This review provides a roadmap to overcoming the pharmacokinetic heterogeneity modulated by systemic inflammation through establishing the link between inflammation and increased antibody clearance. Bridging these insights paves the way for effective bNAbs with promising implications for prospective HIV prevention and cure strategies that are not only effective in controlled clinical trials but also protective in real-world settings.