A systems analysis to understand the differential pharmacokinetics and protective efficacy of anti-malarial monoclonal antibodies in field trials.

Indiana University Indianapolis, Indianapolis IN

Investigators

Abstract

Monoclonal antibodies (mAbs) targeting infectious agents act primarily by direct neutralization but their ability to bind to specific Fc receptors can either extend antibody half-life or enhance cellular activity against the pathogen. The anti-malarial IgG1 mAbs CIS43LS and L9LS are effective at preventing malaria infection in randomized, placebo-controlled clinical trials conducted in individuals who are naturally exposed to Plasmodium falciparum malaria. Both mAbs have increased binding affinity to the neonatal Fc receptor (FcRn), resulting in enhanced IgG recycling and thus longer serum half-life, while retaining the ability to bind to Fcγ receptors (FcγRs). Significant variability in anti-malarial mAb half-lives has been observed in clinical trials, which has implications for the optimizing dosing to extend duration of efficacy. We hypothesize that specific innate signals alter the protective efficacy of anti-malarial mAbs by regulating Fcγ-mediated effector responses or by extending half-life via enhanced FcRn-mediated recycling. To address this, we will leverage prospective clinical data, pharmacokinetic data, and biospecimens from a phase 2 pediatric trial of L9LS to conduct an unbiased, comprehensive analysis of transcriptomic, metabolomic, and cytokine profiles in blood obtained from trial participants before and after receipt of L9LS or placebo. Differential analysis and integrated, multi-omics machine learning will be conducted to determine immune features predictive of L9LS-mediated malaria protection and longer mAb half-life. Immune cells from malaria-protected and malaria-susceptible individuals will be compared using 1) single-cell transcriptomics to assess for differentially activated states within specific cell types and 2) in vitro functional assays to assess antibody-dependent cellular phagocytosis and cytotoxicity. Specific findings will be validated using samples from independent L9LS and CIS43LS trials conducted in malaria-exposed and malaria-naïve adults. The study has the potential to identify molecular signatures predictive of mAb-mediated protection from P. falciparum infection and address fundamental questions applicable to other anti-infective mAbs. Findings from this proposal could determine the impact of innate immune activation, which can vary even in states of apparent health, on the efficacy of anti-infective mAbs and provide insight on potential Fc-mediated mechanisms of action. Determining host features that affect the pharmacokinetics of the mAbs L9LS and CIS43LS has broader implications for understanding the dosing, clearance, and efficacy of other IgG1 mAbs. Successful completion of this project may also reveal strategies for enhancing and prolonging the therapeutic efficacy of IgG1 mAbs targeting other pathogens and clinical conditions. Individualizing mAb dosing based on patient-specific molecular characteristics can potentially reduce costs and improve resource utilization, which may be critical during outbreaks of emerging pathogens or in resource-limiting settings.