Association of IgG1 Antibody Clearance with FcγRIIA Polymorphism and Platelet Count in Infliximab-Treated Patients.

Gilles Thibault,Edouard Louis,David Ternant,Laurie Lajoie,Hsueh Sung,Celine Desvignes,Gilles Paintaud,Hervé Watier,The Getaid ,Valérie Gouilleux-Gruart

doi:10.3390/ijms22116051

Abstract

The FcγRIIA/CD32A is mainly expressed on platelets, myeloid and several endothelial cells. Its affinity is considered insufficient for allowing significant binding of monomeric IgG, while its H131R polymorphism (histidine > arginine at position 131) influences affinity for multimeric IgG2. Platelet FcγRIIA has been reported to contribute to IgG-containing immune-complexe clearance. Given our finding that platelet FcγRIIA actually binds monomeric IgG, we investigated the role of platelets and FcγRIIA in IgG antibody elimination. We used pharmacokinetics analysis of infliximab (IgG1) in individuals with controlled Crohn’s disease. The influence of platelet count and FcγRIIA polymorphism was quantified by multivariate linear modelling. The infliximab half-life increased with R allele number (13.2, 14.4 and 15.6 days for HH, HR and RR patients, respectively). It decreased with increasing platelet count in R carriers: from ≈20 days (RR) and ≈17 days (HR) at 150 × 109/L, respectively, to ≈13 days (both HR and RR) at 350 × 109/L. Moreover, a flow cytometry assay showed that infliximab and monomeric IgG1 bound efficiently to platelet FcγRIIA H and R allotypes, whereas panitumumab and IgG2 bound poorly to the latter. We propose that infliximab (and presumably any IgG1 antibody) elimination is partly due to an unappreciated mechanism dependent on binding to platelet FcγRIIA, which is probably tuned by its affinity for IgG2.

Highlights

The half-life of serum IgG1, IgG2, IgG4 and albumin, which bind to the MHC classI-related neonatal Fc receptor (FcRn) [1], is about 19 to 21 days [2,3], whereas that of IgG3, in which the H435N substitution in the CH3 domain abolishes the affinity for FcRn, is about5 to 7 days [2,3,4]
The goal of this study was to investigate the involvement of FcγRIIA and platelets on eliminating IgG1 monoclonal antibodies (mAbs) in individuals receiving IFX for Crohn’s disease (CD) as a model
We propose that the elimination of IFX and probably that of all IgG1 therapeutic mAbs results in part from an unappreciated elimination mechanism involving the binding of these molecules to platelet FcγRIIA

Summary

Introduction

The half-life of serum IgG1, IgG2, IgG4 and albumin, which bind to the MHC classI-related neonatal Fc receptor (FcRn) [1], is about 19 to 21 days [2,3], whereas that of IgG3, in which the H435N substitution in the CH3 domain abolishes the affinity for FcRn, is about5 to 7 days [2,3,4]. Internalization of soluble proteins involves non-specific fluid-phase pinocytosis and/or specific receptor-mediated endocytosis Following their uptake, proteins traffic into the acidic endosomes, non-FcRn–binding proteins undergo lysosomal degradation [3,6,7,8]. The lack of a glycine at position 236 in the lower hinge of human IgG2 (as compared with other subclasses) was found associated with increased intracellular catabolism in FcRn-expressing cells [13]. This observation was unexpected in light of the similar serum half-lives of IgG1 and IgG2 [2,3]. It may be postulated that an unknown degradation mechanism affecting preferentially IgG1 might compensate for their increased salvage

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