The Dual Targeting of FcRn and FcγRs via Monomeric Fc Fragments Results in Strong Inhibition of IgG-Dependent Autoimmune Pathologies

Abstract

Novel molecules that directly target the neonatal Fc receptor (FcRn) and/or Fc gamma receptors (FcγRs) are emerging as promising treatments for immunoglobulin G (IgG)-dependent autoimmune pathologies. Mutated Fc regions and monoclonal antibodies that target FcRn are currently in clinical development and hold promise for reducing the levels of circulating IgG. Additionally, engineered structures containing multimeric Fc regions allow the dual targeting of FcRn and FcγRs; however, their tolerance needs to first be validated in phase I clinical studies. Here, for the first time, we have developed a modified monomeric recombinant Fc optimized for binding to all FcRns and FcγRs without the drawback of possible tolerance associated with FcγR cross-linking. A rational approach using Fc engineering allowed the selection of LFBD192, an Fc with a combination of six mutations that exhibits improved binding to human FcRn and FcγR as well as mouse FcRn and FcγRIV. The potency of LFBD192 was compared with that of intravenous immunoglobulin (IVIg), an FcRn blocker (Fc-MST-HN), and a trimeric Fc that blocks FcRn and/or immune complex-mediated cell activation through FcγR without triggering an immune reaction in several in vitro tests and validated in three mouse models of autoimmune disease.

The therapeutic age of the neonatal Fc receptor

“…Low-dose antibody blockade of mouse FcRn also ameliorated disease severity in mice expressing the low-affinity human FcγRIIA R variant in the K/BxN model, but without lowering circulating total or pathogenic IgGs; this suggests that FcRn may promote RA through multiple mechanisms that potentially include cooperation with FcγRs in myeloid cells in addition to effects on IgG recycling 43 . Consistent with this, disease burden is also reduced by simultaneously targeting FcRn and FcγRs in the K/BxN and collageninduced arthritis models, which show the important roles that each of these receptors have in promoting RA 162 .…”

“…Total serum anti bodies and anti-GPI-specific IgG antibodies were substantially lower in Fcgrt −/− mice, which indicates that the lowering of pathogenic antibodies plays a major role in this disease model 152 . Abdegs, or IgG1 MST-HN , enhanced degradation of IgGs and dramatically lowered ankle swelling and histological joint damage in the K/BxN model 162,163 . Low-dose antibody blockade of mouse FcRn also ameliorated disease severity in mice expressing the low-affinity human FcγRIIA R variant in the K/BxN model, but without lowering circulating total or pathogenic IgGs; this suggests that FcRn may promote RA through multiple mechanisms that potentially include cooperation with FcγRs in myeloid cells in addition to effects on IgG recycling 43 .…”

“…Autoimmune haematological diseases, such as experimental immune thrombocytopenic purpura (ITP), can be therapeutically ameliorated through FcRn blockade. Prophylactic or therapeutic use of a mouse anti-FcRn antibody restored platelet numbers in the anti-CD41 passive transfer model of ITP and prophylactic blockade with an engineered Fc construct targeting both FcRn and FcγRs prevented the short-term loss of platelets in an ITP model involving passive transfer of a human anti-platelet antibody 121,162 .…”

Systems biology and artificial intelligence analysis highlights the pleiotropic effect of IVIg therapy in autoimmune diseases with a predominant role on B cells and complement system

“…Importantly, FcRn-targeting compounds should be highlighted since our results did not suggest a major relevance of this IVIg target to achieve a response. The FcRn blocker efgartigimod is currently the compound furthest advanced in clinical trials (139)(140)(141)(142), with some of the anti-FcRn monoclonals following not far behind (143,144), while a modified monomeric recombinant Fc optimized for binding to all FcRns and FcgRs is also under development (145). This search for novel molecules specifically targeting Fc receptors contrasts with the results obtained in our study, which suggest that the 'non-specificity' of IVIg and its interaction with a broad spectrum of targets could be key to obtaining a pleiotropic effect and clinical efficacy in very different diseases.…”

Monoclonal Antibody Engineering and Design to Modulate FcRn Activities: A Comprehensive Review

“…The recombinant Fc LFBD192 with Y296W/K334N/P352S/A378V/V397M/N434Y mutations was compared in vitro to other relevant strategies such as IVIg or Fc carrying the MST-HN mutation with promising results. However, to our knowledge, there are currently no therapeutic trials involving LFBD192 [ 89 ]. The main localizations of mutations affecting IgG–FcRn interaction and their effects on mAbs are summarized in Figure 2 .…”