Targeting the Neonatal Fc Receptor in Autoimmune Diseases: Pipeline and Progress

Abstract

Autoimmune diseases are highly prevalent and affect people at all ages, women more often than men. The most prominent immunological manifestation is the production of antibodies directed against self-antigens. In many cases, these antibodies (Abs) drive the pathogenesis by attacking the body's own healthy cells, causing serious health problems that may be life threatening. Most autoantibodies are of the immunoglobulin G (IgG) isotype, which has a long plasma half-life and potent effector functions. Thus, there is a need for specific treatment options that rapidly eliminate these pathogenic IgG auto-Abs. In this review, we discuss how the neonatal Fc receptor (FcRn) acts as a regulator of the high levels of not only IgG Abs, but also albumin, by rescuing both these soluble proteins from cellular catabolism, and how a molecular and cellular understanding of this complex biology has spurred an intense interest in the development of FcRn-targeting strategies for the treatment of IgG-driven autoimmune diseases. We find that this emerging therapeutic class demonstrates efficacy within several autoimmune diseases with distinct pathophysiology. This offers hope for both new therapeutic avenues for highly prevalent diseases currently treated by other means, and rare diseases with no approved therapies to date. In addition, we elaborate on studies that have led to approval of the first FcRn antagonists, the clinical progress and structural design of molecules in the pipeline, their position in the overall therapeutic landscape of autoimmunity, the design of next-generation antagonists as well as the use of this receptor-targeting principle for other therapeutic applications.

Fig. 1

Pathogenic autoreactive antibody (auto-Ab)-driven autoimmune diseases. (a) Autoimmune diseases affect approximately 10% of the population globally, from young to elderly individuals, and the auto-Abs attack organs and tissues throughout the body. (b) Twenty-five percent of the autoimmune diseases are known to be driven by auto-Abs that can bind either soluble or membrane-bound antigens. The auto-Abs are most commonly of the immunoglobulin (Ig)G isotype but can also be on any of the other isotypes. (c) Autoimmune diseases are chronic and require lifelong treatment options, and they encompass multiple conditions from mild to life threatening. There is an urgent medical need for targeted and more specific therapeutic agents with reduced side effects. The administration route impacts patient convenience. i.v. intravenous, s.c. subcutaneous. The figure was made using BioRender

Fig. 2

Neonatal Fc receptor (FcRn) biology. (a) Schematic of the stoichiometry and proposed model of FcRn:ligand binding. (b) FcRn-mediated transport, including both pH-dependent recycling and transcytosis. (c) FcRn in passive immunity. The receptor is expressed in the placental cell layers and mediates directional transport of immunoglobulin G (IgG) from the mother to the fetus. While Fc gamma receptors (FcγRs) are expressed by the placental cells, FcRn has been shown to be pivotal for directional transport to the fetus. (d) FcRn in the immune compartment. The receptor is expressed by distinct immune cells, such as monocytes, macrophages, neutrophils, and dendritic cells. FcRn is there mediating recycling of monomeric IgG and albumin, while IgG immune complexes (ICs) are engaged by classical FcγRs, such as Fc gamma receptor IIa (FcγRIIa), expressed on the cell surface, which will recruit FcRn following cellular uptake and entering of acidified endosomes. This can result in processing of the bound IC and uploading of antigenic peptides on the major histocompatibility complex (MHC) II molecule followed by antigen presentation to CD4⁺ T cells or cross-presentation on MHC I to CD8⁺ T cells, or induction of distinct immune responses depending on the cognate antigen and cell type. β2m β2-microglobulin, CD cluster of differentiation, CH1-CH3 constant heavy chain 1-3, DI, DII, DIII domain I, II, III, DCs dendritic cells, FcγRIIb Fc gamma receptor IIb, TCR T cell receptor. The figure was made using BioRender

Fig. 3

Targeting of the neonatal Fc receptor (FcRn) as a strategy to treat immunoglobulin G (IgG)-mediated autoimmunity. Advances in the biological understanding of the IgG:FcRn interaction paved the way for the development of FcRn-blocking agents as a strategy for depletion of endogenous IgG in autoimmune disease. (a) During the 1970–80s, the effect of competition on the IgG plasma half-life was explored and shown in humans. The link between autoimmune disease was taken and administration of intravenous immunoglobulin (IVIg) was shown to alleviate immune thrombocytopenia (ITP). (b) In the 1990s to early 2000s, the IgG:FcRn binding site and the 1:2 stoichiometry of the interaction was mapped. (c) In the early 2000s to 2010, inhibition of the IgG-FcRn interaction to lower endogenous IgG was studied, and pre-clinical FcRn-blocking agents were explored. An FcRn blockade was first shown to increase IgG catabolism and to reduce the disease burden in a myasthenia gravis (MG) disease model. FcRn the neonatal Fc receptor, IgG immunoglobulin G, IVIg intravenous immunoglobulin, ITP immune thrombocytopenia, MG myasthenia gravis, WT wild-type. The figure was made using BioRender

Fig. 4

Neonatal Fc receptor (FcRn) antagonists approved and in the development pipeline, with those in active clinical development and/or use shown in blue and those in pre-clinical stages shown in green. The reported properties as listed in the table are summarized for efgartigimod, [224] batoclimab, [303] nipocalimab, [270, 271, 429] IMVT-1402 [303], STSA-1301, [306] ARGX-213, [315] VRDN-006, [319] and VRDN-008 [319]. FcRn The neonatal Fc receptor, IgG immunoglobulin G, i.v. intravenous, NHPs non-human primates, s.c. subcutaneous. The figure was made using BioRender