The importance of FcRn in neuro-immunotherapies: From IgG catabolism, FCGRT gene polymorphisms, IVIg dosing and efficiency to specific FcRn inhibitors

Abstract

The neonatal Fc receptor (FcRn) binds endogenous IgG and protects it from lysosomal degradation by transporting it back to the cell surface to re-enter the circulation, extending the serum IgG life span. FcRn plays a role in the function of IVIg because the supraphysiological IgG levels derived from IVIg administrations saturate the FcRn allowing the endogenous IgG to be degraded, instead of being recycled, resulting in high levels of infused IgG ensuring IVIg efficiency. New data in myasthenia gravis patients suggest that the that the Variable Number of Tandem 3/2 (VNTR3/2) polymorphisms in FCGRT, the gene that encodes FcRn, may affect the duration of infused IgG in the circulation and IVIg effectiveness. This review addresses these implications in the context of whether the FCGRT genotype, by affecting the half-life of IVIg, may also play a role in up to 30% of patients with autoimmune neurological diseases, such as Guillain–Barré syndrome, CIDP or Multifocal Motor Neuropathy, who did not respond to IVIg in controlled trials. The concern is of practical significance because in such patient subsets super-high IVIg doses may be needed to achieve high IgG levels and ensure efficacy. Whether FCGRT polymorphisms affect the efficacy of other therapeutic monoclonal antibodies by influencing their distribution clearance and pharmacokinetics, explaining their variable effectiveness, is also addressed. Finally, the very promising effect of monoclonal antibodies that inhibit FcRn, such as efgartigimod, rozanolixizumab and nipocalimab, in treating antibody-mediated neurological diseases is discussed along with their efficacy in the IgG4 subclass of pathogenic antibodies and their role in the blood–brain barrier endothelium, that abundantly expresses FcRn.

Update on Intravenous Immunoglobulin in Neurology: Modulating Neuro-autoimmunity, Evolving Factors on Efficacy and Dosing and Challenges on Stopping Chronic IVIg Therapy

“…VNTR Polymorphism and Outcome of IVIg Therapy As mentioned earlier, the supraphysiological levels of IgG derived from IVIg administrations saturate the FcRn ensuring high serum levels of infused IgG [37] (Fig. 3B).…”

“…Normally, IgG antibodies bind to FcRn to return via endocytotic vesicles intact back into the circulation, being protected from degradation by the lysosomes (Fig. 3A) [37]. The supraphysiological levels of IgG derived from IVIg administrations saturate the FcRn so a portion of endogenously produced pathogenic IgG antibodies are not recycled back to the circulation but degraded [37,38]; as a result, the infused IVIg, by competing with pathogenic autoantibodies for FcRn binding, reduces the serum half-life of autoantibodies by approximately 40% causing reduction of circulating IgG autoantibodies [37][38][39][40] (Fig.…”

“…The clinical importance of FcRn not only on efficacy of IVIg but also in individualized IVIg dosing has been strengthened by the impact of Variable Number of Tandem Repeat (VNTR) polymorphisms in the function of FCGRT, the gene that encodes FcRn [37]. Five VNTR alleles, (VNTR1-VNTR5), result in different expression levels of FcRn mRNA and protein level [37]; as a result, individuals homozygous for VNTR3 (VNTR3/3), the most common allele, have increased promoter activity and increased FcRn expression, compared to heterozygous VNTR3/2 individuals. Because high FcRn expression protects the infused IVIg from degradation, VNTR polymorphisms may affect IVIg efficacy by influencing the sustainability and increased serum IgG level of the infused IVIg.…”

“…The effect of IVIg on complement binding has been demonstrated in vitro, in animal models and in patients treated with IVIg. In early studies, IVIg was shown to prevent death in guinea pigs from the complement-dependent Forssmann shock by inhibiting the uptake of complement C 3 and C 4 In heterozygous VNTR2/3 patients therefore, the IgG serum level from the infused IVIg does not increase as much as in homozygous VNTR3/3 individuals who have fully functioning FcRn, resulting in lower immunomodulatory effect of IVIg and lesser reduction of the pathogenic antibodies; higher IVIg dose to compensate for its catabolism is perhaps needed for the VNTR2/3 heterozygotes (adapted from [37]) fragments to the endothelial cells [44]. In patients with dermatomyositis, a complement-dependent microangiopathy mediated by activation of C3 and deposition of MAC on the endomysial capillaries [45], IVIg is not only clinically effective [46] but also inhibits complement uptake, intercepting the formation and deposition of MAC on the endomysial capillaries [46,47].…”

“…3B). The FcRn is however functionally more effective in homozygous VNTR3/3 patients offering higher protection of the infused IgG compared to heterozygous patients with VNTR3/2 polymorphisms where part of the infused IVIg is degraded [37] (Fig. 3C).…”