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