Why blocking FcRn can be beneficial in the treatment of myasthenia gravis?
Myasthenia gravis is caused by pathogenic autoantibodies that disrupt the neuromuscular transmission. Blocking FcRn accelerates the clearance of endogenous IgG from the bloodstream, including the pathogenic autoantibodies. This improves neuromuscular transmission and alleviates clinical symptoms.
What are the strategies to block FcRn for therapeutic applications?
FcRn blockade can be achieved using IgG-like biologics with higher affinity for FcRn at both neutral and acidic pH (e.g., efgartigimod) or with monoclonal antibodies targeting FcRn (e.g., rozanolixizumab and nipocalimab).
Why are histidine key residues for IgG to interact with FcRn?
The imidazole group of histidine is non-protonated at neutral pH but protonated (positively charged) at acidic pH. Protonation of histidine residues in the Fc fragment of IgG promotes their interaction with negatively charged residues of FcRn within the acidic environment of endosomes and their subsequent release at neutral pH.
Which proteins are protected from lysosomal degradation by FcRn?
- Endogenous IgG
- Exogenous IgG (monoclonal antibodies)
- Albumin
What are the biologics that can be used in the treatment of generalized myasthenia gravis?
- Efgartigimod, an engineered Fc fragment with a higher affinity for FcRn than wild-type IgG at both pH 6 and pH 7.2.
- Rozanolixizumab and nipocalimab, monoclonal antibodies directed to FcRn
- Rituximab: a B cell-depleting monoclonal antibody directed to CD20
- Eculizumab and ravulizumab: monoclonal antibodies directed to C5 fraction of complement
- Zilucoplan: a macrocyclic peptide that binds to C5 fraction of complement
