Discussion

Efgartigimod is indicated in combination with standard treatment for adult patients with generalized MG positive for anti-AChR autoantibodies. It is an immunomodulatory treatment that blocks the function of the neonatal Fc receptor (FcRn). Efgartigimod is administered at a dose of 10 mg/kg through intravenous infusion or 1000 mg via subcutaneous injection. A treatment cycle consists of one weekly administration for 4 weeks. Subsequent treatment cycles are administered based on clinical evaluation. Of note, some patients with refractory MG may require more frequent dosing to achieve a clinical response (1).

Myasthenia gravis

MG is a rare autoimmune disease affecting the neuromuscular junction, with a prevalence of 150-200 cases per million people and an incidence rate of 4-30 cases per million person-years.  MG presents a bimodal distribution with two peaks of incidence. Early-onset MG predominantly affects women in the third decade of life, while late-onset MG primarily affects elderly males after the 6^th decade, as is the case with Hubert, who was diagnosed at the age of 65  (2).

MG is characterized by muscle weakness that worsens with exertion. Ocular manifestations are common, with diplopia (double vision) and ptosis (drooping of the upper eyelid). Ocular MG is characterized by almost exclusively ocular symptoms and can evolve to generalized MG. In generalized MG, ocular symptoms are accompanied with muscle weakness in other areas, such as the limbs, axial muscles, and/or oropharyngeal muscles. For the clinical classification of MG established by the Myasthenia Gravis Foundation of America (MGFA), you can refer to the clinical case “My eyes cross at twilight”.

The muscle weakness in MG is caused by autoantibodies that impair neuromuscular transmission. In most patients, the antibodies are directed against AChR. Anti-AChR antibodies impair neuromuscular transmission at the post-synaptic junction by triggering complement-mediated lysis of the postsynaptic membrane, blocking AChR, thereby preventing the interaction of ACh with its receptor, or causing internalization of AChR, reducing their number on the postsynaptic membrane. Alternative autoantibodies can also cause MG, including anti-MuSK (muscle-specific kinase, a tyrosine kinase involved in the clustering of AChR at the neuromuscular junction) or anti-LRP4 (low-density lipoprotein receptor-related protein 4, the agrin receptor involved in MuSK activation). In addition, autoantibodies directed to intracellular striated muscle proteins may also be found, such as anti-titin antibodies, which are associated with thymoma in patients with MG (3). You can refer to the clinical case “My eyes cross at twilight” for more information on the pathophysiology of MG.

FcRn

FcRn is structurally related to MHC class I molecules. Both proteins are heterodimers composed of an α heavy chain, non-covalently linked to the β2-microglobulin chain. The α chain includes 3 extracellular domains (α1, α2, and α3), a transmembrane domain, and a short intracellular domain.

In contrast to MHC molecules, FcRn exhibits low polymorphism in the human population and is unable to present antigenic peptides to T cells. FcRn is broadly expressed throughout the body, particularly on the surface of vascular endothelial, hematopoietic (especially monocytes and macrophages), and epithelial cells (intestine, liver, kidneys, lungs, blood-brain barrier, mammary gland, and placenta) (4).

FcRn was initially identified in rodents as the receptor responsible for transporting maternal IgG across the intestinal epithelium of neonatal offspring via maternal milk, leading to its designation as the neonatal Fc receptor. In humans, FcRn facilitates the transcytosis of maternal IgG to the fetus through the placenta, mostly during the third trimester of pregnancy, and does not appear to play a major role in the postnatal transfer of maternal IgG to the new born.

One of the major functions of FcRn throughout life is the recycling of IgG and albumin, accounting for their long half-life (≈ 21 days for IgG1, IgG2, IgG4, and albumin). Indeed, IgG, albumin, and other proteins are continuously ingested through pinocytosis by different cells (Figure 2). The resulting endosomes then undergo acidification (pH 5.0-6.5), leading to the degradation of the ingested proteins and a short blood half-life. FcRn is able to interact with IgG and albumin in a pH-dependent manner, leading to their recycling to the blood and therefore longer half-life.

(A) IgG, albumin, and other serum proteins are internalized through pinocytosis. Acidification of the endosome leads to binding of IgG and albumin to FcRn, but not to other proteins. IgG and albumin bound to FcRn are released by exocytosis, whereas proteins that are not bound to FcRn are degraded in lysosomes. This phenomenon takes place notably in macrophages and endothelial cells.

(B) FcRn blockers bind to FcRn at both neutral and acidic pH. Endogenous IgG are unable to interact with FcRn and are degraded in lysosomes rather than being released into the extracellular environment.

 

The binding of FcRn by IgG is mainly mediated by histidine residues (H310 and H435) located in the vicinity of CH2-CH3 interface of IgG (5). Histidine is the only amino acid whose protonation state changes near physiological pH values (pKa ≈ 6-7). At neutral pH, the aromatic imidazole ring of the side chain is neutral (non-protonated), whereas in an acidic environment (pH below 6), it becomes protonated (Figure 2).

 

 

The protonated form of histidine interacts with negatively charged residues. In the case of IgG, the protonated histidine residues interact with negatively charged residues located in the α2 and β2m domains of FcRn in the acidic environment of endosomes. Of note, the substitution of one of the histidine residues involved in the interaction with FcRn (H435 to R435) reduces the affinity for FcRn and accounts for the reduced half-life of IgG3 (9 days) compared to other subclasses that compete for FcRn binding (6). IgG molecules are heterotetramers (consisting of two identical heavy chains and two identical light chains) and thus have two sites of interaction with FcRn. Consequently, two FcRn molecules can bind to a single IgG molecule.

In contrast to IgG, the engagement of FcRn by albumin occurs in a 1:1 ratio, at a site distinct from that of IgG. Thus, FcRn can bind simultaneously one molecule of IgG and one molecule of albumin. Albumin does not directly interact with FcRn through histidine residues. Instead, it interacts with a loop located in the α2 domain of FcRn that is stabilized by a histidine residue (H166) of the α1 domain in a pH-dependent manner (7).  Similarly to IgG, albumin exhibits very low affinity for FcRn at neutral pH but high affinity at the acidic pH of endosomes.

IgG and albumin bound to FcRn are recycled, i.e. transported back to the cell surface. Upon fusion with the plasma membrane and pH rising, IgG and albumin dissociate from FcRn and are released back to the extracellular environment. Other proteins, including excess IgG and albumin not bound to FcRn, are directed to the lysosomal pathway leading to their degradation.

FcRn blockade

Blocking the FcRn prevents its interaction with endogenous IgG, including pathogenic autoantibodies. As a result, IgGs are no longer recycled and are degraded more rapidly (Figure 2B). This is beneficial in conditions where pathogenic autoantibodies play a critical role, such as in MG. The blockade of FcRn is achieved either through engineered forms of the Fc fragment of IgG (e.g., efgartigimod) or by using monoclonal antibodies that target FcRn (e.g., rozanolixizumab and nipocalimab) (Figure 3).

 

FcRn is involved in the recycling of IgG (1) and albumin (2) by interacting at different sites of the receptor in a pH-dependent manner. FcRn blockade can be achieved with IgG-like molecules that interact with FcRn through the Fc part (e.g., efgartigimod) (3) or with monoclonal antibodies targeting FcRn and blocking the interaction between IgG and FcRn (e.g., rozanolixizumab and nipocalimab) (4).

 

Efgartigimod was approved in 2021 in USA and 2022 in Europe for the treatment of generalized MG in adults with anti-AChR antibodies. In Japan, efgartigimod is approved for generalized MG patients regardless of antibody status. Efgartigimod is an engineered human IgG1 antibody Fc-fragment that contains five point mutations (MST-HN: M252Y, S254T, T256E, H433K, N434F). Compared to wild-type IgG, these mutations confer to Efgartigimod a higher affinity to Fc region for FcRn at both pH 6 and pH 7.2. As a result, the binding sites for IgG on FcRn are saturated, preventing the binding of endogenous IgG without affecting serum albumin. In the pivotal Phase III trial, one cycle of treatment with efgartigimod resulted in a mean maximum reduction of 57.6% in anti-AChR antibodies and 61.3% in total IgG, with no reduction in albumin levels (Figure 4) (8). The transient reduction in IgG levels by efgartigimod may increase the risk of infections, particularly upper respiratory tract and urinary tract infections. The administration of live or live-attenuated vaccines is not recommended for patients undergoing treatment with efgartigimod. All other vaccines should be administered at least 2 weeks after the last infusion of a treatment cycle or 4 weeks before the start of a next cycle. Efgartigimod reduces plasma concentrations of molecules that bind to the FcRn, including intravenous immunoglobulins, therapeutic monoclonal antibodies and antibody derivatives containing the Fc domain of the IgG subclass. Therefore, it is recommended to postpone the initiation of treatment with these biologics until 2 weeks after the last dose of an efgartigimod treatment cycle. In cases where treatment with biologics is already ongoing at the start of efgartigimod, the therapeutic response to these agents should be closely monitored. Plasma exchange and plasmapheresis may reduce circulating levels of efgartigimod.

 

 

 

This figure is extracted from the supplementary appendix of the Phase III trial publication (8). The trial enrolled 167 patients with generalized myasthenia gravis (MG), including 129 patients positive for anti-AChR antibodies (65 in the efgartigimod group and 64 in the placebo group).

 

Rozanolixizumab and nipocalimab are two monoclonal antibodies that selectively bind and block the IgG binding site on human FcRn while not overlapping with albumin binding site.

Rozanolixizumab is a humanized IgG4 monoclonal antibody approved for treatment of generalized MG in adult patients positive for anti-AChR or anti-MuSK antibodies. Rozanolixizumab is administered subcutaneously once a week for 6 weeks, with the dose adjusted for patient bodyweight. In the pivotal phase III trial, rozanolixizumab 7 mg/kg and 10 mg/kg achieved a median maximum reduction in AChR antibodies of respectively 73% and 82%, respectively. Similarly, the maximum reduction in total IgG was 73% and 79% for rozanolixizumab 7 mg/kg and 10 mg/kg (9)

Nipocalimab is a fully human IgG1 aglycosylated monoclonal. The absence of ubiquitous N-glycans at N197 precludes effector functions by abolishing Fc binding to Fc γ receptors (FcγR) and the C1q fraction of the complement, while preserving the binding to FcRn. Nipocalimab is currently being tested in a phase III clinical trial for generalized MG (NCT04951622).