Efgartigimod Triggers Regulatory Immune Cells Beyond Simple IgG Reduction in MG

Myasthenia gravis (MG) is a debilitating autoimmune disease in which the immune system produces antibodies that attack proteins at the neuromuscular junction, causing muscle weakness and fatigue. The drug efgartigimod (EFG) works by blocking the neonatal Fc receptor (FcRn), which normally recycles IgG antibodies and prolongs their half-life. By saturating FcRn, efgartigimod accelerates IgG degradation, reducing the pathogenic autoantibodies driving MG. This mechanism was considered the drug's primary — and sole — mode of action. The new study from Milan's Fondazione IRCCS Istituto Neurologico Carlo Besta challenges that assumption by revealing a second, previously unknown immunoregulatory effect.

Researchers enrolled nine patients with generalized, AChR-antibody-positive MG in the GENERATIVE expanded access program. Participants received efgartigimod as 10 mg/kg intravenous infusions in 4-week cycles. Blood samples were collected at seven standardized time points spanning three treatment cycles. The team measured total IgG, IgG subclasses, anti-AChR antibodies, and used flow cytometry to profile circulating T-cell and B-cell subpopulations. They also assessed gene expression of regulatory plasma cell markers — CD38, LAG3, IL-12a, and Ebi3 — in peripheral blood mononuclear cells (PBMCs) using real-time PCR.

The central finding was a statistically significant increase in CD19+/CD27+ memory B cells and CD27+/CD138+ plasma cells at the end of treatment cycles 1 and 2. This plasma cell expansion was sustained through cycle 3 and, critically, significantly correlated with improvement in Quantitative Myasthenia Gravis (QMG) scores — a validated clinical measure of disease severity. QMG scores improved from a mean of 12.7 ± 3.5 at baseline to 9.0 ± 4.0 after cycle 1 and 7.0 ± 3.9 after cycle 2, with MG-ADL scores dropping from 8.4 ± 3.3 to 3.2 ± 2.2 after cycle 1. The plasma cell increase was not simply a rebound phenomenon but appeared linked to a regulatory, non-pathogenic cell phenotype.

To determine whether FcRn blockade itself drives this effect, the team performed in vitro experiments. PBMCs from both healthy controls and MG patients were treated with either an anti-FcRn monoclonal antibody or efgartigimod (Vyvgart) at two doses, alongside appropriate isotype controls. Both the anti-FcRn antibody and efgartigimod significantly upregulated CD38 and LAG3 gene expression compared to untreated cells. In PBMCs from treated patients, overexpression of CD38, LAG3, and IL-12a — genes associated with regulatory plasma cell identity — was also observed, with the IL-12/IL-35 cytokine axis suggesting a shift toward immunosuppressive IL-35 production, a hallmark of regulatory B lineage cells.

These findings carry meaningful clinical implications. The correlation between plasma cell expansion and QMG improvement suggests that monitoring CD27+/CD138+ plasma cell percentages could serve as a real-time pharmacodynamic biomarker during efgartigimod therapy. For clinicians managing MG patients, this adds a new dimension to understanding responders versus non-responders. A key caveat is the small sample size of nine patients, which limits statistical power and generalizability. The heterogeneity in concurrent immunosuppressive therapies across patients also complicates interpretation. Larger, prospective studies are needed to validate these regulatory plasma cell findings and establish their predictive value.