FcRn inhibition with efgartigimod ameliorates muscle weakness and modulates dendritic cell subsets in an experimental...

Myasthenia gravis (MG) is an IgG-mediated autoimmune neuromuscular disorder characterized by exercise-induced skeletal muscle weakness. Reducing circulating IgG levels is a critical therapeutic strategy. Here, we evaluated efgartigimod, a novel neonatal Fc receptor (FcRn) inhibitor that lowers IgG levels, in an experimental autoimmune myasthenia gravis (EAMG) mouse model.

EAMG was induced in mice by immunization with recombinant acetylcholine receptor (AChR). Serum anti-R97-116 IgG titers were quantified by ELISA. Electromyography assessed compound muscle action potentials (CMAPs) in the gastrocnemius muscle using repetitive nerve stimulation. The EAMG+EF group (n = 12) received intraperitoneal efgartigimod (10 mg/kg/week) starting after the third immunization and continuing for 4 weeks, while the EAMG group (n = 12) remained untreated. Control mice (n = 12) underwent mock immunization with CFA. Clinical assessments included body weight, grip strength, and inverted grid test. The proportion of cDC1s, cDC2s, and pDCs, along with their antigen-presenting and co-stimulatory molecules, was analyzed with flow cytometry.

Compared with controls, repetitive nerve stimulation in EAMG mice revealed a > 10 % reduction in gastrocnemius muscle response, accompanied by elevated anti-R97-116 IgG titers and aggravated myasthenia symptoms, confirming successful AChR peptide-induced EAMG. Efgartigimod treatment improved disease severity, significantly decreasing anti-R97-116 IgG levels, mitigating weight loss, enhancing grip strength, and partially restoring performance on the inverted screen test. Additionally, EAMG mice exhibited a significant increase in the cDC1 subset and a decrease in the cDC2 subset compared to controls. The expression of MHCII was reduced in the cDC1 subset, and the expression of MHCII and CD86 were downregulated in cDC2s in EAMG mice. Efgartigimod treatment normalized cDC1 and cDC2 proportions, restoring MHCII expression to control levels in cDC1s and cDC2s. Furthermore, it significantly upregulated CD80, CD86, and CD40 expression on cDC2s compared to EAMG mice. These findings indicate that efgartigimod modulates the frequencies of dendritic cell subsets as well as their surface expression of antigen presentation (via MHCII) and co-stimulatory signaling molecules (CD40/CD80/CD86).

It is indicated that efgartigimod not only alleviates MG symptoms but also exerts immunomodulatory effects on different dendritic cell subsets.