Antibody Function Predicts Efgartigimod Response in Myasthenia Gravis

Patients with generalized myasthenia gravis who responded best to efgartigimod were not the ones with the biggest drop in autoantibody levels. They were the ones whose antibodies lost the most functional bite, according to a laboratory substudy of the phase 3 ADAPT trial published in the Journal of Neurology, Neurosurgery and Psychiatry.¹

Efgartigimod Lowers Antibodies, But a Third Don't Respond

Generalized myasthenia gravis (gMG) is a rare autoimmune disease in which autoantibodies against the acetylcholine receptor (AChR), present in about 85% of patients, disrupt nerve-to-muscle signaling through 3 distinct mechanisms: activating the complement cascade, accelerating AChR internalization and degradation, and physically blocking the receptor's acetylcholine-binding site. Efgartigimod, a neonatal Fc receptor (FcRn) blocker, lowers total immunoglobulin G (IgG), including pathogenic AChR autoantibodies, by interrupting the recycling process that keeps IgG circulating in the blood.

The FDA approved efgartigimod for adults with AChR antibody-positive gMG in December 2021 based on the phase 3 ADAPT trial (NCT03669588), in which 68% of patients receiving the drug met responder criteria on the MG Activities of Daily Living (MG-ADL) scale, compared with 30% on placebo (P < .0001).² Even with that benefit and a clear reduction in IgG, roughly a third of patients did not meet MG-ADL responder criteria, suggesting that overall antibody quantity was not the whole story.

Yale Team Re-Examines Serum From 50 ADAPT Participants

Using live cell-based assays, the researchers analyzed 150 serum samples from 50 AChR antibody-positive patients in the ADAPT trial, 40 of whom received efgartigimod and 10 of whom received placebo, collected at the start of the first treatment cycle, at the point of maximum IgG reduction (day 29), and as IgG levels re-established (day 57). The assays measured each patient's AChR-specific IgG subclasses as well as the antibodies' capacity to activate complement, induce receptor internalization, and block the acetylcholine-binding site.

At baseline, AChR-specific IgG1 was detected in 74% of patients, IgG2 in 26%, and IgG3 in 42%, with no IgG4 detected. Complement activation was the most prevalent pathogenic mechanism (84% of patients), followed by receptor internalization (82%) and binding-site blockade (20%).

Antibody Function, Not IgG Levels, Separates Responders

Efgartigimod significantly reduced AChR-specific IgG titers and all 3 pathogenic mechanisms by day 29 (all P < .0001 except blockade, P = .021), and all rebounded toward baseline by day 57 as the drug's effect wore off. But when the researchers split the efgartigimod group into double responders (meeting both MG-ADL and Quantitative Myasthenia Gravis [QMG] criteria, n = 20), single responders (n = 11), and double nonresponders (n = 9), baseline antibody titers did not differ between groups, and the size of the IgG titer reduction by day 29 was statistically indistinguishable between double responders and double nonresponders (P = .3834).

What did differ was the depth of functional change: double responders showed significantly greater reductions in complement activation (P = .0058) and receptor internalization (P = .0026) than the combined group of single responders and double non-responders. In mixed-effects models, reductions in complement activity and internalization, but not IgG subclass changes, were significantly associated with clinical improvement on the MG-ADL and QMG scales.

“Clinical efficacy may be more closely linked to functional modulation of the AChR-Abs than to AChR-Ab quantity alone,” the researchers wrote.

A Small Sample and One Antibody Mystery Point to Future Biomarkers

In 1 patient, an unusual IgM antibody turned out not to target the AChR directly but to bind the Fc portion of AChR-bound IgG, functioning as a rheumatoid-factor-like antibody; because efgartigimod removed the IgG that the IgM depended on, it indirectly eliminated that interaction too. That patient did not respond to treatment on either clinical scale.

The researchers cautioned that their sample included few non-responders, which limited statistical power, and that their cell-based assays, while informative, do not fully recreate conditions at the neuromuscular junction. They said the findings will need validation in larger, independent cohorts before functional antibody testing could inform treatment decisions.

For clinicians, the findings suggest that a patient's initial antibody profile cannot reliably predict how well they will respond to efgartigimod, but the degree to which treatment suppresses antibody function, not just antibody levels, may eventually help explain who benefits most. For payers and health systems, that distinction points toward a future in which functional antibody assays, rather than simple antibody titers, could help justify continued use of FcRn blockers or guide a switch to complement-targeted therapy for patients who are not responding.

References

1. Khani-Habibabadi F, Verhamme FM, Moshir M, et al. Pathogenic properties of myasthenia gravis AChR autoantibodies associate with clinical response to efgartigimod. J Neurol Neurosurg Psychiatry. 2026;97(10):923-935. doi:10.1136/jnnp-2025-338323
2. FDA approves new treatment for generalized myasthenia gravis. Practical Neurology. December 20, 2021. Accessed October 28, 2026. https://practicalneurology.com/news/fda-approves-new-treatment-for-generalized-myasthenia-gravis