Elucidating novel immunomodulatory mechanisms of neonatal FC receptor blockade by efgartigimod in a T cell-mediated demyelinating neuropathy model

The National Institute of Neurological Disorders and Stroke awarded the University of Texas Health Science Center at Houston $234,000 on September 3, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to elucidate novel immunomodulatory mechanisms of neonatal Fc receptor blockade by efgartigimod in a T cell-mediated demyelinating neuropathy model.

The award funds research examining how efgartigimod, a recombinant human IgG1 Fc fragment that inhibits the neonatal Fc receptor (FcRN), modulates immune responses in inflammatory demyelinating neuropathies including acute inflammatory demyelinating polyneuropathy (AIDP, the demyelinating form of Guillain-Barré syndrome) and chronic inflammatory demyelinating polyneuropathy (CIDP). The investigator will test hypotheses that FcRN inhibition by efgartigimod reduces myelin phagocytosis by macrophages and alters antigen presentation by classical dendritic cells to mitigate excessive T cell responses. Work will include efficacy testing in the spontaneous autoimmune peripheral polyneuropathy (SAPP) model, which mimics CIDP.

Performance occurs at the University of Texas Health Science Center at Houston, Houston, Texas 77030. The period of performance runs from September 3, 2026, through August 31, 2028. The award is structured as a Project Grant, the standard assistance type for investigator-initiated research under NINDS.

Abstract

Inflammatory demyelinating neuropathies, such as acute inflammatory demyelinating polyneuropathy (AIDP), also known as the demyelinating form of guillain-barré syndrome (GBS), and chronic inflammatory demyelinating polyneuropathy (CIDP), are characterized by immune-mediated damage to peripheral nerves. This damage is largely driven by cellular immune factors, including dysregulated T cell responses and the pathological activation of macrophages that contribute to myelin degradation through phagocytosis. Efgartigimod, a recombinant human IGG1 FC fragment, enhances IGG clearance by inhibiting the neonatal FC receptor (FCRN) and was recently approved for the treatment of CIDP in the USA. A clinical study showed that efgartigimod induced clinical improvement in 67% of CIDP patients, most of them previously withdrawn from intravenous immunoglobulin therapy. However, IT is important to note that autoantibodies are detected in only a small subset of CIDP patients, suggesting that efgartigimod's effects likely extend beyond just IGG autoantibody clearance. Notably, research has highlighted the significant role of FCRN in modulating cellular immune responses, including macrophage phagocytosis, and antigen presentation by classical dendritic cells (CDCS), which activate CD4+ and CD8+ T cells. Thus, FCRN inhibition by efgartigimod may provide broader immunomodulatory benefits in inflammatory neuropathies. We hypothesize that efgartigimod mediated FCRN inhibition leads to: 1) reduced myelin phagocytosis by macrophages; 2) altered antigen presentation by CDCS, which mitigates the excessive T cell responses seen in inflammatory neuropathies. To test our hypotheses, aim 1 will examine the efficacy of efgartigimod in the spontaneous autoimmune peripheral polyneuropathy (SAPP) model, which mimics CIDP and demyelinating GBS; aim 2 will investigate whether FCRN blockade with efgartigimod could modulate endoneurial macrophage phagocytosis and T cell activation in SAPP animals. Additionally, the antigen presentation by CDCS following efgartigimod treatment will be examined by an in-vitro assay. Our approaches will include comprehensive flow cytometry analysis of murine sciatic nerves and spleen, in-vitro antigen presentation assay, alongside behavioral, electrophysiological and histological assessments. This translational study aims to elucidate the immunomodulatory mechanisms of efgartigimod-mediated FCRN inhibition beyond IGG clearance, a critical step toward developing more precise and targeted therapies for CIDP and related inflammatory demyelinating neuropathies.