FcRn Antagonism Leads to a Decrease of Desmoglein-Specific B Cells: Secondary Analysis of a Phase 2 Study of Efgartigimod in Pemphigus Vulgaris and Pemphigus Foliaceus

Abstract

BackgroundImmunoglobulin G (IgG) levels are maintained by the IgG-recycling neonatal Fc-receptor (FcRn). Pemphigus vulgaris and pemphigus foliaceus are debilitating autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. Recently, a phase 2 clinical trial (NCT03334058; https://clinicaltrials.gov/NCT03334058) was completed in participants with pemphigus using efgartigimod, an FcRn inhibitor, in combination with prednisone. Efgartigimod demonstrated an early effect on diease activity and was well tolerated. In addition to the safety and efficacy assessment, clinical trials present an opportunity to gain more insights into the mechanism of disease, the mode of action of treatment, and potential for corticosteroid-sparing activity.ObjectiveThe aim of our study was to assess the impact of FcRn antagonism by efgartigimod on immunological parameters known to be directly involved in pemphigus pathology, such as cellular and serological responses.MethodsWe investigated total and antigen-specific IgG subclass level kinetics during and after treatment, assessed antigen-specific B-cell responses, followed T- and B-cell immunophenotypes, and analyzed how different immunophenotypes link to clinical response.ResultsTreatment resulted in reduction of total IgG as well as autoreactive IgG antibody levels. Surprisingly, unlike total IgG and vaccine- or natural-infection-elicited IgG, which returned to baseline levels after stopping efgartigimod treatment, autoreactive antibody levels remained low in several study participants. Efgartigimod showed no effect on total leukocytes, neutrophils, monocytes, or lymphocytes in patients treated with extended efgartigimod therapy. Intriguingly, antigen-specific analyses revealed a loss of desmoglein-specific B cells in several participants responding to efgartigimod, in line with prolonged reduction of pathogenic IgG levels.ConclusionsEfgartigimod treatment of participants with pemphigus improved their conditions and exerted an immunomodulatory effect beyond the blockade of IgG recycling. Further studies in larger populations with an appropriate placebo control are needed to confirm these potentially important observations to establish long-term clinical responses in autoimmune diseases.

The therapeutic age of the neonatal Fc receptor

“…2c; see below). Blockade of the IgG interactions with FcRn via FcRn blockers in humans also reduces serum IgGs and IgG-ICs, showing the physiological relevance of these observations in model systems 20,79,80 . More studies are needed to understand how FcRn directs monomeric IgGs and small IgG-ICs to recycling endosomes for prevention of catabolism while directing relatively large IgG-ICs to antigen presentation compartments and lysosomes for regulated degradation, and how the size of IgG-ICs determines each of these outcomes (see below).…”

“…For example, in the largest study so far, efgartigimod treatment of people with generalized MG reduced pathogenic antibodies and significantly decreased disease severity (Table 1 ). There are indications emerging that these therapies may also be disease modifying by mechanisms that are yet to be understood but are probably linked to the cellular effects that FcRn blockade has on disease-promoting immune cells 80 . Consistently, the observed treatment-emergent adverse events have been mild to moderate and generally comparable between patients in placebo and drug treatment groups, with the most frequent adverse event being headache.…”

“…: 68% reduction of total IgG; 65% reduction of anti-AChR DB: QMG score reduced by 0.7 points; MG-ADL score reduced by 1.4 points; MGC disease severity score reduced by 1.8 points Rand. : QMG score reduced by 5 points; MG-ADL score reduced by 3 points; MGC disease severity score reduced by 6 points Batoclimab 183 (NCT04346888) II 30 ( n P = 9, n D340 = 10, n D680 = 11); subcutaneous DB: 74% reduction of total IgG DB: QMG score reduced by 7 points; MG-ADL score reduced by 2.5 points; MGC disease severity score reduced by 5 points; MG-QoL15r scale reduced by 0.64 points Pemphigus IgGs of IgG4 subclass directed against desmosomes 185 : Anti-DSG1 present in patients with PF and with PV Anti-DSG3 present only in patients with PV Anti-DSC1, anti-DSC2 or anti-DSC3 present in <5% of patients with PV and with PF Efgartigimod 80 , 182 (NCT03334058) II 34 ( n C1 = 6, n C2 = 5, n C3 = 8, n C4 = 15); intravenous 62–66% reduction of total IgG; 61% reduction of anti-DSG1; 49% reduction of anti-DSG3 C1–3: 75% reduction in PDAI activity score C4: 52% reduction in PDAI activity score Orilanolimab 79 (NCT03075904) c Ib/II 8; intravenous 57.6% reduction of total IgG; 55.6% reduction of total circulating IgG-ICs; 26.3% reduction of anti-DSG1; 5.7% reduction of anti-DSG3 23.6% reduction in PDAI activity score Immune thrombocytopenic purpura IgGs mainly of IgG1 subclass directed against platelet membrane glycoproteins in 50–60% of patients 186 Efgartigimod 181 (NCT03102593) II 38; ( n P = 12, n D5 = 13, n D10 = 13); intravenous DB: 60.4–63.7% reduction of total IgG Proportion of patients ≥50 × 10 9 platelets per litre for more than 10 days: D5: 46.2%; D10: 30.8%; P: 0% Patients with decreased bleeding-related events: D5: 46.2% to 7.7%; D10: 38.5% to 7.7%; P: 33.3% to 25% Rozanolixizumab 180 ...…”

“…FcRn blockade has on disease-promoting immune cells 80 . Consistently, the observed treatment-emergent adverse events have been mild to moderate and generally comparable between patients in placebo and drug treatment groups, with the most frequent adverse event being headache.…”

Autoantibodies as Biomarker and Therapeutic Target in Systemic Sclerosis

“…In 2021, the first Fc-based inhibitor, namely efgartigimod (Vyvgart), was approved for treatment of generalized myasthenia gravis by the USA Food and Drug Administration (FDA). Moreover, this technology was evaluated in further diseases, e.g., primary immune thrombocytopenia or pemphigus vulgaris and foliaceus [ 207 , 208 , 209 , 210 , 211 ].…”