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

Background: Immunoglobulin 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://ichgcp.net/clinical-trials-registry/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.

Objective: The 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.

Methods: We 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.

Results: Treatment 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.

Conclusions: Efgartigimod 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.

Keywords: B cells; FcRn; efgartigimod; immunoglobulin G; pemphigus foliaceus (PF); pemphigus vulgaris (PV).

Conflict of interest statement

ZB-C reports consulting fees for Sanofi-Genzyme, Novartis, and argenx. MG has served as a consultant and on advisory boards for argenx, Biotest, GSK, Janssen, LEO Pharma, Lilly, Novartis, and UCB. MS, BB, and PV are employed by argenx. PJ has served as a consultant for Amgen, Principia Biopharma, argenx, AstraZeneca, Janssen, Thermo Fisher, Lilly, Sanofi, Akari, Chugai, Novartis, Kezar, Genentech, and Topas. GV is a paid consultant for argenx. SC, MM-V, and M-LG as employees of INSERM U1234, Normandie University have a collaborative research agreement with argenx. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This study received funding from Argenx. The funder had the following involvement with the study: participated in the study design, research, analysis, data collection, interpretation of data, and review and approval of the publication. Argenx also funded the medical writing support of this manuscript.

Copyright © 2022 Maho-Vaillant, Sips, Golinski, Vidarsson, Goebeler, Stoevesandt, Bata-Csörgő, Balbino, Verheesen, Joly, Hertl and Calbo.

Figures

Figure 1

Sustained clinical responses and transient general reduction of total serum IgG levels following efgartigimod treatment. (A) Clinical responses to efgartigimod are depicted for all participants in cohorts 3 (n = 7) and 4 (n = 15). Participant numbers correspond to those used in Table 1. Blue arrows indicate when efgartigimod was administered, and the blue dotted line indicates every other week administration time period in participants who achieved EoC. (B) Clinical responses of singular representative trial participants with pemphigus foliaceus and pemphigus vulgaris, respectively, are shown. (C) Longitudinal changes in pathogenic (anti-Dsg-3 or anti-Dsg-1) as well as total IgG (tIgG) and PDAI activity scores are represented. The gray shaded area indicates efgartigimod treatment-free follow-up period. Means are compared using two-way ANOVA multiple comparison with Dunnett’s post-test. (D) Pathogenic (anti-Dsg-3 or anti-Dsg-1), total IgG (tIgG), and non-pathogenic antibodies titers (anti-VZV, anti-varicella zoster virus; TT, tetanus toxoid; PCP, pneumococcal capsular polysaccharide) are compared between BL and EoS for all participants. Wilcoxon matched-pairs test was performed. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001. BL, baseline; EoS, end of study; DC, disease control; EoC, end of consolidation; CR, complete clinical remission; CRmin, complete clinical remission with minimal treatment; Pt, participant; ns, non significant.

Figure 2

Efgartigimod reduces antigen-specific B cells in the blood. (A) Among the three PV participants with viable PBMC and sustained clinical response, representative flow cytometry plots depicting frequency of Dsg-3+ switched memory B cells (MBC) for one participant with PV at baseline, CR, and EoT were generated. (B) Frequency of circulating Dsg-3+ switched memory B cells in three participants with PV with sustained clinical response during the study in relation to Dsg-3 autoantibody serum titers at baseline and by time point. (C) Among the three PF participants with viable PBMCs, a representative ELISPOT of total IgG-ASCs with 2.5 × 103 to 1 × 104 PBMCs plated per well (left) and Dsg-1 IgG ASCs with 1 × 105 to 4 × 105 PBMCs plated per well (right) detected in PBMCs of a participant with PF. (D) Frequency of peripheral blood Dsg-1-specific ASCs evaluated by ELISPOT assay in 3 participants with PF during study both in relation to Dsg-1 autoantibody serum titers at baseline and by time point. Frequencies are reported as a percentage of total IgG ASC. ASCs, antibody-secreting cells; BL, baseline; CR, complete clinical remission; EoT, end of treatment; EoS, end of study.

Figure 3

Efgartigimod does not affect frequencies of lymphocyte subsets except B cells. (A) Leukocytes (109/L) and frequency (%) of neutrophils, lymphocytes, and monocytes within leukocytes in peripheral blood of cohort 4 participants (n = 10), median, and IQR are plotted. (B) Frequency of CD4+ T cells within lymphocytes and their subsets of cohort 4 participants with viable PBMC (n = 9), median, and IQR are plotted. (C) Frequency of CD19+ B cells within lymphocytes and their subsets of cohort 4 participants with viable PBMC (n = 9), median, and IQR are plotted. Arrows and lines indicate the way the frequency of a parent population was determined. (D) Frequency and counts of CD19+ B cells at baseline, EoT, and EoS of cohort 4 participants with viable PBMC and sustained clinical response (n = 9). Red lines represent medians and dotted lines represent normal limits. A non-parametric one-way ANOVA with Dunn’s post-test was performed. *p ≤ 0.05; **p ≤ 0.01. EoT, end of treatment; EoS, end of study; IQR, interquartile range.

Figure 4

Prednisone exposure in participants with prolonged efgartigimod treatment and observed B-cell immunomodulation (n = 9). Summary profiles of the PV and PF participants achieving sustained clinical response illustrating prednisone dosages, PDAI activity scores, and frequency of total CD19+ B cells in peripheral blood when available. The gray shaded area indicates efgartigimod-free follow-up period. Error bars represent standard error of the mean (SEM). PV, pemphigus vulgaris; PF, pemphigus foliaceus; PDAI, pemphigus disease area index.