Treatment with anti‐neonatal Fc receptor (FcRn) antibody ameliorates experimental epidermolysis bullosa acquisita in mice

Background and Purpose Pemphigus and pemphigoid diseases are characterized and caused predominantly by IgG autoantibodies targeting structural proteins of the skin. Their current treatment relies on general and prolonged immunosuppression that causes severe adverse events, including death. Hence, novel safe and more effective treatments are urgently needed. Due to its' physiological functions, the neonatal Fc receptor (FcRn) has emerged as a potential therapeutic target for pemphigus and pemphigoid, primarily because IgG is protected from proteolysis after uptake into endothelial cells. Thus, blockade of FcRn would reduce circulating autoantibody concentrations. However, long‐term effects of pharmacological FcRn inhibition in therapeutic settings of autoimmune diseases are unknown. Experimental Approach Therapeutic effects of FcRn blockade were investigated in a murine model of the prototypical autoantibody‐mediated pemphigoid disease, epidermolysis bullosa acquisita (EBA). B6.SJL‐H2s C3c/1CyJ mice with clinically active disease were randomized to receive either an anti‐FcRn monoclonal antibody (4470) or an isotype control over 4 weeks. Key Results While clinical disease continued to worsen in isotype control‐treated mice, overall disease severity continuously decreased in mice injected with 4470, leading to almost complete remission in over 25% of treated mice. These clinical findings were paralleled by a reduction of autoantibody concentrations. Reduction of autoantibody concentrations, rather than modulating neutrophil activation, was responsible for the observed therapeutic effects. Conclusion and Implications The clinical efficacy of anti‐FcRn treatment in this prototypical autoantibody‐mediated disease encourages further development of anti‐FcRn antibodies for clinical use in pemphigoid diseases and potentially in other autoantibody mediated diseases.


| INTRODUCTION
Autoimmune bullous dermatoses (AIBD) comprise a group of diseases characterized and caused by autoantibodies against structural proteins of the skin. AIBD can be classified into pemphigus diseases, where autoimmunity towards desmosomal antigens is the underlying cause, and pemphigoid diseases with autoimmunity against antigens located along the dermal-epidermal junction (Hammers & Stanley, 2016;Kasperkiewicz et al., 2017;Liu, Li, & Xia, 2017;Ludwig et al., 2017;. Despite major advances in diagnostics and treatment, they still pose a considerable therapeutic challenge. In pemphigus, the combination of the anti-CD20 antibody rituximab with systemic corticosteroid leads to remission, off therapy, in almost 90% of the patients after 24 months, but 40% of patients experience grade 3-4 severe adverse events. Furthermore, the time to achieve complete remission is rather long, more specifically ≥6 months after initiation of treatment (Joly et al., 2017).
Faster acting and safer treatment regimens are highly desirable, as are new treatments which could replace the corticosteroid component of the regimen.
The neonatal Fc receptor (FcRn) serves several functions: First, it transfers IgG from the mother to the fetus across the placenta and from the intestine into the circulation of neonates. Second, throughout life, FcRn protects IgG (and albumin) from proteolysis after uptake into endothelial cells and hence is crucial for IgG homeostasis. FcRn is also expressed by antigen-presenting cells (APC), such as monocytes, macrophages, and dendritic cells, as well as on neutrophils. Here, FcRn functions to recycle IgG after its uptake. Furthermore, and independent of IgG recycling, FcRn expressed on APCs is important for phagocytosis of bacteria, and a role in APC processing of immune complexes has been described (Baker, Rath, Pyzik, & Blumberg, 2014). Lastly, FcRn has been implicated in the transport of autoantibodies into keratinocytes, thus contributing to the pathogenesis of pemphigus (Chen, Chernyavsky, Webber, Grando, & Wang, 2015;Roopenian & Akilesh, 2007;Stapleton, Einarsdóttir, Stemerding, & Vidarsson, 2015;Vidarsson et al., 2006).
Here, we selected EBA as a model disease for AIBD because a murine model of EBA, based on immunization, induces a long-lasting disease phenotype and allows for therapeutic intervention in animals with clinically manifest disease (Bieber, Koga, & Nishie, 2017;Iwata et al., 2013;Koga et al., 2018). This model system duplicates the cascade of inflammatory EBA pathogenesis, including loss of tolerance, maintenance of IgG half-life, and autoantibody-induced tissue pathology. EBA is caused by autoantibodies directed against type VII collagen (COL7). Clinically, EBA manifests as either mechano-bullous disease, characterized by skin fragility, scarring, and miliae, or, in the majority of cases, as an inflammatory disease, resembling other pemphigoid diseases. In both forms, EBA is often complicated by involvement of the mucosa of the oesophagus, larynx, or eyes (Amber et al., 2018;Iwata et al., 2018;Koga et al., 2019).
Based on these considerations, we evaluated the effect of anti-FcRn treatment in an experimental murine EBA model and subsequently evaluated the pathways associated with therapeutic efficacy.

What is already known
• The neonatal Fc receptor (FcRn) controls the half-life of IgG (auto)antibodies.
• FcRn-deficient mice are partly protected from induction of certain autoimmune diseases.

What this study adds
• Anti-FcRn treatment improves autoantibody-mediated experimental autoimmune disease in mice.
• Anti-inflammatory effects of FcRn inhibition are paralleled by reduced autoantibody titres.

What is the clinical significance
• Inhibition of FcRn has potential as a therapeutic pathway in autoantibody-mediated diseases.

| Experiments with human samples
All experiments with human samples were approved by the ethical committee of the Medical Faculty of the University of Lübeck and were performed in accordance with the Declaration of Helsinki. Skin and blood samples from patients and healthy volunteers were obtained after written informed consent was obtained.
Immunoadsorption material was obtained from two patients with bullous pemphigoid (BP). BP was diagnosed based on clinical presentation, IgG, and/or C3 deposition along the dermal-epidermal junction in direct immunofluorescent microscopy from a peri-lesional skin biopsy, detection of anti-BP180-NC16A antibodies by ELISA, and binding of patient IgG to the blister roof in indirect immunofluorescent microscopy using human salt split skin as a substrate (Witte, Zillikens, & Schmidt, 2018).

| Induction of experimental EBA and treatment protocol
Adult (8-12 weeks) B6.s mice at an equal sex distribution were immunized with recombinant murine COL7 vWFA2 emulsified in TiterMax ® (TiterMax, Norcross, USA) as previously described (Bieber, Koga, & Nishie, 2017;Iwata et al., 2013;Kasprick, Bieber, & Ludwig, 2019). Four to 10 weeks after immunization, mice were clinically evaluated weekly. Mice developing EBA skin lesions in 2% or more of the body surface area were allocated to either isotype control or anti-FcRn murine antibody (4470) on an alternating basis. In total, 72% (n = 22) of immunized mice achieved this criterion within 7 weeks of immunization. After allocation, isotype or 4470 was administered at a dose of 30 mgÁkg −1 bodyweight i.p. twice weekly. Mice were clinically examined once per week to determine the body surface area affected by EBA skin lesions (primary endpoint of the study) by an investigator not aware of the treatment given to individual mice. Blood was obtained by venepuncture at Weeks 0, 2, and 4 of the treatment period. At the same time points at and after randomization, adverse events were documented. For this, body weight, general condition, spontaneous behaviour, and (if abnormalities were observed) respiration rate and temperature were recorded and scored as outlined in Table S1. Mice were held in individually ventilated cages at the specific pathogen-free animal facility at the University of Lübeck. During the entire lifespan, mice had free access to standard mouse chow and acidified drinking water. Regular health monitoring (every 3 months) is implemented at the facility, and during the experiment, no infections were noted. At the end of the treatment period, anaesthetized (ketamine/xylazin) mice were killed by cervical dislocation and bleeding out. Semi-quantitative scoring of H&E stained sections to determine the magnitude of the dermal infiltration was performed as described (Ludwig et al., 2005). Score values 0-3 correspond to no, mild, moderate, or severe infiltration, respectively. IgG and C3 deposits in the skin were quantified by determining the signal intensity (relative grey value) at the dermal-epidermal junction using ImageJ (RRID:SCR_ 003070).

| Determination of total and mCOL7 vWFA2specific IgG concentrations in serum
Serum levels of circulating total mouse IgG were determined by ELISA using mouse IgG quantification sets (Bethyl, Montgomery, Texas, USA) as described by the manufacturer's protocol using 1:50,000 diluted samples. For detection of circulating anti- 2.6 | Determination of antinuclear antibodies (ANA) ANA were measured using Biochips coated with HEp-2 cells (Cat# FA 520-0010, Euroimmun, Lübeck, Germany) as substrate and a FITClabelled, polyclonal donkey anti-mouse F (ab) 2 antibody (Jackson Immuno Research, Ely, UK). Sera were incubated on the Biochips at a 1:100 dilution. Sera from NZM2410/J mice (RRID:IMSR_JAX:002676) with or without proteinuria (n = 3 per group) from a previous study were included as positive or negative controls (Vorobyev et al., 2019).
ANA were tested in all serum samples obtained at the end of the treatment period (n = 11 per group).

| Cryosection assay
Blister-inducing capacity of patients' autoantibodies was evaluated using the cryosection assay, an ex vivo model of autoantibodyinduced dermal-epidermal separation originally described by Gammon et al. (Gammon et al., 1982) and modified as described (Recke et al., 2010;Sitaru et al., 2002). Human skin cryosections were incubated with IgG fractions from BP immunoadsorption material for 1 hr at 37 C (dilution 1:6 in PBS) and washed once with PBS afterwards. Leukocyte suspension from healthy blood donors was isolated by dextran 500 (ROTH, Karlsruhe, Germany) sedimentation mixed with medium (RPMI, LONZA, Cologne, Germany) and was incubated with different concentrations of the anti-FcRn antibody (100, 10, 1, and 0.1 μgÁml −1 ) or with 100 μgÁml −1 isotype control (both UCB Biopharma SPRL, Brussels, Belgium) for 30 minutes on ice. Subsequently, the different leukocyte fractions were incubated with skin sections for 3 hr at 37 C. After washing with PBS, slides were fixed in formalin and stained with haematoxylin and eosin. Skin sections were photographed, and split formation was determined by measuring section length and split length using ImageJ. According to the guidance for publication in the BJP (Curtis et al., 2015), after ANOVA, post hoc tests were only performed if F had achieved the significance level of P < .05. For animal experimentation, sample size was calculated for the primary endpoint (clinical disease severity 1, 2, 3, and 4 weeks after randomization) using SigmaPlot with the following assumptions: minimum detectable difference of 50%, SD 25%, power 90%, α of 5%, and ANOVA with eight groups (two interventions, four time points). This requires a sample size of 11 per group.

| Materials
The antibodies used were as follows. Rozanolixizumab (UCB7665) is an anti-human FcRn IgG4P mAb under investigation in clinical trials (Kiessling et al., 2017). A pharmacologically equivalent murinised anti-mouse FcRn IgG1 antibody (4470) was used in a preclinical mouse model of an autoantibody-driven autoimmune disease. Generation of the anti-mouse FcRn antibody 4470 and an isotype matched control antibody has recently been described (Smith et al., 2019).

| Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMA-COLOGY (Harding et al., 2018), and are permanently archived in the F I G U R E 1 Anti-FcRn treatment improves already clinically manifest experimental EBA. (a) B6.s mice were immunized with mCOL7 vWFA2 for induction of experimental EBA. Three to 8 weeks after immunization, mice were weekly clinically evaluated. If, in an individual mouse, 2% or more of the body surface area was affected by EBA lesions, it was randomized to either isotype or anti-FcRn antibody treatment. Treatments were carried out for 4 weeks, and clinical disease severity, expressed as affected body surface area, was evaluated weekly. (b) At randomization (Week 0), clinical disease severity, expressed as percentage of affected body surface area, was identical in isotype-and anti-FcRn antibodytreated mice. In isotype-treated mice, clinical EBA symptoms worsened during the 4-week treatment period, while it improved in anti-FcRn treated mice. Starting from Week 2, compared to mice injected with isotype antibody, a significant lower affected body surface area was observed in anti-FcRn-treated mice until the end of the experiment. Data shown are the means ± SEM, from 11 mice per group. *P< .05, significantly different as indicated; two-way ANOVA with Bonferroni t test for pairwise multiple comparisons. (c) Dermal infiltration was semiquantitatively evaluated in biopsies from lesional skin at the end of the experiment. No difference in infiltration among the two groups was noted; Student's t test. Data shown are the individual values with means ± SEM, from 11 mice per group. (d) Burden score (excluding EBA skin lesions) of the mice treated with isotype or anti-FcRn antibody at Week 4 after randomization. The graph shows each score (dots) and the median (

| Treatment of mice with clinically manifest EBA with anti-FcRn improves disease manifestation
To evaluate the effects of anti-FcRn treatment in already manifest AIBD, we induced experimental EBA in mice by immunization. In order to duplicate the experimental set-up of clinical trials, only mice that met pre-defined disease severity were treated with anti-FcRn or the isotype antibody. To prevent observer bias, the investigator scoring the mice for the primary endpoint (clinical disease) was unaware of the applied treatment (Figure 1a). At randomization, mice of both groups presented with similar disease severity (Figure 1b). Furthermore, time taken after immunization to reach the required disease severity was also identical (4.6 ± 1.0 weeks for isotype-, and 4.9 ± 1.0 weeks for anti-FcRn-treated mice). In isotype-treated mice, clinical disease manifestation, expressed as body surface area affected by EBA skin lesions, increased during the 4-week experimental perioid. In this group, the maximum extent of affected body surface area, 7.3% ± 1.8% (representing a 1.7-fold increase in involved body area), was achieved by Week 3. In contrast, mice receiving anti-FcRn antibody were reported to be less severely affected at Weeks 2, 3, and 4 ( Figure 1b,d), and complete remission was noted in some individual animals (Table 1) Table S1). The burden of the mice in the anti-FcRn-treated group was lower compared to the isotype antibody treated group (Figure 1d). In addition, ANA were determined in both groups at the end of the treatment period. In contrast to sera from lupus-prone NZM2410/J mice from a previous study who had developed proteinuria (Vorobyev et al., 2019), which were all ANA positive, no ANA were detected in either isotype-or anti-FcRn-treated mice.

| Pharmacological FcRn inhibition reduces circulating autoantibody concentrations as well as tissue bound IgG deposits in the skin
At this point, therapeutic efficacy of anti-FcRn treatment in experimental EBA had been established. Based on previous observations, this effect could either be modulated by a decrease of IgG half-life (Stapleton et al., 2015), by inhibiting the binding of myeloid cells to the immune complexes (Vidarsson et al., 2006), or by a combination of both effects. To address the effects of FcRn inhibition on total and COL7-specific IgG concentrations, their respective serum concentration was determined at randomization (Week 0), as well as 2 and 4 weeks thereafter. Immunization of mice with COL7 vWFA2 not only led to the induction of a COL7 vWFA2 -specific IgG response, but in parallel also induced an approximate twofold increase in total IgG in isotype-antibody treated mice. In animals injected with 4470, both total and COL7 vWFA2 -specific IgG serum concentrations were significantly lower compared to the isotype antibody-treated mice (Figure 2a,b). Lower concentrations of circulating autoantibodies targeting COL7 vWFA2 were accompanied by reduced deposition of these autoantibodies in the skin, as shown by a reduced linear IgG Note. Mice with clinical EBA manifestations were randomized to either isotype antibody or anti-FcRn treatment. Treatments were carried out over 4 weeks. Treatment outcomes were defined as progression (body surface area affected by EBA increased from Week 1 to Week 4), partial remission (body surface area affected by EBA decreased from Week 1 to Week 4, and total affected body surface area is ≥1%), or complete remission (body surface area affected by EBA decreased from Week 1 to Week 4, and total affected body surface area is <1%). Affected body surface area for mice in "complete remission" were 0.03% and 0.6% in two mice. The difference in proportions (progression versus remission [partial and complete]) is significant (P < .05, chi-squared test).
deposition along the dermal-epidermal junction by direct IF microscopy in mice treated with the anti-FcRn antibody (Figure 2c,e). Hence, compared to isotype antibody-treated mice, the density of tissuebound immune complexes in the skin was lower in mice following inhibition of FcRn.

| Anti-FcRn treatment does not alter neutrophil CD62L expression in vivo
In addition to its expression on epithelial cells, placental syncytiotrophoblasts, and endothelial cells, where the FcRn functions to transport IgG across mucosal cells, from mother to fetus, and regulates IgG half-life, respectively (Stapleton et al., 2015), FcRn is also expressed by monocytes, NK cells, and neutrophils. Upon neutrophil activation, FcRn locates at the plasma membrane of neutrophils. Functionally, neutrophil-expressed FcRn promotes phagocytosis which is triggered by binding of IgG-opsonized bacteria to the neutrophils (Vidarsson et al., 2006). As immune complex activation of neutrophils promotes tissue injury in several autoimmune diseases, including experimental EBA Ludwig et al., 2017), we next investigated if anti-FcRn changes neutrophil CD62L expression in EBA-affected mice. For this purpose, expression of CD62L, which corresponds to the activation status (Rosales, 2018), on neutrophils from different compartments (blood, peripheral lymph node, and bone marrow) was assessed at the end of the 4-week treatment period. No significant difference in CD62L expression on neutrophils was noted between isotype-or anti-FcRn-treated mice in any of the investigated F I G U R E 2 Anti-FcRn treatment reduces circulating anti-COL7 IgG concentrations and decreases IgG deposition in the skin of mice with experimental EBA. Isotype or anti-FcRn antibody treatment was initiated if, in an individual mouse, 2% or more of the body surface area was affected by EBA lesions. At the start of treatment, as well as 2 and 4 weeks thereafter, serum was obtained for determination of total and COL7-specific IgG. (a) In both groups, total IgG concentrations increased during the 4-week treatment period. This increase was less pronounced in mice treated with anti-FcRn. Data shown are the means ± SEM, from 9-10 mice per group, after removal of outliers using ROUT, accounting for the unequal n. *P< .05, significantly different from anti-FcRn; two-way ANOVA with Bonferroni t test for pairwise multiple comparisons.. (b) Concentrations of COL7-specfic IgG remained relatively constant in isotype antibody treated mice, while anti-FcRn antibody treatment reduced the specific autoantibody concentration by approximately 50%. Data shown are the means ± SEM, from 9-10 mice per group, after removal of outliers using ROUT, accounting for the unequal n. *P< .05, significantly different from anti-FcRn; two-way ANOVA with Bonferroni t test for pairwise multiple comparisons. In (c) the deposition of IgG, but not of C3 (d), at the dermal-epidermal junction junction was reduced in mice treated with anti-FcRn antibody, compared with mice injected with isotype control antibody. Data shown are the individual values with means ± SEM, from 9-12 mice per group, after removal of outliers using ROUT. *P< .05, significantly different as indicated; t test (IgG) or rank sum test (C3). (e) Representative images of direct IF microscopy for IgG from peri-lesional skin biopsies obtained at the end of the experiment compartments using ANOVA. However, the Jonckheere Terpstra patterned rank test, which allows detection of trends among different groups, showed a significant trend towards lower CD62L − neutrophils in the blood in TiterMax ® immunized mice, indicating that induction of experimental EBA leads to an activation of neutrophils within the circulation (Figure 3).

| Immune complex-induced activation of neutrophils is not influenced by anti-FcRn treatment
We next evaluated the effects of the FcRn on neutrophil activation in vitro. For this, neutrophils were activated with immune complexes in the absence or presence of the anti-FcRn antibody 4470. Compared to neutrophils incubated with isotype-antibody, lower doses of 4470 had no effect on neutrophil activation (expressed as release of ROS over time), while at higher concentrations, anti-FcRn led to an enhanced ROS release from the neutrophils (Figure 4a,b). This suggests that neutrophil activation leads to enhanced surface expression of the FcRn (Vidarsson et al., 2006). In turn, anti-FcRn can bind to the cell surface and may lead to immune complex enhanced neutrophil activation. However, rapid internalization of this complex limits the duration of effect. This assumption is supported by the unaltered dermal-epidermal separation on skin cryosections incubated with anti-COL7 IgG and neutrophils and anti-FcRn at higher doses ( Figure 4c).

| DISCUSSION
Taking our results together, we have here demonstrated the efficacy of anti-FcRn treatment in experimental murine EBA and concluded F I G U R E 3 Anti-FcRn treatment does not alter neutrophil CD62L function in vivo. After 4 weeks of treatment with either isotype or anti-FcRn antibody, indicated organs from mice with experimental EBA were obtained for isolation of neutrophils, followed by flow cytometry. Mice injected with TiterMax ® alone served as negative controls. (a-c) Percentage of CD62L − CD45 + , CD1b + Gr-1 + , and Ly6G + singlet cells was determined. No differences in neutrophil activation was detected in the three investigated organs. Data are shown as individual values in box and whisker plots with medians, quartiles and ranges, from seven to eight mice per group; unequal sample sizes are due to technical issues (i.e., clotting). For normally distributed data, t test was used for statistical analysis, and for non-equally distributed data, rank sum test was applied.
(d-f) Representative FACS images are shown in panels a-c that the therapeutic effects of anti-FcRn treatment are associated with a reduced concentration of circulating and tissue-bound autoantibodies targeting COL7.
Previous data had indicated that FcRn is involved in the pathogenesis of autoantibody-mediated diseases: First, genetic alterations of the Fc-molecule that alter its binding to FcRn, have been shown to be associated with autoantibody-mediated disease-specifically in pemphigus, where the p.Arg435his variation of IgG3 that has a high affinity to the FcRn is associated with disease susceptibility . Second, in antibody transfer models of pemphigus, bullous pemphigoid, EBA, or myasthenia gravis, FcRn-or β2 microglobulin-deficient mice were completely or partly protected from induction of experimental disease (Li et al., 2005;Liu et al., 1997;Liu et al., 2007;Sesarman et al., 2008). Third, in the K/BxN serum transfer model of arthritis, prophylactic blockade of the FcRn by Fc-engineered antibodies to block FcRn (Abdegs) impaired arthritis development, and in short-term, quasi-therapeutic settings also led to a delayed disease progression (Patel et al., 2011). Similar results were observed in an antibody transfer-enhanced model of murine experimental autoimmune encephalomyelitis (Patel et al., 2011) and in an antibody transfer-induced model of immune thrombocytopenia (Smith et al., 2019).
However, genetic deficiency of either the FcRn α chain or β2 microglobulin has also been reported to enhance the production of certain autoantibodies in the mouse (Singh, Yang, Kim, & Halder, 2013) and to lead to spontaneous arthritis development (Kingsbury et al., 2000). Furthermore, application of FcRn-targeted treatments in long-term therapeutic settings had not been performed so far, although no adverse events were detected in a non-human primate study where animals were administered for long periods of time with high doses of an anti-FcRn monoclonal antibody (Smith et al., 2018).
Hence, the long-term effects of pharmacological FcRn inhibition in therapeutic settings of autoimmune diseases are currently not known.
To investigate if long-term, pharmacological blockade of the FcRn could have therapeutic effects in a prototypical autoantibodymediated disease, we induced experimental EBA by immunization. (c) Dermal-epidermal separation was induced on skin cryosections by incubating these with anti-COL17 IgG and neutrophils. Blockade of the FcRn had no effect on the magnitude of dermal-epidermal separation. If sections were incubated with normal IgG, instead of anti-COL17 IgG, and neutrophils, dermal-epidermal separation ranged between 0% and 5%. Data shown are the individual values with means ± SEM, from 12 samples per group, with the exception of the 100 μgÁml −1 dose, where n = 6. ANOVA, with Bonferroni t test for multiple comparisons, was used to test for statistical difference from isotype clearly different pathogenesis (i.e., pemphigoid versus pemphigus) is based on the finding that the (different) autoantibodies reach their target antigen through the bloodstream, where the half-life is controlled by the FcRn.
FcRn-targeting antibodies alone may be insufficient for many of these diseases, because, with a few exceptions, immunoadsorption/plasmapheresis is insufficient to induce long-term remission in most autoantibody-mediated diseases (Meyersburg, Schmidt, Kasperkiewicz, & Zillikens, 2012). Immunoadsorption in bullous pemphigoid patients induces rapid and long-lasting remission, even in patients receiving no other medications (Hübner et al., 2018).
Hence, in bullous pemphigoid, anti-FcRn antibody may be a preferred treatment option. For most other AIBD, we believe that anti-FcRn treatment, like immunoadsorption, will induce rapid improvement, but additional immunosuppressive treatment would be needed to induce long-term remission. One such candidate may be anti-CD20 therapy (Joly et al., 2017), but due to the IgG clearing effect of anti-FcRn treatment, anti-CD20 mAb would also be cleared rapidly if administered concurrently. As an alternative, B-cell inhibitors such as Bruton's tyrosine kinase (BTK) inhibitors may be used. BTK inhibitors are currently in phase II clinical trials for pemphigus (NCT02704429).
Based on these insights into FcRn biology and FcRn-targeting therapies in a prototypical autoantibody-mediated disease, clinical trials evaluating FcRn-targeting therapies are merited in pemphigoid diseases and may enable an additional treatment option for the still unmet (Lamberts et al., 2019) medical need. As pemphigoid diseases are prototypical autoantibody-mediated diseases, it is tempting to speculate that targeting the FcRn may also be of benefit in AIBD and other autoantibody-mediated diseases.