BACKGROUND:Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are rare, chronic, potentially life-threatening, immunoglobulin (Ig)G-mediated, autoimmune skin and/or mucosal blistering diseases. Efgartigimod, a human IgG1 antibody Fc fragment, blocks the neonatal Fc receptor, decreasing IgG recycling and reducing both healthy and pathogenic IgG autoantibody levels. OBJECTIVES:To investigate the efficacy, safety and impact of subcutaneous efgartigimod PH20 (co-formulated with recombinant human hyaluronidase PH20) in conjunction with prednisone in the treatment of pemphigus. METHODS:Adult participants with newly diagnosed or relapsing moderate-to-severe pemphigus were recruited in this phase III, prospective, multicentre, randomised, double-blinded, placebo-controlled study (NCT04598451). Participants were randomised (2 : 1) to weekly subcutaneous efgartigimod PH20 or placebo. Subcutaneous efgartigimod PH20 2000 mg was administered on days 1 and 8, followed by 1000 mg weekly until complete remission on minimal prednisone therapy (CRmin) (≤ 10 mg daily). All participants received concomitant prednisone starting at 0.5 mg kg-1 daily. The primary outcome was the proportion of participants with PV who achieved CRmin by week 30, while receiving minimal prednisone, for ≥ 8 weeks. Pharmacodynamics and safety were also assessed. RESULTS:Overall, 222 participants (PV: n = 190; PF: n = 32) were randomised (subcutaneous efgartigimod PH20: n = 147; placebo: n = 75). The proportions of participants with PV achieving CRmin within 30 weeks were comparable between the subcutaneous efgartigimod PH20 and placebo groups, with no statistically significant difference observed [44/124 (35.5%) vs. 20/66 (30.3%); P = 0.60; odds ratio 1.19 (95% confidence interval 0.60-2.41)]. Total prednisone consumption over time was comparable between groups. Subcutaneous efgartigimod PH20 resulted in rapid reductions from baseline in total IgG and anti--desmoglein-1 and anti-desmoglein-3 autoantibody levels, but these did not translate to improvements in Pemphigus Disease Area Index scores. The rates of adverse events (AEs) in the subcutaneous efgartigimod PH20 and placebo groups were 89.1% (n = 131/147) and 76.0% (n = 57/75), respectively; most were mild to moderate [serious AEs: 12.2% (n = 18/147) and 13.3% (n = 10/75), respectively]. No deaths occurred. CONCLUSIONS:Subcutaneous efgartigimod PH20 in combination with systemic corticosteroids did not demonstrate clinical benefit over systemic corticosteroids alone in patients with moderate-to-severe pemphigus at 30 weeks, but it was well tolerated in this patient population.

Introduction & Objectives: Efgartigimod is an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor (FcRn), thereby reducing levels of circulating IgG including pathogenic IgG autoantibodies. Pemphigus vulgaris (PV), pemphigus foliaceus (PF), and bullous pemphigoid (BP) are autoimmune blistering diseases. Pemphigus is mediated by IgG autoantibodies targeting desmoglein (Dsg)-3 in PV, and Dsg-1 in mucocutaneous PV (in addition to Dsg-3), while PF is attributed to IgG autoantibodies against Dsg-1 only. Dsg-3 and Dsg-1 are desmosomal proteins mediating keratinocyte cell-cell adhesion. BP is mediated by IgG autoantibodies against BP180 (type XVII collagen) and BP230 structural proteins of the dermal-epidermal junction. Materials & Methods: ADDRESS is a multicenter, randomized, double-blind, placebo-controlled trial evaluating efficacy and safety of efgartigimod in patients with PV or PF (NCT04598451). Participants are undergoing randomization (2:1) to receive subcutaneous efgartigimod co-formulated with PH20 or placebo/PH20 on top of oral prednisone (or equivalent). Primary endpoint is the proportion of patients with PV or PF who achieve complete remission on minimal therapy (CRmin) within 30 weeks. BALLAD is a global, multicenter, phase 2/3, randomized, double-blind, placebo-controlled trial evaluating efficacy and safety of subcutaneously administered efgartigimod in patients with BP (NCT05267600). Part A will be a proof-of-concept study and recruit 40 participants, while the Part B confirmatory study will recruit 120 participants. Parts A and B will be identical in schedule, structure, assessments, and conduct. Primary endpoint is the proportion of participants in complete remission off oral corticosteroid therapy for ≥8 weeks at week 36. Results & Conclusions: As of February 28, 2023, 222 participants have been enrolled into ADDRESS and enrolment of BALLAD has started. It is anticipated that the recruitment of the ADDRESS full study and BALLAD part A will be completed, and a further update will be given at the time of presentation.

Bullous pemphigoid (BP) is an autoimmune blistering disease whereby patients develop autoantibodies against the basement membrane zone (BMZ) antigens BP180 and/or BP230. These autoantibodies exert numerous pathogenic Fc receptor (FcR)-dependent and FcR-independent effects (Cole et al., 2022Cole C. Vinay K. Borradori L. Amber K.T. Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms.Front Immunol. 2022; 13912876Crossref Scopus (15) Google Scholar), and can be readily visualized for diagnosis by direct immunofluorescence (DIF) and indirect immunofluorescence. The neonatal Fc receptor (FcRn) mediates recycling of IgG, extending the half-life of IgG. FcRn is expressed on numerous cell types, including keratinocytes (Cauza et al., 2005Cauza K. Hinterhuber G. Dingelmaier-Hovorka R. Brugger K. Klosner G. Horvat R. et al.Expression of FcRn, the MHC class I-related receptor for IgG, in human keratinocytes.J Invest Dermatol. 2005; 124: 132-139Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). FcRn inhibition has been shown to be efficacious using in vivo models of pemphigoid by reducing circulating antibodies (Pigors et al., 2023Pigors M. Patzelt S. Reichhelm N. Dworschak J. Khil'chenko S. Emtenani S. et al.Bullous pemphigoid induced by IgG targeting type XVII collagen non-NC16A/NC15A extracellular domains is driven by Fc gamma receptor- and complement-mediated effector mechanisms and is ameliorated by neonatal Fc receptor blockade.J Pathol. 2023; PubMed Google Scholar) as well as in vivo or using in vitro models of keratinocytes in pemphigus (Chen et al., 2015Chen Y. Chernyavsky A. Webber R.J. Grando S.A. Wang P.H. Critical Role of the Neonatal Fc Receptor (FcRn) in the Pathogenic Action of Antimitochondrial Autoantibodies Synergizing with Anti-desmoglein Autoantibodies in Pemphigus Vulgaris.J Biol Chem. 2015; 290: 23826-23837Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Li et al., 2005Li N. Zhao M. Hilario-Vargas J. Prisayanh P. Warren S. Diaz L.A. et al.Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases.J Clin Invest. 2005; 115: 3440-3450Crossref PubMed Scopus (222) Google Scholar, Zakrzewicz et al., 2022Zakrzewicz A. Würth C. Beckert B. Feldhoff S. Vanderheyden K. Foss S. et al.Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus?.Cells. 2022; 11Crossref Scopus (11) Google Scholar). The contribution of keratinocyte FcRn to BP pathogenesis is unclear. As the persistence of autoantibodies along the BMZ would presumably sustain inflammation, we questioned whether therapeutic FcRn inhibition could exert a potentially acute therapeutic benefit, accelerating local depletion of deposited anti-BMZ antibodies. To test this, we affinity purified IgG from patients with BP or healthy controls. All donors provided written, informed consent. Enrollment criteria and additional methods are described in the Supplementary Methods. We generated 3D human skin equivalents (HSE), pretreating them with efgartigimod, a recombinant Fc mutant with high affinity for FcRn (Ulrichts et al., 2018Ulrichts P. Guglietta A. Dreier T. van Bragt T. Hanssens V. Hofman E. et al.Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans.J Clin Invest. 2018; 128: 4372-4386Crossref PubMed Scopus (171) Google Scholar), or wild type recombinant Fc (FcWT). 3D HSE were then subsequently treated with BP-IgG, and IgG deposition and blistering measured by DIF and H&E respectively. Pretreatment with efgartigimod resulted in a significant decrease in histologic blistering (Fig 1a, b). Notably, the efgartigimod treated group demonstrated re-attachment by day 7. In contrast, FcWT treated 3D HSE demonstrated stabilization in blistering by day 3 without significant re-attachment. Efgartigimod treated 3D HSE demonstrated a significant decrease in IgG deposition along the BMZ by day 3 (Fig 1 c, d). Interestingly, by day 7, fluorescent intensity of FcWT treated 3D HSE returned to levels consistent with that of the efgartigimod group, demonstrating that IgG presumably becomes depleted in the culture conditions between day 3 and 7. We next questioned whether these findings were due to accelerating metabolism of local IgG via FcRn blockade, or whether BP180/BP-IgG complexes relied on FcRn for internalization. Primary human keratinocytes were treated with BP-IgG to induce characteristic internalization of BP180 as previously described (Hiroyasu et al., 2013Hiroyasu S. Ozawa T. Kobayashi H. Ishii M. Aoyama Y. Kitajima Y. et al.Bullous pemphigoid IgG induces BP180 internalization via a macropinocytic pathway.Am J Pathol. 2013; 182: 828-840Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) (Fig 2a). We next pre-treated cultures with efgartigimod or FcWT prior to the addition of BP-IgG. The percentage of cells demonstrating BP180 internalization at 2 hours was quantified, demonstrating no significant change in BP180 internalization (Fig 2b, c). To further validate this, we added AlexaFluor-488 conjugated BP-IgG and AlexaFluor-568 conjugated dextran to visualize internalization kinetically. Again, efgartigimod did not appear to alter the internalization kinetics, indicating that blockade of FcRn does not abrogate BP-IgG mediated BP180 macropinocytosis (Fig 2d, e). Our data provides critical insight into the role of FcRn inhibition in clearing local deposition of anti-BMZ IgG in pemphigoid. FcRn inhibition causes a decrease in circulating IgG levels, resulting in therapeutic improvement in experimental settings. However, in patients, IgG deposition has already occurred upon onset of symptoms. Finding an efficacious treatment to expedite depletion of antibodies already deposited in the skin remains an important acute therapeutic goal. Our data demonstrate that FcRn inhibition expedites clearance of deposited pathogenic IgG at the BMZ, as well as decreases immune cell-independent blistering. In therapeutic application of FcRn inhibition in vivo, the effect of clearance of already deposited IgG may be counteracted by the rate of autoantibody production by plasma cells, however a systemic blockade of IgG recycling would decrease autoantibodies arriving at the target site. BP-IgG exerts several complement independent, and potentially pathologic effects (Cole et al., 2022Cole C. Vinay K. Borradori L. Amber K.T. Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms.Front Immunol. 2022; 13912876Crossref Scopus (15) Google Scholar). We confirm this functionally using 3D HSE. In contrast to prior cryosection models of blistering, 3D HSE offer the benefit of a viable epithelium. Thus, the direct contribution of autoantibodies on keratinocytes can be further studied (Bao et al., 2022Bao L. Perez White B.E. Li J. Patel P.M. Amber K.T. Gene expression profiling of laminin α3-blocked keratinocytes reveals an immune-independent mechanism of blistering.Exp Dermatol. 2022; 31: 615-621Crossref PubMed Scopus (5) Google Scholar). Several limitations must be considered. To preserve basal keratinocyte morphology, we utilized serum free culture conditions. A potential-downside of this is the inability to perform serum starvation, thus resulting in asynchronous macropinocytosis. This was evident in our experiments as we noted significant variability between replicate experiments, with macropinocytosis being observed in anywhere from 20% to 80% of BP-IgG treated cells at 2 hours depending on the culture length. Despite this, macropinocytosis was comparable between efgartigimod and FcWT treated keratinocytes in each experiment. We also observed a faster onset of macropinocytosis as early as 30 minutes in contrast to that seen by Hiroyasu et al (Hiroyasu et al., 2013Hiroyasu S. Ozawa T. Kobayashi H. Ishii M. Aoyama Y. Kitajima Y. et al.Bullous pemphigoid IgG induces BP180 internalization via a macropinocytic pathway.Am J Pathol. 2013; 182: 828-840Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Lastly, deciphering the kinetics of anti-BMZ deposition and blistering must be taken with some caution. Presumably, anti-BMZ antibodies saturate the cutaneous BMZ. As blistering and intrinsic protease release occurs, autoantigens are lost and then renewed, eventually depleting the free autoreactive IgG. Likewise, decreased blistering presumably extends the half-life of free IgG in the media, due to lack of proteolytic activity resulting in destruction, as evidenced by a decrease in fluorescent signal in areas of blistering (Fig. 1b). We, however, did not assess supernatant IgG concentrations given the need for media changes, and thus could not assess local levels after prolonged courses. There is also likely a delay between early blistering and loss of IgG deposition, as indicated by our finding of blistering occurring before significant loss of fluorescent signal. It is also unclear whether IgG deposits along the BMZ originate from soluble IgG in the media or are caused by keratinocyte FcRn mediated transcytosis. As IgG is found in interstitial fluid and blister fluid, both mechanisms are likely physiologic and would be improved through FcRn inhibition. This mechanistic data provides potential clues for translation to therapy. Acute depletion of deposited autoreactive IgG would potentially indicate a mechanism for acute clinical improvement. This is supported by clinical trial data of IVIg where even a single course resulted in improvement in disease severity despite unchanged circulating anti-BP180 antibody levels (Amagai et al., 2017Amagai M. Ikeda S. Hashimoto T. Mizuashi M. Fujisawa A. Ihn H. et al.A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.J Dermatol Sci. 2017; 85: 77-84Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). In summary, we demonstrate that FcRn inhibition can expedite the clearance of BMZ-bound autoantibodies in vitro, independently of anti-BP180/BP180 complex internalization. This corresponds with an observed decrease in histologic blistering. Further studies with keratinocyte specific Fcgrt knockouts would provide additional insight into the contributory role of keratinocyte FcRn on pemphigoid. No large datasets were generated or analyzed. KV, PV, MS, and MB are employees of argenx and may hold stock or stock options. KTA has a collaborative research agreement with argenx. argenx provided reagent and collaborative discussion regarding study design, but the research was performed and analyzed independently of argenx. During the peer review process argenx was offered an opportunity to review the manuscript. Authors retained full editorial control over the content. Conceptualization – KTA, KV, PV, MS, MB; Data curation – LB, BPW, RC, JL; Formal Analysis RC, KTA; Investigation - LB, BPW, RCC, J; Methodology – KTA, Project administration – KTA, Resources – KV, PV, MS, MB; Supervision – KTA, Validation – BPW, RCC, KTA; Visualization – KTA, Writing – original draft – KTA, writing – review & Editing, LB, BPW, RCC, JL KV, PV, MS, MB. This work was supported by argenx. KTA is supported in part by the Office of Research Infrastructure Programs of the National Institute of Health (R21OD030057) The study was approved by the Rush University Institutional Review Board (IRB#20121406). The study was performed in accordance with the Declaration of Helsinki. All donors provided written informed consent. After obtaining informed consent, blood was drawn from patients with a confirmed diagnosis of BP. BP diagnosis was defined based on current international guidelines1, using the following criteria. 1) clinical suspicion for BP, 2) Positive direct immunofluorescence demonstrating deposition of IgG along the cutaneous BMZ, 3) A positive serologic test detecting BP180 and/or BP230 antibodies, and/or indirect immunofluorescence demonstrating deposition along the roof of salt-split skin. Patient serology is summarized below.Tabled 1PatientMucous Membrane InvolvementDPP4 ExposureBP180 ELISABP230 ELISAIIF titer on human SSSPatient 1NoYes18151:160Patient 2NoNo78621:20,480Patient 3NoNo9341:2,560Patient 4NoNo631011:20,480 Open table in a new tab DPP4 – Dipeptidyl peptidase inhibitor, IIF – indirect immunofluorescence, SSS salt split skin Affinity purification was performed on pooled serum samples utilizing the Nab Protein G spin Column (Thermo Fischer Scientific, Waltham, MA) to minimize variability in the ratio of BP180/BP230 antibodies. Purified IgG was further washed using 3kDa Amicon Ultra-15 centrifugal filter units with a 3kDa filter in PBS (MilliporeSigma, Burlington, MA), followed by azide removal (Nanopartz, Loveland, CO). For 3D HSE experiments, multiple single donor sera were purchased from Innovative Research. For 2D experiments, each biologic replicate utilized pooled IgG from different vendors to increase diversity of normal control (MP Biochemicals, Irvine, CA; Cell Sciences, Newburyport, MA; Sigma-Aldrich, St. Louis, MO). Affinity purified BP-IgG was conjugated to AlexaFluor-488 using the Lightning-Link Conjugation Kit (Abcam, Cambridge, MA). 3D HSEs were initiated and propagated as previously described2 using primary neonatal human keratinocytes. A minimum of three independent cell lines derived from three donors were used for all 3D HSEs. Cultures were treated with efgartigimod (Lonza, UK) or wild type Fc (Evitria, Switzerland) were added to after 7 days of 3D HSE growth at a concentration of 25ug/mL based on prior reported dosing3 (Defined as day 0). After 60 minutes of preincubation, 2mg/mL of BP-IgG or control IgG was added. Cultures were harvested on day 1, 3, and 7. Media changes occurred on day 3 and 5. Primary adult human keratinocytes (PHKs) (Thermo Fisher Scientific) were cultured in EpiLife Medium with Human Keratinocyte Growth Supplement in a CO2 incubator and grown on chamber slides. Culture media changes occurred every 48 h. Cells were pretreated with 25ug/mL of efgartigimod or FcWT followed 30 minutes later by 4mg/mL of BP-IgG. In a second set of experiments, cells were pretreated with efgartigimod or FcWT as previously described, followed by 4mg/mL of AF488-conjugated BP-IgG and 0.1mg/ml of 70kDa AF568-conjugated dextran (Thermo Fisher Scientific). AF-conjugated IgG has previously been shown to functionally bind to FcRn4. To detect anti-BMZ antibodies, 3D HSE were placed in OCT, followed by sectioning. Sections were stained with 1:100 AlexaFluo488 conjugated anti-human IgG (Thermo Fisher Scientific). For 2D cultures, Chamber slides were at 36, 60, 90, or 120 minutes. For imaging BP180 internalization, cells were fixed, permeabilized, then stained with anti-COL17 antibody (Clone SR46-05, Thermo Fisher Scientific). For dextran imaging, cells permeabilization was skipped. All samples were imaged on an Evos FL II . Formalin fixed paraffin embedded portions of 3D HSE were sectioned at 4 μm, stained with hematoxylin and eosin per standard protocol, and imaged using an Zeiss Axioplan 2 light microscope with high resolution AxioCamHR camera. Images were analyzed in ImageJ (National Institute of Health, Bethesda, MD) by an investigator blinded to the experimental conditions. For BP180 and dextran internalization, the morphology of prototypical BP-IgG treated cells demonstrating internalization versus Ctrl-IgG cells were used to define the two populations for performing a count of randomized slide sections. For quantifying the percentage of histologic blistering, length of detached tissue at the BMZ was divided by the total length of tissue and multiplied by 100. For direct immunofluorescence, Ctrl-IgG treated sections were used to establish autofluorescent intensity gates on a scale of 0-255. Mean pixel intensity of intact BMZ exceeding an intensity of 90 (the autofluorescence of control tissue) was measured for each section, and mean RFU was considered as mean RFU minus 90. Data was analyzed using Prism 9 software (Graphpad, La Jolla, CA). Pairwise measures were made by Mann-Whitney U test. All tests were 2 tailed with significance defined as P < 0.05. 1. Borradori L, Van Beek N, Feliciani C, et al. Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol. 2022;36(10):1689-1704. 2. Arnette C, Koetsier JL, Hoover P, Getsios S, Green KJ. In Vitro Model of the Epidermis: Connecting Protein Function to 3D Structure. Methods Enzymol. 2016;569:287-308. 3. Zakrzewicz A, Würth C, Beckert B, et al. Stabilization of Keratinocyte Monolayer Integrity in the Presence of Anti-Desmoglein-3 Antibodies through FcRn Blockade with Efgartigimod: Novel Treatment Paradigm for Pemphigus? Cells. 2022;11(6). 4. Tzaban S, Massol RH, Yen E, et al. The recycling and transcytotic pathways for IgG transport by FcRn are distinct and display an inherent polarity. J Cell Biol. 2009;185(4):673-684.

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies targeting type XVII collagen (Col17) with the noncollagenous 16A (NC16A) ectodomain representing the immunodominant site. The role of additional extracellular targets of Col17 outside NC16A has not been unequivocally demonstrated. In this study, we showed that Col17 ectodomain-reactive patient sera depleted in NC16A IgG induced dermal-epidermal separation in a cryosection model indicating the pathogenic potential of anti-Col17 non-NC16A extracellular IgG. Moreover, injection of IgG targeting the murine Col17 NC14-1 domains (downstream of NC15A, the murine homologue of human NC16A) into C57BL/6J mice resulted in erythematous skin lesions and erosions. Clinical findings were accompanied by IgG/C3 deposits along the basement membrane and subepidermal blistering with inflammatory infiltrates. Disease development was significantly reduced in either Fc-gamma receptor (FcγR)- or complement-5a receptor-1 (C5aR1)-deficient mice. Inhibition of the neonatal FcR (FcRn), an atypical FcγR regulating IgG homeostasis, with the murine Fc fragment IgG2c-ABDEG, a derivative of efgartigimod, reduced anti-NC14-1 IgG levels, resulting in ameliorated skin inflammation compared with isotype-treated controls. These data demonstrate that the pathogenic effects of IgG targeting the Col17 domain outside human NC16A/murine NC15A are partly attributable to antibody-mediated FcγR- and C5aR1 effector mechanisms while pharmacological inhibition of the FcRn represents a promising treatment for BP. The mouse model of BP will be instrumental in further investigating the role of Col17 non-NC16A/NC15A extracellular epitopes and validating new therapies for this disease. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease driven by autoantibodies targeting type XVII collagen (Col17, BP180), which mediates adhesion of basal keratinocytes to the underlying basement membrane in epithelial tissues. Here, we evaluated the therapeutic effects of the murine Fc fragment IgG2c-ABDEG (mABDEG), a derivative of the neonatal Fc receptor (FcRn) inhibitor efgartigimod, in experimental BP. mABDEG targets FcRn, which plays a crucial role in the homeostasis of endogenous IgG, resulting in reduced levels of circulating IgG including autoantibodies. BP was induced in C57BL6/J mice by subcutaneous injections of rabbit anti-murine Col17 IgG every other day. mABDEG or isotype control were administered intraperitoneally every three days. mABDEG-treated mice presented with lower anti-Col17 IgG serum levels from Day 6 throughout Day 12 (p < 0.05) and a significant reduction in the affected body surface area compared to isotype control-treated mice on Day 12 (p < 0.001). This was paralleled by a reduction in tissue-bound IgG (p = 0.05) and C3 binding (p< 0.01) to the basement membrane of perilesional skin in the treatment vs. control group. Moreover, lesional skin biopsies of mABDEG- vs. isotype control-treated mice showed evidence for significantly less inflammation, particularly characterized by strongly decreased frequencies of neutrophils. Our data demonstrate that pharmacological inhibition of the FcRn represents a promising strategy for the treatment of BP and supports ongoing randomized controlled clinical trial evaluation of FcRn antagonists for BP.

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 authors wish to make the following changes to their paper [...].

Background Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. Objectives To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. Methods Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg kg(-1) intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). Results Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10 mg kg(-1) and 13 of 15 (87%) patients receiving 25 mg kg(-1), with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0 center dot 26 mg kg(-1) per day (range 0 center dot 06-0 center dot 48) led to complete clinical remission in 14 of 22 (64%) patients within 2-41 weeks. Conclusions Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus.

To identify evidence gaps in the literature of the burden of illness and treatment of pemphigus vulgaris (PV) and pemphigus foliaceus (PF) to support the launch of efgartigimod to treat these rare diseases. A literature review using a structured search strategy was conducted from 1 July 2011 to 26 October 2021 in PubMed, Embase, and Cochrane regarding disease description, epidemiology, humanistic and economic burden, treatment guidelines, and treatment patterns. Online desktop searches for health technology assessments, competitor labels, and ongoing clinical trials were also conducted. Epidemiology data are limited, and the true incidence and prevalence of pemphigus variants are not completely known worldwide. Unlike ICD-9 codes, ICD-10 codes are specific to PV and PF subtypes, but only a few epidemiology studies have used ICD-10 codes to date. There is a lack of studies that show the effect of treatment to prevent serious complications (e.g., opportunistic infections, cardiovascular disease), hospitalization, and death. Although health-related quality of life is significantly affected in patients with PV/PF, few studies have estimated it, and most used generic instruments. Correspondingly, two studies have reported the impact of PV/PF on caregivers' quality of life (emotional, physical, and with daily activities). Only a few studies that estimate the economic burden of PV/PF are available. No cost-effectiveness (CE) analyses were found, including CE models that supported health technology assessment decisions. Few treatment-pattern studies were found, but one study was found that included rituximab after it was approved. There are many gaps in the literature to support the launch of a new product in pemphigus, including epidemiology for budget-impact models, humanistic and economic burden studies, CE models, and treatment-pattern studies.

Pemphigus vulgaris is an autoimmune blistering disease of the epidermis, caused by autoantibodies against desmosomal proteins, mainly desmogleins 1 and 3, which induce an impairment of desmosomal adhesion and blister formation. Recent findings have shown that inhibition of immunoglobulin G binding on the neonatal Fc receptor, FcRn, results in reduced autoantibody recycling and shortens their half-life, providing a valid treatment option for PV. We have here analyzed the role of FcRn in human keratinocytes treated with antibodies isolated from pemphigus vulgaris patient or with recombinant anti-desmoglein-3 antibodies that induce pathogenic changes in desmosomes, such as loss of monolayer integrity, aberrant desmoglein-3 localization and degradation of desmoglein-3. We show that blocking IgG binding on FcRn by efgartigimod, a recombinant Fc fragment undergoing clinical studies for pemphigus, stabilizes the keratinocyte monolayer, whereas the loss of desmoglein-3 is not prevented by efgartigimod. Our data show that FcRn may play a direct role in the pathogenesis of pemphigus at the level of the autoantibody target cells, the epidermal keratinocytes. Our data suggest that in keratinocytes, FcRn may have functions different from its known function in IgG recycling. Therefore, stabilization of keratinocyte adhesion by FcRn blocking entities may provide a novel treatment paradigm for pemphigus.

Bullous pemphigoid (BP) is an autoimmune blistering disease, characterized by subepidermal blisters and mediated by IgG autoantibodies against BP180 (type XVII collagen) and BP230 structural proteins of the dermal-epidermal junction. Efgartigimod, an engineered Fc fragment, inhibits FcRn activity, thereby decreasing serum IgG and autoantibodies. This pre-registration report describes a Phase 2/3 randomized, double-blind, placebo-controlled trial of efgartigimod in patients with moderate to severe (by PDAI) BP. In Part A (proof of concept, phase 2), 40 participants will be recruited, while in Part B (confirmatory, phase 3) 120 participants will be recruited. Part A and B are identical in schedule, structure, assessments, and conduct. 2000 mg efgartigimod PH20 SC (as two 1000 mg injections) will be given on days 1 (baseline) and 8 (week 1), and 1000 mg efgartigimod PH20 SC will be administered weekly through week 35. The primary endpoint is the proportion of participants who have been in complete remission while receiving minimal oral corticosteroid therapy for ≥8 weeks at week 26.

Binding to the neonatal Fc receptor (FcRn) extends serum half-life of IgG, and antagonizing this interaction is a promising therapeutic approach in IgG-mediated autoimmune diseases. Fc-MST-HN, designed for enhanced FcRn binding capacity, has not been evaluated in the context of a full-length antibody, and the structural properties of the attached Fab regions might affect the FcRn-mediated intracellular trafficking pathway. Here we present a comprehensive comparative analysis of the IgG salvage pathway between two full-size IgG1 variants, containing wild type and MST-HN Fc fragments, and their Fc-only counterparts. We find no evidence of Fab-regions affecting FcRn binding in cell-free assays, however, cellular assays show impaired binding of full-size IgG to FcRn, which translates into improved intracellular FcRn occupancy and intracellular accumulation of Fc-MST-HN compared to full size IgG1-MST-HN. The crystal structure of Fc-MST-HN in complex with FcRn provides a plausible explanation why the Fab disrupts the interaction only in the context of membrane-associated FcRn. Importantly, we find that Fc-MST-HN outperforms full-size IgG1-MST-HN in reducing IgG levels in cynomolgus monkeys. Collectively, our findings identify the cellular membrane context as a critical factor in FcRn biology and therapeutic targeting.

Efgartigimod (EFG) is an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor (FcRn), thereby reducing the levels of circulating immunoglobulin G (IgG), including pathogenic IgG autoantibody, levels. EFG is clinically efficacious and generally well tolerated in phase 2 and 3 trials in multiple IgG-mediated disorders. Bullous pemphigoid (BP) is an autoimmune blistering disease, characterized by subepidermal blisters and mediated by IgG autoantibodies against BP180 (type XVII collagen) and BP230, structural proteins of the dermal-epidermal junction. Administration of an EFG analogue prior to and after that of pathogenic anti-BP180 IgG antibodies in a BP mouse model demonstrated efficacy in reducing skin disease activity. EFG will be evaluated as a therapy for BP in BALLAD, a phase 2/3 randomized, double-blinded, placebo-controlled trial (NCT05267600). BALLAD will be conducted in two parts – a proof-of-concept Part A (N=40) and a confirmatory Part B (N=120). Both parts are identical in schedule, structure, assessments, and conduct. 2000 mg EFG PH20 SC will be given on days 1 and 8, and 1000 mg EFG PH20 SC will be given weekly through week 35. Oral corticosteroids starting at 0.5 mg/kg/day of prednisone will be administered to the EFG PH20 SC and placebo PH20 SC groups and adjusted to each participant's disease status. The primary endpoint is the proportion of participants in complete remission on minimal oral corticosteroid therapy (≤0.1 mg/kg/day) for ≥8 weeks at week 26. Key secondary endpoints include cumulative dose of oral corticosteroids from day 1 to week 36, change in the Bullous Pemphigoid Disease Area Index (BPDAI) score, incidence and severity of adverse events, and quality of life scores.

Efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor (FcRn), was evaluated in an open-label phase 2 adaptive trial (NCT03334058). Thirty-four mild to moderate PV or PF patients were enrolled to evaluate the safety, pharmacodynamics, pharmacokinetics, and efficacy of efgartigimod. In four sequential cohorts, efgartigimod was dosed at 10 or 25 mg/kg intravenously with various dosing frequencies, as monotherapy or add-on therapy to low-dose oral prednisone. Efgartigimod demonstrated a favorable safety and tolerability profile, consistent with previous studies of this FcRn inhibitor. We observed a strong association between serum IgG level reduction, autoantibody level reduction and improvement of pemphigus disease area index (PDAI) scores and clinical outcomes. 90% (28/31) of patients achieved disease control with a median time of 16 days. Fourteen of 22 (64%) patients on efgartigimod treatment with prednisone 0.1-0.5 mg/kg/d achieved complete remission (10 mg/kg: median 35 days, range 13-93; 25 mg/kg: 43 days, range 41-287). These results add to the interim analysis previously presented and support the further evaluation of efgartigimod as a therapy for pemphigus.

The autoimmune, blistering disease pemphigus vulgaris is caused by autoantibodies against the desmosomal cadherins, mainly desmoglein-3. Recently, it has been shown that blocking the neonatal Fc receptor (FcRn) can lead to a rapid decrease of pathogenic IgG and an improvement of various autoimmune diseases, including pemphigus, myasthenia gravis and autoimmune thrombocytopenia. Binding of IgG type antibodies to FcRn results in antibody recycling and increases the plasma half-life of pathogenic autoantibodies, contributing to disease phenotype. Compounds that block the binding of IgG to FcRn, such as efgartigimod, may be useful for the treatment of IgG-mediated autoimmune diseases. To study the pathogenic action of anti-desmoglein antibodies in vitro, mouse monoclonal anti-desmoglein-3 antibodies, especially AK23, have been developed that mimic the pathogenic effect of patient sera (PV IgG) in cultured keratinocytes. However, mouse IgG poorly binds to human FcRn. Therefore, to study the potential function of FcRn in pemphigus in human keratinocytes, we have here used chimeric AK23 anti-desmoglein-3 antibodies that contain human Fc domains. WE show that these antibodies induce changes in desmoglein-3 localization and result in acantholysis in a monolayer dissociation assay in hTert keratinocytes. Surprisingly, the effects on keratinocyte adhesion can be inhibited by blocking IgG binding to FcRn by efgartigimod. These data suggest that in keratinocytes, FcRn may play a further role in the pathogenesis of pemphigus, beyond its known contribution to IgG recycling.

Dysregulation of MET signaling has been implicated in tumorigenesis and metastasis. ARGX-111 combines complete blockade of this pathway with enhanced tumor cell killing and was investigated in 24 patients with MET-positive advanced cancers in a phase 1b study at four dose levels (0.3–10 mg/kg). ARGX-111 was well tolerated up to 3 mg/kg (MTD). Anti-tumor activity was observed in nearly half of the patients (46%) with a mean duration of treatment of 12 weeks. NHance® mutations in the Fc of ARGX-111 increased affinity for the neonatal Fc receptor (FcRn) at acidic pH, stimulating transcytosis across FcRn-expressing cells and radiolabeled ARGX-111 accumulated in lymphoid tissues, bone and liver, organs expressing FcRn at high levels in a biodistribution study using human FcRn transgenic mice. In line with this, we observed, in a patient with MET-amplified (>10 copies) gastric cancer, diminished metabolic activity in multiple metastatic lesions in lymphoid and bone tissues by 18F-FDG-PET/CT after two infusions with 0.3 mg/kg ARGX-111. When escalated to 1 mg/kg, a partial response was reached. Furthermore, decreased numbers of CTC (75%) possibly by the enhanced tumor cell killing witnessed the modes of action of the drug, warranting further clinical investigation of ARGX-111.