The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.
The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood. Here we demonstrate that mice with global or liver-specific FcRn deletion exhibit hypoalbuminemia, albumin loss into the bile, and increased albumin levels in the hepatocyte. In vitro models with polarized cells illustrate that FcRn mediates basal recycling and bidirectional transcytosis of albumin and uniquely determines the physiologic release of newly synthesized albumin into the basal milieu. These properties allow hepatic FcRn to mediate albumin delivery and maintenance in the circulation, but they also enhance sensitivity to the albumin-bound hepatotoxin, acetaminophen (APAP). As such, global or liver-specific deletion of FcRn results in resistance to APAP-induced liver injury through increased albumin loss into the bile and increased intracellular albumin scavenging of reactive oxygen species. Further, protection from injury is achieved by pharmacologic blockade of FcRn-albumin interactions with monoclonal antibodies or peptide mimetics, which cause hypoalbuminemia, biliary loss of albumin, and increased intracellular accumulation of albumin in the hepatocyte. Together, these studies demonstrate that the main function of hepatic FcRn is to direct albumin into the circulation, thereby also increasing hepatocyte sensitivity to toxicity.
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Thromboembolism complicates disorders caused by immunoglobulin G (IgG)–containing immune complexes (ICs), but the underlying mechanisms are incompletely understood. Prior evidence indicates that induction of tissue factor (TF) on monocytes, a pivotal step in the initiation, localization, and propagation of coagulation by ICs, is mediated through Fcγ receptor IIa (FcγRIIa); however, the involvement of other receptors has not been investigated in detail. The neonatal Fc receptor (FcRn) that mediates IgG and albumin recycling also participates in cellular responses to IgG-containing ICs. Here we asked whether FcRn is also involved in the induction of TF-dependent factor Xa (FXa) activity by IgG-containing ICs by THP-1 monocytic cells and human monocytes. Induction of FXa activity by ICs containing IgG antibodies to platelet factor 4 (PF4) involved in heparin-induced thrombocytopenia (HIT), β-2-glycoprotein-1 implicated in antiphospholipid syndrome, or red blood cells coated with anti-(α)-Rh(D) antibodies that mediate hemolysis in vivo was inhibited by a humanized monoclonal antibody (mAb) that blocks IgG binding to human FcRn. IgG-containing ICs that bind to FcγR and FcRn induced FXa activity, whereas IgG-containing ICs with an Fc engineered to be unable to engage FcRn did not. Infusion of an α-FcRn mAb prevented fibrin deposition after microvascular injury in a murine model of HIT in which human FcγRIIa was expressed as a transgene. These data implicate FcRn in TF-dependent FXa activity induced by soluble and cell-associated IgG-containing ICs. Antibodies to FcRn, now in clinical trials in warm autoimmune hemolytic anemia to lower IgG antibodies and IgG containing ICs may also reduce the risk of venous thromboembolism.
In pemphigus foliaceus (PF) and pemphigus vulgaris (PV) IgG autoantibodies to desmogleins (Dsg) 1 and 3 lead to acantholysis, causing painful cutaneous and/or mucosal lesions. The neonatal crystallizable fragment receptor (FcRn) binds to IgG and circulating immune complexes (CIC) at acid pH to regulate their half-life and inflammatory activity. SYNT001 is a humanized IgG4 monoclonal antibody optimized to inhibit FcRn function at low pH. SYNT001-103 (NCT03075904) is an ongoing, open-label phase 1b study evaluating safety and clinical effect of SYNT001 in PV or PF. Up to 3 cohorts (N¼8 subjects each) assessing 5 weekly doses 45 mg/kg SYNT001 IV are planned. Primary objective is safety; secondary objectives include pharmacodynamics and clinical response. Follow-up is through Day 112. The study is approved by each sites IRB; all subjects provide written informed consent. As of 12/31/2017, 3 subjects (2 PV, 1 PF) were enrolled in Cohort 1 (10 mg/kg). All completed 5 doses of SYNT001 and were in varying stages of follow-up. Two subjects had treatmentrelated mild-to-moderate headache after Dose 1 only. The 3rd subject had a transient urticarial infusion reaction after doses 4 and 5 responsive to diphenhydramine. By wDay 30 1 PV subject had decreases of 48% in total IgG, 63% CIC, 30% anti-Dsg1 titer and 40% anti-Dsg3. Pemphigus Disease Area Index (PDAI) was 47 at baseline, 38 on Day 14 and a low of 15 on Day 28. By wDay 30 the other PV subject had decreases of 59% in IgG, 48% CIC, 64% anti-Dsg1 and 61% anti-Dsg3. PDAI was 19 at baseline, 12 on Day 7 and a low of 9 on Day 33. By wDay 30, the PF subject had decreases of 65% in IgG, 47% CIC and 32% anti-Dsg1; Dsg3 was negative. PDAI was 9 at baseline and a low of 7 on Day 21. These interim data show SYNT001 is well tolerated in PV and PF. This first-in-human study in pemphigus provides initial proof-of-concept for anti-FcRn treatment with SYNT001 in this disorder. Patient-Oriented Eczema Measure (POEM) is the preferred patient-reported outcome (PRO) measure to assess atopic dermatitis (AD) symptoms. Dermatology Life Quality Index (DLQI) is a commonly used PRO to assess the burden of skin disease. Previous severity strata were developed for POEM and DLQI in clinical cohorts, which may be biased toward more severe disease. Severity strata were not previously examined in population-based cohorts. Patient-Oriented Scoring AD (PO-SCORAD) is another commonly used PRO for assessing the symptoms of AD, yet severity strata are not established. We sought to confirm previously developed strata for POEM and DLQI, and develop strata for the PO-SCORAD in a population-based cohort of adults with AD. A cross-sectional, population-based study of 8,217 adults was performed using a structured questionnaire. A diagnosis of AD was determined using modified UK Diagnostic Criteria for AD (N¼602). AD severity was assessed using self-reported global AD severity (anchoring question), POEM, PO-SCORAD, and DLQI. Strata were selected using an anchoring approach based on patient-reported disease severit...
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