Sanofi and Regeneron Pharmaceuticals Inc.

IntroductionSteady-state levels of IgG in the blood of adult mice, and likely all mammals, depend on IgG catabolism mediated in part by the MHC class I-related Fc receptor, FcRn (1). FcRn also mediates vectorial transport of IgG across certain epithelial barriers. In suckling mice and rats, intestinal absorption of maternal IgG from breast milk into the systemic circulation depends on FcRn (2). In humans, maternofetal transfer of IgG across the placenta also likely depends on FcRn (3). Thus, FcRn plays critical and well-documented roles in the regulation of IgG metabolism in adults and in the acquisition of humoral immunity in early life. These effects on the physiology of IgG in vivo result from the action of FcRn as an intracellular trafficking receptor (4).FcRn has been cloned from the rat, mouse, and human. The molecule is expressed as a heterodimer composed of a glycosylated heavy (α) chain (51 kDa in rodents and 40-45 kDa in humans) associated noncovalently with β2-microglobulin (β2M) (5). Binding of IgG to FcRn requires contact between solvent-exposed peptide sequences in the CH2 and CH3 domains of IgG and the α1 and α2 domains of FcRn, together with a single contact site in β2M (6-11). A hallmark of FcRn interaction with IgG is its pH dependence, showing high-affinity binding at acidic pH (pH ≤ 6.5) and weak or no binding at neutral pH (pH ≥ 7.0) (12, 13). FcRn is the only Fcγ receptor that exhibits MHC class I structure, and the only Fcγ receptor to exhibit pH dependency in ligand binding.The function of FcRn in the intestine of suckling mice and rats has been well documented (14). In neonatal mice and rats, FcRn is expressed at high levels by intestinal epithelial cells and mediates absorption of IgG by receptor-mediated transcytosis. FcRn expression in the neonatal rodent is developmentally downregulated, resulting in nearly complete loss of intestinal FcRn at the time of weaning (15)(16)(17) The MHC class I-related Fc receptor, FcRn, mediates the intestinal absorption of maternal IgG in neonatal rodents and the transplacental transport of maternal IgG in humans by receptor-mediated transcytosis. In mice and rats, expression of FcRn in intestinal epithelial cells is limited to the suckling period. We have recently observed, however, clear expression of FcRn in the adult human intestine, suggesting a function for FcRn in intestinal IgG transport beyond neonatal life in humans. We tested this hypothesis using the polarized human intestinal T84 cell line as a model epithelium. Immunocytochemical data show that FcRn is present in T84 cells in a punctate apical pattern similar to that found in human small intestinal enterocytes. Solute flux studies show that FcRn transports IgG across T84 monolayers by receptor-mediated transcytosis. Transport is bidirectional, specific for FcRn, and dependent upon endosomal acidification. These data define a novel bidirectional mechanism of IgG transport across epithelial barriers that predicts an important effect of FcRn on IgG function in immune surveillance and host de...

Summary Background Dupilumab blocks the shared receptor component for interleukin (IL)‐4 and IL‐13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate‐to‐severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate‐to‐severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate‐to‐severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. Objectives To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. Methods We evaluated randomized placebo‐controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). Results In most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. Conclusions Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease‐related factors, including AD severity, prior conjunctivitis history and certa...

Streptococcus suis outbreak was associated with exposure to sick or dead pigs.

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