Current factor VIII (FVIII) products display a half-life (t 1/2 ) of ϳ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG 1 to extend circulating rFVIII t 1/2 . This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54-to 1.70-fold longer elimination t 1/2 , 1.49-to 1.56-fold lower clearance, and 1.48-to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ϳ 1.53-to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377. (Blood. 2012;119(13):3031-3037)

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Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine the potential for reduced frequency of dosing. rFVIIIFc has an ϳ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5-to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation. (Blood. 2012;119(13):3024-3030) IntroductionHemophilia A is an X-linked bleeding disorder caused by deficiency of factor VIII (FVIII) activity. 1 The disease is characterized by spontaneous hemorrhage and excessive bleeding after trauma. Over time, repeated bleeding into muscles and joints, which begins in early childhood, results in hemophilic arthropathy and irreversible joint damage. This damage is progressive and leads to pronounced musculoskeletal morbidity. 1 Prophylaxis significantly reduces joint damage and long-term sequelae, and improves quality of life in comparison to on-demand treatment. 2,3 However, the short half-life (10-12 hours) of FVIII necessitates dosing every other day or 3 times per week by IV injection for full prophylaxis. 2,4,5 Therefore, a longer-acting FVIII would represent a key advancement in the management of hemophilia A.We have developed a recombinant factor VIII-Fc (rFVIIIFc) fusion protein to extend the half-life of FVIII by leveraging a naturally occurring biologic pathway. rFVIIIFc is a heterodimeric protein comprising a single B-domain-deleted (BDD) FVIII linked recombinantly to the Fc domain of human IgG1 (IgG1). The Fc domain enables binding to the neonatal Fc receptor (FcRn), which is responsible for protection of IgG from degradation and facilitates its recycling, 6,7 resulting in a half-life for IgG of ϳ 3 weeks in humans. The Fc domain of IgG1 has been fused to growth factors, cytokines, enzymes, and ligand-binding regions of receptors [8][9][10] ; several of these fusion proteins have been approved as therapeutics (eg, etanercept, abatacept, belatacept, alefacept, rilonacept, aflibercept, and romiplostim). However, traditional dimeric Fc fusions, created through the fusion of the monomeric effector p...

Gas sensors based upon semiconductor metal oxides provide for the safe detection of toxic gases, such as carbon monoxide in households, natural gas in coal mines, and ethanol in fermentation processes. However, they still suffer from several limitations, such as long-term response reproducibility and gas sensitivity and selectivity. The need for thermally stable gas sensor materials that possess ultrahigh sensitivity and selectivity, often in the presence of other adsorbing gases, presents a major challenge. In this work, we have synthesized tin-indium oxide (SnO 2 -In 2 O 3 ) nanocomposites that exhibited superior thermal stability against grain growth. Through the introduction of metal clusters and oxide surface coatings, the SnO 2 -In 2 O 3 nanocomposites achieved superb sensitivity for both reducing and oxidizing gases. Our synthesis method provided an inexpensive and flexible wet-chemical route toward tailoring semiconductor metal oxide nanocomposites for the selective and reproducible detection of toxic or combustible gases at parts per million levels.