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F-652 is a recombinant fusion protein consisting of two human interleukin-22 (IL-22) molecules linked to an immunoglobulin constant region (IgG-Fc). IL-22 plays critical roles in promoting tissue repair and suppressing bacterial infection. The safety, pharmacokinetics (PK), tolerability, and biomarkers of F-652 were evaluated following a single dose in healthy male volunteers in a randomized, double-blind, placebo-controlled study. Following single-dose subcutaneous (SC) injection of F-652 at 2.0 µg/kg into healthy subjects, six out of six subjects experienced delayed injection site reactions, which presented as erythematous and/or discoid eczematous lesions 10 to 17 days post-dosing. F-652 was then administered to the healthy subjects via an intravenous (IV) infusion at 2.0, 10, 30, and 45 µg/kg. No severe adverse event (SAE) was observed during the study. Among the IV-dosed cohorts, eye and skin treatment emergent adverse events (TEAEs) were observed in the 30 and 45 µg/kg cohorts. F-652 IV dosing resulted in linear increases in C and AUC, and the T ranged from 39.4 to 206 h in the cohorts. An IV injection of F-652 induced dose-dependent increases in serum marker serum amyloid A, C-reactive protein, and FIB, and decreased serum triglycerides. The serum levels of 36 common pro-inflammatory cytokines/chemokines were not altered by the treatment of F-652 at 45 μg/kg. In conclusion, IV administration of F-652 to healthy male volunteers is safe and well-tolerated and demonstrates favorable PK and pharmacodynamic properties. These results warrant further clinical development of F-652 to treat inflammatory diseases.

The fermentation kinetics of acetic acid production from fructose by Clostridium formicoaceticum was studied at pH 7.6 and 37 degreesC. Recycle batch, fed-batch, and continuous fermentations using immobilized cells in a fibrous-bed bioreactor were studied for their potential application in producing acetic acid from fructose, a fermentable sugar commonly found in corn steep liquor and many other food processing wastes. For the immobilized cell fermentation, acetic acid yield from fructose was approximately 1.0 g/g, with a final acetate concentration of approximately 78 g/L and the overall reactor productivity (based on the fibrous bed bioreactor volume) of approximately 0.95 g/(L.h) in the fed-batch fermentation. For a similar fed-batch fermentation with free cells, acetic acid yield was approximately 0.9 g/g, the highest final acetate concentration was approximately 46 g/L, and the overall productivity was approximately 0.12 g/(L.h). In the continuous fermentation with immobilized cells, the reactor productivity decreased from 3.2 to 1. 3 g/(L.h) as retention time increased from 16 to 72 h to reach 100% conversion. Compared to free-cell fermentations, the superior performance of the fibrous-bed bioreactor can be attributed to the high density (>30 g/L) of viable cells immobilized in the fibrous bed. The fermentation product, acetic acid, was found to be a noncompetitive inhibitor to the cells. However, the immobilized cells had a higher maximum production rate (pmax) and a higher value for the inhibition rate constant (Kp) than those for the free cells, suggesting that the immobilized cells in the fibrous-bed bioreactor were less sensitive to acetic acid inhibition than the free cells. This improvement in kinetic behaviors for immobilized cells confirms that the fibrous-bed bioreactor can be used as an effective tool for adapting and screening for acetate-tolerant strains.

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