Bevifimod

The loading characteristics of recombinant Staphyloccocus aureus protein A (rSPA) on polypropylene (PP) capillary-channeled polymer (C-CP) fibers were investigated through breakthrough curves and frontal analysis. The dynamic adsorption data was fit to various isotherm models to assess the possible mode of rSPA-PP fiber adsorption. Among them, the Langmuir-linear model fit the experimental data best, suggesting a two-stage mechanism of adsorption. The first stage involves the formation of a monolayer coverage, which follows the Langmuir isotherm. When the adsorbate concentration increases, solute starts to adsorb onto the already adsorbed layer, following a linear adsorption response. The relationship between the rSPA loading and flow rate and column length was also investigated. These two parameters are related through the residence time of rSPA in the column. It was determined that loading at the flow rate of 0.5 mL min(-1) (∼28 mm s(-1)) with a 1×10(-5) M (0.5 mg mL(-1)) rSPA feed concentration on a 30-cm (0.762 mm i.d.) column could conveniently produce a reasonable binding capacity of rSPA on PP surface within only 6 min. Under those conditions, the rSPA binding at 50% breakthrough was found to be ∼2.1 mg g(-1) fiber. Operation of the rSPA-modified columns across ten complete processing cycles using clean-in-place conditions (including urea, guanidine HCl, and NaOH) commonly used in the bioprocessing industry allows assessment of the robustness of the rSPA capture layers. In all cases, the robustness was quite good, with the relative responses providing insights to the rSPA/PP surface structure.

Three Good Laboratory Practice safety studies were performed with intravenous injections of highly purified staphylococcal protein A (SPA) in cynomolgus monkeys, in support of a clinical development programme utilizing this protein as an immunomodulator. These studies established a no‐observable‐adverse‐effect level (NOAEL) for up to 12 weekly doses of SPA, as well as toxicokinetic profiles for SPA, evaluation of antiproduct antibodies and biomarkers to better characterize the pharmacodynamic response to SPA. Biomarkers included neopterin, C‐reactive protein (CRP), troponin I and the change in the blood absolute lymphocyte count (ALC) 24 hr after SPA dosing. The transient decrease in ALC noted at 24 hr after dosing was similar to that seen in human Phase 1 trials. The majority of active‐treated monkeys developed antibodies against SPA. Cmax was not affected by development of antidrug antibodies (ADAs), and after the first dose was 87 (SD 19) ng/mL, 330 (SD 84) ng/mL and 1191 (SD 208) ng/mL for 5, 25 and 100 μg/kg doses, respectively. The development of ADAs increased plasma clearance of SPA. By the sixth weekly dose, the AUC was decreased by 76%, 54% and 66% for the 5, 25 and 100 μg/kg dose groups, respectively. These results indicate that SPA can be administered intravenously to non‐human primates without observable toxicity at weekly doses of up to 100 μg/kg.