Pharmacokinetics and Pharmacodynamics of JNJ-55920839, an Antibody Targeting Interferon α/ω, in Healthy Subjects and Subjects with Mild-to-Moderate Systemic Lupus Erythematosus.

BACKGROUND: The interferon (IFN) pathway has been correlated with clinical and serological markers of disease activity in patients with systemic lupus erythematosus (SLE). OBJECTIVE: The pharmacokinetics and pharmacodynamics of JNJ-55920839, a fully human immunoglobulin G1κ antibody targeting IFNα/ω, were investigated. METHODS: In a double-blind, first-in-human study, Part A enrolled 48 healthy adults who received a single dose of placebo/JNJ-55920839 between 0.3 and 15 mg/kg intravenous (IV) or at 1 mg/kg subcutaneous (SC). Part B enrolled 26 adults with SLE who received placebo or JNJ-55920839 10 mg/kg IV 6 times biweekly. Pharmacokinetic parameters were calculated by noncompartmental analysis (NCA) and estimated by nonlinear mixed-effects modeling. RESULTS: JNJ-55920839 pharmacokinetics following a single IV infusion exhibited a biphasic disposition in healthy subjects. Maximum plasma concentration (Cmax) and area under the concentration-time curve values increased dose-proportionally. Mean clearance (CL) after a single IV infusion ranged between 2.28 and 3.09 mL/kg/day. Absolute bioavailability after a single SC injection was ≥ 80.0%. Mean terminal elimination half-life (t1/2) was similar after IV (20.7 to 24.6 days) and SC administration (22.6 days). Steady state of JNJ-55920839 was achieved 6 weeks after multiple 10 mg/kg IV doses in subjects with SLE. Mean steady-state CL and t1/2 were 4.73 mL/kg/day and 14.8 days, respectively. A linear 2-compartment population pharmacokinetic model with 1st-order absorption and elimination adequately characterized the pharmacokinetics; parameters were consistent with NCA estimates. Higher CL was estimated in subjects with SLE compared with healthy subjects, after correcting for body weight. A trend of increased total IFNα/ω levels was observed after treatment with JNJ-55920839. CONCLUSION: Pharmacokinetic and pharmacodynamic analyses of the data from this study demonstrated that there was biphasic disposition in both healthy subjects and subjects with SLE, CL was faster in subjects with SLE, and increases in total IFNα/ω levels were observed in both healthy subjects and subjects with SLE after treatment with JNJ-55920839, thus further development is supported. The study is registered at ClinicalTrials.gov NCT02609789.

Loop-loop interactions govern multiple steps in indole-3-glycerol phosphate synthase catalysis.

Substrate binding, product release, and likely chemical catalysis in the tryptophan biosynthetic enzyme indole-3-glycerol phosphate synthase (IGPS) are dependent on the structural dynamics of the ß1α1 active-site loop. Statistical coupling analysis and molecular dynamic simulations had previously indicated that covarying residues in the ß1α1 and ß2α2 loops, corresponding to Arg54 and Asn90, respectively, in the Sulfolobus sulfataricus enzyme (ssIGPS), are likely important for coordinating functional motions of these loops. To test this hypothesis, we characterized site mutants at these positions for changes in catalytic function, protein stability and structural dynamics for the thermophilic ssIGPS enzyme. Although there were only modest changes in the overall steady-state kinetic parameters, solvent viscosity and solvent deuterium kinetic isotope effects indicated that these amino acid substitutions change the identity of the rate-determining step across multiple temperatures. Surprisingly, the N90A substitution had a dramatic effect on the general acid/base catalysis of the dehydration step, as indicated by the loss of the descending limb in the pH rate profile, which we had previously assigned to Lys53 on the ß1α1 loop. These changes in enzyme function are accompanied with a quenching of ps-ns and µs-ms timescale motions in the ß1α1 loop as measured by nuclear magnetic resonance studies. Altogether, our studies provide structural, dynamic and functional rationales for the coevolution of residues on the ß1α1 and ß2α2 loops, and highlight the multiple roles that the ß1α1 loop plays in IGPS catalysis. Thus, substitution of covarying residues in the active-site ß1α1 and ß2α2 loops of indole-3-glycerol phosphate synthase results in functional, structural, and dynamic changes, highlighting the multiple roles that the ß1α1 loop plays in enzyme catalysis and the importance of regulating the structural dynamics of this loop through noncovalent interactions with nearby structural elements.