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Acetaldehyde can form protein-acetaldehyde adducts (AAs) in vivo and may play a role in the genesis of alcoholic liver disease. The nature of the chemical modification of proteins by acetaldehyde in vivo has not been elucidated. In vitro, acetaldehyde can form reversible adducts including a Schiff's base with lysine (K) and imidazolidinone with terminal amino groups of proteins such as human hemoglobin (Hb). In this study, we used FAB/MS to analyze the products of peptide-AAs (pep-AAs) formed by incubating acetaldehyde with Hb peptides. We then used an octabranched multiple antigen peptide (MAP) system containing Hb peptide-AAs to raise antibodies. Three Hb peptides [i.e., 8-pep consisting of 8 residues (V1HLTPVEK8) at the N-terminus of beta-chain of human sickle-cell Hb, 11-pep-gly consisting of 11 residues (G56NPKVKAHGKK66) in a segment of beta-chain rich in lysine, and 11-pep-pro that consists of the same sequence as 11-pep-gly, except G56 was replaced by proline (P)] were incubated with 1 mM acetaldehyde at 4 degrees C for 7d without NaCNBH3 (nonreduced conditions). Analysis by FAB/MS showed that 8-pep formed an imidazolidinone at the N-terminal valine, 11-pep-gly formed a Schiff's base and imidazolidinone at the N-terminus, whereas 11-pep-pro that lacks a free alpha-amino group formed only a Schiff's base at K59. By contrast, incubation of these Hb peptides with 250 mM acetaldehyde and NaCNBH3 at 37 degrees C for 1 hr (reduced conditions) produced mono- and diethylated modifications of all available K residues, as well as the N-terminal amino group.(ABSTRACT TRUNCATED AT 250 WORDS)

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AIMSTwo phase 1 studies evaluated the pharmacokinetics (PK), safety and biological activity of tabalumab, a human monoclonal antibody against B-cell activating factor (BAFF), administered intravenously (i.v.) or subcutaneously (s.c.) in subjects with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). METHODSIn study A, subjects with RA (n = 23) or SLE (n = 6) received a single i.v. dose of tabalumab (RA 0.01, 0.04, 0.125, 0.5 RESULTSTabalumab PK were non-linear across the 0.01 to 8.0 mg kg -1 dose range. Clearance (CL) decreased from 2.9 to 0.1 l day -1 and terminal half-life (t 1/2 ) increased from about 1.6 to 25 days. Subjects with RA or SLE had similar PK. After s.c. dosing, tabalumab time to maximal concentration (t max ) was 5.5 days. Absolute bioavailability (F) was approximately 62%. Following tabalumab dosing, CD20+ B cells transiently increased from baseline followed by a progressive decrease below baseline. CONCLUSIONA single tabalumab dose administered i.v. or s.c. was well tolerated and had non-linear CL over the dose range investigated in subjects with RA and SLE. The non-linearity likely reflects target-mediated CL due to binding to BAFF. Tabalumab showed biological activity based on changes in peripheral CD20+ lymphocyte numbers in both subjects with RA and SLE. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Compounds that diminish B-cell activity are in development for treating RA and SLE.• A human monoclonal antibody (belimumab) reduces B-cell activity by neutralizing soluble B-cell activating factor (BAFF).• Tabalumab is a human monoclonal antibody that neutralizes both membrane and soluble forms of BAFF. WHAT THIS STUDY ADDS• These phase 1 studies characterized the non-linear PK of tabalumab, bioavailability after s.c. dosing, effects on B cells showing biological activity and no notable differences in PK, biological activity or safety between subjects with RA and SLE.• Tabalumab was well-tolerated and no increases in anti-tabalumab antibodies were detected post-treatment. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2016) 81 908-917 908

4982 Background: AME-133v is a humanized monoclonal antibody that was engineered to have increased affinity to CD20 and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) better than rituximab in vitro. The safety, pharmacokinetics (PK) and preliminary efficacy of AME-133v were assessed in a Phase 1/2 clinical trial in patients with previously treated follicular lymphoma (FL). The objective of this study is to characterize the pharmacokinetics (PK) of AME-133v in the target patient population. Methods: 5 dose levels of AME-133v (2, 7.5, 30, 100, and 375 mg/m2) were tested in a total of 67 patients with previously treated CD20+ FL. AME-133v was administered intravenously in four weekly infusions. Blood samples were obtained pre-dose and 1, 3–5 days after infusion 1, pre-dose and post-dose during infusions 2, 3 and 4, and 1, 5 and 9 weeks after infusion 4. The PK database (399 data points) collected from the patients was analyzed by using the nonlinear mixed-effect model (NONMEM) program. A number of covariates including demographic characteristics and the FcγRIIIa receptor genotype were evaluated for their influence on the AME-133v population PK parameters. Results: Owing to serum concentrations values falling below the limit of detection, the 2 mg/m2 dose group was not included in the analysis. The basic model selected was a two-compartment pharmacokinetic model with first-order elimination. However, a different typical value had to be determined for CL in each dose group. The typical values of V1, Q and V2 were 2.99 L, 0.94 L/day, and 3.31 L, respectively. The typical value for CL was 0.70, 0.53, 0.26, 0.27 L/day-1 for 7.5, 30, 100 and 375 mg/m2, respectively, which indicates a linearization of the elimination rate of AME-133v at doses of 100 mg/m2 and above. Inter-individual variability was moderate to high with CVs of 45.9, 34.1 and 50.0% on CL, V1 and V2, respectively. The only covariate found to influence the PK of AME-133v was BSA which explained 9.6% of the variability observed on V1. The form of the FcγRIIIa receptor was not found to have a significant effect on the PK of AME-133v. Conclusions: The PK of AME-133v were best described by a 2-compartment model. Clearance was found to be dose-dependent with a linearization of the elimination rate at doses of 100 mg/m2 and above. BSA has a statistically significant influence on V1 whereas the FcγRIIIa genotype does not seem to influence the disposition of AME-133v. Disclosures: Cronier: Eli Lilly and Comany: Employment, Equity Ownership. Off Label Use: AME-133v is an investigational agent. Radtke:Eli Lilly and Comany: Employment, Equity Ownership. Wooldridge:Eli Lilly and Company: Employment, Equity Ownership.