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Integrated Pharmacokinetic/Pharmacodynamic Analysis for Determining the Minimal Anticipated Biological Effect Level of a Novel Anti-CD28 Receptor Antagonist BMS-931699.
J Pharmacol Exp Ther
December 2015
Department of Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization (Z.Y., H.W, A.D.R., B.D.C., and P.H.M.), Department of Exploratory Clinical and Translational Research (C.A.F., R.S., S.X.Y.Z.), Department of Protein Structures and Sciences (L.A.S.), Department of Immunology Discovery (S.J.S., J.H.X., and S.G.N.), Department of Bioanalytical Sciences (J.D.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Drug Safety Evaluation (T.W.S.), Bristol-Myers Squibb Research and Development, New Brunswick, New Jersey.
BMS-931699 (lulizumab pegol), a domain antibody (dAb) conjugated with 40-kDa branched polyethylene glycol, is a human anti-CD28 receptor antagonist under development for the treatment of inflammatory and autoimmune diseases. In the present work, the minimal anticipated biologic effect level (MABEL) was determined for BMS-931699 by integrating all the available preclinical data. The relevance of the in vitro mixed lymphocyte reaction (MLR) assay to a whole blood CD28 receptor occupancy (RO) assessment, as well as the relationship between the CD28 RO and the inhibition of T-cell-dependent antibody response to keyhole limpet hemocyanin in vivo, was demonstrated through an integrated pharmacokinetic/pharmacodynamic analysis using anti-hCD28 dAb-001 (differing from BMS-931699 by two additional amino acids at the N-terminus) and a mouse surrogate.
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