title: Integrated Pharmacokinetic/Pharmacodynamic Analysis for Determining the Minimal Anticipated Biological Effect Level of a Novel Anti-CD28 Receptor Antagonist BMS-931699.
abstract: 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. Based on this analysis, the EC10 value (0.32 nM) from the human MLR assay and the human plasma volume (0.04 l/kg) were employed to calculate the MABEL (0.01 mg) of BMS-931699 in humans, with a CD28 RO predicted to be ≤10%. The estimated MABEL dose was threefold higher than the value derived from the binding constant and twofold less than the MABEL converted from animal efficacy studies based on the body surface area. Furthermore, it was 2900-fold lower than the human equivalent dose derived from the no observed adverse effect level in monkeys (15 mg/kg/week for 5 doses, intravenous dosing) with a 10-fold safety factor applied. Therefore, the MABEL dose represented a sound approach to mitigate any potential risk in targeting CD28 and was successfully used as the first-in-human starting dose for BMS-931699.
authors.affiliation: 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 zheng.yang@bms.com.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Haiqing
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Theodora W
authors.initials: TW
authors.lastname: Salcedo
authors.affiliation: 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.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Suchard
authors.affiliation: 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.
authors.forename: Jenny H
authors.initials: JH
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Lumelle A
authors.initials: LA
authors.lastname: Schneeweis
authors.affiliation: 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.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Fleener
authors.affiliation: 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.
authors.forename: James D
authors.initials: JD
authors.lastname: Calore
authors.affiliation: 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.
authors.forename: Rong
authors.initials: R
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Sean X Y
authors.initials: SX
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
authors.affiliation: 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.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Car
authors.affiliation: 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.
authors.forename: Punit H
authors.initials: PH
authors.lastname: Marathe
authors.affiliation: 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.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Nadler
mesh_terms: D000465:Algorithms; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001830:Body Surface Area; D018106:CD28 Antigens / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006433:Hemocyanins / Q000037:antagonists & inhibitors; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000187:drug effects; D011092:Polyethylene Glycols / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D018106:CD28 Antigens; D011092:Polyethylene Glycols; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin; C000604694:lulizumab pegol