title: The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies.
abstract: Dose selection for first-in-human (FIH) clinical trials with monoclonal antibodies (mAbs) is based on specifically designed preclinical pharmacology and toxicology studies, mechanistic ex vivo/in vitro investigations with human and animal cells and pharmacokinetic/pharmacodynamic (PK/PD) modeling approaches and requires a thorough understanding of the biology of the target and the relative binding and pharmacological activity of the mAb in animals and humans. These investigations provide the essential information required for the selection of a safe starting dose and escalation for FIH trials based on toxicology and pharmacology data and the minimal anticipated biological effect level (MABEL) by integrating all available in vivo and in vitro data. In this review, strategies for estimation of the MABEL for mAbs specific for both membrane and soluble targets are presented and the scientific and regulatory challenges highlighted.
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland. patrick.mueller@novartis.com
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Muller
authors.forename: Mark
authors.initials: M
authors.lastname: Milton
authors.forename: Peter
authors.initials: P
authors.lastname: Lloyd
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sims
authors.forename: Frank R
authors.initials: FR
authors.lastname: Brennan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry*; D001702:Biopharmaceutics / Q000379:methods; D002462:Cell Membrane; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage*; D008954:Models, Biological; D008962:Models, Theoretical; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D012107:Research Design
chemical_list: D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D004364:Pharmaceutical Preparations