title: Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targets.
abstract: Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency 'Scientific Discussions'; and the US Food and Drug Administration 'Pharmacology/Toxicology Reviews' and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found.
authors.affiliation: Biologics Toxicology, Janssen Research & Development, division of Johnson & Johnson Pharmaceutical Research & Development, LLC, Radnor, PA 19087, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bugelski
authors.forename: Pauline L
authors.initials: PL
authors.lastname: Martin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020714:Maximum Tolerated Dose; D019055:No-Observed-Adverse-Effect Level; D010601:Pharmacology, Clinical; D011237:Predictive Value of Tests; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D012995:Solubility; D013045:Species Specificity
chemical_list: D000911:Antibodies, Monoclonal; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins