title: Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targets.
abstract: Monoclonal antibodies (mAbs) and fusion proteins directed towards soluble 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 14 currently approved mAbs and fusion proteins targeted to soluble targets. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency 'Scientific Discussions' and United States Food and Drug Administration 'Pharmacology/Toxicology Reviews' and package inserts (United States Prescribing Information). Data on the following approved biopharmaceuticals were included: adalimumab, anakinra, bevacizumab, canakinumab, certolizumab pegol, denosumab, eculizumab, etanercept, golimumab, infliximab, omalizumab, ranibizumab, rilonacept and ustekinumab. Some related biopharmaceuticals in late-stage development were also included for comparison. Good concordance with human pharmacodynamics was found for both non-human primates (NHPs) receiving the human biopharmaceutical and mice receiving rodent homologues (surrogates). In contrast, there was limited concordance for human adverse effects in genetically deficient mice, mice receiving surrogates or NHPs receiving the human pharmaceutical. In summary, the results of this survey show that although both mice and NHPs have good predictive value for human pharmacodynamics, neither species have good predictive value for human adverse effects. No evidence that NHPs have superior predictive value was found.
authors.affiliation: Biologics Toxicology, Janssen Research & Development, Radnor, PA 19087, USA. pmarti27@its.jnj.com
authors.forename: Pauline L
authors.initials: PL
authors.lastname: Martin
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bugelski
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; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity*; D012995:Solubility; D013045:Species Specificity
chemical_list: D000911:Antibodies, Monoclonal; D011993:Recombinant Fusion Proteins