Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment
- 26 October 2017
- journal article
- research article
- Published by Informa UK Limited in mAbs
- Vol. 10 (1), 1-17
- https://doi.org/10.1080/19420862.2017.1389364
Abstract
Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.Keywords
This publication has 71 references indexed in Scilit:
- Protein engineering and preclinical development of a GM‐CSF receptor antibody for the treatment of rheumatoid arthritisBritish Journal of Pharmacology, 2012
- Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritisAnnals Of The Rheumatic Diseases, 2012
- Concordance of preclinical and clinical pharmacology and toxicology of monoclonal antibodies and fusion proteins: soluble targetsBritish Journal of Pharmacology, 2012
- Concordance of preclinical and clinical pharmacology and toxicology of therapeutic monoclonal antibodies and fusion proteins: cell surface targetsBritish Journal of Pharmacology, 2012
- Antibody-Mediated Inhibition of Fibroblast Growth Factor 19 Results in Increased Bile Acids Synthesis and Ileal Malabsorption of Bile Acids in Cynomolgus MonkeysToxicological Sciences, 2012
- Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T‐cellsBritish Journal of Pharmacology, 2010
- Patient-derived Granulocyte/Macrophage Colony–Stimulating Factor Autoantibodies Reproduce Pulmonary Alveolar Proteinosis in Nonhuman PrimatesAmerican Journal of Respiratory and Critical Care Medicine, 2010
- The molecular basis of pulmonary alveolar proteinosisClinical Immunology, 2010
- Immunogenicity of biologically-derived therapeutics: Assessment and interpretation of nonclinical safety studiesRegulatory Toxicology and Pharmacology, 2009
- Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory diseaseNature, 1992