title: Genotoxicity assessment of peptide/protein-related biotherapeutics: points to consider before testing.
abstract: The ICH S6(R1) recommendations on safety evaluation of biotherapeutics have led to uncertainty in determining what would constitute a cause for concern that would require genotoxicity testing. A Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee Workgroup was formed to review the current practice of genotoxicity assessment of peptide/protein-related biotherapeutics. There are a number of properties of peptide/protein-related biotherapeutics that distinguish such products from traditional 'small molecule' drugs and need to be taken into consideration when assessing whether genotoxicity testing may be warranted and if so, how to do it appropriately. Case examples were provided by participating companies and decision trees were elaborated to determine whether and when genotoxicity evaluation is needed for peptides containing natural amino acids, non-natural amino acids and other chemical entities and for unconjugated and conjugated proteins. From a scientific point of view, there is no reason for testing peptides containing exclusively natural amino acids irrespective of the manufacturing process. If non-natural amino acids, organic linkers and other non-linker chemical components have already been tested for genotoxicity, there is no need to re-evaluate them when used in different peptide/protein-related biotherapeutics. Unless the peptides have been modified to be able to enter the cells, it is generally more appropriate to evaluate the peptides containing the non-natural amino acids and other non-linker chemical moieties in vivo where the cleavage products can be formed. For linkers, it is important to determine if exposure to reactive forms are likely to occur and from which origin. When the linkers are anticipated to be potential mutagenic impurities they should be evaluated according to ICH M7. If linkers are expected to be catabolic products, it is recommended to test the entire conjugate in vivo, as this would ensure that the relevant 'free' linker forms stemming from in vivo catabolism are tested.
authors.forename: Veronique
authors.initials: V
authors.lastname: Thybaud
authors.affiliation: Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kasper
authors.affiliation: Pfizer Inc., Worldwide Research and Development, Groton, CT, USA.
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Sobol
authors.affiliation: Novartis Institutes for Biomedical Research, Preclinical Safety, Basel, Switzerland.
authors.forename: Azeddine
authors.initials: A
authors.lastname: Elhajouji
authors.affiliation: AstraZeneca, Innovative Medicines and Early Development, Milton Science Park, Cambridge, UK.
authors.forename: Mick
authors.initials: M
authors.lastname: Fellows
authors.affiliation: F. Hoffmann-La Roche Ltd, Genetic Toxicology, Roche Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Melanie
authors.initials: M
authors.lastname: Guerard
authors.affiliation: GlaxoSmithKline, Genetic Toxicology, Ware, UK.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Lynch
authors.affiliation: Bayer HealthCare, Investigational Toxicology, Global Drug Discovery - Global Early Development, Bayer Pharma AG, Berlin, Germany and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sutter
authors.affiliation: ILSI Health and Environmental Sciences Institute (HESI), Washington, DC, USA jtanir@hesiglobal.org.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Tanir
mesh_terms: D000818:Animals; D017408:Guidelines as Topic; D006801:Humans; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000009:adverse effects / Q000633:toxicity*; D010455:Peptides / Q000009:adverse effects / Q000627:therapeutic use / Q000633:toxicity*
chemical_list: D009153:Mutagens; D010455:Peptides