Considerations in assessing the developmental and reproductive toxicity potential of biopharmaceuticals

Abstract

This report discusses the principles of developmental and reproductive toxicity (DART) testing for biopharmaceuticals. Biopharmaceuticals are large‐molecular‐weight proteins or peptides produced by modern biotechnology techniques incorporating genetic engineering and hybridoma technologies. The principles of DART testing for biopharmaceuticals are similar to those for small‐molecule pharmaceuticals and in general follow the regulatory guidance outlined in International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) document S5(R2). However, because many biopharmaceuticals are species‐specific, alternate approaches may be needed to evaluate DART potential as outlined in ICH S6. For molecules that show species‐specific cross‐reactivity restricted to non‐human primates (NHP), some aspects of DART may require NHP testing. For biopharmaceuticals that are uniquely specific and only active on intended human targets or human and chimpanzee targets, surrogate molecules that cross‐react with the more traditional rodent species may need to be developed and used for DART testing. Alternatively, genetically modified transgenic animals may also need to be considered. Surrogate molecules and transgenic animals may also be considered for DART testing even if the biopharmaceutical is active in NHPs in order to reduce the use of NHPs. Because of the unique properties of biopharmaceuticals, a case‐by‐case approach is needed for DART and general toxicity evaluation, which requires consideration of specific product attributes including biochemical and biophysical characteristics, pharmacological activity, and intended clinical indication. Birth Defects Res (Part B), 33:176–203, 2009. © 2009 Wiley‐Liss, Inc.

Development in the cynomolgus macaque following administration of ustekinumab, a human anti‐il‐12/23p40 monoclonal antibody, during pregnancy and lactation

“…In order to evaluate any potential effects of ustekinumab treatment during pregnancy, it was necessary to conduct developmental studies in cynomolgus macaques. The cynomolgus macaque is a species frequently used for the non-clinical safety evaluation of human therapeutic monoclonal antibodies (Chellman et al, 2009;Martin, 2008;Martin et al, 2007Martin et al, , 2009Wehner et al, 2009). The cynomolgus macaque is physiologically and endocrinologically similar to humans (Chellman et al, 2009;Weinbauer et al, 2008a,b).…”

Preclinical development of monoclonal antibodies

“…If reproductive toxicology studies are shown to be necessary and no potential alternative options to the NHP exist (e.g., rodent with the clinical or homologous protein 33 ) the approach proposed by Jarvis et al could be undertaken. 34,35 The paper describes an 'enhanced' PPND study design, which is conducted as a single study to replace the embryo fetal development (EFD) and the traditional PPND, which have historically function and cytotoxicity.…”

Assessing Male Reproductive Toxicity during Drug Development

“…Several animal characteristics must be taken into account when selecting a species for toxicological studies in order to achieve the most similar toxic reactions to those of humans: should have a good reproductive capacity; number of animals required and associated costs; sexually mature, with the presence of semen checked prior to drug exposure; spermatogenesis of immature animals may be erroneously misinterpreted as impaired spermatogenesis; immature animals, rich in spermatogonia stem cells, could be excellent animal models for child medicines [52]; qualitative and quantitative measurements, such as hormonal levels [53], animal weight and overall health status, must be carefully examined; determine drug cell and tissue metabolism, and the pharmacological curve; define length of treatment and dose used; document late onset events such as chronic toxicity [54][55][56]. Despite the relevant importance for human diseases, experiments should also minimize animal suffering [57].…”