Industry experiences with immune-mediated findings in biotherapeutic nonclinical toxicology studies

• Published in: Regulatory toxicology and pharmacology 2021-02, Vol.119, p.104825, Article 104825
• Main Authors: MacLachlan, Timothy K., Kronenberg, Sven, Marshall, Nikki, Andrews, Laura, Berens, Shawn Jay, Brouta, Frederic, Fogal, Birgit, Freebern, Wendy, Herzyk, Danuta, Kamperschroer, Cris, Kiessling, Andrea, Schneidkraut, Marlowe, Maier, Curtis
• Format: Article
• Language: English
• Subjects: Adverse; Allergic reaction; Antibody; Autoimmune; Biotherapeutic; Hypersensitivity; Immune complex; Immune responses; Immunogenicity; Non-human primate
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2020.104825

With the growth of monoclonal antibodies and other proteins as major modalities in the pharmaceutical industry, there has been an increase in pharmacology and toxicity testing of biotherapeutics in animals. Animals frequently mount an immune response to human therapeutic proteins. This can result in asymptomatic anti-drug antibody formation, immune complexes that affect drug disposition and/or organ function such as kidney, cytokine release responses, fatal hypersensitivity, or a range of reactions in between. In addition, an increasing number of oncology therapeutics are being developed that enhance or directly stimulate immune responses by a variety of mechanisms, which could increase the risk of autoreactivity and an autoimmune-like syndrome in animals and humans. When evaluating the risk of biotherapeutics prior to entering the clinic, the nonclinical safety data may include any of these responses and it is critical to understand whether they represent a safety liability for humans. The DruSafe Leadership group of the IQ Consortium conducted a survey of industry to understand sponsors' experiences with these immune reactions in nonclinical studies related to both immunogenicity and pharmacologically-mediated immune perturbations. The survey covered what pathways were affected, how the immune responses were presented, how the company and health authorities interpreted the data and whether the immune responses were observed in the clinic. Additionally, the survey gathered information on association of these findings with anti-drug antibodies as well as sponsor's use of immunogenicity predictive tools. The data suggests that the ability of a biotherapeutic to activate the immune system, intended or not, plays a significant role on characteristics of the response and whether theys are translatable. •Dosing biologics in animals may result in toxicological immune responses.•We conducted a survey assessing animal immune reactions and regulatory strategy.•Findings can be attributed to anti-drug antibodies (ADAs) and/or pharmacology.•Often, health authorities did not comment on NOAELs or request changes in starting doses.•Nonclinical findings attributed to ADAs were not translatable to clinical experience.