Braun Armin, Dehmel Susann
Department for Preclinical Pharmacology and Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hanover, Germany.
Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hanover, Germany.
J Immunotoxicol. 2024 Oct;21(sup1):S96-S98. doi: 10.1080/1547691X.2024.2390920. Epub 2024 Dec 10.
The chances and opportunities in modern biology inspired devising new therapeutics are mind blowing. The promises reach from successfully treating so-far incurable diseases like cancer and certain infections, to modulating and fine tuning the immune response to prolong the lifespan by inhibiting aging. However, as underlying therapies become more and more complex and sophisticated, it becomes increasingly difficult to find ways to ensure and predict the safety of these new therapeutics. The ICH guideline S6 (R1) from June 2011 EMA/CHMP/ICH/731268/ 1998 Committee for Medicinal Products for Human Use (CHMP) already stated "Conventional approaches to toxicity testing of pharmaceuticals may not be appropriate for biopharmaceuticals due to the unique and diverse structural and biological properties of the latter that may include species specificity, immunogenicity, and unpredicted pleiotropic activities" and is committed to a "flexible, case-by-case, science-based approach to preclinical safety evaluation". Initial approaches to this are described in the OECD Test Guidelines for new approach methods (NAM) with the newest update released in 2023 and alternative non-animal test guidelines (https://www.icapo.org/test-guidelines) provided from the International Council on Animal Protection in OECD Programmes (ICAPO; https://www.icapo.org). Beyond that, the European Union-funded innovative medicine initiative project Immune Safety Avatar (imSAVAR) decided to develop a systematic and holistic framework for non-clinical safety assessment of biopharmaceuticals and Advanced Therapy Medicinal Products (ATMP); thereby, the consortium focuses on immuno-regulatory therapeutics. Science-based approaches, such as the mechanistic description of adverse outcomes would be essential to demonstrate the safety of a particular new immuno-therapeutic agent. Here, we re-use the concept of adverse outcome pathways (AOP) to capture immune-related adverse outcomes (irAO), which are aimed to guide us to the use of relevant test systems and experiments. Thus, the focus within imSAVAR is on the use and (further) develop-ment of human and alternative models.
现代生物学中激发新型疗法设计的机遇令人惊叹。其前景涵盖从成功治疗诸如癌症和某些感染等迄今无法治愈的疾病，到通过抑制衰老来调节和微调免疫反应以延长寿命。然而，随着基础疗法变得越来越复杂和精细，找到确保和预测这些新型疗法安全性的方法变得越来越困难。人用药品委员会（CHMP）于2011年6月发布的ICH指南S6（R1）（EMA/CHMP/ICH/731268/1998）已经指出，“由于生物制药具有独特且多样的结构和生物学特性，可能包括物种特异性、免疫原性和不可预测的多效性活动，传统的药物毒性测试方法可能不适用于生物制药”，并致力于采用“灵活的、逐案的、基于科学的临床前安全性评估方法”。经合组织（OECD）新方法（NAM）测试指南中描述了对此的初步方法，其最新更新于2023年发布，以及经合组织项目中的国际动物保护理事会（ICAPO；https://www.icapo.org）提供的替代非动物测试指南（https://www.icapo.org/test-guidelines）。除此之外，欧盟资助的创新药物倡议项目免疫安全阿凡达（imSAVAR）决定为生物制药和高级治疗药物产品（ATMP）的非临床安全性评估制定一个系统且全面的框架；因此，该联盟专注于免疫调节疗法。基于科学的方法，如对不良后果的机制描述，对于证明特定新型免疫治疗药物的安全性至关重要。在此，我们重新运用不良后果途径（AOP）的概念来捕捉免疫相关不良后果（irAO），旨在引导我们使用相关测试系统和实验。因此，imSAVAR的重点在于人类和替代模型的使用及（进一步）开发。
