Department of Safety Assessment and Laboratory Animal Resources, Merck Research Laboratories, Merck & Co. Inc, 770 Sumneytown Pike, Mail Stop: WP45-233, PO Box 4, West Point, Pennsylvania, 19486-0004, USA.
Drug Safety Evaluation, Bristol-Myers Squibb, New Brunswick, New Jersey, USA.
AAPS J. 2018 Feb 7;20(2):28. doi: 10.1208/s12248-017-0184-3.
The development of novel therapies that can harnass the immune system to eradicate cancer is an area of intensive research. Several new biopharmaceuticals that target the immune system rather than the tumor itself have recently been approved and fundamentally transformed treatment of many cancer diseases. This success has intensified the search for new targets and modalities that could be developed as even more effective therapeutic agents either as monotherapy or in combination. While great benefits of novel immunotherapies in oncology are evident, the safety of these therapies has to also be addressed as their desired pharmacology, immune activation, can lead to "exaggerated" effects and toxicity. This review is focused on the unique challenges of the nonclinical safety assessment of monoclonal antibodies that target immune checkpoint inhibitors and costimulatory molecules. This class of molecules represents several approved drugs and many more drug candidates in clinical development, for which significant experience has been gained. Their development illustrates challenges regarding the predictivity of the animal models for assessing safety and setting starting doses for first-in-human trials as well as the translatability of nonclinical in vitro and in vivo data to the human findings. Based on learnings from the experience to date, factors to consider and novel approaches to explore are discussed to help address the unique safety issues of immuno-oncology drug development.
新型疗法的开发能够利用免疫系统来消灭癌症，这是一个研究热点。最近，一些针对免疫系统而非肿瘤本身的新型生物制药已获得批准，并从根本上改变了许多癌症疾病的治疗方法。这一成功促使人们加紧寻找新的靶点和治疗方法，以便作为单一疗法或联合疗法开发出更有效的治疗药物。虽然新型免疫疗法在肿瘤学方面的益处显而易见，但这些疗法的安全性也必须得到解决，因为它们所期望的药理学、免疫激活作用可能会导致“过度”的效果和毒性。本综述重点介绍了针对免疫检查点抑制剂和共刺激分子的靶向单克隆抗体的非临床安全性评估的独特挑战。这一类分子代表了几种已批准的药物和许多处于临床开发阶段的候选药物，在这方面已经积累了丰富的经验。它们的开发说明了在评估安全性和确定首次人体试验起始剂量方面，动物模型的预测性以及非临床体外和体内数据转化为人体研究结果的可转化性方面存在挑战。基于迄今为止的经验教训，讨论了需要考虑的因素和探索的新方法，以帮助解决免疫肿瘤学药物开发的独特安全性问题。
