Sewell Fiona, Chapman Kathryn, Couch Jessica, Dempster Maggie, Heidel Shawn, Loberg Lise, Maier Curtis, Maclachlan Timothy K, Todd Marque, van der Laan Jan Willem
a UK National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs) , London , UK.
b Genentech, Inc. , South San Francisco , CA , USA.
MAbs. 2017 Jul;9(5):742-755. doi: 10.1080/19420862.2017.1324376. Epub 2017 May 5.
The market for biotherapeutic monoclonal antibodies (mAbs) is large and is growing rapidly. However, attrition poses a significant challenge for the development of mAbs, and for biopharmaceuticals in general, with large associated costs in resource and animal use. Termination of candidate mAbs may occur due to poor translation from preclinical models to human safety. It is critical that the industry addresses this problem to maintain productivity. Though attrition poses a significant challenge for pharmaceuticals in general, there are specific challenges related to the development of antibody-based products. Due to species specificity, non-human primates (NHP) are frequently the only pharmacologically relevant species for nonclinical safety and toxicology testing for the majority of antibody-based products, and therefore, as more mAbs are developed, increased NHP use is anticipated. The integration of new and emerging in vitro and in silico technologies, e.g., cell- and tissue-based approaches, systems pharmacology and modeling, have the potential to improve the human safety prediction and the therapeutic mAb development process, while reducing and refining animal use simultaneously. In 2014, to engage in open discussion about the challenges and opportunities for the future of mAb development, a workshop was held with over 60 regulators and experts in drug development, mechanistic toxicology and emerging technologies to discuss this issue. The workshop used industry case-studies to discuss the value of the in vivo studies and identify opportunities for in vitro technologies in human safety assessment. From these and continuing discussions it is clear that there are opportunities to improve safety assessment in mAb development using non-animal technologies, potentially reducing future attrition, and there is a shared desire to reduce animal use through minimised study design and reduced numbers of studies.
生物治疗性单克隆抗体（mAb）市场规模庞大且增长迅速。然而，损耗对单克隆抗体的开发以及一般生物制药来说都是一项重大挑战，会在资源和动物使用方面带来巨大的相关成本。候选单克隆抗体的终止可能是由于从临床前模型到人体安全性的转化不佳。制药行业解决这一问题以维持生产力至关重要。尽管损耗对一般药品来说是一项重大挑战，但与基于抗体的产品开发相关存在一些特定挑战。由于物种特异性，对于大多数基于抗体的产品而言，非人类灵长类动物（NHP）通常是唯一用于非临床安全性和毒理学测试的药理学相关物种，因此，随着更多单克隆抗体的开发，预计NHP的使用将会增加。整合新出现的体外和计算机技术，例如基于细胞和组织的方法、系统药理学和建模，有潜力改善人体安全性预测和治疗性单克隆抗体的开发过程，同时减少并优化动物使用。2014年，为了就单克隆抗体开发的未来挑战与机遇展开公开讨论，举办了一次研讨会，有60多位药物开发、机制毒理学和新兴技术方面的监管人员和专家参加，以讨论这一问题。该研讨会利用行业案例研究来讨论体内研究的价值，并确定体外技术在人体安全性评估中的机遇。从这些讨论以及持续的讨论中可以清楚地看出，利用非动物技术改善单克隆抗体开发中的安全性评估存在机遇，这有可能减少未来的损耗，并且大家都有通过最小化研究设计和减少研究数量来减少动物使用的共同愿望。
