Next Generation Specificity Screening for Biotherapeutics using an Extracellular Proteome Array

摘要 详细的特异性分析对药物至关重要，因为即使是最小的脱靶结合也可能导致严重的不良反应。 事件因此，特异性分析已成为FDA对单克隆抗体（MAb）的要求， 以及其他新兴的生物疗法类别，如CAR-T细胞疗法。目前的分析方法 生物治疗的特异性，主要是组织交叉反应性研究和斑点蛋白阵列， 预测针对天然人蛋白质组的交叉反应性，具有低灵敏度，并且难以 翻译。需要一种新的特异性分析方法来更好地预测MAb的脱靶结合， 风险生物多样性发现计划。在这里，我们建议开发一种技术， 降低进入临床前开发的生物治疗药物风险的有效性。该产品将对 几乎每个生物制药公司的临床管道，具有巨大的商业潜力， 以极低的风险实施。由此产生的产品将是体外毒理学的第一个重大创新 自35年前采用组织交叉反应性研究以来，生物治疗药物的检测一直是一个热门话题。

ABSTRACT Detailed specificity analysis is critical for drugs, as even minimal off-target binding can cause serious adverse events. As a result, specificity profiling has become an FDA requirement for monoclonal antibodies (MAbs) as well as other emerging biotherapeutic categories such as CAR-T cell therapy. Current methods for profiling the specificity of biotherapeutics, primarily tissue cross-reactivity studies and spotted protein arrays, are poorly predictive of cross-reactivity against the native human proteome, have low sensitivity, and are difficult to interpret. A novel approach for specificity profiling is needed to better predict off-target binding of MAbs and de- risk biotherapeutic discovery programs. Here we propose to develop a technology that has the predictive validity to de-risk biotherapeutics entering preclinical development. This product would have a large impact on the clinical pipelines of nearly every biopharmaceutical company, has significant commercial potential, and can be implemented with very low risk. The resulting product will be the first major innovation in in vitro toxicology testing for biotherapeutics since tissue cross-reactivity studies were adopted 35+ years ago.