Next Generation Specificity Screening for Biotherapeutics using an Extracellular Proteome Array

摘要 详细的特异性分析对药物来说至关重要，因为即使是最小的脱靶结合也会导致严重的不良反应 事件。因此，特异性分析已成为FDA对单抗(MAb)的要求，因为 以及其他新兴的生物治疗类别，如CAR-T细胞疗法。当前的分析方法 生物疗法的特异性很差，主要是组织交叉反应研究和斑点蛋白质阵列。 预测与天然人类蛋白质组的交叉反应，灵敏度低，很难 翻译一下。需要一种新的特异性分析方法来更好地预测单抗和去靶标结合。 风险生物治疗发现计划。在这里，我们建议开发一种具有预测能力的技术 去风险生物疗法进入临床前开发的有效性。这一产品将对 几乎每一家生物制药公司的临床流水线，都具有巨大的商业潜力，并且可以 以非常低的风险实施。由此产生的产品将是体外毒理学的第一个重大创新。 自从组织交叉反应研究在35年前被采用以来，生物疗法的测试。

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.