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Next Generation Specificity Screening for Biotherapeutics using an Extracellular Proteome Array

使用细胞外蛋白质组阵列进行下一代生物治疗药物特异性筛选

基本信息

批准号：
10206171
负责人：
Benjamin Jacob Doranz
金额：
$ 50.24万
依托单位：
INTEGRAL MOLECULAR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206171
关键词：
Abbreviations Adopted Adverse event Antibodies Binding Biological Products Biological Response Modifier Therapy CAR T cell therapy Categories Cells Clinical Clinical Trials Clinical Trials Design Data Analyses Ensure Epitopes FDA approved Failure Funding Gene Chips Human Human Resources In Vitro Industry Investigational Drugs Link Measures Membrane Membrane Proteins Methodology Methods Molecular Molecular Conformation Monoclonal Antibodies Patients Pharmaceutical Preparations Phase Phase II Clinical Trials Plasmids Process Production Protein Array Proteins Proteome Public Health Reporting Reproducibility Research Risk Safety Serious Adverse Event Services Small Business Innovation Research Grant Specificity Technology Testing Therapeutic Therapeutic Monoclonal Antibodies Time TimeLine Tissues Toxicology Validation chimeric antigen receptor T cells clinical development cross reactivity data integrity extracellular human disease improved innovation interest lead candidate new technology next generation novel strategies pre-clinical preclinical development preclinical trial predictive test programs protein expression quality assurance screening side effect therapeutic candidate therapeutic development tool

项目摘要

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.

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药物的特异性较差，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。