Implementation of a three-tiered approach to identify and characterize anti-drug antibodies raised against HIV-specific broadly neutralizing antibodies
Implementation of a three-tiered approach to identify and characterize anti-drug antibodies raised against HIV-specific broadly neutralizing antibodies
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DOI：
10.1016/j.jim.2020.112764
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发表时间：
2020-04-01
影响因子：
2.2
通讯作者：
Weiner, Joshua A.
中科院分区：
文献类型：
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作者：
Bharadwaj, Pranay;Riekofski, Cassidy;Weiner, Joshua A.
检测、量化和询问针对生物疗法产生的免疫应答的特性的能力不仅对我们理解这些分子很重要，而且对它们在临床上的成功也很重要。用于鉴别抗药抗体（ADA）应答的存在、特异性和滴度的分层测定方法已被行业领导者、FDA和EMA采纳为金标准。为了支持临床前和临床试验，这些测定必须标准化，其性能必须充分表征，以确保在相关测试条件下结果的准确性和重现性。在这里，我们介绍了符合药物临床试验质量管理规范的5种HIV广泛中和抗体（3BNC 117、3BNC 117-LS、10-1074、PGT 121和PGDM 1400）ADA检测分层范例的电化学发光检测的实施。评价了试验灵敏度和基质效应，并用于确定阳性临界点。确定临界点后，定义试验精密度、专属性、游离药物耐受性和耐用性。在所有情况下，检测试剂盒特征均符合或超过FDA提出的建议。为了进一步评价这些试验和分层方法的性能，评价了来自已接受五种治疗剂的子集的非人灵长类动物的样品。总之，本研究报告了随着广泛HIV中和抗体的临床前和临床试验的进行，科学界可用的一组ADA检测方法的鉴定，以及随着新药在临床中的进展，易于适应的框架。
The ability to detect, quantify, and interrogate the properties of immune responses raised against biological therapeutics is not only important to our understanding of these molecules, but also to their success in the clinic. A tiered assay approach to identify the presence, specificity, and titer of anti-drug antibody (ADA) responses has been adopted as a gold standard by industry leaders, the FDA, and the EMA. In order to support pre-clinical and clinical trials, these assays must be standardized, and their performance sufficiently characterized to ensure the accuracy and reproducibility of results under relevant testing conditions. Here we present implementation of electrochemiluminiscence assays that fit into the tiered paradigm of ADA testing for five HIV broadly neutralizing antibodies (3BNC117, 3BNC117-LS, 10-1074, PGT121, and PGDM1400) in compliance with Good Clinical Laboratory practices. Assay sensitivities and matrix effects were evaluated and used to inform the development of positivity cut points. Once cut points were established, assay precision, specificity, free-drug tolerance, and robustness were defined. In all cases, assay characteristics met or surpassed recommendations set forth by the FDA. To further evaluate the performance of these assays and the tiered approach, samples from non-human primates that had received a subset of the five therapeutics were evaluated. In sum, this study reports qualification of a set of ADA assays available to the scientific community as pre-clinical and clinical trials of broadly HIV-neutralizing antibodies proceed, and a framework that is easily adapted as new drug products are advanced in the clinic.