The recent identification of human monoclonal antibodies with broad and potent neutralizing activity against HIV-1 (bnAbs) has resulted in substantial efforts to develop these molecules for clinical use in the prevention and treatment of HIV-1 infection. As with any protein therapeutic drug product, it is imperative to have qualified assays that can accurately detect and quantify anti-drug antibodies (ADA) that may develop in patients receiving passive administration of HIV-1 bnAbs. Here, we have optimized and qualified a functional assay to assess the potential of ADA to inhibit the neutralizing function of HIV-1 bnAbs. Using a modified version of the validated TZM-bl HIV-1 neutralization assay, murine anti-idiotype antibodies were utilized to optimize and evaluate parameters of linearity, range, limit of detection, specificity, and precision for measuring inhibitory ADA activity against multiple HIV-1 bnAbs that are in clinical development. We further demonstrate the utility of this assay for detecting naturally occurring ADA responses in non-human primates receiving passive administration of human bnAbs. This functional assay format complements binding-antibody ADA strategies being developed for HIV-1 bnAbs, and when utilized together, will support a multi-tiered approach for ADA testing that is compliant with Good Clinical Laboratory Practice (GCLP) procedures and FDA guidance.

中文翻译：

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HIV-1 bnAbs功能性抗药物抗体检测方法的优化和鉴定。

最近鉴定出具有针对HIV-1（bnAbs）的广泛而有效的中和活性的人单克隆抗体，导致人们为开发用于预防和治疗HIV-1感染的临床用途的这些分子付出了巨大的努力。与任何蛋白质治疗药物产品一样，必须具有能够准确检测和定量在被动接受HIV-1 bnAb的患者体内产生的抗药物抗体（ADA）的合格检测方法。在这里，我们已经优化和鉴定了一种功能测定方法，以评估ADA抑制HIV-1 bnAbs中和功能的潜力。使用经过验证的TZM-bl HIV-1中和试验的改良版，利用鼠类抗独特型抗体来优化和评估线性，范围，检测限，特异性，和精确度，用于测量针对临床开发中的多种HIV-1 bnAb的抑制性ADA活性。我们进一步证明了该测定法用于检测接受人bnAbs被动给药的非人灵长类动物中自然发生的ADA反应的效用。这种功能性测定形式可补充针对HIV-1 bnAb研发的结合抗体ADA策略，当一起使用时，将支持符合良好临床实验室规范（GCLP）程序和FDA指南的多层ADA测试方法。