a The Lilly Research Laboratories, Eli Lilly and Company , Indianapolis , IN , USA.
MAbs. 2019 Jul;11(5):861-869. doi: 10.1080/19420862.2019.1612699. Epub 2019 May 17.
Despite recent advances in the development of tools to predict immunogenicity risk of biotherapeutic molecules, the ability of a protein to elicit the formation of anti-drug antibodies (ADA) remains one of the most common causes for termination of clinical development programs. In this study, we use ADA assays to detect and measure pre-existing reactivity or the ability of a molecule to produce an ADA-like response in serum from treatment-naïve, healthy donors. We report herein that the magnitude of pre-existing reactivity evaluated pre-clinically and expressed as the 90th percentile of Tier 2 inhibition correlates with the subsequent rate of ADA emergence in the clinic. Furthermore, a multi-domain biotherapeutic (IgG-scFv bispecific antibody) showed the highest pre-existing reactivity and incidence of treatment-emergent ADA (TE-ADA) (57% and 93%, respectively). Using the components of the multidomain molecule in the Tier 2 step of the ADA assay, we were able to identify the scFv as the target of the serum pre-existing reactivity. Most importantly, the domain specificity of pre-existing ADA was the same as that of the TE-ADA from patients treated with the molecule. Based on these data, we propose the evaluation of the magnitude and of the domain specificity of pre-existing reactivity as a powerful tool to understand the immunogenic potential of novel biotherapeutics.
尽管最近在开发预测生物治疗性分子免疫原性风险的工具方面取得了进展，但蛋白质引发抗药物抗体（ADA）形成的能力仍然是导致临床开发计划终止的最常见原因之一。在这项研究中，我们使用 ADA 测定法来检测和测量预先存在的反应性，或在未经治疗的健康供体的血清中产生 ADA 样反应的能力。我们在此报告，临床前评估的预先存在的反应性的程度，以 Tier 2 抑制的第 90 百分位数表示，与临床后续 ADA 出现的速度相关。此外，一种多结构域生物治疗药物（IgG-scFv 双特异性抗体）显示出最高的预先存在的反应性和治疗后出现 ADA（TE-ADA）的发生率（分别为 57%和 93%）。使用 ADA 测定的 Tier 2 步骤中的多结构域分子的成分，我们能够确定 scFv 是血清预先存在的反应性的靶标。最重要的是，预先存在的 ADA 的结构域特异性与用该分子治疗的患者的 TE-ADA 相同。基于这些数据，我们提出评估预先存在的反应性的程度和结构域特异性作为一种强大的工具来了解新型生物治疗药物的免疫原性潜力。
