PDF(Pubmed)
Abstract：
An appropriately designed pharmacokinetic (PK) assay that is sensitive for anti-drug antibody (ADA) impact on relevant exposure is an alternative strategy to understand the neutralizing potential of ADAs. However, guidance on how to develop such PK assays and how to confirm the functional ADA impact on exposure is missing. Here, the PK assay of a T-cell-engaging bispecific antibody, cibisatamab, was developed based on its mechanism of action (MoA). Using critical monoclonal anti-idiotypic (anti-ID) antibody positive controls as ADA surrogates, the impact on exposure was evaluated pre-clinically. In a phase I clinical trial (NCT02324257), initial data suggest that the combination of ADA and PK assays for correlation of the ADA response with cibisatamab exposure. To understand the neutralizing potential of patient-derived ADAs on drug activity, advanced ADA characterization has been performed. Structural binding analysis of ADAs to antibody domains of the drug and its impact on targeting were assessed. For this purpose, relevant patient ADA binding features were identified and compared with the specific monoclonal anti-ID antibody-positive controls. Comparable results of target binding inhibition and similar impacts on exposure suggest that the observed reduction of Cmax and Ctrough levels in patients is caused by the neutralizing potential of ADAs and allows a correlation between ADA response and loss of exposure. Therefore, the described study provides important functional aspects for the development of an appropriately designed PK assay for bispecific antibodies as an alternative option towards understanding the neutralizing ADA impact on exposure.
摘要：
对于抗药物抗体(ADA)对相关暴露的影响敏感的适当设计的药代动力学(PK)测定是了解ADA的中和潜力的替代策略。然而,缺少有关如何开发此类PK测定以及如何确认ADA对暴露的功能性影响的指南。这里,T细胞接合双特异性抗体的PK测定，Cibisatamab,是根据其作用机制(MoA)开发的。使用关键的单克隆抗独特型（抗ID）抗体阳性对照作为ADA替代，对暴露的影响进行了临床前评估.在I期临床试验（NCT02324257）中，初始数据表明，ADA和PK测定的组合用于ADA反应与Cibisatamab暴露的相关性。为了了解患者来源的ADAs对药物活性的中和潜力，先进的ADA表征已经进行。评估了ADA与药物抗体结构域的结构结合分析及其对靶向的影响。为此,我们确定了相关患者ADA结合特征,并将其与特异性单克隆抗ID抗体阳性对照进行了比较.靶标结合抑制的可比较结果和对暴露的类似影响表明,在患者中观察到的Cmax和Ctrugh水平的降低是由ADAs的中和潜力引起的,并且允许ADA响应与暴露损失之间的相关性。因此,所描述的研究为开发适当设计的双特异性抗体PK测定提供了重要的功能方面,作为了解中和ADA对暴露影响的替代选择.
