生物治疗剂具有在患者中引发不期望的免疫应答的潜力。对于治疗性蛋白质,免疫原性表现为抗药物抗体(ADA)。因为ADA会损害药代动力学,功效,和安全,监管机构需要在临床开发期间进行免疫原性评估。建议采用分层生物分析方法来监测临床免疫原性,和中和抗体(NAb)在第4级研究,如果该分子是免疫原性的。虽然基于细胞的检测,这反映了药理作用机制,在某些情况下是检测NAb的首选检测形式,它们与操作复杂性和有时次优的测定性能有关。或者,还开发并实施了非基于细胞的测定。在我们目前的研究中,开发了一种竞争性配体结合测定法(CLBA)来检测α胰岛素的NAb(efsitora,基础胰岛素Fc,LY3209590),一种用于治疗1型糖尿病和2型糖尿病的新型融合蛋白。CLBA显示出可接受的灵敏度,药物耐受性,精度,和鲁棒性,并因此提供了一种针对efsitora检测NAb的合适方法。
Biotherapeutics have the potential to trigger undesired immune responses in the patients. For therapeutic proteins, immunogenicity is manifested as anti-drug antibodies (ADA). Because ADA could compromise pharmacokinetics, efficacy, and safety, regulatory agencies require immunogenicity assessment during clinical development. A tiered bioanalytical approach is recommended to monitor clinical immunogenicity, and neutralizing antibodies (NAb) are studied in Tier 4 if the molecule is immunogenic. Although cell-based assays, which reflect the pharmacological mechanism of action, are in some cases the preferred assay format for detecting NAbs, they are associated with operational complexity and sometimes suboptimal assay performance. Alternatively, non-cell-based assays have also been developed and implemented. In our current study, a competitive ligand binding assay (CLBA) was developed to detect NAbs for insulin efsitora alfa (efsitora, basal insulin Fc, LY3209590), a novel fusion protein being studied for the treatment of Type 1 diabetes and Type 2 diabetes. The CLBA demonstrated acceptable sensitivity, drug tolerance, precision, and robustness, and thus provides a suitable approach for detecting NAbs against efsitora.