Han Chao, Gunn George R, Marini Joseph C, Shankar Gopi, Han Hsu Helen, Davis Hugh M
Janssen R&D, Spring House, Pennsylvania
Janssen R&D, Spring House, Pennsylvania.
Drug Metab Dispos. 2015 May;43(5):762-70. doi: 10.1124/dmd.114.062679. Epub 2015 Mar 4.
The pharmacokinetics (PK) of biologic therapeutics, especially monoclonal antibodies (mAbs), in monkeys generally presents the most relevant predictive PK information for humans. However, human mAbs, xenogeneic proteins to monkeys, are likely to be immunogenic. Monkeys previously treated with a human mAb (non-naïve) may have developed antidrug antibodies (ADAs) that cross-react with another test mAb in subsequent studies. Unlike PK studies for small-molecule therapeutics, in which animals may be reused, naïve monkeys have been used almost exclusively for preclinical PK studies of biologic therapeutics to avoid potential pre-existing immunologic cross-reactivity issues. The propensity and extent of pre-existing ADAs have not been systematically investigated to date. In this study, the PK and immunogenicity of mAb A, a human anti-human interkeukin-17 mAb, were investigated in a colony of 31 cynomolgus monkeys previously exposed to other human mAbs against different targets. We screened the monkeys for pre-existing antibodies to mAb A prior to the PK study and showed that 44% of the monkeys had pre-existing cross-reactive antibodies to mAb A, which could affect the PK characterization of the antibody. In the subcolony of monkeys without measurable pre-existing ADAs, PK and immunogenicity of mAb A were successfully characterized. The impact of ADAs on mAb A PK was also demonstrated in the monkeys with pre-existing ADAs. Here we report the results and propose a pragmatic approach for the use of non-naïve monkeys when conducting PK studies of biologic therapeutics.
生物治疗药物，尤其是单克隆抗体（mAb）在猴子体内的药代动力学（PK）通常能提供与人类最为相关的预测性PK信息。然而，人源单克隆抗体对于猴子来说是异种蛋白，很可能具有免疫原性。先前接受过人源单克隆抗体治疗的猴子（非初次接触）在后续研究中可能已产生与另一种受试单克隆抗体发生交叉反应的抗药物抗体（ADA）。与小分子治疗药物的PK研究不同，小分子治疗药物研究中动物可重复使用，而对于生物治疗药物的临床前PK研究几乎只使用初次接触的猴子，以避免潜在的预先存在的免疫交叉反应问题。迄今为止，尚未系统研究预先存在的ADA的倾向和程度。在本研究中，我们在一个由31只食蟹猴组成的群体中研究了人抗人白细胞介素-17单克隆抗体A的PK和免疫原性，这些猴子先前已接触过针对不同靶点的其他人源单克隆抗体。在PK研究之前，我们对猴子进行了针对单克隆抗体A的预先存在抗体的筛查，结果显示44%的猴子预先存在与单克隆抗体A发生交叉反应的抗体，这可能会影响该抗体的PK特征。在没有可检测到的预先存在的ADA的猴子亚群中，成功地对单克隆抗体A的PK和免疫原性进行了表征。在预先存在ADA的猴子中也证明了ADA对单克隆抗体A PK的影响。在此，我们报告研究结果，并提出一种在进行生物治疗药物PK研究时使用非初次接触猴子的实用方法。
