Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and.
J Immunol. 2014 Jul 1;193(1):48-55. doi: 10.4049/jimmunol.1400063. Epub 2014 Jun 2.
Immunogenicity remains the "Achilles' heel" of protein-based therapeutics. Anti-drug Abs produced in response to protein therapeutics can severely limit both the safety and efficacy of this expanding class of agent. In this article, we report that monotherapy of mice with tofacitinib (the JAK inhibitor) quells Ab responses to an immunotoxin derived from the bacterial protein Pseudomonas exotoxin A, as well as to the model Ag keyhole limpet hemocyanin. Thousand-fold reductions in IgG1 titers to both Ags were observed 21 d post immunization. In fact, suppression was evident for all IgG isotypes and IgM. A reduction in IgG3 production was also noted with a thymus-independent type II Ag. Mechanistic investigations revealed that tofacitinib treatment led to reduced numbers of CD127+ pro-B cells. Furthermore, we observed fewer germinal center B cells and the impaired formation of germinal centers of mice treated with tofacitinib. Because normal Ig levels were still present during tofacitinib treatment, this agent specifically reduced anti-drug Abs, thus preserving the potential efficacy of biological therapeutics, including those used as cancer therapeutics.
免疫原性仍然是基于蛋白质的治疗药物的“阿喀琉斯之踵”。针对蛋白质治疗药物产生的抗药物抗体可能严重限制这一不断扩大的药物类别在安全性和疗效两方面的表现。在本文中，我们报告称，托法替尼（JAK 抑制剂）单药治疗可抑制源自细菌蛋白绿脓杆菌外毒素 A 的免疫毒素以及模型抗原血蓝蛋白的抗体反应。在免疫后 21 天，观察到针对两种抗原的 IgG1 滴度降低了千倍。实际上，所有 IgG 同种型和 IgM 都显示出抑制作用。也观察到与 T 细胞非依赖性 II 型抗原相关的 IgG3 产生减少。机制研究表明，托法替尼治疗导致 CD127+前 B 细胞数量减少。此外，我们观察到用托法替尼治疗的小鼠的生发中心 B 细胞减少，生发中心的形成受损。由于在托法替尼治疗期间仍存在正常的 Ig 水平，因此该药物特异性地减少了抗药物抗体，从而保留了生物治疗药物的潜在疗效，包括那些用于癌症治疗的药物。
