Herskovitz Jonathan, Ryman Josiah, Thway Theingi, Lee Stephanie, Zhou Lei, Chirmule Narendra, Meibohm Bernd, Jawa Vibha
The Department of Medical Sciences, Amgen Inc., One Amgen Center Dr, Thousand Oaks, California, 91320, USA.
University of Tennessee Health Science Center, Memphis, Tennessee, USA.
AAPS J. 2017 Mar;19(2):447-455. doi: 10.1208/s12248-016-0026-8. Epub 2017 Jan 9.
In the clinical setting, anti-drug antibodies (ADA) against biotherapeutics can influence patient safety and interfere with product efficacy. High immunogenicity has been addressed in clinic by concomitant immune suppression, such as co-administration of methotrexate with enzyme replacement therapy (ERT) and combination tacrolimus/sirolimus treatment for prophylaxis against organ transplant rejection. This study investigates the use of such immune suppressants in mitigating ADA responses to a fully human monoclonal antibody (mAb1) in preclinical animal studies. Three groups of Sprague Dawley rats (n = 18) were treated with low (0.01 mg/kg), moderate (50 mg/kg), or high (300 mg/kg) doses of mAb1. Experimental groups also received either methotrexate or tacrolimus/sirolimus immune suppressive regimens. ELISA-based methods were utilized to measure and characterize ADA and mAb1 pharmacokinetics (PK). Results demonstrated a stepwise increase in immunogenicity with mAb1 dosage. Methotrexate significantly lowered incidence of anti-variable region antibodies at moderate mAb1 dose (P < 0.05), while tacrolimus/sirolimus did likewise at moderate and high doses (P < 0.01) of mAb1. Except for low-dose mAb1 + methotrexate, all immunosuppressed groups displayed more than a 70-fold decrease in ADA magnitude (P < 0.05). This abrogation in ADA response correlated with more mAb1 in circulation by week 4 for moderate- and high-dosed mAb1 groups. These data provide an approach to mitigate preclinical immunogenicity by the use of immunosuppressant regimens. Such preconditioning can support preclinical drug development of human therapeutics that are antigenic to animals. Similar approaches could be investigated for wider application to novel therapeutics.
在临床环境中，针对生物治疗药物的抗药抗体（ADA）会影响患者安全并干扰产品疗效。临床上已通过联合免疫抑制来解决高免疫原性问题，例如甲氨蝶呤与酶替代疗法（ERT）联合使用，以及使用他克莫司/西罗莫司联合治疗预防器官移植排斥反应。本研究在临床前动物研究中调查了此类免疫抑制剂在减轻对全人单克隆抗体（mAb1）的ADA反应方面的应用。将三组斯普拉格-道利大鼠（n = 18）分别用低剂量（0.01 mg/kg）、中等剂量（50 mg/kg）或高剂量（300 mg/kg）的mAb1进行治疗。实验组还接受了甲氨蝶呤或他克莫司/西罗莫司免疫抑制方案。采用基于酶联免疫吸附测定（ELISA）的方法来测量和表征ADA以及mAb1的药代动力学（PK）。结果表明，随着mAb1剂量增加，免疫原性呈逐步上升趋势。甲氨蝶呤在mAb1中等剂量时显著降低了抗可变区抗体的发生率（P < 0.05），而他克莫司/西罗莫司在mAb1中等剂量和高剂量时也有同样效果（P < 0.01）。除了低剂量mAb1 + 甲氨蝶呤组外，所有免疫抑制组的ADA水平均下降了70倍以上（P < 0.05）。对于中等剂量和高剂量mAb1组，到第4周时，ADA反应的这种消除与循环中更多的mAb1相关。这些数据提供了一种通过使用免疫抑制方案减轻临床前免疫原性的方法。这种预处理可以支持对动物具有抗原性的人类治疗药物的临床前药物开发。对于更广泛地应用于新型治疗药物，可以研究类似的方法。
