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TAK-062(一种治疗乳糜泻的工程酶)的面筋降解、药代动力学、安全性和耐受性


来源: Ingrid Swanson Pultz et al  发布日期: 2021-11-03  访问量: 75


乳糜泻(CeD)是一种因摄入麸质而引发的免疫性疾病。尽管坚持无麸质饮食(这是CeD患者唯一的管理选择),许多患者仍然出现症状和肠道损伤。麸质多肽的免疫原性部分在胃中的降解已被提议为减少摄入麸质的毒性的一种方法;然而,迄今为止评估的任何酶都没有证明在复杂的膳食中充分降解麸质。TAK-062是一种新型的、经过计算设计的内肽酶,正在开发中,用于治疗CeD患者。...
标签: TAK-062面筋降解、药代动力学、安全性和耐受性
 

Gluten Degradation, Pharmacokinetics, Safety, and Tolerabilityof TAK-062, an Engineered Enzyme to Treat Celiac Disease

TAK-062(一种治疗乳糜泻的工程酶)的面筋降解、药代动力学、安全性和耐受性

Ingrid Swanson Pultz,1 Malcolm Hill,1 Joanne M. Vitanza,1 Clancey Wolf,1 Lasse Saaby,Tina Liu,3 Peter Winkle,4 and Daniel A. Leffler3
1PvP Biologics, Inc, San Diego, California: 2Bioneer A/S, Hørsholm, Denmark; 3Takeda Pharmaceuticals International Co,
Cambridge, Massachusetts; and 4Anaheim Clinical Trials, Anaheim, California

BACKGROUND AND AIMS:

Celiac disease (CeD) is an immunemediated disorder triggered by the ingestion of gluten. Despite adhering to a gluten-free diet (the only management option available to patients with CeD), many patients continue to experience symptoms and intestinal injury. Degradation of immunogenic fractions of gluten peptides in the stomach has been proposed as an approach to reduce toxicity of ingested gluten; however, no enzymes evaluated to date have demonstrated sufficient gluten degradation in complex meals. TAK-062 is a novel, computationally designed endopeptidase under development for the treatment of patients with CeD.

乳糜泻(CeD)是一种因摄入麸质而引发的免疫性疾病。尽管坚持无麸质饮食(这是CeD患者唯一的管理选择),许多患者仍然出现症状和肠道损伤。麸质多肽的免疫原性部分在胃中的降解已被提议为减少摄入麸质的毒性的一种方法;然而,迄今为止评估的任何酶都没有证明在复杂的膳食中充分降解麸质。TAK-062是一种新型的、经过计算设计的内肽酶,正在开发中,用于治疗CeD患者。


METHODS: Pharmacokinetics, safety, and tolerability of TAK- 062 100–900 mg were evaluated in a phase I dose escalation study in healthy participants and patients with CeD. Gluten degradation by TAK-062 was evaluated under simulated gastric conditions in vitro and in healthy participants in the phase I study, with and without pretreatment with a proton pump inhibitor. Residual gluten (collected through gastric aspiration in the phase I study) was quantified using R5 and G12 monoclonal antibody enzyme-linked immunosorbent assays.

在一项I期剂量升级研究中,在健康参与者和CeD患者中评估了TAK-062 100-900毫克的药代动力学、安全性和耐受性。在I期研究中,在体外模拟胃条件下和在健康参与者中,在有或没有质子泵抑制剂预处理的情况下,评估了TAK-062对谷蛋白的降解作用。使用R5和G12单克隆抗体酶联免疫吸附法对残余麸质(在I期研究中通过胃部抽吸收集)进行量化。

RESULTS:
In vitro, TAK-062 degraded more than 99% of gluten (3 g and 9 g) within 10 minutes. In the phase I study, administration of TAK-062 was well tolerated and resulted in a median gluten degradation ranging from 97% to more than 99% in complex meals containing 1–6 g gluten at 20–65 minutes postdose.

在体外消化模拟,TAK-062在10分钟内降解了99%以上的面筋(3克和9克)。在I期研究中,服用TAK-062耐受性良好,在服用后20-65分钟,在含有1-6克麸质的复合餐中,麸质降解的中位数从97%到99%以上。


CONCLUSIONS: TAK-062 is well tolerated and rapidly and effectively degrades large amounts of gluten, supporting the development of this novel enzyme as an oral therapeutic for patients with CeD.

TAK-062具有良好的耐受性,并能快速有效地降解大量麸质,支持开发这种新型酶作为宿主疾病患者的口服治疗方法。


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