دورية أكاديمية

Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo

التفاصيل البيبلوغرافية
العنوان: Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo
المؤلفون: Haipeng Liu, Danmei Su, Jinlong Zhang, Shuaishuai Ge, Youwei Li, Fei Wang, Michel Gravel, Anne Roulston, Qin Song, Wei Xu, Joshua G. Liang, Gordon Shore, Xiaodong Wang, Peng Liang
المصدر: Scientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
بيانات النشر: Nature Portfolio, 2017.
سنة النشر: 2017
المجموعة: LCC:Medicine
LCC:Science
مصطلحات موضوعية: Medicine, Science
الوصف: Abstract TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) has long been considered a tantalizing target for cancer therapy because it mediates activation of the extrinsic apoptosis pathway in a tumor-specific manner by binding to and trimerizing its functional receptors DR4 or DR5. Despite initial promise, both recombinant human TRAIL (native TRAIL) and dimeric DR4/DR5 agonist monoclonal antibodies (mAbs) failed in multiple human clinical trials. Here we show that in-frame fusion of human C-propeptide of α1(I) collagen (Trimer-Tag) to the C-terminus of mature human TRAIL leads to a disulfide bond-linked homotrimer which can be expressed at high levels as a secreted protein from CHO cells. The resulting TRAIL-Trimer not only retains similar bioactivity and receptor binding kinetics as native TRAIL in vitro which are 4–5 orders of magnitude superior to that of dimeric TRAIL-Fc, but also manifests more favorable pharmacokinetic and antitumor pharmacodynamic profiles in vivo than that of native TRAIL. Taken together, this work provides direct evidence for the in vivo antitumor efficacy of TRAIL being proportional to systemic drug exposure and suggests that the previous clinical failures may have been due to rapid systemic clearance of native TRAIL and poor apoptosis-inducing potency of dimeric agonist mAbs despite their long serum half-lives.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2045-2322
Relation: https://doaj.org/toc/2045-2322
DOI: 10.1038/s41598-017-09518-1
URL الوصول: https://doaj.org/article/689ba978ac0b499ca617fd53fe206c90
رقم الأكسشن: edsdoj.689ba978ac0b499ca617fd53fe206c90
قاعدة البيانات: Directory of Open Access Journals