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

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 initia...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/689ba978ac0b499ca617fd53fe206c90
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spelling	oai:doaj.org-article:689ba978ac0b499ca617fd53fe206c902021-12-02T11:41:11ZImprovement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo10.1038/s41598-017-09518-12045-2322https://doaj.org/article/689ba978ac0b499ca617fd53fe206c902017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09518-1https://doaj.org/toc/2045-2322Abstract 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.Haipeng LiuDanmei SuJinlong ZhangShuaishuai GeYouwei LiFei WangMichel GravelAnne RoulstonQin SongWei XuJoshua G. LiangGordon ShoreXiaodong WangPeng LiangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo
description	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.
format	article
author	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
author_facet	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
author_sort	Haipeng Liu
title	Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo
title_short	Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo
title_full	Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo
title_fullStr	Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo
title_full_unstemmed	Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo
title_sort	improvement of pharmacokinetic profile of trail via trimer-tag enhances its antitumor activity in vivo
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/689ba978ac0b499ca617fd53fe206c90
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Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo

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