Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo
Open Access
- 21 August 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 7 (1), 1-11
- https://doi.org/10.1038/s41598-017-09518-1
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.Keywords
This publication has 56 references indexed in Scilit:
- Structural basis of fibrillar collagen trimerization and related genetic disordersNature Structural & Molecular Biology, 2012
- A Death Effector Domain Chain DISC Model Reveals a Crucial Role for Caspase-8 Chain Assembly in Mediating Apoptotic Cell DeathMolecular Cell, 2012
- Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC levelCell Death & Differentiation, 2010
- The Structure of the Trimer of Human 4-1BB Ligand Is Unique among Members of the Tumor Necrosis Factor SuperfamilyOnline Journal of Public Health Informatics, 2010
- In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugsBritish Journal of Cancer, 2008
- Differential Inhibition of TRAIL-Mediated DR5-DISC Formation by Decoy Receptors 1 and 2Molecular and Cellular Biology, 2006
- Functional expression of TRAIL receptors TRAIL-R1 and TRAIL-R2 in esophageal adenocarcinomaEuropean Journal of Cancer, 2006
- HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivoBritish Journal of Cancer, 2005
- A Small Molecule Smac Mimic Potentiates TRAIL- and TNFα-Mediated Cell DeathScience, 2004
- Stabilization of short collagen-like triple helices by protein engineeringJournal of Molecular Biology, 2001