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Molecular superglue-mediated higher-order assembly of TRAIL variants with superior apoptosis induction and antitumor activity.

Abstract
Prompting higher-order death receptor (DR) clustering by increasing the valency of DR agonist is efficient to induce apoptosis of tumor cells. As an attractive DR agonist with superior biosafety, the trimeric tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exerts limited antitumor effect in patients, which is predominantly attributed to its low DR clustering ability and short serum half-life. Previous antibody scaffolds-based engineering strategies to increase the valency and/or prolong the serum half-life of TRAIL improve apoptosis induction, however, often produce large proteins with poor tumor penetration. Covalent protein ligation mediated by small molecular superglues such as SpyTag/SpyCatcher might be a novel strategy to assemble higher-order TRAIL variants. Upon fusion to TRAIL promotor, SpyTag/SpyCatcher molecular superglue preferentially ligated two trimeric TRAIL to produce a hexameric TRAIL variant, HexaTR, exhibiting a significantly increased apoptosis induction. In addition, an albumin-binding HexaTR, ABD-HexaTR, with a prolonged serum half-life by binding to endogenous albumin was also produced using the same strategy. Compared to the trimeric TRAIL, the hexameric HexaTR and ABD-HexaTR showed 20-50 times greater in vivo antitumor effect, resulting in eradication of several types of large (150-300 mm3) tumor xenografts. Combination with bortezomib carried by liposome further improved the antitumor effects of the hexavalent HexaTR and ABD-HexaTR in refractory cancer. Our results indicate that the superglue-mediated higher-order assembly is promising to improve the DR clustering and proapoptotic signaling of TRAIL, showing great advantages in constructing the next generation of DR agonists for cancer therapy.
AuthorsHao Yang, Heng Li, Fen Yang, Ze Tao, Qiuxiao Shi, Tianshan She, Yanru Feng, Zhao Li, Jie Chen, Yi Zhong, Tao Su, Wengjuan Zeng, Yong Zhang, Shisheng Wang, Lan Li, Tingting Long, Dan Long, Jingqiu Cheng, Hong Zhu, Xiaofeng Lu
JournalBiomaterials (Biomaterials) Vol. 295 Pg. 121994 (04 2023) ISSN: 1878-5905 [Electronic] Netherlands
PMID36775789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2023 Elsevier Ltd. All rights reserved.
Chemical References
  • Ligands
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha
  • Albumins
Topics
  • Humans
  • Cell Line, Tumor
  • Ligands
  • TNF-Related Apoptosis-Inducing Ligand (metabolism)
  • Apoptosis
  • Tumor Necrosis Factor-alpha (pharmacology)
  • Albumins (pharmacology)

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