Theranostics 2018; 8(9):2459-2476. doi:10.7150/thno.23880

Research Paper

Endogenous IgG-based affinity-controlled release of TRAIL exerts superior antitumor effects

Hao Yang1*, Yanru Feng 1*, Huawei Cai2, Dianlong Jia1,4, Heng Li1, Ze Tao1, Yi Zhong3, Zhao Li1, Qiuxiao Shi1, Lin Wan1, Lin Li2, Xiaofeng Lu1 ✉

1. Key Lab of Transplant Engineering and Immunology, MOH;
2. Department of Nuclear Medicine;
3. Proteomics and Metabolomics Laboratory, West China-Washington Mitochondria and Metabolism Research Center; West China Hospital, Sichuan University, Chengdu, 610041, China
4. Present address: College of Pharmacy, Liaocheng University, Liaocheng, Shandong, 252000, China
*These authors contribute equally to this work.

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Citation:
Yang H, Feng Y, Cai H, Jia D, Li H, Tao Z, Zhong Y, Li Z, Shi Q, Wan L, Li L, Lu X. Endogenous IgG-based affinity-controlled release of TRAIL exerts superior antitumor effects. Theranostics 2018; 8(9):2459-2476. doi:10.7150/thno.23880. Available from https://www.thno.org/v08p2459.htm

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Abstract

The inefficiency of recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based clinical regimens has been dominantly attributed to the short half-life of TRAIL. Affinity-controlled release using endogenous long-acting proteins, such as IgG and albumin, as carriers is extremely attractive for improving the pharmacokinetics of TRAIL. Up to now, it is unclear whether IgG-binding is efficient for affinity-controlled release of TRAIL.

Methods: An IgG-binding affibody, IgBD, was genetically fused to the N-terminus of TRAIL to produce IgBD-TRAIL.The IgG-binding ability, cytotoxicity, serum half-life, and in vivo antitumor effect of IgBD-TRAIL were compared with that of TRAIL. In addition, an albumin-binding affibody, ABD, was fused to TRAIL to produce ABD-TRAIL. The cytototoxicity, serum half-life, and antitumor effect of IgBD-TRAIL and ABD-TRAIL were compared.

Results: IgBD fusion endowed TRAIL with high affinity (nM) for IgG without interference with its cytotoxicity. The serum half-life of IgBD-TRAIL is 50-60 times longer than that of TRAIL and the tumor uptake of IgBD-TRAIL at 8-24 h post-injection was 4-7-fold that of TRAIL. In vivo antitumor effect of IgBD-TRAIL was at least 10 times greater than that of TRAIL. Owing to the high affinity (nM) for albumin, the serum half-life of ABD-TRAIL was 80-90 times greater than that of TRAIL. However, after binding to albumin, the cytotoxicity of ABD-TRAIL was reduced more than 10 times. In contrast, binding to IgG had little impact on the cytotoxicity of IgBD-TRAIL. Consequently, intravenously injected IgBD-TRAIL showed antitumor effects superior to those of ABD-TRAIL.

Conclusions: Endogenous long-acting proteins, particularly IgG-based affinity-controlled release, prolonged the serum half-life as well as significantly enhanced the antitumor effect of TRAIL. IgBD-mediated endogenous IgG binding might be a novel approach for the affinity-controlled release of other protein drugs.

Keywords: drug delivery, affinity-controlled release, biopharmaceuticals, immunoglobulin, albumin