Theranostics 2018; 8(9):2459-2476. doi:10.7150/thno.23880
Endogenous IgG-based affinity-controlled release of TRAIL exerts superior antitumor effects
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.
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
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