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One-month zero-order sustained release and tumor eradication after a single subcutaneous injection of interferon alpha fused with a body-temperature-responsive polypeptide

Wang, Zhuoran, Guo, Jianwen, Ning, Jing, Feng, Xiaoyu, Liu, Xinyu, Sun, Jiawei, Chen, Xiangmei, Lu, Fengmin, Gao, Weiping
Biomaterials science 2018 v.7 no.1 pp. 104-112
adverse effects, animal models, antibodies, biopharmaceuticals, biosafety, half life, humans, neoplasms, patient compliance, polypeptides, subcutaneous injection, therapeutics
Most therapeutic proteins except antibodies necessitate frequent dosing at high concentrations due to their short circulation half-lives, leading to limited therapeutic efficacy, serious adverse side effects and poor patient compliance. Herein we report a strategy of thermoresponsive polypeptide fusion to genetically engineer a super-long-acting interferon alpha fused with a body-temperature-responsive polypeptide. After a single subcutaneous injection in a mouse model, this interferon alpha can in situ form a depot to show a one-month zero-order sustained release, which would enable a once-trimonthly dosing in humans. As a result, it exhibits greatly enhanced tumor accumulation and tumor eradication as well as substantially improved tolerability and biosafety. This strategy provides a promising solution to dramatically enhance the pharmacological performance of therapeutic proteins with short circulation half-lives while reducing the side effects.