Guo Jianwen, Sun Jiawei, Liu Xinyu, Wang Zhuoran, Gao Weiping
Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China.
Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing, 100081, China; Biomedical Engineering Department, Peking University, Beijing, 100191, China.
Biomaterials. 2020 Aug;250:120073. doi: 10.1016/j.biomaterials.2020.120073. Epub 2020 Apr 23.
Genetic fusion of a therapeutic protein to albumin can improve its stability and pharmacokinetics, but it usually leads to considerably reduced bioactivity and poor tumor penetration due to increased steric hindrance, resulting in limited antitumor efficacy. Herein we report head-to-tail macrocyclization of albumin-binding domain fused interferon alpha (IFN-ABD) to form a cyclic fusion protein (c-IFN-ABD) with well-retained albumin-binding affinity. Notably, c-IFN-ABD showed not only greater thermal and enzymatic stability and thus antiproliferative activity than IFN-ABD and IFN due to the macrocyclization, but also exhibited considerably better pharmacokinetics than IFN and cyclic IFN owing to the albumin-binding affinity. More importantly, c-IFN-ABD showed deeper tumor penetration, greater tumor retention, and thus higher antitumor efficiency than all the controls without significant systemic side effects in mice bearing melanoma. These results implicate that head-to-tail macrocyclization of ABD fused therapeutic proteins is an enabling strategy for the design of highly potent protein therapeutics for tumor therapy.
将治疗性蛋白质与白蛋白进行基因融合可提高其稳定性和药代动力学，但由于空间位阻增加，通常会导致生物活性大幅降低和肿瘤穿透性差，从而使抗肿瘤疗效受限。在此，我们报告了将白蛋白结合域融合干扰素α（IFN-ABD）进行头对尾大环化，以形成具有良好保留的白蛋白结合亲和力的环状融合蛋白（c-IFN-ABD）。值得注意的是，由于大环化，c-IFN-ABD不仅表现出比IFN-ABD和IFN更高的热稳定性和酶稳定性，进而具有抗增殖活性，而且由于白蛋白结合亲和力，其药代动力学也比IFN和环状IFN好得多。更重要的是，在携带黑色素瘤的小鼠中，c-IFN-ABD比所有对照显示出更深的肿瘤穿透性、更高的肿瘤滞留率，因此具有更高的抗肿瘤效率，且无明显的全身副作用。这些结果表明，ABD融合治疗性蛋白质的头对尾大环化是设计用于肿瘤治疗的高效蛋白质治疗药物的一种可行策略。
