Brin Elena, Wu Katherine, Dagostino Eleanor, Meng-Chiang Kuo Mario, He Yudou, Shia Wei-Jong, Chen Li-Chang, Stempniak Mariusz, Hickey Richard, Almassy Robert, Showalter Richard, Thomson James
Polaris Pharmaceuticals, San Diego, CA, USA.
Oncotarget. 2018 Dec 11;9(97):36914-36928. doi: 10.18632/oncotarget.26398.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) binds to death receptors and induces apoptosis in various cancer cell lines while sparing normal cells. Recombinant TRAIL has shown good safety and efficacy profiles in preclinical cancer models. However, clinical success has been limited due to poor PK and development of resistance to death receptor-induced apoptosis. We have addressed these issues by creating a fusion protein of TRAIL and arginine deiminase (ADI). The fusion protein benefits from structural and functional synergies between its two components and has an extended half-life . ADI downregulates survivin, upregulates DR5 receptor and sensitizes cancer cells to TRAIL induced apoptosis. ADI-TRAIL fusion protein was efficacious in a number of cell lines and synergized with some standard of care drugs. In an HCT116 xenograft model ADI-TRAIL localized to the tumor and induced dose-dependent tumor regression, the fusion protein was superior to rhTRAIL administered at the same molar amounts.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）与死亡受体结合，可诱导多种癌细胞系发生凋亡，同时对正常细胞无影响。重组TRAIL在临床前癌症模型中已显示出良好的安全性和有效性。然而，由于药代动力学较差以及对死亡受体诱导的凋亡产生耐药性，其临床应用效果有限。我们通过创建TRAIL与精氨酸脱氨酶（ADI）的融合蛋白来解决这些问题。该融合蛋白受益于其两个组分之间的结构和功能协同作用，并且半衰期延长。ADI可下调survivin，上调DR5受体，并使癌细胞对TRAIL诱导的凋亡敏感。ADI-TRAIL融合蛋白在多种细胞系中有效，并与一些标准护理药物协同作用。在HCT116异种移植模型中，ADI-TRAIL定位于肿瘤并诱导剂量依赖性肿瘤消退，该融合蛋白优于以相同摩尔量给药的重组人TRAIL（rhTRAIL）。
