Despite the weak clinical efficacy of TRAIL death receptor agonists, a search is under way for new agents that more efficiently activate apoptotic signaling. We previously created a TRAIL DR5-selective variant DR5-B without affinity for the DR4, DcR1, DcR2, and OPG receptors and increased proapoptotic activity in tumor cells. Here we showed that DR5-B significantly inhibited tumor growth in HCT116 and Caco-2 but not in HT-29 xenografts. The antitumor activity of DR5-B was 2.5 times higher in HCT116 xenografts compared to TRAIL. DR5-B at a dose of 2 or 10 mg/kg/d for 10 days inhibited tumor growth in HCT116 xenografts by 26% or 50% respectively, and increased animal survival. Unexpectedly, DR5-B at a higher dose (25 mg/kg/d) inhibited tumor growth only during the first 8 days of drug exposure, while at the end of the monitoring, no effect or even slight stimulation of tumor growth was observed. The pharmacokinetic parameters of DR5-B were comparable to those of TRAIL, except that the half-life was 3.5 times higher. Thus, enhancing TRAIL selectivity to DR5 may increase both antitumor and proliferative activities depending on the concentration and administration regimens.

尽管TRAIL死亡受体激动剂的临床疗效较弱，但仍在寻找能更有效地激活凋亡信号的新药物。我们先前创建了对DR4，DcR1，DcR2和OPG受体没有亲和力的TRAIL DR5-选择性变体DR5-B，并增加了肿瘤细胞的促凋亡活性。在这里，我们显示DR5-B显着抑制HCT116和Caco-2中的肿瘤生长，但不抑制HT-29异种移植物中的肿瘤生长。与TRAIL相比，HCT116异种移植物中DR5-B的抗肿瘤活性高2.5倍。DR5-B的剂量为2或10 mg / kg / d，持续10天，分别抑制HCT116异种移植物中的肿瘤生长26％或50％，并提高了动物存活率。出乎意料的是，较高剂量（25 mg / kg / d）的DR5-B仅在药物暴露的前8天抑制肿瘤生长，而在监测结束时，没有观察到影响或什至轻微刺激肿瘤生长。DR5-B的药代动力学参数与TRAIL相当，除了半衰期高3.5倍。因此，取决于浓度和给药方案，增强对DR5的TRAIL选择性可以增加抗肿瘤和增殖活性。