Genetically Modified DR5-Specific TRAIL Variant DR5-B Revealed Dual Antitumor and Protumoral Effect in Colon Cancer Xenografts and an Improved Pharmacokinetic Profile

• Published in: Translational oncology 2020-04, Vol.13 (4), p.100762-100762, Article 100762
• Main Authors: Yagolovich, Anne V., Artykov, Artem A., Karmakova, Tatiana A., Vorontsova, Maria S., Pankratov, Andrey A., Andreev-Andrievsky, Alexander A., Dolgikh, Dmitry A., Kirpichnikov, Mikhail P., Gasparian, Marine E.
• Format: Article
• Language: English
• Subjects: Original article
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2020.100762

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.