| 摘要 |
Disclosed are TNF-related apoptosis-inducing ligand (TRAIL) trimers (TR3) and nucleic acids encoding covalently linked TRAIL trimers. A TRAIL trimer can have greater stability compared to native TRAIL, and can retain the native killing ability of TRAIL. Target specificity of a TR3 can be shown by blocking its activity with soluble death receptor 5 (DR5-Fc). Also disclosed are modified TRAIL trimers and nucleic acids encoding them. These modifications include additional functional domains, such as antibody fragments (scFvs). A TR3 comprising an additional functional domain can allow for cell-specific delivery of the TR3. In some configurations, a modification such as the addition of a functional domain can be stoichiometrically controlled. In some configurations, a modification can be inconsequential with regard to the bioactivity of TRAIL. In various embodiments, a TR3, including a modified TR3, can be a cancer-selective drug. In some configurations, a TR3 that comprises an additional biologically active moiety such as a functional domain of a protein can have fewer off-target toxicities compared to TRAIL alone. In some configurations, a TR3 that comprises an additional biologically active moiety such as a functional domain of a protein can have enhanced killing capacities compared to the moiety alone. In some aspects, TR3 activity can be targeted to an RBC membrane. The inventors disclose TR3-decorated RBCs that target cell killing in a model of pancreatic cancer. |
