RESUMO
Interleukin-17 (IL-17) is a T-cell-derived cytokine that promotes inflammatory pathology in autoimmune diseases. Blocking IL-17A interactions with its endogenous IL-17 receptor (IL-17RA) can constitute an important target for therapeutic intervention. Here, we utilized a directed evolution approach to generate soluble IL-17RA mutants that exhibit increased IL-17A binding affinity and thermostability, relative to the wild-type. Human fibroblast cell-based assay and in vivo analysis in mice indicated that two improved IL-17RA mutants efficiently inhibit the secretion of IL-17A-induced proinflammatory cytokines. Analysis of one of these mutants in a psoriasis mouse model showed its efficacy in promoting the recovery of psoriasis plaques. This mutant can be used as a promising drug candidate for the treatment of psoriasis and may be a therapeutic agent for various other autoimmune diseases.
Assuntos
Evolução Molecular Direcionada , Interleucina-17/metabolismo , Psoríase/tratamento farmacológico , Receptores de Interleucina-17/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Cinética , Camundongos , Mutação , Ligação Proteica , Estabilidade Proteica , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: We developed a new method of brachytherapy, termed diffusing alpha-emitters radiation therapy (DaRT), based on the use of intratumoral (224)Ra-loaded wires, which release short-lived alpha-emitting atoms by recoil. Here, we examined their ability to destroy and control the development of several human-derived tumors implanted in athymic mice. MATERIALS AND METHODS: The experiments were performed on athymic mice bearing malignant human-derived tumors including prostate (PC-3), glioblastoma (GBM, U87-MG), colon (HCT15), squamous cell carcinoma (FaDu) and melanoma (C32). One or more (224)Ra-loaded wires were inserted into the tumors, and mice were assessed for tumor growth rate and survival. RESULTS: In vivo studies showed that DaRT can effectively destroy the tumors, and in vitro tests confirmed the sensitivity of the studied cells to alpha particles. While the C32 cells were relatively resistant, other tumor types (e.g. HCT15) exhibited sensitivity in both measured aspects. CONCLUSION: DaRT could potentially be combined with chemotherapy or other treatment modalities to effectively treat non-resectable tumors.