RESUMEN

BACKGROUND: In a previous work, an IL-2Rßγ biased mutant derived from human IL-2 and called IL-2noα, was designed and developed. Greater antitumor effects and lower toxicity were observed compared to native IL-2. Nevertheless, mutein has some disadvantages, such as a very short half-life of about 9-12 min, propensity for aggregation, and solubility problems. OBJECTIVE: In this study, PEGylation was employed to improve the pharmacokinetic and antitumoral properties of the novel protein. METHODS: Pegylated IL-2noα was characterized by polyacrylamide gel electrophoresis, size exclusion chromatography, in vitro cell proliferation and in vivo cell expansion bioassays, and pharmacokinetic and antitumor studies. RESULTS: IL-2noα-conjugates with polyethylene glycol (PEG) of 1.2 kDa, 20 kDa, and 40 kDa were obtained by classical acylation. No significant changes in the secondary and tertiary structures of the modified protein were detected. A decrease in biological activity in vitro and a significant improvement in half-life were observed, especially for IL-2noα-PEG20K. PEGylation of IL-2noα with PEG20K did not affect the capacity of the mutant to induce preferential expansion of T effector cells over Treg cells. This pegylated IL-2noα exhibited a higher antimetastatic effect compared to unmodified IL-2noα in the B16F0 experimental metastases model, even when administered at lower doses and less frequently. CONCLUSION: PEG20K was selected as the best modification strategy, to improve the blood circulation time of the IL-2noα with a superior antimetastatic effect achieved with lower doses.

Asunto(s)

Interleucina-2 , Proteínas , Humanos , Polietilenglicoles/química

RESUMEN

Over the last 4 years, various drugs have been approved for the treatment of metastatic cutaneous melanoma. Ipilimumab, an anti-CTLA-4 inhibitor that stimulates antitumor immunity, was the first agent to improve overall survival both in first line and in previously treated patients. Ipilimumab results in long term disease control in approximately 20% of the patients. Vemurafenib was the first BRAF inhibitor (BRAFi) approved and also resulted in improved overall survival compared with dacarbazine in patients with BRAF mutated metastatic melanoma. More recently, another BRAFi, dabrafenib, and a MEK inhibitor, trametinib, were approved either alone or in combination as they each showed significant antitumor activity relative to dacarbazine and the combination appeared superior to dabrafenib monotherapy. The major feature of such tumor targeted therapy is its high response rate (40-70%) and the rapidity of the responses, resulting in prompt clinical improvement. However, unlike immunotherapy, targeted therapy does not result in long-term treatment free survival. In this paper, we discuss how best to integrate the currently available treatment options including high-dose interleukin-2 (HD IL-2), systemic chemotherapy, ipilimumab and tumor targeted therapy in various clinical scenarios.