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ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

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Research Article

PEGylation Strategy for Improving the Pharmacokinetic and Antitumoral Activity of the IL-2 No-alpha Mutein

Author(s): Marianniz Díaz-Hernández*, Janoi Chang-Calderón, Miguel Angel Álvarez, Ingrid Ruiz Ramírez, Olga Lidea Fernández Saez, Armando López Medinilla, Carlos Yordan González Castillo, Claudia Diaz Borges, Sum Lai Lozada Chang, Kalet León and Tania Carmenate*

Volume 29, Issue 44, 2023

Published on: 11 December, 2023

Page: [3579 - 3588] Pages: 10

DOI: 10.2174/0113816128279062231204110410

Price: $65

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Abstract

Background: In a previous work, an IL-2Rβγ 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.

Keywords: PEGylation, Interleukin-2 (IL-2) mutant, pharmacokinetic, protein structure, antitumor activity, lower toxicity.

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