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Abstract
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Interleukin-2 (IL-2)-based immunotherapy, one of the earliest immunomodulatory
approaches in cancer treatment, has played a pivotal role in activating cytotoxic T cells and
natural killer (NK) cells. Nonetheless, the clinical application of IL-2 encounters obstacles
such as a brief half-life, significant toxicity, and inadvertent stimulation of regulatory
T cells. This review intends to scrutinize recent advancements in the development of
engineered IL-2 derivatives, furnish a comprehensive overview of the cytokine’s structural
and functional attributes, evaluate clinical and preclinical research, and investigate novel
strategies to mitigate adverse effects while enhancing therapeutic efficacy. Evidence
suggests that emerging variants such as Bempegaldesleukin, THOR-707, and MDNA11
hold promise for safer and more efficacious treatments, with improved pharmacokinetics
and targeted cellular activity. Furthermore, the utilization of computational methods and
structural modeling as supplementary tools for predicting receptor interactions and biological
outcomes is vital in the advancement of next-generation immunotherapies. Despite notable
progress, considerable gaps in understanding persist regarding the molecular mechanisms
and structure-function relationships of IL-2 derivatives, underscoring the need for more
comprehensive and integrative research.
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