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IL-2K35C-moFA, a Long-Acting Engineered Cytokine with Decreased Interleukin 2 Receptor α Binding, Improved the Cellular Selectivity Profile and Antitumor Efficacy in a Mouse Tumor Model.
- Source :
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Cancers . Oct2022, Vol. 14 Issue 19, p4742. 13p. - Publication Year :
- 2022
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Abstract
- Simple Summary: The application of IL-2 for treating cancer is limited owing to its toxicity and short half-life. Its high binding ability to IL-2 receptor α expands immunosuppressive Treg cells, which represents an undesirable toxicity in cancer immunotherapy. Moreover, its small molecular size is the reason for its short half-life. We solved these problems by using a covalent modification strategy of IL-2 variant IL-2K35C with fatty acid by maleimide chemistry, namely, IL-2K35C-moFA. The experiments performed in vitro and in vivo proved that IL-2K35C-moFA is a novel immunotherapeutic agent with the potential to selectively stimulate CD8+ T cells and NK cells. Compared to IL-2WT, IL-2K35C-moFA showed a specifically reduced potency for the stimulation of Treg cells. Our results also showed that fatty acid conjugation appears to be effective in half-life extension. The combination of selective lymphocyte expansion and its long half-life means IL-2K35C-moFA should be evaluated as a potential human immunotherapeutic in the future. Human interleukin 2 (IL-2) has shown impressive results as a therapeutic agent for cancer. However, IL-2-based cancer therapy is limited by strong Treg amplification owing to its high binding affinity to IL-2 receptor α (IL-2Rα) and its short half-life owing to its small molecular size. In this study, we solved these problems using a covalent modification strategy of the IL-2 variant, i.e., substituting cysteine (C) for lysine (K) at position 35, using octadecanedicarboxylic acid through maleimide chemistry, creating IL-2K35C-moFA. IL-2K35C-moFA was equipotent to human IL-2 wild type (IL-2WT) in activating tumor-killing CD8+ memory effector T cells (CD8+ T) and NK cells bearing the intermediate affinity IL-2 receptors, and less potent than IL-2WT on CTLL-2 cells bearing the high-affinity IL-2 receptors. Moreover, it was shown to support the preferential activation of IL-2 receptor β (IL-2Rβ) over IL-2Rα because of the mutation and fatty acid conjugation. In a B16F10 murine tumor model, IL-2K35C-moFA showed efficacy as a single dose and provided durable immunity for 1 week. Our results support the further evaluation of IL-2K35C-moFA as a novel cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Subjects :
- *INTERLEUKINS
*DRUG efficacy
*BIOLOGICAL models
*IN vitro studies
*IN vivo studies
*GENETIC mutation
*HIGH performance liquid chromatography
*ANIMAL experimentation
*LIQUID chromatography
*ANTINEOPLASTIC agents
*IMMUNOLOGIC receptors
*T-test (Statistics)
*MASS spectrometry
*ENZYME-linked immunosorbent assay
*CELL proliferation
*STATISTICAL hypothesis testing
*TUMORS
*POLYMERASE chain reaction
*DATA analysis software
*IMMUNOTHERAPY
*MICE
*SPECTRUM analysis
*PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 20726694
- Volume :
- 14
- Issue :
- 19
- Database :
- Academic Search Index
- Journal :
- Cancers
- Publication Type :
- Academic Journal
- Accession number :
- 159669688
- Full Text :
- https://doi.org/10.3390/cancers14194742