Abstract
Stabilization of IL-2 eliminates its dependence on CD25 and enhances its potency.
Major finding: Stabilization of IL-2 eliminates its dependence on CD25 and enhances its potency.
Approach: IL-2 variants with improved IL-2Rβ and IL-2Rγ binding were selected for in vitro.
Impact: An optimized IL-2 variant elicits superior antitumor responses with lower toxicity.
Interleukin-2 (IL-2) is an immunostimulatory cytokine that has been approved by the U.S. Food and Drug Administration for treatment of metastatic melanoma and renal cell carcinoma. Usually, IL-2 effectively stimulates expansion of cytotoxic T cells in the presence of IL-2 receptor α (IL-2Rα, or CD25), which increases the affinity of IL-2 for IL-2Rβ and IL-2Rγ. However, IL-2 binding to CD25-expressing nonimmune cells (such as pulmonary endothelial cells) has been shown previously to be principally responsible for IL-2–induced toxicity. Moreover, IL-2 also elicits the expansion of immunosuppressive T-regulatory cells that promote tumor immune evasion. To create an optimized version of IL-2 with decreased dependence on CD25 and improved target cell specificity, Levin and colleagues used an in vitro evolution strategy that involved displaying an error-prone PCR library of the human IL-2 coding sequence on the surface of yeast and selecting for variants with increased IL-2Rβ and IL-2Rγ affinity and signaling potency. The first generation resulted in selection of an IL-2 variant with a mutation affecting an α-helix (helix C) inside the hydrophobic core, and additional surrounding residues were mutated in the second generation. Collectively, these mutations stabilized the helix C core and linker region and eliminated the dependence of IL-2 on CD25 for leukocyte stimulation. Compared with wild-type IL-2, treatment with an engineered IL-2 variant led to increased expansion of cytotoxic CD8+ T cells and growth suppression of 3 different xenograft tumor models. Notably, the improved antitumor activity of the IL-2 variant was associated with a proportionally lower expansion of T-regulatory cells and decreased pulmonary edema. Together, these findings suggest that structural changes to the recombinant IL-2 currently used for cancer immunotherapy could improve clinical responses while mitigating adverse effects.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
RSS Feeds