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Comparison of vascular leak syndrome in mice treated with IL21 or IL2
Pallavur V Sivakumar1, Richard Garcia, Kimberly S Waggie
1ZymoGenetics, a Bristol-Myers Squibb Company, Seattle, Washington, USA.
Abstract:
Interleukin 21 (IL21) is a T-cell-derived 4-helix-bundle cytokine that has sequence homology to the IL2 family. Recombinant human interleukin 2 (rIL2) is approved for the treatment of metastatic melanoma and renal cell carcinoma. However, toxicity of rIL2, including induction of vascular leak syndrome (VLS), has limited use of this cytokine to a small proportion of eligible patients. Both rIL2 and murine IL21 (mIL21) have potent antitumor efficacy in murine models. The purpose of the current study was to compare the ability of mIL21 and rIL2 to induce vascular leakage in a mouse model. Pulmonary and hepatic uptake of Evans blue dye, serum cytokine levels, spleen cell immunophenotype, and histologic changes in lung and liver were evaluated to detect VLS. High-dose (200 μg) rIL2 treatment induced vascular leakage in mice, evidenced by inflammatory cell infiltration and fluid extravasation into the lung and liver and increased levels of TNFα, IFNγ, IL5, MCP1, and IL6 in serum. In contrast, an equivalent dose of mIL21 resulted in minimal vascular leakage with no evidence of cytopenia or cytokine production. These results support the use of IL21 as a cancer immunotherapeutic agent, potentially providing an antitumor response without induction of VLS.
Insights
Interleukin 21 (IL21) may be a safer cancer immunotherapy than recombinant Interleukin 2 (rIL2). IL21 demonstrated potent antitumor efficacy in mice without causing the vascular leak syndrome associated with rIL2 treatment.
Area of Science:
- Immunology
- Oncology
- Cytokine Biology
Background:
- Recombinant human interleukin 2 (rIL2) treats metastatic melanoma and renal cell carcinoma but causes toxic vascular leak syndrome (VLS).
- Interleukin 21 (IL21) is a T-cell-derived cytokine with potential as a cancer therapeutic.
- Both rIL2 and murine IL21 (mIL21) show antitumor efficacy in preclinical models.
Purpose of the Study:
- To compare the vascular leakage induced by mIL21 and rIL2 in a mouse model.
- To evaluate IL21 as a potential cancer immunotherapy with reduced toxicity compared to rIL2.
Main Methods:
- Mice were treated with high-dose rIL2 or mIL21.
- Vascular leakage was assessed by Evans blue dye uptake in pulmonary and hepatic tissues.
- Serum cytokine levels, spleen cell immunophenotype, and lung/liver histology were analyzed to detect VLS.
Main Results:
- High-dose rIL2 induced significant vascular leakage, characterized by inflammatory cell infiltration and fluid extravasation in the lungs and liver.
- rIL2 treatment led to increased serum levels of TNFα, IFNγ, IL5, MCP1, and IL6.
- In contrast, mIL21 treatment at an equivalent dose caused minimal vascular leakage, with no observed cytopenia or significant cytokine production.
Conclusions:
- IL21 demonstrates potent antitumor efficacy in preclinical models with significantly less vascular leakage compared to rIL2.
- IL21 represents a promising cancer immunotherapy candidate, potentially offering antitumor benefits without the dose-limiting toxicity of VLS associated with rIL2.
