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XTX301, a tumor-activated Interleukin-12 has the potential to widen the therapeutic index of IL-12 treatment for solid tumors as evidenced by pre-clinical studies.

ABSTRACT: Interleukin-12 (IL-12) is a proinflammatory cytokine, that has shown promising anti-tumor activity in mice and humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic intravenous administration of IL-12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to have preferential IL-12 bioactivity in the tumor. We have generated XTX301, a half-life extended IL-12 molecule fused to the human Fc protein via a protease cleavable linker and pharmacologically inactivated by an interleukin-12 receptor subunit beta 2 (IL-12Rβ2) masking domain. Intravenous administration of a mouse surrogate molecule (mXTX301) demonstrated significant tumor growth inhibition in mouse models of colorectal cancer and melanoma without causing systemic toxicities. Here, we performed gene expression analysis of tumor samples to characterize the mechanism of action of mXTX301. MC38 tumor-bearing mice were treated with vehicle, mXTX301, or an unmasked positive control. A comprehensive examination of global gene expression revealed a similar pattern of molecular changes for mXTX301 and unmasked control on Day 4 and Day 7 compared to vehicle, with both molecules inducing the upregulation of several immune-related genes such as Stat1, Il12rb1, Irf1 and Cxcl9 . Thus, mXTX301 demonstrated pharmacodynamic effects in mouse tumors that are consistent with known IL-12 biology.

ORGANISM(S): Mus musculus

PROVIDER: GSE237982 | GEO | 2023/12/05

REPOSITORIES: GEO

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Phosphoproteomic analysis of IL-2 MSA and IL-12 MSA combination on T cell signaling

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2024-01-26 | PXD044740 | Pride

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