Interleukin-12 (IL-12), a potent inducer of cell-mediated immunity, can stimulate the anti-tumor effector functions of the activated T and NK cells for solid tumors rejection. However, clinical administration of IL-12 has been limited because of its short half-life, low efficacy, and dose-limiting systemic toxicity.
In a study published in Science Immunology, Prof. Peng Hua at the Institute of Biophysics of the Chinese Academy of Sciences and Prof. Fu Yangxin at the University of Texas Southwestern Medical Center, and collaborators, developed a new generation IL-12, the pro-IL-12, with low toxicity, tumor restriction, and high anti-tumor efficiency.
The researchers first constructed an IL-12-Fc fusion protein to extend the in vivo half-life of IL-12 and further engineered a pro-IL-12 with the functional site blocked by an MMP-cleavable peptide-linked IL-12 natural extracellular receptor-binding domains. Pro-IL-12 could be reactivated when the linker was cleaved by tumor-enriched MMP14. Systemic treatment with pro-IL-12 resulted in effective tumor control and prolonged mouse survival.
This next-generation IL-12 directly activated the preexisting intratumoral tumor-specific CD8+ T cells to release IFNγ within the TME. Pro-IL-12 could improve the therapeutic outcomes when combined with both tyrosine kinase inhibitors (TKI)-targeted therapy and immune checkpoint blockade (ICB) therapy, providing a new therapeutic regimen to reduce tumor resistance to the existing treatments.
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