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 entitled "A tumor-specific pro-IL-12 activates preexisting cytotoxic T cells to control established tumors" published in the Journal of Science Immunology on January 7, 2022, by Prof. PENG Hua at the Institute of Biophysics, Chinese Academy of Sciences and Prof. FU Yang-Xin at the University of Texas Southwestern Medical Center 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.

Overall, the researchers developed a tumor-conditional pro-IL-12 to overcome the limitations of IL-12-based therapies and provided a platform for future anti-tumor procytokine design.

Article links: https://www.science.org/doi/10.1126/sciimmunol.abi6899

Contact: PENG Hua

Institute of Biophysics, Chinese Academy of Sciences

Beijing 100101, China

Email: hpeng@ibp.ac.cn

(Reported by Dr. PENG Hua's group)