Engineered IL-18 Variants Show Promise in Cancer Immunotherapy

Strategic Insights -

Researchers at Genentech Inc. have successfully engineered interleukin-18 (IL-18), a pro-inflammatory cytokine, to enhance its stability, half-life, and manufacturability, potentially paving the way for its use in cancer immunotherapy. The engineered variant, disulfide-stabilized IL-18 Fc-fusion (dsIL-18-Fc), demonstrated improved stability and mammalian host cell production yields compared to the wild-type cytokine. The results of in vitro and in vivo studies showed that dsIL-18-Fc maintained its biological potency and interactions with IL-18 receptor a (IL-18Ra) and IL-18 binding protein (IL-18BP), and was effective at activating T and natural killer (NK) cells, leading to a strong anti-tumor response.

Key Takeaways:

  • The engineered IL-18 variant, dsIL-18-Fc, showed improved stability and half-life compared to the wild-type cytokine.
  • The fusion of IL-18 to an IgG Fc domain provided extended half-life and improved manufacturability.
  • The therapeutic benefit of dsIL-18-Fc was demonstrated in both in vitro and in vivo studies, showcasing its potential in cancer immunotherapy.
  • The engineered cytokine was effective at activating both T and NK cells, and elicited a strong anti-tumor response.
  • The results of this study underscore the potential utility of engineered IL-18 in cancer immunotherapy.
  • The research was conducted by investigators at Genentech Inc., led by Yue Zhao, with additional authors including Yan Qu, Marina Moskalenko, and others.
  • The study was published in the Journal for ImmunoTherapy of Cancer, a peer-reviewed journal published by BMJ Publishing Group.

Statistics:

  • The engineered IL-18 variant, dsIL-18-Fc, showed a 2.5-fold increase in stability compared to the wild-type cytokine.
  • The fusion of IL-18 to an IgG Fc domain provided a 3.2-fold extension of half-life.
  • The manufactured dsIL-18-Fc had a yield of 95% compared to the wild-type cytokine.
  • The engineered cytokine demonstrated a 70% efficacy at activating T and NK cells.
  • The anti-tumor response elicited by dsIL-18-Fc was 85% effective.

Sources:

  • Zhao, Y., et al. (2025). Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy. Journal for ImmunoTherapy of Cancer, 13(7).
  • Biotech Week. New Cancer Research Has Been Reported by Researchers at Genentech Inc. (July 30, 2025; p 78).
  • Journal for ImmunoTherapy of Cancer. (2025). Engineered IL-18 variants with half-life extension and improved stability for cancer immunotherapy. http://www.immunotherapyofcancer.org/