Unleashing Natural IL18 Activity Using an Anti-IL18BP Blocker Induces Potent Immune Stimulation and Antitumor Effects

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Recombinant cytokines show limited anticancer efficacy due to narrow therapeutic windows and systemic side effects.
• Interleukin-18 (IL18) is a proinflammatory cytokine that boosts T- and NK-cell activity but is inhibited by IL18-binding protein (IL18BP) in the tumor microenvironment (TME).
• IL18BP is upregulated in the TME as a negative feedback mechanism, sequestering IL18 and limiting its therapeutic potential.

Purpose of the Study:

• To investigate the potential of restoring IL18 activity within the TME for cancer treatment.
• To develop and evaluate a novel therapeutic strategy targeting the IL18:IL18BP interaction.

Main Methods:

• Analysis of IL18 and IL18BP levels in human tumor tissues and peripheral blood.
• Development of COM503, a high-affinity antibody against IL18BP, to block IL18BP:IL18 interaction.
• In vivo studies using surrogate anti-IL18BP in mouse tumor models, alone and in combination with anti-PD-L1.

Main Results:

• IL18 is upregulated and predominantly bound by IL18BP within the TME across multiple human tumors.
• Administration of anti-IL18BP (alone or with anti-PD-L1) significantly inhibited tumor growth and improved survival in mouse models.
• Treatment induced localized TME immune modulation, increasing polyfunctional, non-exhausted T- and NK-cells without systemic inflammatory effects.

Conclusions:

• Blocking IL18BP is a viable strategy to unleash the anticancer potential of endogenous IL18.
• Targeting the IL18:IL18BP axis represents a promising approach for cancer immunotherapy by enhancing T- and NK-cell-mediated anti-tumor immunity.
• Localized immune activation within the TME, rather than systemic effects, is key to the therapeutic efficacy of anti-IL18BP therapy.