1340 Preclinical efficacy and immune activity of half-life extended IL-18 fusion proteins resistant to IL-18BP suppression

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Background The promising immunological effects of recombinant wild-type interleukin-18 (IL-18) for cancer immunotherapy have been limited in clinical studies by rapid upregulation of IL-18 binding protein (IL-18BP), which serves as a negative feedback checkpoint of the IL-18 pathway. Additionally, cytokines are rapidly cleared from circulation limiting efficacy and necessitating difficult dosing regimens for patients. To overcome these limitations, IL-18 variants resistant to IL-18BP binding were generated and fused to half-life extension protein scaffolds with a goal to create an improved IL-18-based therapeutic. Methods Human IL-18 variants were tested in vitro for human PBMC-mediated tumor cell growth inhibition by live cell imaging of mixed cultures. In vivo pharmacokinetics and pharmacodynamics of human variants and mouse orthologs were examined in either humanized or wildtype mouse models by assessing plasma exposure, cytokines and chemokines, and immune profiling by flow cytometry. Mouse orthologs were assessed for in vivo efficacy in the syngeneic MC38 heterotopic model of colorectal cancer. Potency of human variants on cynomolgus PBMCs was measured in vitro by an IFN-g release assay. Results Human IL-18 variants stimulated PBMC-dependent growth inhibition of human tumor cells. In humanized mouse models, the human variants displayed a pharmacodynamic profile consistent with IL-18 pathway activation, and a pharmacokinetic profile confirming half-life extension. Mouse IL-18 orthologs displayed dose-dependent anti-tumor activity when administered as monotherapy in the MC38 model. At optimal dose levels, complete responses, improved survival and greater than 90% tumor growth inhibition were observed, which was superior to a half-life extended IL-18BP-sensitive variant. Immune profiling by flow cytometry revealed expansion of effector CD8+ T cells and cytotoxic NK cells in the peripheral blood of non-tumor bearing wildtype mice following a single treatment, which were of greater magnitude and duration when compared to a non-half-life extended variant. Activity of human IL-18 variants on cynomolgus PBMCs has been confirmed in vitro. Conclusions In summary, half-life extended IL-18 variants with strong resistance to IL-18BP displayed robust monotherapy efficacy in preclinical models and suggest that both IL-18BP resistance and half-life extension are critical for maximal monotherapy efficacy. Durable expansion of key effector immune cell types associated with cancer immunotherapy, and plasma cytokine and chemokine elaboration, support both on target biology and promotion of anti-tumor immunity. These promising results identify protein engineering solutions with potential to unlock the full therapeutic benefit of IL-18, as we progress with studies to enable testing of our molecules in the clinic.

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