Recombinant IL-2 (aldesleukin) is a potent T cell proliferation and differentiation factor and is an approved immunotherapy for advanced melanoma and renal cell carcinoma. Despite the remarkable and durable remissions induced by IL-2 in a subset of these late stage patients, clinical use of this drug has been limited due to the severe systemic toxicity triggered by the indiscriminate activation of immune cells. Thus, new IL2-based therapies are needed that harness the cytokine’s activity specifically to the tumor site while safeguarding healthy tissues. We have developed next-gen cytokine-based immunotherapies, On Demand Cytokines or ODCs. ODCs are engineered fusion proteins in which the cytokine is linked to a cytokine-inhibitory moiety via a short proprietary peptide motif. These recombinant proteins are designed to exploit the unique characteristics of the tumor microenvironment (TME) and enable the local release of active cytokine, which then mounts an anti-tumor immune response. ODCs are cytokine prodrugs that are activated and retained at the tumor site, while remaining inactive in circulation. This innovative platform technology thus minimizes the severe systemic toxicity associated with traditional cytokine therapies and can be applied to generate a wide array of safe and effective cytokine drugs. Here, we report the pre-clinical characterization of our lead asset ODC-IL2. ODC-IL2 is efficiently activated in vitro and releases functional IL-2. Further in vitro characterization shows the fusion protein is stable when incubated with serum collected from either naïve or tumor-bearing mice, thus indicating prodrug conversion to active cytokine does not occur systemically. Moreover, ODC-IL2 has a favorable pharmacokinetic profile following a single IV injection and exhibits dramatic single agent anti-tumor activity in subcutaneous murine cancer models with no systemic toxicity. Analysis of TME-associated immune cells revealed that ODC-IL2 treated tumors show a marked increase of tumor-infiltrating lymphocytes, in particular CD25/CD8 positive T cells and NK cells. We have successfully generated and characterized ODC-IL2 candidates containing TME binding modules to further enhance their site-specific activity. Single agent efficacy of ODC-IL2 in subcutaneous syngeneic tumor models with diverse TME composition is shown. In conclusion, we have demonstrated proof of concept of the On Demand Cytokine platform and its potential to deliver safe and effective immunotherapies.
Citation Format: Emma J. Langley, Chen Li, Tani-Ann Lee, Brian Grot, Jessica Zaid, Johnavon Kim, Deepak Yadav, Phillip Kim. On demand cytokine, a novel cytokine prodrug, demonstrates robust single agent efficacy without systemic toxicity in syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1745.
by Emma Langley
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