Saturday, May 18, 2024
5/18/2024
Abstract Interleukin-2 (IL-2) is an immunostimulatory cytokine that plays a central role in antitumor immunity, particularly in the activation and proliferation of T cells and natural killer (NK) cells for tumor eradication. Proleukin® is the first FDA approved immunotherapy drug with curable responses in a subset of renal and skin cancer patients. However, significant immune-related toxicities, short half-life, and inadvertent activation of immune tolerant regulatory T cells (Tregs) restrict the wide clinical adoption of Proleukin® therapy. Pleotropic effect of IL-2 in the activation of both immune suppressive Tregs and tumor killing CD8+ T cells and NK cells drove the development of IL-2 mutein superkines with polarized affinity toward CD8+ T/NK cells. Moreover, tumor acidity has been shown to deactivate wildtype IL-2, which spurred the design of low pH- resistant IL-2 muteins. Long circulating IL-2 has also been developed by fusion of Fc or albumin proteins to IL-2. Despite extensive efforts, most protein-engineered IL-2 still encounter significant systemic toxicities that limit the dose and efficacy in cancer therapy. The long-term goal of this application is to establish tumor- activatable IL-2 mutein superkine nanoparticles as an integrated paradigm for IL-2 therapy. We aim to combine nanoparticle engineering with protein engineering to minimize systemic toxicity while maintaining antitumor efficacy in the acidic tumor microenvironment. In the past decade, our lab invented a library of ultra- pH sensitive (UPS) nanoparticles with cooperative micelle/unimer phase transitions in response to a specific pH threshold. Preliminary data show UPS delivery of wildtype IL-2 Fc greatly reduced systemic toxicities (e.g., >100-fold reduction in interferon-¿ levels) while maintaining the antitumor efficacy of IL-2 Fc. Our collaborator Dr. Tao Yue’s lab recently identified a low pH-resistant IL-2 superkine with 20-fold higher binding to IL-2 receptor ¿ (R¿) than wildtype IL-2 while maintaining high activity at pH 6.4 whereas wildtype IL-2 lost its activity. In this application, we will test the central hypothesis that tumor-activatable delivery of R¿-tropic, acidity-resistant IL-2 superkine by the ultra-pH sensitive nanoparticles will effectively mask the systemic toxicity in normal tissues while achieving robust activation of cytotoxic lymphocytes in tumors for efficacious therapy. We will carry out three specific aims. Aim 1: Establish acidity-resistant IL-2 superkine-UPS nanoparticles with stable loading and pH-activatable release. Aim 2: Investigate the safety and antitumor efficacy of IL-2 Fc superkine-UPS nanoparticles in tumor-bearing mice and elucidate tropism of CD8+ T/NK cell activation over Tregs. Aim 3: Investigate the synergy of sodium lactate treatment with IL-2 Fc superkine nanoparticle therapy. We anticipate successful execution of the proposed application will lead to a new paradigm in interleukine-2 therapy with improved safety and antitumor efficacy outcomes.
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