Abstract 1744: STK-012, an alpha/beta selective IL-2 mutein for the activation of the antigen-activated T cells in solid tumor

Abstract

Abstract Interleukin-2 (IL-2) is a potent stimulator of T and NK cell proliferation, survival, and cytotoxic function. High dose IL-2 induces complete responses as a single agent in certain cancers. Its use is limited due to toxicities such as severe hypotension and vascular leak syndrome (VLS). A better understanding of the mechanisms of IL-2 efficacy and toxicity and development of more selective therapies are needed to improve the use of IL-2. Next generation IL-2 therapeutics have been engineered to bias activity towards the dimeric form of the IL-2 receptor, which consists of IL-2Rβ (CD122) and IL-2Rγ (CD132), and away from the high affinity trimeric form of the receptor, which also includes IL-2Rα (CD25). This approach is designed to stimulate NK cells and naïve effector T-cells, which express the dimeric, and not the trimeric, form of the receptor. However, this approach largely misses antigen-activated and tumor-specific T-cells, which have high expression of both CD25 and CD122. In addition, this approach expands peripheral NK cells, which have been shown in mice to cause VLS (1-3).To specifically stimulate antigen-activated CD25+ effector T cells in cancer patients and avoid systemic NK and naïve T cell activation, we have developed a PEGylated, CD25/CD122-selective IL-2 mutein (STK-012) and its mouse surrogate (STK-014). Here we present efficacy and safety of STK-014 compared to wild type IL-2 (wtIL-2) and a CD122/CD132 biased IL-2 (βγIL-2). We also present safety of STK-012 in non-human primates (NHP). STK-012/STK-014 selectively induced STAT5 phosphorylation and proliferation in antigen activated T cells but not in NK cells and naïve T cells. In mice, STK-014 showed reduced toxicity compared to wtIL-2 and βγIL-2. In particular, wtIL-2 and βγIL-2 induced VLS while STK-014 did not. Moreover, STK-014 demonstrated complete responses both as single agent and in combination with a PD-1 antibody in syngeneic tumor models. In general, STK-014 demonstrated improved efficacy compared to wtIL-2 and βγIL-2. STK-014 dramatically increased intratumoral T cells and intratumoral cytotoxic activity compared wtIL-2 and βγIL-2 while avoiding T cell activation in the spleen. STK-014 treatment drastically increased the CD8+ T cell to Treg ratio within the tumor when compared to control tumors (25-fold), but also in comparison to wtIL-2 (2.75-fold) and to βγIL-2 (5.2-fold).In NHP, STK-012 was well tolerated at doses supra-efficacious in mice. Weekly dosing of STK-012 led to continuous elevated serum concentrations, demonstrating selectivity for CD25/122+ T cells. STK-012 selectively induced memory T cell expansion, including CD28+ CD95+ CD8 T cells. In summary, STK-012 avoids IL-2 mediated toxicity and may enable the specific expansion of antigen activated memory T cells in cancer patients, leading to durable tumor response. 1 Peace DJ and Cheever MA. JEM, 1989.2 Gatley MK et al. JI, 1988.3 Assier E et al. JI; 2004. Citation Format: Jan Emmerich, Michele Bauer, Marie Semana, Bhargavi Jayaraman, Sandro Vivona, Scott McCauley, Romina Riener, Rene De Waal Malefyt, Paul-Joseph Aspuria, Deepti Rokkam, Patrick Lupardus, Rob Kastelein, Martin Oft. STK-012, an alpha/beta selective IL-2 mutein for the activation of the antigen-activated T cells in solid tumor [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 1744.

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