Interleukin-2 (IL-2), a potent stimulator of T and NK cell proliferation, survival, and cytotoxic function, plays a major role in the immune system functions such as NK cell-stimulated immune responses. It also mediates the essential functions of regulatory T cells. IL-2 is implicated in autoimmune disease and is associated with apoptosis and thus, possesses an antitumor response. It mediates CD41+ T-cells differentiation into T-helper cell 1 and 2 effector subsets, preventing T-helper 17 differentiation. IL-2 induces γ-interferon and B cell growth factor secretion and modulates the expression of the IL-2 receptor.
High-dose IL-2 induces complete responses as a single agent in certain cancers. However, its use is limited due to toxicities such as severe hypotension and vascular leak syndrome (VLS). A better understanding of the mechanisms of IL-efficacy and toxicity and the development of more selective therapies are needed to improve the use of IL-2.
Preclinical data presented at the 2021 annual meeting of the American Association of Cancer Research demonstrates that the alpha/beta selective IL-2 partial agonist, STK-012, being developed by Synthekine, induced potent anti-tumor activity while avoiding the toxicities that have hindered the development of IL-2 therapeutics, including vascular leak syndrome (VLS). Synthekine also presented new data on its orthogonal IL-2 and CD-19 CAR-T system (STK-009 and SYNCAR-001).[1]
“IL-2 offers a wealth of therapeutic promises and challenges. While wild-type IL-2 is a potent T-cell stimulator and has shown single-agent activity in late-stage cancers, its broad and non-specific activation leads to critical, dose-limiting toxicities,” said Martin Oft, M.D., chief development officer at Synthekine.
“We believe that the efficacy of IL-2 is driven by the proliferation and activation of antigen-activated T cells, while the toxicity of IL-2 is driven by its broad and non-specific proliferation, extravasation, and activation of all lymphocytes, including NK cells and naïve T cells. We have designed our alpha/beta IL-2 to selectively bias towards antigen-activated T-cells and avoid NK cells and naïve T cells, a new approach designed to improve both the efficacy and the toxicity of wild-type IL-2. STK-012 demonstrates an improved therapeutic index compared to wild-type IL-2 and a non-alpha comparator. We look forward to advancing this program to an IND filing in 2021.”
Efficacy
Efficacy of STK-012 was evaluated in multiple mouse models using a mouse surrogate of STK-012 (alpha/beta IL-2). In these studies, the alpha/beta IL-2 achieved superior efficacy in the control of tumor growth and rate of complete responses compared to both wild-type IL-2 and non-alpha IL-2.
Synthekine’s alpha/beta IL-2 was significantly more effective than these comparators at increasing intratumoral CD8+ T-cells, including the ratio of CD8 T cells to Tregs. Importantly, studies showed the alpha/beta IL-2 did not induce lethality or VLS at therapeutic or supratherapeutic doses. Both wild-type and non-alpha IL-2 showed vascular toxicity, including VLS and lethality in mice. This finding was also supported by data from non-human primates, with the comparators resulting in significantly more infiltration of inflammatory cells in the lung relative to STK-012.
Summary
Overall, this study confirms that STK-012 was well tolerated at doses supra-efficacious in mice. Weekly dosing of STK-012 led to continuously 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.
Synthekine also presented new data on its orthogonal IL-2 and CD-19 CAR-T system (STK-009 and SYNCAR-001). New analyses further demonstrate STK-009 upregulates markers for expansion and activation of SYNCAR-001 cells in a CAR refractory lymphoma model and confers a gene signature indicative of long-term memory T cell development.
Reference
[1] Emmerich J, Ratti N, Bauer M, Vivona S, Semana M, Jayaraman B, McCauley S, Riener R, et al. STK-012, an alpha/beta selective IL-2 mutein for the activation of antigen-activated T cells in solid tumors. Abstract # 1744 Presented at: American Association of Cancer Research (AACR); held April 10 – 15, 2021.[Poster][Abstract]
Featured Image: Poster Session During the 2019 Annual Meeting of the American Association for Cancer Research. Photo Courtesy 2019 – 2021 AACR.
