On November 3, 2023 Synthekine Inc., an engineered cytokine therapeutics company, reported new data from preclinical studies of STK-026, its biased IL-12 partial agonist program, during the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting in San Diego (Press release, Synthekine, NOV 3, 2023, View Source [SID1234636936]). STK-026 is designed to retain the potent antitumor activity of IL-12 while avoiding its systemic toxicities and is currently in IND-enabling studies.
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"In the quest for developing new and effective cancer treatments, the pro-inflammatory cytokine IL-12 has shown tremendous potential but clinical use of IL-12 is limited by systemic toxicities and a very narrow therapeutic window," said Martin Oft, M.D., chief scientific officer of Synthekine. "Through our deep insights into the biology of IL-12 and our industry-leading cytokine engineering capabilities, we designed STK-026 to uncouple efficacy from the toxicities that are typically seen with wild-type IL-12. The data presented today adds to the growing body of evidence that STK-026’s novel approach, biasing IL-12’s activity toward activated T cells and avoiding hyperactivation of NK cells, has potential to harness anti-tumor efficacy without dose-limiting toxicity."
Title: Preclinical Pharmacodynamic Characterization of STK-026: A Novel IL-12 Partial Agonist for Cancer with Maintained CD8 T cell activity, Reduced NK-mediated Toxicity and an Improved Therapeutic Window
Session Title: Immune-Stimulants and Immune Modulators
Session Date & Time: Friday, Nov. 3, 2023, 9 am – 7 pm PT
Poster Board Number: 1053
Summary & Key Findings:
STK-026 is a biased IL-12 agonist engineered to exhibit preferential activity on antigen-activated T cells, which drive the efficacy of IL-12, while avoiding broad systemic activation of resting T cells and NK cells, which are linked to the toxicity of IL-12.
In tumor bearing mouse models, a mouse surrogate of STK-026 was well-tolerated and showed meaningful anti-tumor efficacy as both a single agent and in combinations. Notably, compared to wild-type IL-12 treatment, STK-026 monotherapy demonstrated a substantial improvement in therapeutic window which was associated with reduced NK activation and systemic cytokine induction.
In cynomolgus macaques, STK-026 was well-tolerated at very high doses (up to 5mg/kg) without signs of CRS. Further, compared to wild-type IL-12, STK-026 treatment resulted in reduced induction of liver enzymes, organ weight gains and lymphocyte activation in peripheral tissues, thus avoiding the detrimental toxicity associated with IL-12 therapy.
Overall, assessments of STK-026 in mouse and cyno show that its properties successfully avoid spikes of early NK activation but still effectively activate T cells. Preclinical studies and pharmacology support the idea that this rebalancing of IL-12 driven innate and adaptive immune responses can achieve efficacy without dose-limiting toxicity.
The poster will be available on Synthekine’s website following presentation at the meeting.