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1053 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
  1. Zhenya Koliesnik1,
  2. Michael Totagrande1,
  3. Ryan Burgess1,
  4. Kim Q Tran1,
  5. Michele Bauer1,
  6. Bharghavi Jayaraman1,
  7. Cindy Buffone1,
  8. Priyanka Balasubrahmanyam1,
  9. Jan Emmerich2,
  10. Deepti Chaturvedi1,
  11. Deepti Rokkam1,
  12. Rene De Waal Malefyt1,
  13. Heiko Greb1,
  14. Navneet Ratti1,
  15. Sandro Vivona1,
  16. Robert Kastelein1,
  17. Patrick Lupardus1,
  18. Luis Zuniga1,
  19. David B Rosen1 and
  20. Martin Oft1
  1. 1Synthekine, Menlo Park, CA, USA
  2. 2Synthekine, Germany
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Interleukin-12 (IL-12) is a pro-inflammatory cytokine composed of p35 and p40 subunits produced by antigen-presenting cells to stimulate Th1 cells, cytotoxic CD8 T cells, and NK cells. IL-12 has potent anti-tumor properties in multiple preclinical models, however clinical applications of wild type IL-12 (IL-12wt) or IL-12wt-Fc fusions are hampered by severe dose-limiting toxicities.1 Preclinically, IL-12 toxicity is mediated by NK cell activation.2

Here we report on a novel human IL-12 partial agonist (STK-026) with diminished binding to IL-12Rb1. STK-026 was designed to increase selectivity towards antigen activated T cells, which strongly upregulate IL-12Rb1 upon activation, and to reduce stimulation of NK cells or resting T cells, which express modest levels of IL-12Rb1.

Methods To understand the preclinical pharmacology of STK-026, we generated a half-life extended mouse surrogate of the IL-12 partial agonist (mSTK-026) for pharmacokinetic (PK) and pharmacodynamic (PD) assessment in healthy and tumor bearing mice. Further, PK and PD parameters of human STK-026 were analyzed in healthy cynomolgus macaques.

Results At efficacious doses, systemic administration of a half-life extended version of wild type mouse IL-12 (mIL-12wt-Fc) induced significant weight loss and lethality with early proinflammatory cytokine release and systemic NK cell activation. Conversely, mSTK-026 was well tolerated, and avoided rapid NK cell activation seen with mIL-12wt-Fc. Both mSTK-026 and mIL-12wt-Fc showed robust single-agent anti-tumor efficacy in syngeneic tumor models however mSTK-026 demonstrated a >10-fold higher therapeutic index than mIL-12wt-Fc. Depletion of NK cells did not diminish anti-tumor efficacy of either IL-12 and efficacy of mSTK-026 was associated with intratumoral CD8 T cell activation and myeloid cell activation. In cynomolgus macaques, human STK-026 demonstrated antibody like PK, was well-tolerated at all doses tested (highest: 5mg/kg), and induced no detectable systemic IL-6 or TNFα. Compared to hIL-12wt-Fc, STK-026 avoided early spikes in NK cell activity and systemic chemokine levels, reduced lymphocyte activation in peripheral tissues, and reduced ALT/AST induction at doses activating effector and memory CD8 T cells.

Conclusions Overall, mSTK-026 retained anti-tumor efficacy without spikes of early NK activation and induction of severe toxicities seen with mIL-12wt-Fc. Similarly, human STK-026 avoided early spikes of NK activity in cynomolgus macaques and showed reduced signs of systemic toxicities compared to hIL-12wt-Fc. These data suggest that STK-026 is a novel immunotherapy approach with the potential to maintain anti-tumor efficacy while avoiding dose limiting toxicities classically associated with IL-12 therapy.


  1. Atkins M, et al. Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clinical Cancer Research. 1997;3(3):409–17.

  2. Carson W, et al. A fatal cytokine-induced systemic inflammatory response reveals a critical role for NK cells. J Immunology. 1999;162(8):4943–4951.

Ethics Approval All animal experiments were carried out in accordance with local government and institutional guidelines and regulations. All in vivo protocols were approved by a local Institutional Animal Care and Use Committee, or other appropriate review board, before study execution. All animals were housed in accordance with local regulations.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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