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1087 SOT201 is a novel cis-acting immunocytokine targeting IL-15Rβγ to reinvigorate PD-1+tumor infiltrating lymphocytes and potentiate anti-tumor efficacy
  1. Irena Adkins1,
  2. Zuzana Antosova1,
  3. Katerina Behalova2,
  4. Petr Danek1,
  5. Klara Danova1,
  6. Matej Fabisik1,
  7. Kamila Hladikova1,
  8. Nataliia Kalynovska1,
  9. Lucie Kosinova1,
  10. Pavel Marasek1,
  11. Vladyslav Mazhara2,
  12. Nada Podzimkova1,
  13. Jan Praslicka1,
  14. Katerina Sajnerova1,
  15. Milada Sirova2,
  16. David Bechard3,
  17. Ulrich Moebius1,
  18. Marek Kovar2,
  19. Lenka Palova Jelinkova1,
  20. Radek Spisek1 and
  21. Martin Steegmaier1
  1. 1Sotio Biotech a.s., Prague, Czech Republic
  2. 2Institute of Microbiology of ASCR, Prague, Czech Republic, Czech Republic
  3. 3Cytune Pharma, Nantes, France, France
  • 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 SOT201 is a novel cis-acting immunocytokine consisting of a humanized, Fc-silenced monoclonal antibody against PD-1 fused to a covalent RLI-15 complex of a human attenuated IL-15 mutein linked to the high-affinity binding site of the IL-15Rα, the sushi+ domain. The activity of SOT201 is based on spatiotemporal reinvigoration of PD-1+ CD8+tumor infiltrating lymphocytes (TILs) via cis activation and concomitant activation of innate immunity by IL-15-mediated signaling via the IL-2/IL-15βγ receptor.

Methods Human PBMC, wt or PD-1-transfected Kit225 or Raji cells and in vitro exhausted human T cells were used to evaluate cis/trans activity of SOT201. Mouse surrogate SOT201-induced expansion and activation of ovalbumin-primed adoptively transferred OT-I CD8+ T cells in vivo was detected by flow cytometry. PD-1 responsive (MC38, CT26) and resistant mouse models (B16F10, CT26 STK11 ko) were used to determine the anti-tumor efficacy. The pharmacodynamics and pharmacokinetics of SOT201 were evaluated in cynomolgus monkeys.

Results SOT201 delivers attenuated RLI-15 mutein to PD1+ TILs via cis presentation, stimulates in vitro exhausted T cells and expands antigen-specific PD-1+ CD8+ T cells in vivo. SOT201 treatment showed strong anti-tumor efficacy in PD-1 responsive and resistant tumor models in vivo and was shown to be superior to mouse PD-1-IL-2Rβγ agonist. Studies in cynomolgus monkeys showed that decreased affinity of the novel IL-15 mutein in SOT201 for reduced IL-15Rβγ binding is well optimized to ensure favorable pharmacokinetic properties while potently stimulating PD-1+ CD8+ T cells and NK cells.

Conclusions This data confirms SOT201 to be a promising therapeutic candidate molecule directed preferentially to the PD-1+ T cell tumor microenvironment. SOT201 is currently being prepared for evaluation in a Phase I clinical study in metastatic advanced cancer patients as well as for PD-1 resistant/refractory patients.

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