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.