1190 OSE-cytomask®, a novel CIS-demasking cytokine technology to increase therapeutic index of immunocytokine

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Background Immunocytokines are promising therapeutic approaches to enhance T-cell response by delivering interleukins directly into the tumor. The fusion of interleukins with anti-PD-1 antibodies has shown some efficacy in preferentially cis-activating PD1+ T-cells. However, off-target activation of PD1-negative cells remains a significant challenge due to the high receptor/cytokine affinity, leading to unwanted systemic effects, toxicity and low tumor biodistribution, which ultimately limits the clinical potential of many immunocytokines. To overcome these limitations, we developed OSE-Cytomask® platform based on linker technology by designing a universal and non-cleavable linker that allows CIS-cytokine demasking upon binding of the fused antibody to its target. This platform enables precise cytokine activation on the right T cell population to improve immunocytokine therapeutic index.Methods A series of linkers were screened and fused to a high-affinity anti-PD1 antibody and multiple cytokines (IL-2/-15/-10/-18...). I n vitro and in vivo activity was compared to the conventional immunocytokine constructed with (G4S)3 linker.Results OSE-Cytomask® linker technology strongly decreases cytokine activity on PD1neg cells while maintaining strong activation of PD1+ T cells using transduced and/or primary T cells. OSE®Cytomask linker decreased affinity of the cytokine to its receptor as measured by Octet, confirming masking properties of the linker in absence of PD-1 targeting. Importantly, Anti-PD1/IL-15 or IL-2 OSE-Cytomask® technology strongly reduced toxicity of the immunocytokine while maintaining anti-tumor efficacy in MC38 ectopic model. OSE-Cytomask® Anti PD-1/IL2v immunocytokine demonstrated a large therapeutic window with therapeutic index calculated at 52-fold (therapeutic dose from 0.6mg/kg up to 25-30mg/kg (3 doses) in contrast the same molecule constructed with (G4S)3 conventional linker had a narrow therapeutic index at 2-fold with a toxic dose at 2mg/kg (3 doses on Day 10/12/14 post-tumor inoculation). High antitumor efficacy of OSE-Cytomask IL-2v was confirmed in Anti PD-1 resistant PanC02 models.Conclusions OSE-Cytomask® linker technology illustrates specific intrinsic property to mask cytokine on naïve peripheral immune cells not expressing the Antibody target while allowing selective CIS-demasking and activation of the cytokine on PD1 expressing cells. Unlike protease-cleavable linker technologies, OSE-Cytomask® does not rely on enzymatic activity, making it a more stable and adaptable solution across different TME conditions. We have validated properties of OSE®Cytomask linker technology with various targeting antibodies and multiple cytokines (8 tested to date, wild-type and mutant sequence) including IL-15, IL-2, IL-10 By reducing off-tumor cytokine activity and selectively activating immune cells, OSE-Cytomask® platform offers a promising strategy for the clinical development of immunocytokine with more effective and safer properties.

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