Abstract 1734: Modulation of immune responses to cancer by bi-specific IL-2/IL-13 superkines

Abstract

Abstract Introduction: The IL-2 pathway plays a vital role in stimulating a pro-inflammatory (Th1) response against cancer through expansion and activation of effector CD8 T and NK cells. In contrast, the IL-4/IL-13 pathway stimulates myeloid derived suppressor cells (MDSCs) and M2 skewing of tumor associated macrophage (TAM) to foster an anti-inflammatory (Th2) response that is often exploited by cancers as a means to dampen the effects of the Th1 pathway. Therefore, suppression of MDSC and M2 TAM through inhibition of the IL-4/IL-13 pathway together with stimulation of effector immune cells through activation of the IL-2 pathway have the potential to invigorate a pro-inflammatory response in an otherwise immune suppressive tumor microenvironment (TME). To achieve this goal, we leveraged the versatility of our IL-2 and IL-13 superkine platforms to engineer long-acting bi-specific constructs to co-target surface receptors of these respective pathways. Experimental Procedure: Studies included binding analyses by BLI/Octet and Biacore/SPR, signaling analyses using IL-2 and IL-4/IL-13 reporter assays, signaling analysis in human PBMC, and in vitro M1/M2 macrophage polarization assay. Summary of Data: sIL2M-Fc-sIL13M is a bi-specific superkine composed of an IL-2 super-agonist (sIL2M) and IL-13 super-antagonist (sIL13M) linked together by human IgG1 Fc. sIL2M binds CD122 with superior affinity over IL-2 but does not engage CD25, which is expressed on immune-suppressive Tregs. sIL13M has higher affinity than IL-13 for IL13Rα1, which together with IL-4Rα forms a functional receptor complex. In pSTAT5 assay using primary human PBMCs, sIL2M-Fc-sIL13M showed enhanced potency over IL-2 in the activation of CD8 T-cells and NK cells while exhibiting limited activity on Treg. In an IL-4/IL-13 dependent pSTAT6 reporter assay, sIL2M-Fc-sIL13M demonstrated dose-dependent antagonism against stimulatory activity of both IL-4 and IL-13. This antagonistic effect was further validated with inhibition of IL-13 induced M2 polarization of macrophages in vitro. Conclusion: sIL2M-Fc-sIL13M is a bi-specific superkine capable of concomitantly stimulating a Th1 response through activation of the IL-2 pathway and suppressing a Th2 response through inhibition of the IL-4/IL-13 pathway. Additional bi-specific superkine constructs are currently under testing, including those designed to enable accumulation in TME by engaging the decoy IL-13Rα2 that is overexpressed on a number of different tumor types. Citation Format: Fahar Merchant, Minh To. Modulation of immune responses to cancer by bi-specific IL-2/IL-13 superkines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1734.