Abstract 2354: Targeted IRAK-M degradation as a novel and efficacious cancer-immunotherapy overcoming innate-driven immunosuppression

Abstract

Abstract IRAK-M has an important role in tightly controlling innate immune responsiveness to preserve homeostasis, mediating immune tolerance, and acts as a negative feedback regulator of TLR/IL-1R signaling pathway. Targeting IRAK-M, which expression is restricted to myeloid cells, would be potentially limiting adverse events against non-target tissues. From supporting evidence for the role of IRAK-M in innate immunosuppressive capacity of tumor-associated macrophages (TAMs) or dendritic cells (DCs), we have developed compounds targeting IRAK-M as an effective cancer-immunotherapy strategy. Since IRAK-M is a pseudokinase which is characterized by the lack of conserved motifs involved in catalytic kinase activity, drug design for inhibition of IRAK-M has been challenging because the conventional small molecule could not modulate its function in cells. Therefore, we conceived and optimized heterobifunctional for degradation comprising IRAK-M-binding moiety linked to the our proprietary XIAP binders to eliminate the IRAK-M protein via ubiquitin-proteasome system. We demonstrated a concentration-dependent degradation of IRAK-M protein in THP1 human monocytic leukemia cells with degraders, and this degradation activity was confirmed to be proteasome-dependent by rescue of depletion following pre-incubation with the proteasome inhibitor epoxomicin. In addition, to estimate the cellular degradation selectivity of our degrader to IRAK-M in an unbiased manner, we carried out whole proteome mass spectrometry in THP1 cells and exhibited good selectivity against identified quantifiable proteins including IRAK-4. As functional studies, we performed MDSC suppression assays in a co-culture model with T cells and found IRAK-M degrader could release the suppressive function of MDSC. Lead optimization steps for IRAK-M degraders have conducted by applying RaPPIDSTM which is a proprietary divergent degrader synthetic platform and already identified multiple drug candidates within a year. Finally, in LLC Lewis lung carcinoma syngeneic model, treatment with candidate resulted in significant tumor growth inhibition. Pre-clinical toxicological studies have been entered and backup compounds are also in development. Taken together, these results highlight the promise of combined IRAK-M silent binder and targeted protein degradation technology as a novel therapeutic strategy for the cancer-immunotherapy that shifts the balance between tolerance and immunity by releasing immunosuppressive activity and in turn by unleashing tumor-specific T-lymphocytes. Citation Format: Kanae Gamo, Naomi Kitamoto, Yoshihide Tomata, Yusuke Tominari. Targeted IRAK-M degradation as a novel and efficacious cancer-immunotherapy overcoming innate-driven immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2354.