Abstract 2656: The selective IKZF2 molecular glue degrader, PVTX-405, counters Treg immune suppression,shows significant tumor growth delay as single agent and synergistic response with immune checkpoint therapies (ICTs)

Abstract Immunosuppressive regulatory T-cells (Tregs) are key modulators of tumor immune evasion and resistance to immune checkpoint therapies (ICTs). IKZF2 (Helios) is a transcription factor that is selectively expressed by Treg and has been shown to be essential for maintaining function and stability of Tregs in the face of inflammatory conditions that include autoimmune disease as well as cancer. Here we describe the discovery of PVTX-405, a potent and selective IKZF2 molecular glue degrader (DC50=6. 3 nM). Our molecular glue degrader promotes a productive ternary complex with the E3 ubiquitin ligase substrate receptor cereblon (CRBN) to selectively degrade IKZF2 while sparing other CRBN neosubstrates (IKZF1/3, GSPT1, CK1a). PVTX-405 demonstrates rapid and selective degradation of IKZF2 in Jurkat cells in vitro, human PBMC derived Tregs ex vivo, and in cynomolgus monkeys in vivo. Degradation of IKZF2 in Jurkat cells leads to dose dependent increase in production of inflammatory cytokine IL-2. In ex vivo co-cultures of Tregs and effector T-cells, PVTX-405 reduces the suppressive activity of Tregs. To determine whether the relief of Treg suppressive activity observed in vitro and ex vivo can translate to anti-tumor activity in vivo we utilized CRBNI391V (humanized CRBN) mice. We developed a novel MC38 syngeneic tumor model to test both monotherapy and combination efficacy in an immune-competent setting. Once daily oral administration of PVTX-405 as single agent significantly delays the growth of MC38 tumors. Further, in vivo treatment of PVTX-405 in combination with ICTs, anti-PD1 or anti-LAG3, significantly increased animal survival and led to durable tumor regressions compared to ICTs alone. Together, these results demonstrate a strong synergy between ICTs and Treg destabilization through pharmacological degradation of IKZF2 and represent a promising combination strategy for treatment of cancer. Citation Format: Harshil D. Dhruv, Donna McEachern, Longchuan Bai, Xuqing Zhang, Zhixiang Chen, Rakesh Nagilla, Elham Behshad, Bomie Han, Peter Orth, Rohan Rej, Paul Kirchhoff, Niu Shin, Larry Jolivette, Corey Strickland, Zhihua Sui, Scott Priestley, Shaomeng Wang, Helai Mohammad. The selective IKZF2 molecular glue degrader, PVTX-405, counters Treg immune suppression, shows significant tumor growth delay as single agent and synergistic response with immune checkpoint therapies (ICTs) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2656.