Abstract 3427: ICP-490 is a highly potent and selective IKZF1/3 degrader with robust anti-tumor activities against multiple myeloma and non-Hodgkin’s lymphoma

Abstract

Background: Cereblon (CRBN)-targeting immunomodulatory drugs (IMiDs), i.e., thalidomide and lenalidomide, play pivotal roles in treating multiple myeloma (MM) patients. This class of drugs induce rapid ubiquitination and degradation of two lymphoid transcription factors (IKZF1 and IKZF3) by recruiting them to CRBN-CRL4 E3 ubiquitin ligase, which result in pleiotropic anti-tumor effects including autonomous tumor cell death and immune activation. However, prolonged IMiD treatment eventually becomes resistant and leads to tumor relapse in MM patients, mostly due to down-regulation of CRBN. All approved IMiDs also exert adverse effects such as teratogenicity, attributed to CRBN-mediated degradation of neo-substrates SALL4, PLZF1 and ΔNp63/TAp63. Here we report the development of a novel selective IKZF1/3 degrader ICP-490, which can robustly inhibit MM and NHL tumor growth, and overcome lenalidomide resistance. Results: ICP-490 induces potent, deep, and selective degradation of IKZF1 and IKZF3 with sub-nanomolar IC50, but no significant degradation of IKZF2, IKZF4, GSPT1, SALL4 and PLZF1. Cell viability assays reveal robust in vitro efficacies of ICP-490 against various MM and NHL(DLBCL) cell lines with nanomolar IC50. It also exhibits potent anti-proliferative activity in lenalidomide-resistant cell lines. In contrast to its tumor killing effect, ICP-490 shows no cytotoxicity against normal human cells, such as HEK293 and PBMC cells. ICP-490 induces IKZF1/3 degradation in distinct human lymphocyte lineages, leads to immune cell activation with elevated IL-2 and IFN-γ production and down-regulation of TNF-α in PBMC. The immune modulation activity of ICP-490 has also been illustrated in a combinatory treatment with daratumumab, where low dose of ICP-490 leads to robust induction of IL-2 and granzyme B, and much improved efficacy of daratumumab in MM cell line NCI-H929. In vivo efficacy studies have further confirmed the effectiveness of ICP-490 against MM and DLBCL xenografts, including MM1.S, MM1.R, NCI-H929 multiple myeloma lines, and TMD-8, WSU-DLCL2 DLBCL lines. ICP-490 also eradicates lenalidomide-resistant NCI-H929 xenografts. ICP-490 has overall favorable pharmacokinetic parameters with high oral bioavailability. Nonclinical safety evaluations of ICP-490 exhibit acceptable drug tolerability in SD rats and cynomolgus monkeys. Conclusions: ICP-490 is a highly potent, orally bioavailable, next-generation CRBN-targeting IMiD with selective IKZF1/3 degradation. In various MM and NHL tumor models, it demonstrates superior tumor killing activities than currently approved IMiDs, including overcoming lenalidomide resistance. ICP-490 is now in phase I clinical trial. Citation Format: Ruixia Liang, Yucheng Pang, Yingrui Han, Haipeng Xu, Zuopeng Wang, Richard Liu, Charles Ying Wang, Jason Bin Zhang, Xiangyang Chen, Davy Xuesong Ouyang. ICP-490 is a highly potent and selective IKZF1/3 degrader with robust anti-tumor activities against multiple myeloma and non-Hodgkin’s lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3427.