Abstract 5131: HDM2021, a potent and selective CBL-B inhibitor exhibits robust immunomodulatory efficacy for anti-tumor therapy

Abstract Introduction: The E3 ligase Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is a critical negative regulator of immune activation. It controls T-cell and NK cell activation by lowering the threshold for effector cell activation, driving effector cell proliferation and inflammation, and reducing susceptibility to suppression by Tregs, MDSCs, and macrophages. Tumors exploit this pathway as a mechanism of immune evasion. To address this resistance, we are developing a potent CBL-B inhibitor designed to enhance intrinsic immune cell function, rescue anti-tumor immunity, and achieve clinical efficacy in immunotherapy-resistant patients. Methods: A series of CBL-B inhibitors with novel scaffolds have been synthesized and screened for activity and drug-like properties. Compound binding to the CBL-B protein was evaluated using TR-FRET and surface plasmon resonance (SPR) assays. Immunomodulatory activity was assessed in vitro in T cells or NK cells by measuring cytokine release via ELISA. Pharmacokinetic studies were conducted in mice and dogs, with serial blood samples analyzed by LC-MS/MS. The toxicology assessment was conducted using an in vitro safety panel and in vivo 14-day dose range finding (DRF) study in mice. Proof-of-concept in vivo efficacy was demonstrated in subcutaneous xenograft mouse models. Results: Through systematic molecular design and rigorous drug-likeness screening, we have identified HDM2021 as a promising drug candidate. This compound demonstrated high-affinity binding to CBL-B (Kd 1 nM) and a prolonged target dissociation half-life. Functionally, it activated both T cells and NK cells and exhibited potent tumor-killing activity in T cell-tumor cell co-culture assays. Furthermore, HDM2021 exhibited excellent target selectivity in safety panel assays (44 targets) and minimal hERG channel inhibition (IC50 20 µM). In particular, HDM2021 was well tolerated in mice at a dose of 80 mg/kg in a DRF study, indicating an optimal safety profile. It also displayed moderate pharmacokinetic properties in both mice and dogs. Notably, in multiple xenograft models, HDM2021 demonstrated robust antitumor efficacy in combination with PD-1 antibody, and sustained tumor regression was maintained after treatment withdrawal. Conclusion: HDM2021 has demonstrated potent CBL-B inhibition and robust efficacy in both in vitro and in vivo models. It also exhibits improved pharmacokinetic properties, high target selectivity, and a favorable safety profile. These findings support its further development as a novel immunomodulatory drug candidate for anti-tumor therapy. IND-enabling studies have been initiated for clinical studies. Citation Format: Shulun Chen, Mengting Zhao, Zhimin Zhang, Jingwen E, Xi Yang, Xinyu Dai, Zhenna Xia, Xin Xu, Dongzhou Liu. HDM2021, a potent and selective CBL-B inhibitor exhibits robust immunomodulatory efficacy for anti-tumor therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5131.