ALV2 is an effective and selective degrader of Helios (IKZF2). ALV2 binds to CRBN with an IC50 of 0.57μM[1-2]. Helios is a zinc-finger transcription factor that maintains a stable regulatory T cell (Treg) phenotype within the inflammatory tumor microenvironment. ALV2 is used in research investigating the regulation of T cell function and the tumor immune microenvironment[3-4].
In vitro, ALV2 (1μM) was used to pre-treat human naive CD4+ T cells for 5 days, followed by activation with anti-CD3/CD28 antibodies for 2 days. This treatment significantly upregulated the production of CD25 and effector cytokines (such as IL-21 and IFNγ), and enhanced the ability of these cells to infiltrate inflammatory tissues in a human-synovial tissue-mouse chimeric model[5]. In RAW 264.7 murine macrophages infected with Salmonella for 1 hour, ALV2 (10μM; 24-hour treatment) significantly reduced the secretion of tumor necrosis factor-alpha (TNF-α)[6].
In vivo, in a mouse model with the humanized CrbnI391Vgenotype, administration of ALV2 via intraperitoneal injection (100mg/kg; twice daily; for 7 days) significantly reduced the protein levels of Helios (IKZF2) in splenic CD4+ FoxP3+ regulatory T cells (Tregs), without affecting Ikaros (IKZF1) levels[7].
References:
[1] Zhang Y, Li L, Xu J, et al. A Novel Paradigm for Targeting Challenging Targets: Advancing Technologies and Future Directions of Molecular Glue Degraders. Molecules (Basel, Switzerland). 2026 Jan;31(3):459.
[2] Słabicki M, Park J, Nowak RP, et al. Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation. Molecular Cell. 2025 Aug;85(16):3184-3201.e14.
[3] Xue F, Zhang M, Li S, et al. SE(3)-equivariant ternary complex prediction towards target protein degradation. Nature Communications. 2025 Jul;16(1):5514.
[4] Chen Z, Dhruv H, Zhang X, et al. Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy. Nature Communications. 2025 May;16(1):4095.
[5] Zhang H, Jadhav RR, Cao W, et al. Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses. Nat Immunol. 2023 Jan;24(1):96-109.
[6] Santelices J, Schultz A, Walker A, et al. Targeting deubiquitinating enzymes and ubiquitin pathway modulators to enhance host defense against bacterial infections. mBio. 2025 Oct 8;16(10):e0031225.
[7] Wang ES, Verano AL, Nowak RP, et al. Acute pharmacological degradation of Helios destabilizes regulatory T cells. Nat Chem Biol. 2021 Jun;17(6):711-717.
ALV2是一种有效和选择性的Helios降解剂，ALV2可以结合CRBN（IC50=0.57μM）[1-2]。Helios是一种锌指转录因子，可以在炎症性肿瘤微环境中维持稳定的Treg细胞表型。ALV2可用于调节T细胞功能和肿瘤免疫微环境的相关研究[3-4]。
在体外，ALV2（1μM）体外预处理人源初始CD4+ T细胞5天，随后用抗CD3/CD28抗体激活2天，显著上调CD25和效应细胞因子（如IL-21和IFNγ）的产生，并增强这些细胞在人类-滑膜组织-小鼠嵌合模型中向炎症组织的浸润能力[5]。以沙门氏菌（Salmonella）感染鼠RAW 264.7巨噬细胞1小时后，ALV2（10μM；处理细胞24小时）显著降低肿瘤坏死因子α（TNF-α）的分泌[6]。
在体内，对人源化CRBN（humanized CrbnI391V）基因型的小鼠模型，通过腹腔注射给药ALV2（100mg/kg；每日两次；共7天），显著降低脾脏组织中CD4+ FoxP3+ 调节性T细胞的Helios（IKZF2）的蛋白水平，同时不影响Ikaros（IKZF1）的水平[7]。