Paediatric Immunology, Infectious Diseases & Allergy Department, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
Department of Medicine, University of Cambridge, Cambridge, UK.
J Allergy Clin Immunol Pract. 2024 Jan;12(1):69-78. doi: 10.1016/j.jaip.2023.09.016. Epub 2023 Sep 28.
The phosphoinositide 3-kinase (PI3K) pathway regulates diverse cellular processes, with finely tuned PI3Kδ activity being crucial for immune cell development and function. Genetic hyperactivation of PI3Kδ causes the inborn error of immunity activated phosphoinositide 3-kinase δ syndrome (APDS). Several PI3Kδ inhibitors have been investigated as treatment options for APDS, but only leniolisib has shown both efficacy and tolerability. In contrast, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematological malignancies. We propose that leniolisib is distinguished from other PI3Kδ inhibitors due to its structure, specific inhibitory properties selectively targeting the δ isoform without overinhibition of the δ or γ isoforms, and the precise match between APDS mechanism of disease and drug mechanism of action.
磷酸肌醇 3-激酶 (PI3K) 途径调节多种细胞过程，精细调节的 PI3Kδ 活性对于免疫细胞的发育和功能至关重要。PI3Kδ 的遗传过度激活会导致先天性免疫激活磷酸肌醇 3-激酶 δ 综合征 (APDS)。已经研究了几种 PI3Kδ 抑制剂作为 APDS 的治疗选择，但只有 leniolisib 表现出疗效和耐受性。相比之下，其他 PI3Kδ 抑制剂，特别是那些用于血液恶性肿瘤的抑制剂，已经观察到严重的免疫介导的不良反应，如结肠炎、中性粒细胞减少症和肝毒性。我们提出，leniolisib 与其他 PI3Kδ 抑制剂不同，是因为它的结构、选择性靶向 δ 同工型而不过度抑制 δ 或 γ 同工型的特异性抑制特性，以及疾病的 APDS 机制与药物作用机制之间的精确匹配。
