Effects of orelabrutinib, a BTK inhibitor, on antibody‐mediated platelet destruction in primary immune thrombocytopenia

作者：Tianshu Yu, Shouqing Han, Lingjun Wang, Haoyi Wang, Xiaofei Ni, Ruting Wang, Guangping Li, Yu Hou, Jun Peng, Zhenyu Yan, Yajing Zhao, Hou Ming, Xinguang Liu · 发表于：British Journal of Haematology · 年份：2025 · DOI：10.1111/bjh.20045 · 被引用次数：5 · 研究领域：Platelet Disorders and Treatments、Chronic Lymphocytic Leukemia Research、Autoimmune Bullous Skin Diseases

Primary immune thrombocytopenia (ITP) is a haemorrhagic disorder with a complex pathogenesis, wherein autoreactive B-cell-mediated platelet destruction plays a crucial role. Bruton's tyrosine kinase (BTK) is widely expressed and essential for immune cells. Several BTK inhibitors have been used clinically to treat haematological malignancies, while few studies are focusing on the regulatory role of BTK in ITP. This study aims to explore the feasibility and underlying mechanisms of a novel BTK inhibitor orelabrutinib in the treatment of ITP through in vitro and in vivo experiments. Orelabrutinib could inhibit B-cell receptor-mediated B-cell activation, proliferation, differentiation and pro-inflammatory cytokine secretion. Transcriptome sequencing revealed that B cells of ITP patients were more hyper-responsive in inflammation and secretion activity compared to healthy controls, and orelabrutinib might alter B-cell status through downregulating ribosome and mitochondrial metabolism. Fcγ receptor-mediated platelet phagocytosis and pro-inflammatory cytokine production by macrophages were also suppressed by orelabrutinib. Furthermore, orelabrutinib treatment considerably elevated the platelet count in active ITP murine models by inhibiting plasma cell differentiation, anti-platelet antibody production, pro-inflammatory factor secretion and platelet phagocytosis in the livers and spleens. Taken together, orelabrutinib could serve as a potential therapeutic agent for ITP by blocking...