自身免疫性疾病中的双特异性T细胞接合剂：作用机制、临床证据挑战和治疗前景

摘要(中文译文)

双特异性T细胞衔接器（TCEs）代表了新一代免疫疗法，旨在将细胞毒性T淋巴细胞重定向至特定的细胞靶点，尤其是B细胞及其分化后代。TCEs最初在血液学领域被开发用于治疗恶性B细胞和浆细胞疾病，如今作为严重或难治性自身免疫性疾病的潜在疗法正日益受到关注。通过同时结合T细胞上的CD3和B系细胞上的抗原（如CD19、CD20或BCMA（B细胞成熟抗原）），TCEs可诱导对负责产生自身抗体的自身反应性B细胞和浆细胞的靶向清除。该方法结合了细胞疗法所实现的深度免疫清除与单克隆抗体的可控性，具有实现快速、深度且持久免疫调节的潜力。然而，它也引发了关于安全性、可行性和成本的重要问题。与CAR-T细胞疗法相比，TCEs提供了一种更易获得且可即时部署的策略，同时可能达到相当的B细胞和浆细胞清除水平，尽管暴露时间更短且长期持久性可能降低。本综述对TCEs在自身免疫性疾病中应用的机制、临床前及新兴临床数据进行了综合概述，并讨论了其在这一不断发展领域中的治疗潜力和局限性。

Abstract

Bispecific T-cell engagers (TCEs) represent a new generation of immunotherapies designed to redirect cytotoxic T lymphocytes toward specific cellular targets, particularly B cells and their differentiated progeny. Initially developed in hematology for the treatment of malignant B-cell and plasma-cell disorders, TCEs are now gaining growing interest as potential therapies for severe or refractory autoimmune diseases. By simultaneously binding CD3 on T cells and antigens such as CD19, CD20, or BCMA (B-cell maturation antigen) on B-lineage cells, TCEs induce the targeted elimination of autoreactive B cells and plasma cells responsible for autoantibody production. This approach combines the depth of immune depletion achieved with cellular therapies and the controllability of monoclonal antibodies, offering the potential for rapid, profound, and durable immunomodulation. However, it also raises important questions regarding safety, feasibility, and cost. Compared with CAR-T cell therapies, TCEs offer a more accessible and immediately deployable strategy, while potentially achieving comparable levels of B-cell and plasma-cell depletion, though with shorter exposure and possibly reduced long-term persistence. This review provides an integrated overview of mechanistic, preclinical, and emerging clinical data on the use of TCEs in autoimmune diseases, and discusses their therapeutic potential, and limitations in this evolving field.

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