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嵌合自身抗体受体 T 细胞靶向肌肉特异性酪氨酸激酶抗体阳性重症肌无力患者的自身反应性 B 细胞。

Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells.

机构信息

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Cabaletta Bio, Philadelphia, PA, USA.

出版信息

Nat Biotechnol. 2023 Sep;41(9):1229-1238. doi: 10.1038/s41587-022-01637-z. Epub 2023 Jan 19.

DOI:10.1038/s41587-022-01637-z
PMID:36658341
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10354218/
Abstract

Muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness due to anti-MuSK autoantibodies that disrupt neuromuscular junction signaling. To avoid chronic immunosuppression from current therapies, we engineered T cells to express a MuSK chimeric autoantibody receptor with CD137-CD3ζ signaling domains (MuSK-CAART) for precision targeting of B cells expressing anti-MuSK autoantibodies. MuSK-CAART demonstrated similar efficacy as anti-CD19 chimeric antigen receptor T cells for depletion of anti-MuSK B cells and retained cytolytic activity in the presence of soluble anti-MuSK antibodies. In an experimental autoimmune MG mouse model, MuSK-CAART reduced anti-MuSK IgG without decreasing B cells or total IgG levels, reflecting MuSK-specific B cell depletion. Specific off-target interactions of MuSK-CAART were not identified in vivo, in primary human cell screens or by high-throughput human membrane proteome array. These data contributed to an investigational new drug application and phase 1 clinical study design for MuSK-CAART for the treatment of MuSK autoantibody-positive MG.

摘要

肌肉特异性酪氨酸激酶重症肌无力（MuSK MG）是一种自身免疫性疾病，由于抗 MuSK 自身抗体破坏神经肌肉接头信号，导致危及生命的肌肉无力。为了避免当前治疗方法的慢性免疫抑制，我们设计了表达 MuSK 嵌合自身抗体受体与 CD137-CD3ζ 信号域（MuSK-CAART）的 T 细胞，用于精确靶向表达抗 MuSK 自身抗体的 B 细胞。MuSK-CAART 显示出与抗 CD19 嵌合抗原受体 T 细胞相似的功效，可耗尽抗 MuSK B 细胞，并在存在可溶性抗 MuSK 抗体的情况下保持细胞溶解活性。在实验性自身免疫性重症肌无力小鼠模型中，MuSK-CAART 减少了抗 MuSK IgG，而不减少 B 细胞或总 IgG 水平，反映了 MuSK 特异性 B 细胞耗竭。在体内、原代人细胞筛选或高通量人膜蛋白质组阵列中，均未发现 MuSK-CAART 的特定脱靶相互作用。这些数据为 MuSK-CAART 治疗 MuSK 自身抗体阳性 MG 的研究性新药申请和 1 期临床研究设计提供了依据。

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