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用嵌合自身抗体受体T细胞精确靶向肌肉特异性酪氨酸激酶重症肌无力中自身抗原特异性B细胞
作者:小柯机器人 发布时间:2023/1/27 11:23:52


美国宾夕法尼亚大学Aimee S. Payne和美国卡巴莱塔生物公司Samik Basu共同合作,近期取得重要工作进展。他们研究发现可以用嵌合自身抗体受体T细胞精确靶向肌肉特异性酪氨酸激酶重症肌无力中自身抗原特异性B细胞。相关研究成果2023年1月19日在线发表于《自然—生物技术》杂志上。

据介绍,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,由于破坏神经肌肉连接信号的抗MuSK自身抗体而导致危及生命的肌肉无力。

为了避免当前疗法的慢性免疫抑制,研究人员设计了T细胞表达具有CD137-CD3ζ信号域的MuSK嵌合自身抗体受体(MuSK-CAART),以精确靶向表达抗MuSK自身抗体的B细胞。MuSK-CAART表现出与抗CD19嵌合抗原受体T细胞类似的功效,用于消除抗MuSK B细胞,并在可溶性抗MuSK抗体存在下保持细胞溶解活性。在实验性自身免疫性MG小鼠模型中,MuSK-CAART在不降低B细胞或总IgG水平的情况下降低了抗MuSK IgG,反映了MuSK特异性B细胞的耗竭。MuSK-CAART的特异性脱靶相互作用在体内、原代人类细胞筛选或高通量人类膜蛋白质组阵列中均未鉴定。

总之,这些数据有助于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。

附:英文原文

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

Author: Oh, Sangwook, Mao, Xuming, Manfredo-Vieira, Silvio, Lee, Jinmin, Patel, Darshil, Choi, Eun Jung, Alvarado, Andrea, Cottman-Thomas, Ebony, Maseda, Damian, Tsao, Patricia Y., Ellebrecht, Christoph T., Khella, Sami L., Richman, David P., OConnor, Kevin C., Herzberg, Uri, Binder, Gwendolyn K., Milone, Michael C., Basu, Samik, Payne, Aimee S.

Issue&Volume: 2023-01-19

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.

DOI: 10.1038/s41587-022-01637-z

Source: https://www.nature.com/articles/s41587-022-01637-z

期刊信息

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:68.164
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex

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