* 이번 세미나는 목요일이 아니고 금요일에 있습니다. 확인바랍니다.
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* 일시: 10/06(금) 16:30 –
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* 연사: 오상욱(한림대학교)
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* 장소: 벤처관 711호
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* 제목: Developing a genetically engineered cellular immunotherapy for autoimmune diseases
*Abstract:
Muscle-specific tyrosine kinase (MuSK) myasthenia gravis is an autoimmune disease that causes life-threatening muscle weakness due to MuSK autoantibodies that disrupt acetylcholine receptor (AChR) clustering and neuromuscular junction signaling. MuSK myasthenia gravis therapy with steroids and the anti-CD20 monoclonal antibody rituximab aims to suppress or eliminate antibody-producing B cells, although disease often relapses due to incomplete B cell depletion and even transient B cell depletion risks serious infections. The ideal therapy would eliminate only the autoantibody-producing B cells while preserving healthy B cells to protect from infection.
Chimeric antigen receptor T (CART) cells have transformed cancer treatment by re-programming T cells to eradicate B cell cancers, raising hope that precision medicine cures can be extended to other B cell-mediated diseases. By expressing the MuSK autoantigen as the extracellular targeting domain of a chimeric autoantibody receptor (CAAR) with 4-1BB/CD3ζ cytoplasmic signaling domains, we genetically engineered human MuSK CAAR T cells (MuSK-CAART) to selectively kill anti-MuSK B cells expressing a surface-bound autoantibody (anti-MuSK B cell receptor). We demonstrate that MuSK CAAR directs primary human T cell cytotoxicity toward B cells targeting a broad range of physiologic MuSK epitopes. MuSK-CAART demonstrated comparable efficacy as anti-CD19 CAR T cells in eliminating anti-MuSK B cells in immunodeficient NSG mice xenografted with anti-MuSK Nalm6 cells, in the presence or absence of soluble anti-MuSK antibodies. In an immunocompetent experimental autoimmune myasthenia gravis model using mouse CA(A)R T cells, anti-CD19 CAR T cell treatment depleted B cells and decreased both serum anti-MuSK IgG and total IgG levels, whereas MuSK CAAR T cells induced comparable decreases in anti-MuSK IgG titers without decreasing total B cells or IgG levels, reflecting MuSK-specific B cell depletion. Toxicology studies in the NSG xenograft model and screens of a high-throughput human membrane proteome array and primary human cells did not identify MuSK-CAART off-target cytotoxic interactions.
These data in part formed the basis of an investigational new drug (IND) application for MuSK-CAART, which has been allowed by the FDA for the treatment of MuSK autoantibody-positive myasthenia gravis.