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

    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 / O'Connor, Kevin C / Herzberg, Uri / Binder, Gwendolyn K / Milone, Michael C / Basu, Samik / Payne, Aimee S

    Nature biotechnology

    2023  Volume 41, Issue 9, Page(s) 1229–1238

    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 ... ...

    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.
    MeSH term(s) Humans ; Mice ; Animals ; Receptors, Cholinergic/therapeutic use ; Autoantigens/therapeutic use ; Myasthenia Gravis, Autoimmune, Experimental/drug therapy ; T-Lymphocytes ; Autoantibodies/therapeutic use ; Immunoglobulin G ; Protein-Tyrosine Kinases/therapeutic use ; Muscles
    Chemical Substances Receptors, Cholinergic ; Autoantigens ; Autoantibodies ; Immunoglobulin G ; Protein-Tyrosine Kinases (EC 2.7.10.1)
    Language English
    Publishing date 2023-01-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/s41587-022-01637-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2167: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 137: Show issues
    Zs.MG 43: Show issues

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  2. Article ; Online: Interaction of Neisseria meningitidis Group X N-acetylglucosamine-1-phosphotransferase with its donor substrate.

    Ming, Shonoi A / Cottman-Thomas, Ebony / Black, Natalee C / Chen, Yi / Veeramachineni, Vamsee / Peterson, Dwight C / Chen, Xi / Tedaldi, Lauren M / Wagner, Gerd K / Cai, Chao / Linhardt, Robert J / Vann, Willie F

    Glycobiology

    2018  Volume 28, Issue 2, Page(s) 100–107

    Abstract: Neisseria meningitidis Group X is an emerging cause of bacterial meningitis in Sub-Saharan Africa. The capsular polysaccharide of Group X is a homopolymer of N-acetylglucosamine α(1-4) phosphate and is a vaccine target for prevention of disease ... ...

    Abstract Neisseria meningitidis Group X is an emerging cause of bacterial meningitis in Sub-Saharan Africa. The capsular polysaccharide of Group X is a homopolymer of N-acetylglucosamine α(1-4) phosphate and is a vaccine target for prevention of disease associated with this meningococcal serogroup. We have demonstrated previously that the formation of the polymer is catalyzed by a phosphotransferase which transfers N-acetylglucosamine-1-phosphate from UDP-N-acetylglucosamine to the 4-hydroxyl of the N-acetylglucosamine on the nonreducing end of the growing chain. In this study, we use substrate analogs of UDP-GlcNAc to define the enzyme/donor substrate interactions critical for catalysis. Our kinetic analysis of the phosphotransferase reaction is consistent with a sequential mechanism of substrate addition and product release. The use of novel uracil modified analogs designed by Wagner et al. enabled us to assess whether the CsxA-catalyzed reaction is consistent with a donor dependent conformational change. As expected with this model for glycosyltransferases, UDP-GlcNAc analogs with bulky uracil modifications are not substrates but are inhibitors. An analog with a smaller iodo uracil substitution is a substrate and a less potent inhibitor. Moreover, our survey of analogs with modifications on the N-acetylglucosamine residue of the sugar nucleotide donor highlights the importance of substituents at C2 and C4 of the sugar residue. The hydroxyl group at C4 and the structure of the acyl group at C2 are very important for specificity and substrate interactions during the polymerization reaction. While most analogs modified at C2 were inhibitors, acetamido analogs were also substrates suggesting the importance of the carbonyl group.
    MeSH term(s) Bacterial Capsules/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Neisseria meningitidis/enzymology ; Polysaccharides, Bacterial/metabolism ; Protein Binding ; Transferases (Other Substituted Phosphate Groups)/chemistry ; Transferases (Other Substituted Phosphate Groups)/metabolism
    Chemical Substances Bacterial Proteins ; Polysaccharides, Bacterial ; Transferases (Other Substituted Phosphate Groups) (EC 2.7.8.-) ; UDP-N-acetylglucosamine-lysosomal-enzyme-N-acetylglucosaminephosphotransferase (EC 2.7.8.17)
    Language English
    Publishing date 2018-02-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1067689-2
    ISSN 1460-2423 ; 0959-6658
    ISSN (online) 1460-2423
    ISSN 0959-6658
    DOI 10.1093/glycob/cwx100
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3150: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

    Order via subito

    This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.

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