Figure 2 Patient-derived recombinant MuSK antibodies can activate or inhibit MuSK phosphorylation and AChR clustering depending on the antibody valency.

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Figure 2 Patient-derived recombinant MuSK antibodies can activate or inhibit MuSK phosphorylation and AChR clustering depending on the antibody valency Patient-derived recombinant MuSK antibodies can activate or inhibit MuSK phosphorylation and AChR clustering depending on the antibody valency Bivalent monospecific recombinant MuSK antibodies (clones 11-3F6 and 13-3B5) activated MuSK phosphorylation in the presence and absence of agrin (A). Activation of MuSK phosphorylation was dose dependent (B). Clone 13-3B5 was slightly more potent compared with 11-3F6. A biotin control antibody did not affect (agrin dependent) MuSK phosphorylation. Monovalent Fab fragments generated from these recombinant MuSK monoclonals inhibited MuSK phosphorylation (C). Agrin-dependent AChR clustering was unaffected when exposed to a biotin control antibody or Fab fragments thereof. Bivalent monospecific recombinant IgG4 MuSK antibodies and Fab fragments inhibited the number of agrin-dependent AChR clustering significantly compared with the biotin control antibody (for IgG4: p < 0.001, for Fab fragments: p < 0.001, one-way analysis of variance (ANOVA) test, Dunnett corrected). Fab fragments reduced AChR clusters to the level of purified patient IgG4 and the “no agrin” condition. Bivalent monospecific antibodies significantly increased AChR clustering compared with Fab fragment–mediated inhibition that seems independent from agrin (D & E; 11-3F6: p < 0.001, 13-3B5: p = 0.03, biotin antibody: p = 0.30, unpaired t test, no agrin conditions 11-3F6: p = 0.03, 13-3B5: p = 0.20 one-way ANOVA Dunnett corrected). Data represent mean ± SEM. Scale bar represents 50 μm. AChR = acetylcholine receptor; MuSK = muscle-specific kinase. Maartje G. Huijbers et al. Neurol Neuroimmunol Neuroinflamm 2019;6:e547 Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.