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

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / therapeutic use
  • Autoantigens / therapeutic use
  • Humans
  • Immunoglobulin G
  • Mice
  • Muscles
  • Myasthenia Gravis, Autoimmune, Experimental* / drug therapy
  • Protein-Tyrosine Kinases / therapeutic use
  • Receptors, Cholinergic* / therapeutic use
  • T-Lymphocytes

Substances

  • Receptors, Cholinergic
  • Autoantigens
  • Autoantibodies
  • Immunoglobulin G
  • Protein-Tyrosine Kinases