{
  "abstract": "Background Efgartigimod, a neonatal Fc receptor (FcRn) blocker, effectively reduces total IgG, including pathogenic acetylcholine receptor (AChR) autoantibodies in myasthenia gravis (MG); however, clinical responses vary. To investigate this variability, we studied how efgartigimod impacts AChR-specific autoantibody profiles and associated pathogenic mechanisms, including complement activation, AChR internalisation and ACh-binding site blockade.Methods Serum samples (N=150) were sourced from 50 AChR autoantibody-positive generalised MG patients participating in the phase 3 ADAPT study, randomised to receive efgartigimod (N=40) or placebo (N=10) in cycles of 4-weekly infusions. Samples were collected at baseline, day 29 and day 57 during the first cycle. Live cell-based assays quantified AChR-specific IgG subclasses and isotypes and assessed their capacity to mediate pathomechanisms.Results Efgartigimod decreased all detectable AChR-specific IgG subclasses. At baseline, AChR autoantibody-mediated C3b deposition, AChR internalisation and ACh-binding site blockade were detected in 42 (84%), 41 (82%) and 10 (20%) patients, respectively. After 4-weekly infusions of efgartigimod, the magnitude of all three pathomechanisms was significantly decreased. However, the extent of this reduction varied across individuals. Double responders on both MG-activities of daily living and quantitative MG scores demonstrated a greater reduction in complement activity and AChR internalisation compared with patients who responded on only one score or were double non-responders. In addition, efgartigimod reduced IgG-dependent IgM binding to AChR.Conclusions These findings suggest that clinical efficacy may be more closely associated with functional modulation of the AChR-specific autoantibodies than with their absolute quantity alone. These results support the evaluation of mechanistic pathway monitoring as a potential strategy to predict or guide efgartigimod treatment response.",
  "authors": [
    {
      "affiliations": [
        "Neurology, Yale School of Medicine, New Haven, Connecticut, USA",
        "Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Fatemeh Khani-Habibabadi"
    },
    {
      "affiliations": [
        "argenx BV, Ghent, Belgium"
      ],
      "name": "Fien M Verhamme"
    },
    {
      "affiliations": [
        "argenx BV, Ghent, Belgium"
      ],
      "name": "Mahan Moshir"
    },
    {
      "affiliations": [
        "argenx BV, Ghent, Belgium"
      ],
      "name": "Tine Casneuf"
    },
    {
      "affiliations": [
        "argenx BV, Ghent, Belgium"
      ],
      "name": "Vijayaraghava T S Rao"
    },
    {
      "affiliations": [
        "argenx BV, Ghent, Belgium"
      ],
      "name": "Sophie Steeland"
    },
    {
      "affiliations": [
        "argenx BV, Ghent, Belgium"
      ],
      "name": "Peter Ulrichts"
    },
    {
      "affiliations": [
        "Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Minh C Pham"
    },
    {
      "affiliations": [
        "Neurology, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Richard J Nowak"
    },
    {
      "affiliations": [
        "Neurology, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Bhaskar Roy"
    },
    {
      "affiliations": [
        "Neurology, Yale School of Medicine, New Haven, Connecticut, USA",
        "Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA"
      ],
      "name": "Kevin C O’Connor"
    }
  ],
  "title": "Pathogenic properties of myasthenia gravis AChR autoantibodies associate with clinical response to efgartigimod",
  "uid": "79a0a830-7553-5ebb-9a80-cc53746179cf"
}