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The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a...
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Antibodies, or immunoglobulins, are critical players in the immune system's arsenal against invading pathogens. Produced by B cells and plasma cells, their primary role is to detect and bind to specific antigens, molecules found on the surface of pathogens like bacteria or viruses. Beyond antigen recognition, antibodies perform several vital functions that contribute to immune defense.
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Inhibition of Classical and Alternative Complement Pathway by Ravulizumab and Eculizumab.

Lea Gerischer1,2, Frauke Stascheit1,2, Maximilian Mönch3

  • 1Department of Neurology With Experimental Neurology and Integrated Myasthenia Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Berlin, Germany.

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Alternative pathway activity (AH50) may predict treatment response in generalized myasthenia gravis (gMG) patients receiving ravulizumab. Higher AH50 levels correlate with diminished therapeutic effects and earlier symptom recurrence, suggesting its potential as a biomarker.

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complement inhibitioncomplement pathwayeculizumabmyasthenia gravisravulizumab

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Area of Science:

  • Immunology
  • Neurology
  • Pharmacology

Background:

  • Generalized myasthenia gravis (gMG) is an autoimmune disorder affecting neuromuscular transmission.
  • Complement pathway activation plays a role in gMG pathogenesis.
  • Current C5 inhibitors like eculizumab and ravulizumab target this pathway.

Purpose of the Study:

  • To assess classical (CH50) and alternative (AH50) complement pathway activity as biomarkers for ravulizumab therapy in gMG.
  • To compare complement activity monitoring with therapeutic drug monitoring of eculizumab.
  • To explore AH50's role in predicting treatment response and duration.

Main Methods:

  • Prospective, exploratory real-world study of 61 AChR-ab positive gMG patients.
  • Assessed CH50 and AH50 levels, and eculizumab/ravulizumab levels at end-of-dose.
  • Correlated laboratory data with patient-reported duration of ravulizumab effect.

Main Results:

  • AH50 levels were less suppressed with ravulizumab (5%) compared to eculizumab (1%) at end-of-dose.
  • Patients discontinuing ravulizumab due to insufficient effect had higher AH50 levels (7% vs 5%).
  • 81% of patients experienced diminished ravulizumab effect before the 8-week interval; higher AH50 correlated with earlier recurrence.

Conclusions:

  • Ravulizumab and eculizumab may differ in complement pathway suppression over their dosing intervals.
  • Elevated AH50 levels may indicate poor response and faster wearing off of ravulizumab.
  • Further validation in large multicenter studies is necessary.