Engineered Pan-Immunoglobin G (IgG) Enzymes Show Promise in Treating Myasthenia Gravis

Strategic Insights -

Research published in the Proceedings of the National Academy of Sciences (PNAS) reveals that immunoglobin G (IgG) cleaving enzymes can target the primary pathogenic mechanism in myasthenia gravis by degrading immunoglobulins in circulation and immune complexes. Seismic Therapeutic's engineered pan-IgG enzymes successfully cleaved pathogenic AChR autoantibodies, thereby inhibiting complement activation. The study also highlighted the significant role of AChR-IgM in driving complement deposition in myasthenia gravis, acting alone or synergistically with IgG in distinct patient subsets.

Key Takeaways:

  • The study demonstrated that immunoglobin G (IgG) cleaving enzymes can address the primary pathogenic mechanism in myasthenia gravis by degrading immunoglobulins in circulation and immune complexes.
  • Seismic's engineered pan-IgG enzymes cleaved pathogenic AChR autoantibodies in both circulation and as part of immune complexes, effectively inhibiting complement activation.
  • AChR-IgM was found to be a significant driver of complement deposition in myasthenia gravis, acting alone or synergistically with IgG in distinct patient subsets.
  • The study showed that an IgM-specific protease engineered by Seismic fully blocked the pathogenic effects of AChR-IgM.
  • The research was led by Kevin O'Connor, Ph.D., Professor of Neurology and Immunobiology at Yale School of Medicine.
  • The study revealed the power of Seismic's platform to engineer proteases that can uniquely target mechanisms underlying disease pathology.
  • The publication in PNAS can be accessed via this link (https://www.pnas.org/doi/10.1073/pnas.2505984122).
  • The research is part of an ongoing multi-year collaboration between Seismic and Yale University.

Statistics:

  • 3 pathogenic mechanisms contribute to myasthenia gravis, including activation of the complement system (primary driver of structural damage at the neuromuscular junction).
  • Seismic's engineered pan-IgG enzymes cleaved pathogenic AChR autoantibodies in both circulation and as part of immune complexes.
  • The study investigated the cleavage of anti-acetylcholine receptor (AChR) autoantibodies.
  • The published experiments investigated the cleavage of anti-AChR autoantibodies.

Sources:

  • Original Press Release: "Seismic Therapeutic issued the following news release: - Preclinical results demonstrate that immunoglobin G (IgG) cleaving enzymes can address the primary pathogenic mechanism in myasthenia gravis, an autoimmune disorder, by degrading immunoglobulins in circulation and in immune complexes, thereby eliminating complement deposition - Findings also reveal the role of immunoglobin M (IgM) in activation of the complement system in myasthenia gravis disease pathology - Publication in Proceedings of the National Academy of Sciences results from a collaboration between Seismic and academic investigators"
  • Proceedings of the National Academy of Sciences (PNAS), titled "Therapeutic IgG and IgM-specific proteases disarm the acetylcholine receptor autoantibodies that drive myasthenia gravis pathology."