IgG-MEDIATED AUTOIMMUNE DISORDERS
Many severe autoimmune diseases are driven by pathogenic IgG auto-antibodies, including Pemphigus Vulgaris, Guillain-Barre, and others. Current pharmaceutical interventions are limited
• IdeS is a clinically approved enzyme that reduces IgG levels by >95% within minutes (Hansa Biopharma’s Imlifidase); however, this version of IdeS has a short half-life and is highly immunogenic
• Cyrus’ IdeS demonstrates greatly improved half life and reduced immunogenicity, representing a superior therapeutic in IgG-mediated autoimmune disorders
Non-IdeS approaches are slower and less potent
• Inhibition of IgG recycling by blocking FcRn only reduces IgG levels by 60-80% and requires days of treatment for full effect. This MOA was first approved in 2021 for Myasthenia Gravis (Argenx’ Vyvgart)
– Cyrus’ IdeS reduces IgG levels >95% in minutes instead of days
• Current standard of care is primarily non-pharmaceutical: IVIG, Plasmapheresis
• Some control via corticosteroids
IMMUNOGLOBULIN G
• IgG is the major class (75%) of immunoglobulins (a type of antibody) which form humoral immunity to respond to infection
• Binds to pathogens, removing them from the circulation and triggering immunological responses
• Can form as autoantibodies against self-proteins and cause severe inflammation and autoimmune disease, the are IgG mediated diseases
Origin
Because the system is bacterial in origin, a proportion of treated patients may mount an immune response against the enzyme — pre existing adaptive immunity was very clearly shown in 2019 by Charlesworth et al in Nature Medicine https://www.nature.com/articles/s41591-018-0326-x. At a minimum this response could sharply reduce the utility of this system, requiring pre-screening of prospective recipients or prophylactic immune suppression. Cyrus and The Broad Institute in Cambridge, MA are collaborating on the deimmunization of CRISPR systems with the goal of eliminating the risk of such immune responses.
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