Preclinical pharmacology of S-1117, a novel engineered Fc-fused IgG cleaving enzyme, for chronic treatment of autoantibody-mediated diseases

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B859
Abstract ID: 4428

Presenting Author:
Liliana Sanmarco , Senior Scientist at Seismic Therapeut.

Abstract:

Pathogenic autoantibodies are key effectors of inflammation, promoting complement activation and immune cell responses that cause tissue damage in autoantibody-mediated diseases such as myasthenia gravis. IgG-proteases represent a new therapeutic opportunity. Here we present S-1117, a novel Fc-fused pan-IgG protease, engineered using a proprietary machine learning enabled platform to reduce immunogenicity and augment manufacturability and stability while maintaining enzyme activity. S-1117 cleaves soluble IgG and the BCR on memory B cells with comparable potency and significantly reduces antibody-dependent cytotoxicity (ADCC) and immune complex-mediated PBMC activation in vitro. When tested in vivo, a deep reduction of human IgG (>90%) occurred within 30 minutes after dosing. A PK/PD model developed for human projections predicts rapid, deep and sustained reduction of IgG levels. In addition, in an anti-glomerular basement membrane (GBM) model, a prototype Fc-fused pan-IgG protease reduced complement activation, IC deposition, which correlated with reduced proteinuria, blood urea nitrogen and renal pathology. In summary, S-1117 is a novel engineered pan-IgG protease that demonstrates rapid and sustained reduction of IgG levels and reduces multiple pathological manifestations in a murine nephritis model. Given its ability to address multiple pathogenic mechanisms as a single drug, it has the potential to achieve improved clinical outcomes in autoantibody-mediated diseases.