W121 - Preclinical Pharmacology of S-1117, a Novel Engineered Fc-fused IgG Cleaving Enzyme, for Chronic Treatment of Autoantibody-mediated Diseases

Jordan Anderson – Seismic Therapeutic; Liliana Sanmarco – Seismic Therapeutic; Tobias Green – Seismic Therapeutic; Nathan Higginson-Scott – Seismic Therapeutics; Julia Manasson – Seismic Therapeutic; Andita Newton – Seismic Therapeutic; Kevin Otipoby – Seismic Therapeutic; Ryan Peckner – Seismic Therapeutics; Alex Pellerin – Seismic Therapeutic; Natahan Rollins – Seismic Therapeutic; John Sundy – Seismic Therapeutics; Yi Xing – Seismic Therapeutic

Abstract Text: 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.