To assess the pharmacokinetics (PK), pharmacodynamics (PD) and preclinical efficacy of an engineered pan-IgG protease.

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 and chronic inflammatory demyelinating polyneuropathy. IgG-proteases represent a new therapeutic opportunity.

S-1117, a novel Fc-fused pan-IgG protease, was engineered using a proprietary machine learning enabled platform to reduce immunogenicity and augment manufacturability and stability while maintaining enzyme activity. S-1117 addresses multiple mechanisms of autoimmunity by lowering IgG and immune complex levels, reducing IgG effector functions and cleaving the antigen receptor (BCR) on memory B cells.

Soluble IgG in plasma, BCR, and immune complex (IC) cleavage assays were performed in vitro. A murine PK/PD model and a murine nephritis model evaluated S-1117 function in vivo.

S-1117 cleaves soluble IgG and the BCR on memory B cells with comparable potency. A Fc-fused pan-IgG protease 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, sustained reduction of IgG levels. In an anti-glomerular basement membrane (GBM) model, a prototype Fc-fused pan-IgG protease reduced complement, IC deposition, and reduced proteinuria (protein score 3.3 disease vs. 1.9 treated), blood urea nitrogen (49 mg/dl disease vs. 1.9 mg/dl treated) and renal pathology (crescent score 3.6 disease vs. 0.6 treated).

S-1117 is a novel engineered pan-IgG protease that demonstrates rapid and sustained reduction of human IgG levels in a murine PK model 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.