W138 - Preclinical Polypharmacology of S-1117, a Novel Engineered Fc-Fused IgG Degrading Enzyme, for Chronic Treatment of Autoantibody-Mediated Diseases

Abstract Text: Tobias Green, Liliana Sanmarco, Alex Pellerin, Jordan Anderson, Nathan Rollins, Agustin Plasencia, Andita Newton, Cecilia Ramello, Ryan Peckner, Yi Xing, Heather Vital, Nathan Higginson-Scott, John S. Sundy, Kevin L. Otipoby, Ivan Mascanfroni

Seismic Therapeutic, Watertown, MA USA

Pathogenic autoantibodies are key effectors of inflammation, promoting immune cell responses that cause tissue damage in autoantibody-mediated diseases. 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 all IgG subclasses in human plasma. It directly eliminates IgG effector function, reducing antibody-dependent and complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and IC-mediated immune cell activation in vitro. Moreover, S-1117 cleaves the IgG+ BCR on human memory B cells in vitro. In vivo, a single dose of S-1117 provides greater (>90%), faster ( < 24 hours), and more prolonged (>10 days) IgG reduction compared to a benchmark FcRn inhibitor (maximal IgG reduction of ~70% at 7 days). This correlates with superior efficacy in prophylactic and therapeutic murine models of ITP.

Human PK/PD modeling predicts that infrequent chronic low doses of S-1117 can achieve a range of IgG reductions up to 90% or greater, titrated to the clinical needs of each patient.

Advantages of enzymatic degradation, sustained PK and titratable PD demonstrate superiority in human IgG cleavage compared to a benchmark FcRn inhibitor and are expected to enable a convenient patient-tailored treatment regimen.