Background/Purpose: Pathogenic autoantibodies are key effectors of inflammation, promoting immune cell responses that cause tissue damage in autoantibody-mediated diseases such as idiopathic inflammatory myopathies, lupus nephritis, Sjogren’s syndrome, antiphospholipid syndrome, and ANCA-associated vasculitis. Antibody degradation using an IgG protease represents a new therapeutic opportunity.

S-1117 is a novel pan-IgG protease fused to an effector function silent human IgG1 Fc domain and engineered for chronic subcutaneous administration using a proprietary machine learning enabled platform to reduce immunogenicity and augment manufacturability while maintaining potency. S-1117 cleaves and reduces soluble IgG, disrupts IgG effector function, degrades IgG immune complexes (IC), and cleaves the membrane-bound IgG+ B cell receptor (BCR) on memory B cells. These features allow S-1117 to simultaneously address multiple mechanisms of autoimmunity.

Methods: Plasma IgG, IgG+ BCR, IC cleavage, and antibody mediated effector function assays were performed in vitro. S-1117 function was tested pre-clinically in rabbits, cynomolgus monkeys, and mice in vivo.

Results: S-1117 potently cleaves all IgG subclasses in plasma from healthy individuals. It directly eliminates IgG effector function, including antibody-dependent and complement-dependent cytotoxicity, and IC-mediated immune cell activation in vitro. Moreover, it cleaves the IgG+ BCR on memory B cells in humans in vitro and rabbits in vivo.

In vivo, a single dose of S-1117 induces rapid (< 24 hours), deep ( >90%), and sustained (10 or more days) reduction of endogenous IgG in rabbits and of human IgG administered in cynomolgus monkeys. Chronic administration of S-1117 in mice is well tolerated and demonstrates maintenance of drug exposure and activity. Human pharmacokinetic (PK) / pharmacodynamic (PD) quantitative systems pharmacology 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.

Conclusion: S-1117 is a novel engineered pan-IgG protease that demonstrates rapid, deep, and sustained reduction of IgG levels and IgG effector function, as well as cleavage of the IgG+ BCR on memory B cells. Advantages of enzymatic degradation, sustained PK, and titratable PD are expected to enable a convenient patient-tailored treatment regimen. Since S-1117 addresses multiple pathogenic mechanisms as a single drug, it has the potential to provide superior clinical outcomes in autoantibody-mediated diseases with complex pathology.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preclinical-polypharmacology-of-s-1117-a-novel-engineered-fc-fused-igg-degrading-enzyme-for-chronic-treatment-of-autoantibody-mediated-diseases/