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

Introduction:

Pathogenic autoantibodies are key effectors of inflammation, promoting immune cell responses that cause tissue damage in autoantibody-mediated diseases such as immune thrombocytopenia (ITP), warm autoimmune hemolytic anemia, and Evans syndrome. 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 activity and selectivity. S-1117 cleaves and reduces soluble IgG, eliminates 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, and IC cleavage assays, as well as antibody-mediated effector function assays were performed in vitro. In vivo, human IVIG was injected into mice and IVIG reduction was compared between S-1117 and a benchmark FcRn inhibitor. Prophylactic and therapeutic efficacy of S-1117 were tested in murine ITP models, where disease was induced with rabbit anti-mouse platelet serum (RAMS). Quantitative systems pharmacology (QSP) modeling was used to estimate human pharmacokinetics (PK) and pharmacodynamics (PD).

Results:

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 against RAMS-induced platelet depletion in prophylactic and therapeutic murine models of ITP.

Human PK/PD QSP 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.

Conclusions:

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 demonstrate superiority in human IgG cleavage compared to a benchmark FcRn inhibitor and are expected to enable a convenient patient-tailored treatment regimen. Given its ability to addresses multiple pathogenic mechanisms as a single drug, S-1117 has the potential to provide improved clinical outcomes in autoantibody-mediated diseases with complex pathology, such as ITP and other cytopenias, as demonstrated in the prophylactic and therapeutic ITP murine models.