Background/Purpose: Pathogenic autoantibodies are key effectors of inflammation, promoting tissue damage in autoantibody-mediated diseases such as inflammatory myopathies, lupus nephritis, Sjogren’s syndrome, antiphospholipid syndrome, and ANCA-associated vasculitis. Antibody degradation using an IgG protease represents a new therapeutic opportunity.We present S-1117, a novel pan-IgG protease fused to an effectorless 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 IgG+ B cell receptor (BCR) on surface of memory B cells, reducing IgG+ BCR mediated activation. These features allow S-1117 to simultaneously address multiple mechanisms of autoimmunity.

Methods: Immunogenicity of S-1117 was assessed in vitro by major histocompatibility complex (MHC)-associated peptide proteomics (MAPPs) and validated by CD4 T cell proliferation assays. In vivo, IgG antidrug antibody (ADA) was quantified in C57BL/6 mice in response to S-1117 protease domain administration vs the parental protease. The polypharmacology of S-1117 was determined through in vitro plasma IgG, IgG+ BCR, and IC cleavage, as well as antibody mediated effector function assays. S-1117 function was tested pre-clinically in vivo in rabbits and mice.

Results: In vitro, S-1117 demonstrates reduced epitope display compared to the wildtype protease by MAPPs. Furthermore, the wildtype protease elicits CD4 T cell proliferation responses from 65% of healthy donors with a response index of 2.60 (magnitude of response over background signal). In comparison, S-1117 demonstrates a reduction in the number of responders to 20% and a 10-fold lower response index.In vivo, a single dose of S-1117 induces rapid ( < 24 hours), deep ( >90%), and sustained (over 10 days) reduction of endogenous IgG in rabbits. In mice, repeat dosing of parental protease induced immediate hypersensitivity reactions, causing mortality in 60% of mice and high ADA response. In contrast, all mice treated with the protease domain of S-1117 survived multiple doses without anaphylactic reactions or induction of ADA.Functionally, S-1117 cleaves all IgG subclasses in human plasma. It directly eliminates IgG effector function and IC-mediated immune cell activation. Moreover, it cleaves the IgG+ BCR on memory B cells in humans in vitro, reducing IgG+ BCR driven B cell activation.

Conclusion: S-1117 is a novel pan-IgG protease engineered with our machine learning enabled platform to reduce immunogenicity. It demonstrates rapid, deep, and sustained reduction of IgG levels, IgG effector function, and cleavage of the IgG+ BCR on memory B cells, reducing BCR mediated B cell activation. 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/characterization-of-s-1117-a-novel-pan-igg-protease-engineered-for-reduced-immunogenicity-using-the-impact-platform/