Tu119 - Characterization of S-1117, a Novel pan-IgG Protease Engineered by IMPACT Platform to Reduce Immunogenicity

Abstract Text: Proteases derived from human pathogens can specifically cleave IgG antibodies. This unique trait represents a novel opportunity to use these molecules to treat IgG-mediated diseases. Due to the immunogenic nature of these proteases, their use as biologics is limited. S-1117 is 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.

In vitro, compared to the wildtype parental protease, S-1117 demonstrates reduced binding to pre-existing antibodies in plasma from healthy donors and reduced epitope display by MAPPs demonstrating removal of B and T cell epitopes, respectively. Furthermore, wildtype parental protease elicits CD4 T cell proliferation responses from 65% of healthy donors with a mean response index (RI) of 2.60 (magnitude of response over background signal). In comparison, S-1117 demonstrates a significant reduction in the number of responders to 20% and a 10-fold reduction in mean RI of 0.26 which are associated with reduced clinical immunogenicity. In vivo, repeated dosing of wildtype parental protease in C57BL/6 mice induced immediate hypersensitivity reactions, causing death in 60% (3/5) of mice and high ADA levels (>5ug/mL) in surviving mice. In contrast, all mice exposed to repeat doses of S-1117 survived without severe immune reactions and only 20% (1/5) of mice presented ADA levels.

In summary, S-1117 is a novel pan-IgG protease engineered to remove B and T cell epitopes to overcome pre-existing immunogenicity and prevent de novo responses, while enhancing manufacturability and removing chemical liabilities without impacting enzyme activity.