# Optimization of a synoviocyte-targeted biologic for inflammatory arthritis in combination or bispecific administration with TNF inhibitors

## TL;DR

This paper explores a new biologic targeting synoviocytes to treat arthritis, showing improved effectiveness when combined with TNF inhibitors.

## Contribution

The study introduces an optimized PTPRS-targeted biologic that can be used in combination or bispecific therapy with TNF inhibitors for arthritis.

## Key findings

- Engineered Ig1&2-Fc showed improved effectiveness in reducing synoviocyte migration and arthritis in mice.
- Combining Ig1&2-Fc with TNF inhibitors enhanced arthritis suppression beyond single-agent treatments.
- Bispecific fusion of Ig1&2-Fc with mTnfr2 was more efficacious than mTnfr2 alone in suppressing arthritis.

## Abstract

Rheumatoid arthritis (RA) is a common systemic autoimmune disorder. Fibroblast-like synoviocytes (FLS) have emerged as an attractive target for nonimmunosuppressive RA therapy, but there are no approved drugs targeting FLS. The receptor protein tyrosine phosphatase sigma (PTPRS) negatively regulates FLS migration and has been proposed as a target for FLS-directed RA therapy. Here we examined the impact of sequence variations on efficacy of an FLS-targeted biologic composed of Fc-fused PTPRS IgG-like domains Ig1 and Ig2 (Ig1&2-Fc). Engineering the linker and Fc tag improved effectiveness of human Ig1&2-Fc in assays of FLS migration and a mouse model of arthritis. Treatment of mice with Ig1&2-Fc over 4 months revealed no signs of toxicity or organ pathology. Finally, we show potential of Ig1&2-Fc coadministration in combination or as a bispecific fusion with a tumor necrosis factor-α inhibitor. Combination treatment of mouse tumor necrosis factor receptor 2 (mTnfr2) with Ig1&2-Fc resulted in increased efficacy in suppressing arthritis beyond single-agent treatment. When administered as a dual-action bispecific, Ig1&2 fused to mTnfr2 proved more efficacious at suppressing arthritis than mTnfr2 alone. This study illustrates the potential of Ig1&2-Fc as a combination or bispecific therapy with disease-modifying antirheumatic drugs to improve patient outcomes in RA.

Optimization of PTPRS-targeted biologic for RA that reduces FLS migration and arthritis in mice and enhances TNF inhibitor efficacy as a combination or bispecific therapy