Optimization of a synoviocyte-targeted biologic for inflammatory arthritis in combination or bispecific administration with TNF inhibitors
Sterling H. Ramsey, Zixuan Zhao, Megan C. Lee, Thales Hein da Rosa, Ava C. Schneider, Miriam Bollmann, Nour Dada, Katie E. Frizzi, May M. Han, Jaeyeon Kim, Martina Zoccheddu, Nigel A. Calcutt, Gary S. Firestein, James W. Bryson, Mattias N.D. Svensson, Eugenio Santelli, Stephanie M. Stanford, Nunzio Bottini
Sterling H. Ramsey, Zixuan Zhao, Megan C. Lee, Thales Hein da Rosa, Ava C. Schneider, Miriam Bollmann, Nour Dada, Katie E. Frizzi, May M. Han, Jaeyeon Kim, Martina Zoccheddu, Nigel A. Calcutt, Gary S. Firestein, James W. Bryson, Mattias N.D. Svensson, Eugenio Santelli, Stephanie M. Stanford, Nunzio Bottini
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Research Article Cell biology

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

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.

Authors

Sterling H. Ramsey, Zixuan Zhao, Megan C. Lee, Thales Hein da Rosa, Ava C. Schneider, Miriam Bollmann, Nour Dada, Katie E. Frizzi, May M. Han, Jaeyeon Kim, Martina Zoccheddu, Nigel A. Calcutt, Gary S. Firestein, James W. Bryson, Mattias N.D. Svensson, Eugenio Santelli, Stephanie M. Stanford, Nunzio Bottini

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Figure 2

Four-month study shows no adverse effects of Ig1&2-Fc in mice.

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Four-month study shows no adverse effects of Ig1&2-Fc in mice. (A) F...
(A) Fold-change in serum alanine aminotransferase (ALT; left) and aspartate aminotransferase (AST; right) activity in mice treated with PBS or Ig1&2-Fc during months 1 and 4 of Ig1&2-Fc treatment. Mean ± SEM relative to PBS is shown. (B) Serum creatinine concentration in mice treated with PBS or Ig1&2-Fc during months 1 and 4 of treatment. (C) Electrocardiogram results of mice treated with PBS or Ig1&2-Fc after 4 months of treatment. (D) Serum atrial natriuretic peptide (ANP) in mice treated with PBS or Ig1&2-Fc after 4 months of treatment. (E) Nerve conduction velocity (NCV) of sciatic nerve in mice treated with PBS or Ig1&2-Fc before treatment (baseline) and after month 4 of treatment with Ig1&2-Fc. (F) Average force (in grams) of Von Frey filaments able to elicit a paw withdrawal response 50% of the time in mice treated with PBS or Ig1&2-Fc during months 2–4 of treatment (PWT, paw withdrawal threshold). (G) Paw withdrawal latency in response to heat of mice treated with PBS or Ig1&2-Fc during months 2–4 of treatment. (H) Total nerve area of sub basal nerve plexus (left) and stromal nerves (right) as observed by CCM during each month of treatment. (A–H) PBS: n = 9; Ig1&2-Fc: n = 10. Mean ± SEM is shown. NS, nonsignificant; 2-way ANOVA with Šídák’s correction (A, B, and E–H) or Mann-Whitney U test (C and D).