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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
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An Adoptive Transfer Model of Rheumatoid Arthritis in Mice

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Optimization of a synoviocyte-targeted biologic for inflammatory arthritis in combination or bispecific

Sterling H Ramsey1, Zixuan Zhao1, Megan C Lee1

  • 1Department of Medicine, Altman Clinical and Translational Research Institute, UCSD, La Jolla, California, USA.

JCI Insight
|September 30, 2025
PubMed

Insights

Engineered Ig1&2-Fc shows promise for rheumatoid arthritis (RA) therapy by targeting fibroblast-like synoviocytes (FLS). This novel biologic, Ig1&2-Fc, demonstrated safety and efficacy, offering potential for combination or bispecific treatments to improve RA patient outcomes.

Area of Science:

  • Immunology
  • Rheumatology
  • Biotechnology

Background:

  • Rheumatoid arthritis (RA) is a systemic autoimmune disease with fibroblast-like synoviocytes (FLS) as a therapeutic target.
  • Receptor protein tyrosine phosphatase sigma (PTPRS) regulates FLS migration and is a potential target for RA treatment.
  • Currently, no approved drugs specifically target FLS in RA therapy.

Purpose of the Study:

  • To evaluate the efficacy and safety of an engineered Fc-fused PTPRS biologic (Ig1&2-Fc) for RA.
  • To investigate the potential of Ig1&2-Fc as a monotherapy, combination therapy, or bispecific therapy for RA.

Main Methods:

  • Engineering of human Ig1&2-Fc by optimizing linker and Fc tag for enhanced efficacy.
  • In vitro assays assessing FLS migration and in vivo studies using a mouse model of arthritis.
  • Evaluation of Ig1&2-Fc toxicity and its combination or bispecific administration with a tumor necrosis factor-α inhibitor (mTnfr2).

Main Results:

  • Engineered Ig1&2-Fc demonstrated improved effectiveness in inhibiting FLS migration and reducing arthritis severity in mice.
  • Four-month treatment with Ig1&2-Fc showed no signs of toxicity or organ pathology in mice.
  • Combination and bispecific administration of Ig1&2-Fc with mTnfr2 exhibited superior efficacy in suppressing arthritis compared to single-agent treatments.

Conclusions:

  • Engineered Ig1&2-Fc is a safe and effective FLS-targeted biologic for RA.
  • Ig1&2-Fc holds significant potential as a combination or bispecific therapy to enhance RA treatment outcomes.
  • This approach could offer a new strategy for managing RA by targeting FLS and other inflammatory pathways.
Keywords:
ArthritisAutoimmunityCell biologyProteoglycansRheumatology

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