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Updated: Feb 26, 2026
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
Efficiency and Safety of CRAC Inhibitors in Human Rheumatoid Arthritis Xenograft Models
Shuang Liu1, Hitoshi Hasegawa2, Erika Takemasa3
1Department of Pharmacology, Ehime University Graduate School of Medicine, Shitsugawa, Toon-shi, Ehime 791-0295, Japan; liussmzk@m.ehime-u.ac.jp.
Abstract:
Store-operated Ca2+ release-activated Ca2+ (CRAC) channels are involved in the pathogenesis of rheumatoid arthritis (RA) and have been studied as therapeutic targets in the management of RA. We investigated the efficacy and safety of CRAC inhibitors, including a neutralizing Ab (hCRACM1-IgG) and YM-58483, in the treatment of RA. Patient-derived T cell and B cell activity was suppressed by hCRACM1-IgG as well as YM-58483. Systemically constant, s.c. infused CRAC inhibitors showed anti-inflammatory activity in a human-NOD/SCID xenograft RA model as well as protective effects against the destruction of cartilage and bone. hCRACM1-IgG appeared to be safe for systemic application, whereas YM-58483 showed hepatic and renal toxicity in xenograft mice. Treatment with both CRAC inhibitors also caused hyperglycemia in xenograft mice. These results indicate the potential of hCRACM1-IgG and YM-58483 as anti-immunological agents for the treatment of RA. However, some safety issues should be addressed and application methods should be optimized prior to their clinical use.
Insights
Store-operated calcium release-activated calcium (CRAC) channel inhibitors show potential for rheumatoid arthritis (RA) treatment by suppressing immune cells. While one inhibitor (hCRACM1-IgG) appears safe, both caused hyperglycemia and YM-58483 showed toxicity in preclinical RA models.
Area of Science:
- Immunology
- Rheumatology
- Pharmacology
Background:
- Store-operated calcium release-activated calcium (CRAC) channels are implicated in rheumatoid arthritis (RA) pathogenesis.
- CRAC channels represent a potential therapeutic target for RA management.
Purpose of the Study:
- To evaluate the efficacy and safety of CRAC inhibitors, specifically a neutralizing antibody (hCRACM1-IgG) and YM-58483, for RA treatment.
- To assess the anti-inflammatory and protective effects of CRAC inhibitors in a human-NOD/SCID xenograft RA model.
Main Methods:
- Investigated the impact of hCRACM1-IgG and YM-58483 on patient-derived T cell and B cell activity.
- Administered CRAC inhibitors systemically via subcutaneous infusion in a human-NOD/SCID xenograft RA model.
- Monitored for anti-inflammatory activity, protection against cartilage and bone destruction, and potential toxicities (hepatic, renal, hyperglycemia).
Main Results:
- Both hCRACM1-IgG and YM-58483 suppressed T cell and B cell activity.
- Systemic CRAC inhibition demonstrated anti-inflammatory effects and protected against joint destruction in the RA xenograft model.
- hCRACM1-IgG showed a favorable safety profile, while YM-58483 exhibited hepatic and renal toxicity. Both induced hyperglycemia.
Conclusions:
- CRAC inhibitors, hCRACM1-IgG and YM-58483, show promise as anti-immunological agents for RA treatment.
- Further research is needed to address safety concerns and optimize administration methods before clinical application.
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