Efficiency and Safety of CRAC Inhibitors in Human Rheumatoid Arthritis Xenograft Models

• Published in: The Journal of immunology (1950) 2017-09, Vol.199 (5), p.1584-1595
• Main Authors: Liu, Shuang, Hasegawa, Hitoshi, Takemasa, Erika, Suzuki, Yasuyuki, Oka, Keizou, Kiyoi, Takeshi, Takeda, Hiroyuki, Ogasawara, Tomio, Sawasaki, Tatsuya, Yasukawa, Masaki, Maeyama, Kazutaka
• Format: Article
• Language: English
• Subjects: Anilides - adverse effects; Anilides - therapeutic use; Animal models; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - therapeutic use; Antibodies, Neutralizing - adverse effects; Antibodies, Neutralizing - therapeutic use; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - therapy; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Calcium channels; Calcium Release Activated Calcium Channels - antagonists & inhibitors; Cartilage; Cells, Cultured; Disease Models, Animal; Heterografts; Humans; Hyperglycemia; Hyperglycemia - etiology; Immunoglobulin G; Immunology; Immunosuppression; Immunotherapy - methods; Inflammation; Inhibitors; Kidneys; Lymphocytes B; Lymphocytes T; Mice; Mice, SCID; Rheumatoid arthritis; Safety; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Thiadiazoles - adverse effects; Thiadiazoles - therapeutic use; Toxicity; Xenografts
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1700192

Store-operated Ca release-activated Ca (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.