An LFA-1 ({alpha}L{beta}2) Small-Molecule Antagonist Reduces Inflammation and Joint Destruction in Murine Models of Arthritis

• Published in: The Journal of immunology (1950) 2010-04, Vol.184 (7), p.3917-3926
• Main Authors: Suchard, Suzanne J, Stetsko, Dawn K, Davis, Patricia M, Skala, Stacey, Potin, Dominique, Launay, Michele, Dhar, T. G. Murali, Barrish, Joel C, Susulic, Vojkan, Shuster, David J, McIntyre, Kim W, McKinnon, Murray, Salter-Cid, Luisa
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Cell Adhesion - drug effects; Cell Proliferation - drug effects; Cytokines - biosynthesis; Cytokines - drug effects; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation - drug therapy; Inflammation - immunology; Inflammation - pathology; Lymphocyte Culture Test, Mixed; Lymphocyte Function-Associated Antigen-1 - immunology; Lymphocyte Function-Associated Antigen-1 - metabolism; Mice; Spiro Compounds - pharmacology; Thiophenes - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0901095

LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1-mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.