Method for treating rheumatoid arthritis using anti-S100A9 antibody

#The present invention relates to inhibitors, antagonists and methods for modulating the factors involved in body inflammation reactions and diseases. Particularly, the present invention relates to a method for reducing or inhibiting the symptoms and manifestations associated with body inflammations.

#The acute articular inflammation of gouty arthritis is caused by crystallisation of sodium urate in an articulation. Interaction between monosodium urate crystals (MSU crystals) and monocytes, platelets, synoviocytes, macrophages and neutrophils within the articulation initiates an inflammatory response by stimulating the secretion of proinflammatory agents and chemotactic factors from these different cell types. Some of these mediators induce the accumulation of neutrophils, which further enhances the inflammatory response and release of oxygen radicals and proteolytic enzymes, leading to the destruction of the articulations.

#Arthritis is a chronic syndrome characterized by the inflammation of peripheral joints, while gout manifests itself as an inflammation of the lower leg. Although the causal agents differ between the two diseases, the mechanism of migration of neutrophils is similar in both diseases. Therefore, for the sake of brevity, whenever reference hereinbelow is made to arthritis, it should be understood as encompassing gout, since both diseases are similar. There is a wide spectrum of disease severity and many patients run a course of intermittent relapses and remissions with an overall pattern of slowly progressive joint destruction and deformity. Persistent inflammation produces symptoms and damages tissue causing loss of cartilage, erosion of bone matter and subluxation of the joint. This results in a high degree of morbidity resulting in disturbed daily life of the patient. Diagnosis of arthritis is typically carried out by determination of rheumatoid factors in the blood and radiological changes in peripheral joints.

#FIGS. 1A and 1B illustrate the MSU crystals-induced accumulation of leukocytes in the mouse air pouch model;

#FIGS. 2A to 2C illustrate the release of S100A8, S100A9, and S100A8/A9 in air pouches of mice injected with MSU crystals;

#FIGS. 3A and 3B illustrate that S100A8, S100A9, and S100A8/A9 stimulate neutrophil accumulation in vivo;

#In accordance with the present invention, there is provided a method and compositions for the modulation of the activity of different factors involved in the manifestations or reactions of body inflammation. The factors can cause migration of cells, such as for example but without limiting it to, neutrophils, or can cause oxidation by radicals, or proteolysis by different enzymes of proteases.

#The present invention shows that myeloid-related proteins (MRP) play a role in the process of neutrophil migration to inflammatory site. MRP proteins are a subfamily of S100 proteins in which three members have been characterized, namely S100A8, S100A9, and S100A12. These small proteins are constitutively expressed at high levels in the cytosol of neutrophils. S100A8 and S100A9 are also expressed by activated endothelial cells, certain epithelial cells, keratinocytes, monocytes and activated macrophages. In the presence of calcium, S100A8 and S100A9 associate noncovalently to form the heterodimer S100A8/A9.

#Several proinflammatory activities have been identified for these proteins. In vitro studies described herein bellow demonstrate that S100A8, S100A9, and S100A8/A9 are involved in neutrophil and monocyte migration and stimulate neutrophil adhesion to fibrinogen by activating the β2 integrin Mac-1. In addition, intraperitoneal injection of murine S100A8 in mice stimulates the accumulation of activated neutrophils and macrophages. It is also shown that S100A9 and S100A8/A9 enhance monocyte adhesion to and migration through endothelial cells via Mac-1/ICAM-1 interactions.