Chemokines are small protein families that play a central role in inflammation. During the inflammatory process, chemokines are locally produced at the site of noxious stimuli and act as central agents to recruit immune cells expressing their cognate receptors, 7 transmembrane G protein-coupled receptors (GPCRs). CCL20, an alternatively named liver and activation-regulated chemokine, is a soluble chemokine expressed by epithelial cells. Epithelial keratinocytes and synovial-lining cells are known to produce large amounts of CCL20 during homeostatic as well as inflammatory and pathological conditions such as cancer, psoriasis and rheumatoid arthritis. The homologous receptor for CCL20 is CC chemokine receptor 6; CCL20 antibody is the only chemokine known to interact with CCR6. In response to CCL20 signaling, immune cells with CCR6, such as immature dendritic cells, effector/memory T-cells, and B cells, migrate and infiltrate surrounding tissues, thereby activating the inflammatory cascade.
Because ccl20 cancer expression is significantly enhanced in inflammation induced by inflammatory cytokines such as interleukin-1 and tumor necrosis factor alpha, CCL20-CCR6 interaction is thought to be pathologically inflammatory. The process plays a role.
Rheumatoid arthritis is one of the most common autoimmune diseases. The first sign of RA is often synovitis, which appears as a swollen, painful joint. Although specific factors that initiate synovitis are not known, synovial lining epithelial cells and synovial fibroblasts are considered to be major inducers of the inflammatory response. Synovial fluid from RA patients is effective chemistries - attracting human monocytes and pro-inflammatory T helper 17 cells, which then induce and worsen the RA inflammatory process. Because reactive synoviocytes produce large amounts of CCL20, and CCR6 is the major receptor for Th17 cells, the CCL20-CCR6 interaction is thought to play during the inflammatory process. play a key role in.
The CCL20-CCR6 interaction can also play an important role in certain types of dermatitis. Psoriasis, for example, a harmful psoriasis event that begins in the skin is followed by infiltration of Th17 cells. Because CCR6 is expressed on the surface of Thl7 cells, B cells, dendritic cells, and tissue damage effector T cells, CCL20 can represent the major chemoattractant of these cell types in psoriasis. Further evidence for the importance of the CCL20-CCR6 interaction can be found in the study of the psoriasis mouse model induced by interleukin 23. In this model, injection of IL-23 resulted in inflammation of interleukin 22 (IL-22)-dependent psoriasis. However, Ccre+ mice did not present psoriasis-like symptoms when injected with IL-23, indicating that CCR6 requires the development of psoriasis.
Human keratinocytes produce large amounts of CCL20, particularly under the influence of the cytokine interleukin-17, IL-22 and TNF-α derived from Th17. While CCL20 and CCR6 are rarely detected in normal skin, both present increased expression levels in atopic dermatitis and pustular psoriasis. Strong induction of CCL20 and accumulation of CCR6+ cells can be observed in microscopic immunohistochemical analysis of human dermatitis lesions. These observations provide additional evidence for the role of CCL20 and CCR6 in the inflammatory process of dermatitis.
MAb biologics currently available for the treatment of immune disorders can be roughly divided into three groups: immunostimulatory cytokine inhibitors, immune cell depletion, and A subsidiary molecular blocker. These biological products may be useful for treating inflammatory diseases; however, due to the gradual decrease in the rate of non-response or response to these treatments, for patients with new mechanisms of action to cater for, for example, CCL20/CCR6-mediated disorders There is an urgent need for alternative biological products for medical needs. The antibodies of the subject invention represent the alternative biological product.