Discovery and characterization of olokizumab

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a central role in immune regulation and inflammation. Its importance in moderating both innate and adaptive immune responses is evidenced by the broad array of cells that secrete this cytokine, including monocytes, macrophages, T cells, and B cells. IL-6 directs chemokine-regulated trafficking of leukocytes and induces proliferation and differentiation of T cells, as well as antibody production by B cells. IL-6 also contributes to the transition from innate to adaptive immunity through the regulation of leukocyte activation, differentiation, and proliferation. IL-6 interacts with two receptors, gp80 (also known as IL-6 receptor [IL-6R], CD126) and the signal-transducing co-receptor molecule gp130 (CD130), to form a hexameric signaling complex. Formation of this signaling complex is thought to be a stepwise process during which the IL-6 molecule first binds to gp80 at Site 1 to form a dimer, and subsequently to gp130 at Site 2 to form a heterotrimer. Two heterotrimers then combine to form the final active hexameric signaling complex (gp80:IL6:gp130) 2 through interaction between Site 3 on IL-6 and domain 1 of gp130. The order of IL6:gp80 complex interactions with gp130 is controversial, as the higher affinity of the Site 3 vs. Site 2 interaction suggests that heterotrimer formation may actually be driven via Site 3. The full hexameric complex is required for effective IL-6 signaling, and neither the IL-6:gp80 dimer nor the gp80:IL-6:gp130 trimer is able to initiate signal transduction. IL-6 signaling can be mediated via a signaling complex that incorporates either membrane-bound gp80 (cis-signaling) or a soluble form of gp80 (trans-signaling), which is produced as a result of proteolytic cleavage or alternative splicing. While gp130 is ubiquitously expressed, gp80 is present only on certain leukocyte subsets and hepatocytes. Soluble gp80-mediated trans-signaling therefore enables IL-6-driven stimulation of cells that do not express gp80, thereby expanding the range of cell types capable of responding to IL-6. In addition, some activated immune cells, such as T cells, progressively lose their ability to respond to IL-6 cis-signaling because they shed their membranebound gp80; trans-signaling is thought to maintain these effector T cells in an activated state over prolonged periods of time. Both cisand trans-signaling induce an intracellular signaling cascade following tyrosine phosphorylation on the cytoplasmic tail of gp130, with subsequent activation of downstream factors, including the Janus-activated kinases (JAK) and the signal transduction and activators of transcription (STATs). IL-6 also regulates the expression of acute phase proteins via Ras-Raf and subsequent phosphorylation of mitogen-activated protein kinase (MAPK). Given its critical immunoregulatory function, it is not surprising that IL-6 signaling is implicated in the progression of several autoimmune diseases, including rheumatoid arthritis (RA), Crohn disease, and systemic lupus erythematosus. During acute inflammation in RA, IL-6 is released by monocytes, macrophages, and endothelial cells. Stimulation of B cells by IL-6 leads to increased levels of polyclonal γ-globulins and rheumatoid factor. T-cell activation by IL-6 in the presence of autoantigens induces differentiation along the T h 2 pathway and the activation of autoreactive T h 17 cells. In the synovium, infiltration of inflammatory cells contributes to pannus formation