Unknown Manufacturer
Olokizumab is a humanized anti-IL-6 IgG4κ antibody under investigation for use in autoimmune conditions including rheumatoid arthritis.
Olokizumab is a humanized anti-IL-6 IgG4κ antibody under investigation for use in autoimmune conditions including rheumatoid arthritis.
Interleukin-6 (IL-6) plays a role in numerous autoimmune diseases by perpetuating tissue damage and inflammation. IL-6 acts as an essential differentiation factor for T17 cells, which, when activated through dendritic cells displaying antigen-specific signals, induce tissue damage and act pathogenically. IL-6 also functions in B cell differentiation and development, including in the production of pathogenic autoantibodies. Combined with other roles for IL-6 in cell proliferation and differentiation, these mechanisms underly the importance of IL-6 in a variety of autoimmune conditions. IL-6 signalling involves a corresponding IL-6 receptor (IL-6R/gp80/CD126) and a co-receptor gp130 (CD130). Complex assembly is thought to involve binding of IL-6 to gp80 at Site 1 followed by binding to gp130 at Site 2 to form a heterotrimer; two heterotrimers then combine through Site 3 on IL-6 binding to domain 1 of gp130. The resulting heterohexameric complex is responsible for signal transduction. Curiously, although IL-6R is typically membrane-bound, it can also exist in a soluble form (sIL-6R) through limited proteolysis or alternative splicing. This leads to three distinct signalling paradigms: classic signalling, where IL-6R and gp130 exist within the same cell membrane, trans-signalling, where sIL-6R interacts with membrane-bound gp130, and trans-presentation, where IL-6R from one cell forms a complex with gp130 on a different cell. It is thought that trans-signalling is responsible for the majority of IL-6-associated pathology. Olokizumab is a humanized anti-IL-6 IgG4κ antibody whose epitope lies within IL-6 Site 3. Structural analysis revealed that olokizumab binding induces conformational changes in IL-6 that cause occlusion of the gp130 binding site between trp157 and residues 50-60. By inhibiting gp130 binding, olokizumab inhibits both classical and trans-signalling.
