Cancer Cell Highlights . . . "The gorgeous turn of antibody drugs" - autoimmune disease drugs into anti-cancer drugs.

CD40, a receptor on the surface of human immune cells, plays a key role in stimulating human immune response with ligand CD40L, which helps antigen-presenting cells (such as dendritic cells) to activate B and T cells more effectively.in autoimmune diseases, CD40 is considered to over stimulate the immune system, causing the immune system to attack its own healthy tissues.on the contrary, in cancer, CD40 is considered to be insufficiently stimulated, allowing tumor cells to escape the immune system's monitoring of cell variations.in the treatment of these two diseases with opposite mechanisms, IgG antibodies targeting CD40 are being actively used in clinical trials.among the CD40 targeted antibodies, the antagonistic IgG can prevent the binding of CD40L and CD40, so as to achieve the inhibition effect and reduce the autoimmune attack; the excited IgG can activate the CD40 signal pathway and increase the anti-cancer effect of the immune system.these two types of CD40 antibodies help patients with autoimmune diseases and cancer to slow down the disease in clinical trials, respectively.the mechanism of antagonistic IgG and excited IgG is traditionally considered to be determined by the specificity of variable region (FAB), and its constant region (FC) is often ignored.on May 21, 2020, Mark S. Cragg and Martin J. Glennie of the antibody and vaccine group of the University of Southampton, UK, published the article isotype switching converters anti-CD40 anti-CD40 antibody to agonism to elicit potent antumor activity When FC segment changes from human IgG1 or IgG4 subtype to adult IgG2 subtype, this antagonistic IgG changes to excited IgG. Br / > the number of dendritic cells activated by T < 8 in mice was also significantly enhanced.one of the antagonistic antibodies bleselumab (IgG4) is currently in clinical trials for plaque psoriasis and renal transplant rejection. After being transformed into IgG2, its excitability exceeds that of CD40 antibody in all clinical stages and is regarded as a "super" stimulant.further studies have found that the mechanism of antagonistic transactivation is locked in the ch1 and hine segments of IgG2 FC.compared with other IgG subtypes, the FC segment of IgG2 has a very different disulfide bond structure, which reduces the relative flexibility of F (ab ') 2 segment and effectively promotes the aggregation of CD40 on cell surface.the specificity of Fab remains unchanged, only FC subtype transformation can exchange the antagonism and excitability of antibody, which provides a new idea for antibody engineering.Dr. Yu Xiaojie, a member of the team, called this subtype a molecular "switch".through a simple molecular "switch", antibody drugs previously developed for the treatment of autoimmunity can be transformed into drugs with strong anticancer activity.this molecular "switch" is being used in other immune targets, such as 41bb and OX40.Professor Mark Cragg, who led the study, said: "our findings are based on the history of the Southampton CD40 study, which is surprising and exciting.this mechanism takes the antibody that suppresses the immune system and turns it through a relatively simple process to activate the cancer immune system, which is unprecedented. in addition, the same method can also be used for other immune targets, and we look forward to testing this in the near future. ". original link: plate maker: Qi sauce