Progress in research on the mechanism of action of immune-activated antibody drugs October 30, 2018 Source: Chinese Academy of Sciences Life lies in exercise, and immunity lies in balance. The immune cells in a healthy individual are sufficient to destroy the constantly occurring diseased cells in the body, including some cells that may become cancerous. T cells are the main force of all anti-tumor immune systems in the body. The activity of T cells is largely regulated by two types of molecules, namely, "yin" and "yang", which are inhibitory and activated "immunoassay" balance molecules. The interaction between these inhibitory immunological checkpoint molecule receptor-ligands is blocked by antibodies, thereby suppressing the inhibition of T cells, so that tumor-specific T cells can restore their tumor killing ability, thereby achieving the effect of treating tumors. American scientist James Allison, who made a pioneering contribution to the research and application of T cell negative regulation mechanism, and Japanese scientist Tasuku Honjo jointly won the 2018 Nobel Prize in Physiology or Medicine. In addition to suppressive immunological checkpoints, T cell activity is also regulated by activated immune checkpoint molecules. 4-1BB (gene: CD137) is an important activation-type immune checkpoint molecule. A variety of 4-1BB-activated antibodies have been introduced into clinical research, including Bristol-Myers Squibb. Urelumab antibodies and Pfizer's utomilumab antibodies, which alone or in combination with other cancer treatments, can significantly improve tumor treatment efficiency (Figure). Therefore, the study of the mechanism of action of 4-1BB and its ligands and activated antibodies not only clarifies its activation mechanism, but also has important value for the development of tumor immunotherapeutic drugs targeting 4-1BB. The Cell Reports magazine published on October 24th reported that the research team of the Institute of Biomedical Engineering and Technology of the Chinese Academy of Sciences, the alpine team, and the Chinese Academy of Sciences Institute of Microbiology, Chinese Academy of Sciences, Gao Fu, Tian Bo team on the mechanism of action of 4-1BB and ligands and activated antibodies. Research results. The team found that the 4-1BB ligand (4-1BBL) binds three 4-1BB monomer molecules (mono-4-1BB) in the form of a trimer. It was further found that there was a certain degree of overlap between the 4-1BB ligand (4-1BBL) and the activated antibody utomilumab bound 4-1BB, suggesting that the two competitively bind to 4-1BB. The experimental results of flow cytometry and Octet interaction analysis showed that there was a significant competition between the two and 4-1BB. The binding of utomilumab to 4-1BB inhibited the binding of 4-1BB to 4-1BBL, indicating that it was in utomilumab. The 4-1BBL-mediated 4-1BB activation signal is blocked during the course of action. Previous reports reported that the antibody drug urelumab against another clinical stage of the 4-1BB target did not block the 4-1BBL-mediated 4-1BB activation signal. Clinical studies of Utomilumab and urelumab have shown that utomilumab has better clinical tolerance, suggesting that its blockade of 4-1BBL-mediated 4-1BB activation signaling may be one of the factors that contribute to this clinical difference. By detecting activated T cells, it was found that T cells can express both monomeric (mono-4-1BB) and dimeric (di-4-1BB) forms of 4-1BB molecules, and two different forms of 4 The binding mode of the -1BB molecule, especially the di-4-1BB interaction with the ligand, was investigated. By studying the binding mode of di-4-1BB and 4-1BBL, it was found that a trimer 4-1BBL can only bind two di-4-1BB. Further, the formation mechanism of di-4-1BB was studied. It was found by mutation experiments that the formation of dimer forms by 121-cysteine. In the evolutionary conservation analysis, it was found that compared with 4-1BB molecules of different species, there were only 121 cysteines in primates and some mammals, indicating that the 121-cell cysteine-mediated dimer form exists. It is unique and the formation of 4-1BB dimers may be related to the evolution of the immune system. This study provides an important theoretical basis for the development of activating immunological checkpoint antibody drugs represented by 4-1BB. In recent years, the three teams have carried out a series of research work on the mechanism of antibody drug action at the immune checkpoint. The binding mechanism of PD-1, PD-L1 and CTLA-4, and the PD-1 glycosylation modification pair New progress has been made in the influence of antibody drugs, which provides an important theoretical basis for the development of related target drugs. Paper Information: Li Y#, Tan S#, Zhang C#, Chai Y, He M, Zhang CW, Wang Q, Tong Z, Liu K, Lei Y, Liu W, Liu Y, Tian Z, Cao X, Yan J, Qi, J, Tien P*, Gao S*, Gao GF* Limited cross-linking of 4-1BB by 4-1BB ligand and the agonist monoclonal antibody utomilumab. Cell Rep. 2018. Volume 25, Issue 4, 23 October 2018, Pages 909-920.e4. doi.org/10.1016/j.celrep.2018.09.073. Figure: 4-1BB molecule has important application value in tumor antibody drug development and CAR-T cell therapy NINGBO MEDICAL EQUIPMENT CO.,LTD , https://www.techartmeds.com