Structure And Function Of GITR-GITRL

The research and development of tumor immunotherapy especially immunomotherapy target molecules has received more and more attention,we have also worked on the structure and function of immune molecules.Antibody drugs targeting molecules such as PD-1 and CTLA-4 have been applied to the treatment of tumor patients.At the same time,durg combination strategy of targeted co-stimulation molecules and PD-1,CTLA-4 and other molecules gradually became the future trend of tumor immunotherapy.As the 18 th member of TNF family,the glucocorticoidinduced TNF receptor-related protein(GITR)is also one of the potential drug targets.Most of the clinical trials of GITR antibodies are currently phase I,with a few in Phase II.The structure of mouse GITR ligand(m GITRL)and human GITR ligand(h GITRL)have been resolved.m GITRL is a dimer structure,and h GITRL is a trimer structure.This suggests that there may be a 2-plus-2 mode in addition to the traditional 3-plus-3 mode of the TNF superfamily molecule.At present,the structure of the interaction between GITR and GITRL complex has not been resolved.In order to explore the specific mode of GITR and GITRL and the physiological significance of the presence of dimer form of GITR,we solved the structure of m GITR and m GITRL complex.We found that m GITR and m GITRL interacted with each other via 2 plus 2 mode,and the key sites in m GITRL were different from the traditional sited in TNF family molecules,which might explain the molecular mechanism of their interaction.Also,we screened several GITR antibody strains that binded to both humans and mice GITRs.Our findings are important to better understand the interaction mechanism and physiological significance of GITR and GITRL.And the screening of antibodies also provided a research basis for screening new therapeutic antibodies.