Clinical-stage company Immutep (ASX:IMM) has announced new findings published in Science Immunology that resolve how human lymphocyte activation gene 3 (LAG-3) binds to its main ligand MHC Class II (MHC-II), also known as HLA Class II (HLA-II) in humans.
Immutep is developing novel LAG-3 immunotherapies for cancer and autoimmune diseases.
The company said the publication is the first to show the crystal structure of a human LAG-3/HLA-II complex and provides a better foundation for the development of blocking LAG-3 therapeutics, including Immutep’s anti-LAG-3 small molecule program. It said the data supports its efti’s (soluble LAG-3) preferential binding to a subset of MHC-II molecules on antigen-presenting cells, leading to their activation.
Dr Jan Petersen, first author of the study, said, “The way the PD-1 and CTLA-4 immune checkpoint molecules bind to their respective ligands has been resolved for many years. However, the resolution of the interface between another important checkpoint molecule, LAG-3, and its main ligands, HLA-II molecules, has remained elusive. Solved using data collected at the Australian Synchrotron, a structure of a LAG-3/HLA-II complex provides a structural foundation to harness rationally for future development of antibodies and small molecule therapeutics designed to block LAG-3 activity.”
Immuntep CSO Dr Frédéric Triebel, Immutep’s CSO, added, “It is thrilling to be able to see and analyse the interactions taking place at the interface between the soluble homodimeric LAG-3 protein and its main ligand. We now better understand how efti uniquely acts as an MHC-II agonist by preferentially binding to a subset of MHC-II molecules clustered in lipid raft microdomains on the surface of antigen-presenting cells. These findings add to the strong foundation of our work with Professor Rossjohn and his team to develop a deeper understanding of the structure and function of the LAG-3 immune control mechanism, particularly as it relates to our anti-LAG-3 small molecule program.”
