Unlocking the potential to better target cancer with immunotherapy
Monash University-led research is unlocking new ways for immunotherapy to better target cancer.
Cancer immunotherapy has revolutionised treatment for patients, whereby the body’s own immune system is harnessed to destroy cancer cells.
Typically, several molecules restrain the ability of T cells to target cancer cells and developing approaches to limit this restraining effect can lead to improved effectiveness of cancer immunotherapy.
Research published in Science Immunology has determined the structure of how an inhibitory molecule, LAG3, interacts with its main ligand and provides a new targeted approach to improving the effectiveness of immunotherapy for certain forms of cancer.
The publication is the first to show the crystal structure of a human LAG-3/HLA-II complex and provides a better foundation for development of blocking LAG-3 therapeutics.
Led by Professor Jamie Rossjohn at Monash University’s Biomedicine Discovery Institute (BDI), in collaboration with Immutep, this research resolves how the human LAG-3 receptor binds to HLA II molecules.
First author Dr Jan Petersen 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.”
Figure 1: Human LAG-3 homodimer (with domains D1, D2, D3 and D4) binding to two separate HLA-II (MHC-II) molecules on the surface of an antigen-presenting cell (APC), imposing a distinct 38° offset angle.
Dr Frédéric Triebel, Immutep’s CSO, added: “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.”
Read the full paper published in Science Immunology, titled Crystal Structure of the Human LAG-3–HLA-DR1–Peptide Complex
About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the Monash Biomedicine Discovery Institute (BDI) at Monash University brings together more than 120 internationally-renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.
About Immutep
Immutep is a clinical-stage biotechnology company developing novel LAG-3 immunotherapy for cancer and autoimmune disease. We are pioneers in the understanding and advancement of therapeutics related to Lymphocyte Activation Gene-3 (LAG-3), and our diversified product portfolio harnesses its unique ability to stimulate or suppress the immune response. Immutep is dedicated to leveraging its expertise to bring innovative treatment options to patients in need and to maximise value for shareholders. For more information, please visit www.immutep.com.
DOI: 10.1126/sciimmunol.ads5122
