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Immutep is working to understand and develop therapeutics that relate to Lymphocyte Activation gene-3 or ‘LAG-3’ which is a cell surface molecule that plays a vital role in regulating the immune system. LAG-3 was discovered by Frederic Triebel, CSO, Immutep, putting the company at the forefront of immunotherapy drugs for cancer and autoimmune diseases. He speaks about the significance of this with Lu Rahman.
LR: What is LAG-3 and can you provide some background on its discovery and potential?
FT: LAG-3, or Lymphocyte-Activation gene-3, is a protein, which belongs to the immunoglobulin superfamily. It is a cell surface molecule with biologic effects on T cell function, namely regulating T cell homeostasis and optimising immune responses. LAG-3’s key interaction is in its binding to major histocompatibility complex (MHC) class IIIt has been shown to be expressed by CD4 and CD8 T cells.
Currently, LAG-3 is the most promising new immune-checkpoint to target. Its inhibition could revitalise tumour-specific memory T cells and promote tumour cell killing. The increasing number of LAG-3 related research projects shows that scientists just like big pharma are conscious that it can be the next big step in immuno-oncology.
I discovered this gene in 1988. The first blocking of the LAG-3/MHC II interaction by an anti-LAG-3 antibody was published in 1994. The first LAG-3-related product reaching the clinic was a soluble LAG-3 protein (now called eftilagimod alpha) in 2005.
LR: Why is it so important to big pharma? What opportunities does it hold globally?
FT: Merck and Co, Boehringer Ingelheim, Regeneron and Novartis are all developing anti-LAG-3 mAbs, the last one actually has licenced LAG525, leramilimab from Immutep. Immunotherapy is attractive because it provides cancer patients with better and longer survival than traditional treatments and does this with less side effects. It makes use of the patients’ own immune system, which is well equipped to eliminate tumour cells from the body.
The immune system is in fact so powerful that evolution created ways to regulate/activate/suppress its activity. Immune checkpoints, like LAG-3, serve this purpose as well. The tumour, on the other hand, makes use of these existing pathways to suppress immune cells. There are many immune checkpoints that a tumour could utilise and we are currently only able to block two of them (CTLA-4, PD-1/PD-L1), that gives the tumour the possibility to switch strategy in immune evasion. The more immune checkpoints we can target the more patients can benefit from immunotherapies.
LR: BMS published some positive results on LAG-3 can you elaborate on its findings?
FT: BMS’s phase III RELATIVITY-047 study with anti-LAG-3 mAb relatlimab results demonstrated that simultaneous blockade of LAG-3 and PD-1 is more effective compared to anti-PD-1 standard treatment in first-line metastatic melanoma. Since 2015 when anti-PD-1 were first registered, this is the first time that a new immuno-oncology (IO) product – an Immune Checkpoint Inhibitor (ICI) – was validated in a phase III study. In the case of further validation in other settings like advanced carcinomas, LAG-3 could become the third immune checkpoint molecule besides CTLA-4 and PD-1/PDL-1 to be widely used in the clinic.
LR: What is Immutep’s involvement with LAG-3 at the moment and what particular expertise can you share about your lead product candidate, efti?
FT: Immutep has a leadership position in LAG-3 development with four product candidates in immuno-oncology and autoimmune diseases. Our lead product candidate eftilagimod alpha or efti is a soluble LAG-3 protein. It acts as an MHC II agonist, systemically activating dendritic cells and monocytes which are antigen presenting cells (APC)within a few hours. Efti has a potential to fight tumour growth through adaptive immunity activation followed by adaptive immunity activation. We are investigating this mechanism of action in a variety of applications.
LR: Where do you see the future for Immutep?
FT: We are dedicated to developing efti further as it holds a lot of promise for future treatment of many different types of cancers. In addition, Immutep leads the way in the LAG-3 field as it is the only company that is able to develop four products with different mechanisms of actions around LAG-3, two in immuno-oncology and two in auto-immune diseases.