A short history of the emerging immune checkpoint LAG-3

I have been asked frequently – especially in the past few weeks – about what Lymphocyte Activation Gene 3 (“LAG-3”) actually is and how it has grown in prominence to become the most promising new immune checkpoint in oncology today. While the journey of LAG-3 started about 3 decades ago, it is far from being finished and from a medical point of view it's never been more exciting!

LAG-3 is an emerging immune checkpoint, or a regulator of our immune system. There are a number of different immune checkpoints present on T cells, the most well-known is PD-1. Approved drugs using PD-1, or its major ligand PD-L1, as a target have profoundly changed the way many patients are treated in clinics around the world.

Immune checkpoints are very important for tolerating self-tissues (to avoid autoimmune diseases) and ensuring a functioning immune system which is in a good balance. However, some cancers can evade being detected and attacked by the immune system by stimulating immune checkpoint targets and switching off cancer killing cells, e.g. CD8 T-cells.

As mentioned, the discovery of many immune checkpoints happened decades ago, for example PD-1 was discovered in the early 1990’s and CTLA-4 in the mid 1980’s. LAG-3 was also discovered and cloned by Prof. @Frederic Triebel (CSO/CMO of Immutep Limited) in the early 1990’s, when he was leading the cellular immunology group in the Department of Clinical Biology at the Institut Gustave Roussy in Paris, France. The initial research took years and great dedication, but were ultimately very successful with the first characterisation of the major histocompatibility complex (MHC) class II binding sites on LAG-3 being published in 1997.

The basic principle of the unique LAG-3 – MHC class II interaction is illustrated below:

LAG-3 is a trans-membrane protein which forms dimers on the surface of activated CD4+ and CD8+ T cells. It binds to a subset of MHC class II molecules, which are crucial for immune response induction, particularly for triggering and controlling the development of cellular responses (i.e. cytotoxic CD8 T cells) in inflamed secondary lymphoid organs or tissues, such as human tumours. Thus, LAG-3 has a direct role in activating antigen presenting cells (“APCs”) and downstream immune system responses in infectious diseases and cancer. Also, it can negatively regulate the T cells and down modulate the immune system in a way that prevents cancerous cells from being attacked.

The complexity of the LAG-3 – MHC class II interaction offers therefore many ways for therapeutic intervention in:

1.     Oncology by either blocking LAG-3 on the T cell to keep T cells active (e.g. antagonistic antibodies like relatilimab or leramilimab) or activating the antigen presenting cells via MHC class II and leading to a broader immune response including the generation of more CD8, NK or CD4 T cells. The later is referred to as MHC II agonism and this is how eftilagimod alpha (“efti”) works.

2.     Autoimmune diseases by bringing under control the auto-reactive and chronically LAG-3 activated and exhausted CD8 T cells either by destroying them (the depleting antibody GSK’781) or switching them temporally off (the LAG-3 agonist antibody IMP761)

Years of advancing basic, pre-clinical and clinical research has delivered strong advances in the LAG-3 field. A very significant contribution has come from Immutep through various peer reviewed publications and data presentations. In March 2021, this work has led to the clinical validation of LAG-3 – MHC class II interaction by Bristol Meyers Squibb (BMS) which announced their anti-LAG 3 (antagonistic) antibody had successfully met the primary endpoint (PFS) of its phase II/III study in patients with 1st line melanoma. This result validated the LAG-3 – MHC class II interaction.

Following this validation, there is even more interest in efti which is part of a new class of immunostimulants (the antigen presenting cell activators or APC activators) as well as in other LAG-3 related approaches. Eftis mechanism of action is different from the widely used immune checkpoint inhibitors (e.g. anti-CTLA-4, -PD-1/PDL-1 or -LAG-3 mAbs) and exciting data from patients with a variety of different cancer types such as NSCLC, HNSCC and MBC has been presented at prominent scientific conferences over recent years.

Eftilagimod alpha is a truly unique approach and the only MHC class II agonist in oncology. Following the recent validation of the LAG-3 immune checkpoint, we have never been more excited about its potential to help patients!