LAG-3: The next big checkpoint inhibitor target

November 29, 2022 - 7 minutes

Since their first approval a decade ago, immune checkpoint inhibitors have been gaining momentum in the treatment of cancer. The Australian-French firm Immutep explains why the immune checkpoint target LAG-3 is ripe for innovation in the space.

Immune checkpoint inhibitors have revolutionized the field of immuno-oncology in the last decade, especially since the approval of the antibody drug ipilimumab (Yervoy) in 2011. 

Immune checkpoints sit on the surface of immune cells, including T killer cells — also known as CD8-positive cells — and T helper cells, which are known as CD4-positive cells. These cells are instrumental in fighting against cancer.

When the checkpoint proteins are activated by ligands such as major histocompatibility complex (MHC) proteins, they brake the activity of the immune cell. Cancer cells can hijack this process by activating immune checkpoints and escaping the immune cells. Checkpoint inhibitor drugs can protect immune cells from suppression by the cancer, and allow them to fight back against the tumor.

Some of the most established immune checkpoint targets include cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1), which is found on cancer cells rather than immune cells. 

One emerging target in the space is lymphocyte activation gene-3 (LAG-3). The target was first discovered by Frédéric Triebel, professor in Immunology at Paris University, over three decades ago. Triebel moved from academic research to founding the French firm Immutep S.A. in 2001.

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After the acquisition of Immutep S.A. by the Australian company Prima BioMed in 2014, Triebel served as the company’s chief scientific officer and chief medical officer. Also in 2014, the company’s chief financial officer and chief business officer, Marc Voigt, occupied the CEO position.

While LAG-3 has been on the checkpoint inhibitor space’s radar for decades, it wasn’t until 2021 that the target captured the imagination of investors, when Bristol Myers Squibb’s LAG-3 blocker relatlimab showed promise in a phase 3 trial. In March 2022, relatlimab in combination with another checkpoint inhibitor called nivolumab was approved by the U.S. Food and Drug Administration (FDA).

Immutep is keen to follow through with the increasing interest in LAG-3. The company’s phase 2b-stage lead candidate is eftilagimod alpha (efti), a soluble version of the LAG-3 protein that boosts the number of immune cells to fight tumors. The rest of Immutep’s pipeline includes antibodies and small molecules blocking the emerging drug target in addition to antibodies to treat autoimmune diseases.

In an interview with Voigt and Triebel, we discussed the progress of the checkpoint inhibitor space in addition to Immutep’s drug development activities.

What is LAG-3 and why has it been a target of interest in cancer therapies?

Frédéric Triebel: LAG-3 is a gene that codes a protein that is involved in the regulation of the immune system. The interaction between LAG-3 and MHC class II molecules controls the signaling between specific immune cells, T cells and antigen presenting cells (APCs), which are involved in both the adaptive and innate immune response.

LAG-3 is unique among the three approved checkpoints (CTLA-4, PD-1, LAG-3) in that both its inhibition on T cells and activation of dendritic cells engage the immune system against cancer. 

By inhibiting or blocking the LAG-3/MHC II interaction on T cells, you can increase the cytotoxicity of the pre-existing CD8 T cell anti-tumor response. You can also utilize a soluble LAG-3 protein to bind with MHC II ligands on APCs, e.g., immature dendritic cells, to activate them and in turn stimulate the innate and adaptive immune systems to fight cancer.

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What led you to study the LAG-3 gene, and how do you see your work changing the way cancer is treated?

Frédéric Triebel: I discovered LAG-3 in the late 1980s while working on a project cloning mRNA expressed in activated T cells and not resting T cells. 

After finding that LAG-3 binds to MHC class II proteins — which are at the center of the immune response — I realized there was a potential path to valuable therapeutics to help patients suffering from cancer and autoimmune diseases and launched Immutep to work on LAG-3 based drugs.

The work of Immutep in LAG-3 therapeutics in oncology offers significant potential to: (1) improve responses to standard-of-care immunotherapy and/or chemotherapy, and (2) offer chemotherapy-free options in select indications.

How does Immutep’s technology stand out amongst similar cancer treatments in development?

Marc Voigt: We believe Immutep is currently the only company with therapeutic candidates in its broad pipeline focused on both the activation and inhibition characteristics of the LAG-3/MHC II interaction.

Efti is Immutep’s proprietary soluble LAG-3 clinical stage candidate that is a first-in-class APC activator for the treatment of cancer, capitalizing on LAG-3’s unique characteristics to stimulate both innate and adaptive immunity.

Simplistically speaking, this soluble LAG-3 protein acts as a key to unlock broad activation of the immune system. Through its high affinity for a subset of MHC II ligands, efti binds to and activates APCs leading to the expansion and proliferation of CD8-positive T cells, CD4-positive T cells, dendritic cells, natural killer cells, and monocytes. It also upregulates the expression of key biological molecules like CXCL10 that further boost the immune system’s ability to fight cancer.

On the inhibition side of LAG-3, ieramilimab is an anti-LAG-3 antagonist antibody that is fully out-licensed to and under development by Novartis. Additionally, Immutep is working on a first-in-class anti-LAG-3 small molecule treatment that could offer cancer patients the convenience of an oral tablet at a fraction of the cost of existing anti-LAG-3 antibody candidates.

Why has this checkpoint target been struggling for a long time to yield promising clinical results?

Marc Voigt: The field of immunotherapy has seen significant improvements over the past 10 years, with the approval of ipilimumab (anti-CTLA-4) in 2011 and subsequently pembrolizumab and nivolumab (anti-PD-1) in 2014. These two checkpoint approvals represent some of the most important advancements in the field of oncology. 

A subsequent approval also deserves attention, as it further broadened the reach of immunotherapy approaches against cancer. In late 2015, nivolumab (anti-PD-1) and ipilimumab became the first immunotherapy combination to receive regulatory approval for the treatment of metastatic melanoma.

The initial clinical work with anti-LAG-3 began in 2013 via Bristol Myers Squibb’s relatlimab. Much of the effort around relatlimab, including the original trial, was as a monotherapy or in combination with the anti-PD-1 nivolumab given the encouraging signals from this dual approach in pre-clinical studies. 

These trials involved a large number of patients and time, yet the approval of relatlimab combined with nivolumab earlier this year make it just the third immune checkpoint to receive this distinction. The commercial journey of LAG-3 is just beginning.

Why has the LAG-3 space seen a turning point this year?

Marc Voigt: Despite the overwhelming success of anti-PD-(L)1 therapies, a significant portion of patients do not respond to monotherapy. 

In an effort to enable more efficacious therapies, a significant majority of anti-PD-(L)1 trials today are combination trials. A large portion of these combination trials are immunotherapy combination approaches such as anti-PD-1 and anti-LAG-3, which bring the promise of increased efficacy and durability without the increase in toxicity from chemotherapy.

The FDA approval of relatlimab in combination with nivolumab (branded Opdualag) in March 2022 is a key turning point for the field, as it validates the LAG-3/MHC II interaction and added LAG-3 as the third immune checkpoint to receive approval. Additionally, the early commercial success of Opdualag this year is a positive sign.

In addition, our unique LAG-3 approach in oncology, and more specifically in first-line NSCLC, has garnered a lot of attention as of late with two oral presentations at two major conferences this year.

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