Technology

LAG-3, an immune checkpoint molecule.


LAG-3 stands for Lymphocyte Activation Gene-3 (LAG-3 or CD223), a protein, which is involved in the regulation of the immune system.

Discovered in 1990 by our Chief Scientist and Medical Officer, Professor Frederic Triebel, we are the global leader in LAG-3 products with more LAG-3-related intellectual property and more product candidates in clinical development, including our partnered programs than any other company in the industry.

The LAG-3 protein controls the signaling between specific immune cells, T cells and antigen presenting cells (APCs), which are responsible for the adaptive immune response. Our lead product candidate is eftilagimod alpha which is in late-stage clinical development (please see) for the treatment of cancer. Other products are in preclinical (IMP761) or earlier clinical development (IMP701, IMP731) for cancer or autoimmune diseases.

With our lead product candidate eftilagimod alpha, we are investigating the LAG-3 immune control mechanism in three areas of application to boost the immune system with a unique mechanism of action.

Areas of application:

Chemo-Immunotherapy

The combination of eftilagimod alpha (efti) and chemotherapy aims to amplify the body’s immune system response using the antigens released by the dying tumour cells induced by chemotherapy.

Chemotherapies and immunotherapies (such as efti) have synergistic effects which make them an ideal combination. The chemotherapy causes the “immunogenic” death of tumour cells which results in the release of tumour specific proteins (antigens). These antigens can be taken up by certain immune cells (called antigen presenting cells or APCs) and are then presented to cytotoxic T cells leading to a host immune response against other cancer cells. Under this general concept, pembrolizumab (a PD-1 antagonist) in combination with chemotherapy was approved by the US FDA for the treatment of non-small cell lung cancer in 2017.

Injections of efti are known to boost the activation of the APCs. As a result, strong and sustained responses of cytotoxic immune cells are achieved and destroy the antigen bearing tumour cells. These synergistic effects have been shown in initial Phase I clinical trials. This concept is being investigated in a randomised double blind placebo controlled Phase IIb clinical study in metastatic breast cancer, called AIPAC. Supportive efficacy data from AIPAC showed that efti provided an improvement for patients compared to a placebo group. Encouraging results were also reported in some of the pre-defined patient subgroups.

We believe this approach will be applicable for use in a number of cancer indications where (first-line) chemotherapy is the standard of care.

Immuno-Immunotherapy (IO-IO combo) - Adjuvant to cancer vaccines or in situ immunisation through intra-tumoral injection

The combination of eftilagimod alpha (efti) and other immunotherapies with complementary mechanisms of action (such as checkpoint inhibitors) aim to synergistically boost the body’s immune system response.



Cancer immunotherapies, and in particular monoclonal antibodies blocking the inhibitory programmed cell death 1 pathway (PD-1/PD-L1), have made a significant impact on the treatment of cancer to date. However, patient response rates are often less than 30%. We hypothesise that the combination of two synergistic immunotherapies can overcome these limitations by using complementary mode of actions i.e. releasing the brakes and/or pushing the accelerator of the immune system at two different positions in the cancer immunity cycle.

Even though this approach is relatively new, it has already been proven to be an effective strategy. Initial evidence, for example with combined inhibition of PD-1 and CTLA-4 in melanoma and non-small cell lung cancer (NSCLC) are quite promising, but relatively toxic.

Using our eftilagimod alpha (efti) to activate the antigen presenting cells (APCs) in combination with a checkpoint inhibitor on, for example T cells like PD-1/PDL-1) has shown synergistic antitumor effects in preclinical models. The combination of efti and pembrolizumab was investigated in a Phase I dose escalating clinical trial, called TACTI-mel. It showed an excellent safety profile together with encouraging antitumor activity, with deep and durable responses to the combination treatment in patients with melanoma. Half of the patients in the trial had a decrease of ≥ 75% in their target lesions.

This same combination (efti and pembrolizumab) is now being evaluated in a Phase II clinical trial, called TACTI-002, which is being conducted in collaboration with Merck & Co., Inc., Kenilworth, NJ, USA (known as “MSD” outside the United States and Canada). Interim results so far are promising, with some patients with 2nd line head and neck squamous cell carcinoma (HNSCC) and 1st line non-small cell lung cancer (NSCLC), showing a complete disappearance of all lesions. Progression-free survival results are also very encouraging for both patient types.

In a separate Phase I study, called INSIGHT-004, the combination of efti and Merck KGaA and Pfizer Inc.’s avelumab, a human anti-PD-L1 antibody, is being evaluated in patients with different advanced solid malignancies, primarily with gastrointestinal indications. This combination is showing promising early anti-tumour activity signals in a variety of cancer indications not typically sensitive to immune checkpoint inhibitor therapy.

Adjuvant to cancer vaccines or in situ immunisation through intra-tumoural injection

The use of eftilagimod alpha (efti) as an adjuvant for a vaccine aims to locally boost the immune response with abscopal (non-target lesion) effects.

In addition to its use as chemoimmunotherapy and as the IO-IO combo, efti has been trialled at much lower doses as an adjuvant to cancer vaccines to boost local APC activation. A number of Phase I clinical trials have been performed with our academic partners. An investigator-initiated Phase I clinical trial, called INSIGHT, is ongoing with local (intra-tumoral or intra-peritumoral) administration.

In addition, efti is being evaluated by Immutep’s collaboration partner, CYTLIMIC, as part of a cancer peptide vaccine, called CYT001, in patients with advanced or metastatic solid cancer. CYTLIMIC reported positive results from a Phase I clinical trial of CYT001 where patients showed an immune response and a second Phase I study where tumour cell death and infiltration of T cells into tumour regions was observed in patients.

 

LAG-3 as an antigen presenting cell (“APC”) activator

Through binding of soluble LAG-3 (such as IMP321/eftilagimod alpha) to major histocompatibility complex (MHC) class II molecules on the surface of APCs, APC activation takes place. In this way, LAG-3 can lead to an activation of the antigen presenting cells such as monocytes and dendritic cells.

This results in a physiological increase in the number and activation of cytotoxic CD8+ T cells, hence an active immunotherapy mechanism important for fighting cancer. Through these mechanisms of action, soluble LAG-3 (such as IMP321/eftilagimod alpha) can increase the immune response to cancer antigens.

LAG-3 as a negative regulator of T cells

On T cells, LAG-3 is a co-inhibitory receptor physically associated with the T cell receptor and expressed on activated T cells and consequently, if LAG-3 is expressed on T cells, it has an inhibitory effect on activated T cells.

When LAG-3 expressed on an activated CD8+ T cell binds to MHC class II at the same time as the T cell receptor (TCR) is binding to MHC class I on an APC, the LAG-3 binding stops calcium signaling which leads to a reduction in cytokine production and a decline in immune response.

Such a negative feedback mechanism is necessary to actively switch off an immune response when it is no longer required. In this way it negatively regulates cellular proliferation, activation, and homeostasis of T cells, in a similar fashion to CTLA-4 and PD-1 and has been reported to play a role in Treg suppressive function. This mechanism plays a role for cancer and autoimmune diseases.

Based on these two different mechanisms of action, Immutep has developed four product candidates that are currently being developed at Immutep or have been out-licensed to one of our pharmaceutical partners for development and commercialization.

Lag-3 Therapeutics


Eftilagimod alpha (IMP321) – an APC activator

Eftilagimod alpha is the International Nonproprietary Name (INN) for IMP321 (a LAG-3Ig fusion protein). Each INN is a unique name that is globally recognized to identify pharmaceutical substances or active pharmaceutical ingredients, and is regulated by the World Health Organisation (WHO).

Eftilagimod alpha is a recombinant protein consisting of a dimer of LAG-3 that has been engineered to be soluble rather than expressed on the surface of cells.

It is a first-in-class antigen presenting cell (APC) activator, which has been proven to induce sustained immune responses in cancer patients when used at low dose, as a cancer vaccine adjuvant or used at higher doses to get a systemic effect (i.e. general APC activation). Other classes of APC activators include toll like receptor (TLR) agonists, STING agonist or anti-CD40 mAb agonist.

Pushing the accelerator on immune responses

In addition, it has been shown to be safe and well tolerated, thus making it an ideal combination partner for other drugs or drug candidates. Combining different therapeutic approaches is the most promising way to fight cancer and is attracting considerable industry investment. Our Phase I and Phase II(b) clinical trials with eftilagimod alpha are combination trials with either chemotherapy or immunotherapy.

IMP731, a killer anti-LAG-3 antibody for autoimmune diseases

IMP731 (or GSK2831781) is in clinical development by our partner Glaxo-Smith-Kline (GSK).

This is an autoimmune disease cytotoxic monoclonal antibody (mAb) that will kill the few LAG-3+ activated T cells that infiltrate autoimmune disease sites. It belongs to the next wave of innovative products that target the underlying cause of autoimmune diseases, namely the few auto-reactive T cells that accumulate at an organ site to destroy it. In other words, LAG-3 is there targeted as a marker for antigen-specific auto-immune effector T cells.

At the present time, drugs such as corticoids or anti-TNF antibodies don’t treat the underlying cause of the disease; they only address the symptoms (e.g. inflammation) and therefore have to be chronically administered.

In contrast, it is expected that killing the few self-reactive T cells will have an enduring effect induced by a single injection.

The product candidate is currently about to start Phase II clinical trials, with the GSK partnership set to deliver development milestones and royalty payments subject to its development progress and ultimate success.

IMP701, a blocking anti-LAG-3 antibody for cancer

IMP701 (or LAG525) is in clinical development by our partner Novartis.

This is an antagonist monoclonal antibody (mAb) meaning it blocks the LAG-3-mediated inhibitory signal given to tumor infiltrating T cells. This allows the CD8 T cell to generate a better cytotoxic response against cancer cells.

LAG-3 is a prime target for immune checkpoint blockade in immuno-oncology as it is readily expressed at high levels on tumor infiltrating lymphocytes in many human tumors. Most of the LAG-3 related development is occurring in the anti-LAG-3 antagonist antibody field.

The product candidate is currently in Phase II clinical trials, with the Novartis partnership set to deliver development milestones and royalty payments subject to its development progress and ultimate success.

IMP761, an agonist LAG-3 antibody for autoimmune diseases

Our new product candidate IMP761 is being developed as the first known agonist antibody of LAG-3. It is a humanised IgG4 monoclonal antibody and is mechanistically distinct from any of the known LAG-3 antibodies.

IMP761 represents the first potential opportunity for fine tuning the immune response to an immune checkpoint target such as LAG-3 or PD-1. It is therefore mechanistically different from the more drastic approach developed by GSK with IMP731, the cytotoxic anti-LAG-3 antibody. Using an agonist antibody that targets the LAG-3 receptor on the surface of activated T cells is expected to result in a stronger inhibitory signal being delivered directly into the T cell to stop it from continuing to proliferate and react against a patient’s own tissues. Our aim for the clinical development of IMP761 is to address the root cause of autoimmune diseases by suppressing the few self-antigen overactive T cells though a physiological mechanism (LAG-3 inhibitory signalling into activated T cells), rather than just treating the consequences of this overactivation, such as by reducing inflammation.

Currently, this product candidate is at preclinical stage.