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LAG-3, a dual mechanism of control

LAG-3 stands for Lymphocyte Activation Gene-3 (LAG-3 or CD223).

 

It is a protein which in humans is encoded by the LAG-3 gene. It is a cell surface molecule, which is involved in the regulation of T cells.

 

The LAG-3 protein has a dual mechanism of action and controls the signaling between T cells and antigen presenting cells (APC’s).

 

As a checkpoint molecule it is a target for drug development programs in cancer and autoimmune diseases.

 

 

LAG-3 as an APC activator

 

Through engagement of major histocompatibility complex (MHC) class II molecules by LAG-3 in some conditions (e.g. multiplexed LAG-3 on the membrane or cross-linked soluble LAG-3), APC activation takes place.

 

This results in an increase in antigen presentation to cytotoxic CD8+ T cells, hence an active immunotherapy mechanism.

 

IMP321, an activator

IMP321 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).

In addition it has been shown to be safe and well tolerated.

 

IMP321 used in chemoimmunotherapy

When IMP321 is administered s.c. into patients, it is a highly potent APC activator that binds to MHC class II molecules expressed by monocytes and immature dendritic cells (DC).

This leads to DC maturation, migration to the lymph nodes and enhanced cross-presentation of antigens to CD8+ T cells.

As a result, strong and sustained cytotoxic T cell responses are obtained with repeated IMP321 injections.

IMP321 is used in chemoimmunotherapy, which is the combination of chemotherapy and active immunotherapy. When patients undergo chemotherapy, the drugs are aimed at killing off rapidly dividing cells, like cancer cells. The dying tumor cells release cancer antigens into their circulation. It is now understood that antigens from the dying cancer cells will be picked up by antigen presenting cells (APC’s) belonging to the APC network of the body.

The APC network covers the human skin or mucosa surface as a first line defense against pathogens. It is consisting of dendritic cells, monocytes and macrophages in tissues.

Cancer antigens are taken up by the APC's (mostly by dendritic cells, which are called the professional APC's), are digested and presented to the patient’s T cells. These T cells, the CD8+ T cells, are educated to circulate and kill off any cancer cells expressing the specific antigens that the CD8+ T cells have already been exposed to.

By boosting the APC network over a period of time with IMP321 being repeatedly injected the day after chemotherapy, Prima has been able to demonstrate the induction of a sustained (e.g. lasting over several months) APC activation and memory CD8+ T cell response in patients.

To sum this up, the primary mechanism of action (MoA) for IMP321 is to activate the APC network in the body, which results in a boosted and sustained CD8+ T cell response leading to an enhanced removal of cancer cells. In short, the body’s own immune system is pushed by IMP321 to fight against cancer cells.

In addition, there is a negative regulation of LAG-3 expressing T cells called a secondary MoA. While binding to MHC class II, IMP321 prevents the binding of activated T cells to APC’s. This is called an "atypical immune checkpoint inhibitor" as IMP321 blocks the LAG-3 MHC II interaction not at the level of the T cell, like an antagonist anti-LAG-3 monoclonal antibody would do, but at the level of the APC. The effect of this secondary MoA is synergistic with the APC activation effect described above as it would unleash the cytotoxicity of the induced CD8+ T cells towards antigens on the cancer cell surface at the tumor site.

Prima believes this approach will be applicable for use in a number of cancer indications using first-line chemotherapy as standard of care.



IMP321 used at low dose as a therapeutic vaccine adjuvant

In addition to its use in chemoimmunotherapy, IMP321 has been trialed 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 academic partners.

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

IMP731 is under development by partner Glaxo-Smith-Kline (GSK).

It’s 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, that is the few auto-reactive T cells that accumulate at one organ site and destroy it.

At the present time, drugs such as corticoids or anti-TNF antibodies don’t treat the underlying cause of the disease; they just control inflammation and therefore have to be given on a chronic basis.

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

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

IMP701 is under development by partner Novartis.

It’s an antagonist mAb which 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 prima target for immune checkpoint blockade in immuno-oncology as it is readily expressed at high level on tumor infiltrating lymphocytes in many human tumors.

IMP761, an agonist antibody of LAG-3

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

Until now, therapeutic antibodies with agonistic properties have not been described for any of the three major immune checkpoints, CTLA-4, PD-1 or LAG-3.

IMP761 promises the first opportunity for fine tuning of the immune response to an immune checkpoint target. Using an agonist antibody that targets the LAG-3 receptor on the surface of activated T cells is expected to result in an inhibitory signal being delivered directly into the T cell to stop it from continuing to proliferate and react against a patient’s own tissues.

LAG-3 as a negative regulator of T cells

 

Conversely, LAG-3 is a co-inhibitory receptor physically associated with the T cell receptor on activated T cells and consequently, LAG-3 has an inhibitory effect on activated T cells following antigen recognition.

 

When LAG-3 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.