Technology

A closer look at the development of autoimmune diseases and how Imotopes^TM tackle the key players in the immune cascade for a specific, safe and long lasting therapy.

Autoimmune disorders (AIDs) occur when the immune system mounts an attack to self-proteins and initiates an immune cascade that ultimately attacks the body’s own tissues and organs.

In healthy individuals, unwanted immune responses to self-proteins are kept in check, which is called tolerance. When tolerance is broken for a specific self-protein, it is able to stimulate an immune response and, are then called autoantigen. Like all proteins, these autoantigens are routinely taken up by antigen-presenting cells (APCs) but only when tolerance is broken, they ultimately activate disease causing autoreactive T cells, also called pathogenic T cells, a key first step in the inception of autoimmune disease.

On the surface of APCs MHCII molecules present protein fragments, also called epitopes, to T cells. A given autoantigen has many different epitopes which are presented on MHCII molecules. The MHCII molecules and the genes encoding them are highly variable between individuals and are the strongest genetic risk factor to develop a certain autoimmune disease, demonstrating the critical role of these MHCII molecules and the epitopes they present to T-cells in the development of autoimmune diseases. For example, Type-1 diabetes is associated with MHCII molecules DR3 and DR4 that can present preproinsulin-derived epitopes reported to play a role in this autoimmune disease.

Antigen presentation by APCs is not only critical in generating pathogenic cells in the first place, it is also key in restimulating existing pathogenic T cells further driving/progressing the pathology (extends their life span). Without constant antigen presentation, T cells will simply wane in their activity and fade into a death spiral.

Imcyse’s Imotope™ approach aims to break this aberrant immune cascade and reset the immune system by using these disease causing epitopes. This is made possible through the Imotope’s™ unique design which targets specific MHCII haplotypes.

The first step in designing the Imotope^TM is to examine the proteins that have become autoantigens and the epitopes that cause the disease. Once the epitope that we wish to use has been identified, it is then modified by adding a sequence from an enzyme called Thioredoxin (which we call a “thioredox” sequence or motif). The addition of the thioredox motif gives the peptide, now called an Imotope^TM, the power to drive T cells into a different phenotype, called a cytolytic CD4+ T cell. Cytolytic CD4+ T cells have previously been reported during viral infections and are shown to kill virus-infected APCs. We are re-deploying this mechanisms for the treatment of AIDs.

As the Imotope™ has the autoantigen’s epitope at its core, the cytolytic T cells that are generated are epitope specific. For example, we chose an epitope from pro-insulin as the core of our Type 1 diabetes Imotope™ which when injected generates insulin specific cytolytic T cells. This makes the response to the treatment very targeted and allows for a treatment that is both safe and effective.

Not only does an Imotope™ induce a cytolytic CD4+ T cell soon after treatment, it also induces a memory phenotype, like vaccines do. Memory cytolytic CD4+ T cells are long lived and are able to continue to counter the aberrant immune response for long periods of time. This means that an Imotope™ course of therapy will have a very long duration of action/efficacy, which has been observed in our pre-clinical experiments so far, and could even lead to disease remission or cure.

In addition to inducing apoptosis in the APC, we also observe that cytolytic CD4+ T cells can induce apoptosis of the pathogenic T cells, as they are interacting with the same APCs. This is a second and equally important component of the therapeutic efficacy of Imotopes™ as they eliminate pathogenic T cells further contributing to potential remission or cure.

Bystander Effect

Most autoimmune diseases have several self-proteins which have the potential to become immunogenic (autoantigens), sometimes increasing in number as the disease progresses and the immune dysregulation rages more and more out of control. As APCs at the site of tissue damage will be processing many of the proteins found in the local environment, we have confirmed it is likely that one APC will be presenting several autoantigens at any one time and the pathogenic T cells primed from a number of related autoantigens and epitopes will all be interacting with a single APC. We have observed that a cytolytic CD4+ T cell primed with one epitope can in these circumstances induce apoptosis in related pathogenic T cells which enables the Imotope™ to block a wider range pathogenic T cells, maximizing the therapeutic benefit.

In summary, the Imotopes^TM are able to block the abnormal immune responses and recalibrate the immune system, breaking the disease pathway responsible for tissue damage. Imotope^TM-induced cytolytic T cells specifically eliminate antigen-presenting cells and pathogenic T cells, thereby avoiding autoimmune attacks without affecting other functions of the immune system.