Technology: Bringing solutions to global health problems
Bioniz Technology: Selective Inhibitions of multiple Cytokines
Bioniz is committed to developing novel therapeutics for treatment of immune-mediated diseases, many of them unmet medical needs. Immune-mediated diseases encompass many disorders including auto-immune diseases - such as rheumatoid arthritis, multiple sclerosis, and lupus - and inflammatory diseases - such as allergy and asthma. Although these diseases have very different clinical manifestations, they do have one thing in common: a hyper-activated immune response that is damaging the body. The ultimate challenge of treating immune-mediated diseases is to suppress the activated immune response sufficiently, without shutting down the entire immune system. The danger of a complete immune system blockade is repeated viral and bacterial infection as well as increased chance of cancer.
The current therapeutics in the market are general immune-suppressants and have a broad effect in shutting down the entire immune system. Examples of such therapeutics are corticosteroids and cyclosporine. Although they can control the symptoms of an activated immune response, they weaken the immune system and cause major side effects in the long run. In recent years, a new generation of immune-modulators has been introduced to the market. Some of them, such as TNF-ALPHA inhibitors, interrupt a major cascade of the immune response and inhibit its over activation. Although effective, this class of therapeutics has shown side effects during long term administration.
With over 50 years of combined experience in the field of immunology, Bioniz scientists have developed a novel platform technology to develop first-in-class therapeutics that inhibits the activated immune response narrowly without compromising the entire immune system. This technology is based on rationale-drug design and engineering of non-antibody molecules against well-characterized cellular targets, a strategy that is referred to as targeted therapy.
How do targeted therapies work?
The development of targeted therapies requires the identification of good targets—that is, targets that are known to play a key role in cellular functions such as immune activation. The majority of the targeted therapies focus on proteins that are involved in cell signaling pathways, which form a complex communication system that governs basic cellular functions and activities, such as cell division, activation, and even cell death. An example of a signaling pathway is demonstrated in Figure 1.
Receptors are proteins that are located on the cell surface membrane. These receptors are specific to soluble proteins that are called ligands. Binding of the ligand to its receptor initiates a cascade of intracellular events. Signal transducing molecules downstream to the receptor become activated and they, in turn, transfer the activation signal into the nucleus. Based on the type of stimulation, nucleus commands the cell to become activated, divide, or perform specific functions.
Blocking each step of this signaling pathway can prevent the cells of the immune system to become over-activated, a property that is required for treating the immune-mediated diseases.
How are targeted therapies developed?
Once a target has been identified, a therapy must be developed. Most targeted therapies are either small-molecule drugs or monoclonal antibodies. Small-molecule drugs are typically able to diffuse into cells and can act on targets that are found inside the cell, for example on signal transducing molecules. Most monoclonal antibodies, by contrast, usually cannot penetrate the cell’s plasma membrane and are directed against targets that are on the cell surface, for example on receptors.
Candidates for small-molecule drugs are usually identified in studies known as drug screens—laboratory tests that look at the effects of thousands of test compounds on a specific target. The best candidates are then chemically modified to produce numerous closely related versions, and these are tested to identify the most effective and specific drugs. The problem with small molecules is often the lack of specificity. The small molecules may interfere with other signaling pathways and disrupt their functions which results in side effects.
Monoclonal antibodies are prepared first by immunizing animals (typically mice) with purified target molecules which boost mice immune response to the target protein that results in antibody production. Through several highly specified steps, many monoclonal antibodies are generated, each of them recognize a specific part of the target protein. These monoclonal antibodies are then tested to find the ones that not only recognize the target protein, but inactivate its function.
Although there are several effective small molecules and monoclonal antibody therapeutics currently in the market, there are limitations to each strategy for developing effective treatments for immune-mediated diseases. The main problem with small molecules is the lack of specificity. It is usually common that small molecules interfere with other intracellular pathways and disrupt their functions which results in side effects. The challenge with antibody directed therapies is the technical limitation in developing a monoclonal antibody that can effectively block the target protein. Generating blocking monoclonal antibodies against specific targets has not always been successful.
How does Bioniz technology improve developments of targeted therapeutics?
Bioniz platform technology allows the rational design of peptides that interrupt the functions of receptors by preventing their binding with their ligands, a mechanism similar to those of monoclonal antibodies. However, the advantage of Bioniz technology is the flexibility in the design of these antagonist peptides. Since the peptides are rationally designed, Bioniz scientists can engineer the peptides to block specific parts of the receptor. This technology becomes even more valuable when a receptor is utilized by more than one ligand. Using Bioniz novel technology, our scientists have developed peptides that can selectively inhibit the binding of only some ligands – but not all – that are used by a common receptor. This strategy provides not only a targeted therapy but one that is highly specific. Furthermore, the flexibility in engineering the antagonist peptides allows the “custom design” of antagonist peptides. This aspect of Bioniz technology provides the critical advantage of blocking pathways that are specific to any given immune-mediated disease without shutting down the rest of the immune system, a property that is highly desired in any therapeutic developed for this group of disorders.