TopAct™:
How Does it Work?
TopAct™ is the proprietary technology platform applied by ActoGeniX to produce its novel ActoBiotics™.
In a first step, sophisticated genetic engineering techniques are used to insert a gene encoding the desired therapeutic protein (or peptide), into the chromosome of a Lactococcus lactis bacterium. The technology also ensures that the bacterium is able to express the gene at sufficient levels, that the relevant protein is efficiently secreted, and that the protein folds in the appropriate three-dimensional structure required for proper biological activity. As part of the same engineering process, a gene essential for survival of the bacterium is deleted. The newly created organism now becomes entirely dependent on an external source of a particular nutrient (thymidine) to be able to survive. This elegant containment system ensures that the newly created Lactococcus strain cannot survive outside the human body or a specifically designed culturing system, and that it dies quickly if released into the environment.
When such a newly-engineered bacterial strain of Lactococcus has been created in the laboratory, the next step involves its production at large scale. This is accomplished by industrial fermentation. Because Lactococcus is a well-known species and its manufacturing at large scale has been optimized by the food industry, this is a very efficient, well-characterized and straightforward process. After fermentation, the bacteria are freeze-dried and milled as a dry powder. This powder is then formulated into capsules for oral administration. A new ActoBiotic™ is ready!
When a patient ingests an ActoBiotic™ capsule, it will pass through his stomach and subsequently dissolve in his intestinal tract, where it will release the Lactococcus bacteria. Once the bacteria are released into the intestinal tract, they become metabolically active and start secreting their therapeutic protein. Because Lactococcus is a non-colonizing species, it cannot multiply in the gut or invade tissues. This means that it will only remain in the patient’s intestines for about 8-48 hours. During this time, it will continuously secrete appropriate amounts of therapeutically active protein, ensuring an efficient interaction of the therapeutic protein with target receptors located in or around the intestinal tissues.
Clearly, this concept of oral therapeutic protein delivery opens exciting possibilities, many of which have already been explored by ActoGeniX scientists. Lactococcus is able to not only secrete and deliver a wide variety of bioactive cytokines, including Interleukin (IL)-2, IL-6 and IL-10, but also antibody fragments, growth factors, hormones and neuropeptides. Another exciting application is the delivery of antigens or allergens by Lactococcus into the gut, which has been shown to result in the development of specific tolerance of the immune system to these antigens. This discovery has far-reaching implications for the development of novel therapies to treat autoimmune diseases and allergies. Programs are ongoing in all these areas and ActoGeniX intends to broadly exploit the potential of its promising TopAct™ platform through the design of a broad portfolio of ActoBiotics™.