Throughout history lactic acid bacteria have been used in the production of food and drinks such as cheese, yoghurt, beer and wine. Today, a new application for these food grade microbes can be found in ActoBiotics®, a novel approach to medical treatment. ActoBiotics® is based on using genetically engineered Lactococcus lactis as biofactories and deliverers of diverse biopharmaceuticals. Its many advantages have the potential to revolutionize gastro-intestinal medicine.
ActoBiotics® is a very flexible technology platform
- Pieter Rottiers, Ph.D., Managing Director,
Intrexon Actobiotics NV (wholly-owned subsidiary of Intrexon Corporation)
ActoBiotics® was originally developed by ActoGeniX, a spin-off company founded by the VIB and UGent in 2006. In 2015, the US-based synthetic biology giant Intrexon paid $60 million for the acquisition of ActoGeniX and their proprietary technology.
Through genetic modification, Lactococcus lactis can be engineered to produce all kinds of protein-based therapeutics, such as cytokines, enzymes, hormones and antibody fragments. The bacteria themselves are contained in a capsule and are administered orally. Once inside the body, production of the desired therapeutic is initiated. This combines the specificity and relatively low toxicity of modern molecular treatment methods while circumventing many of its drawbacks in terms of drug delivery. The choice for L. lactis is clearly preferred, since it is one of the few bacteria that has been given the GRAS-status (generally recognized as safe) by the FDA and is suitable for human consumption.
The strength of bacterial delivery
One of the main advantages of this approach is that the ingested bacteria produce and secrete therapeutics in the gastro-intestinal tract. As the drugs are produced locally, drug delivery is very efficient, lowering the dosage needed for the therapeutic to be effective. Since systemic exposure to the drug is negligible, the chance of side effects is also significantly lower. Additionally, ActoBiotics® have a more favorable pharmacokinetic profile than classical medication: slow release and prolonged activity of the produced therapeutic protein is superior compared to the high peak and fast decline characteristic of traditional administration methods.
Compared to the intravenous injection of therapeutic proteins, ActoBiotics® have the advantage of oral administration. This is not only more convenient for the patient, but also can reduce the treatment cost. Combined with their straightforward and cost-effective manufacturing process, ActoBiotics® will have a marked economical edge over the current expensive biological therapies.
"We can quickly develop an idea into a medical product. After constructing L. lactis libraries, we can screen them for specific functions such as anti-inflammatory or bactericidal activity," says Rottiers. "When we have a hit in the screening, we immediately have a medical product. Also, because a single product can contain multiple therapeutic proteins, combined therapy is easy to implement and offers many possibilities."
For any therapy or treatment, safety is a top priority. L. lactis in ActoBiotics® does not replicate within the human body and cannot colonize the mucosa of the oral cavity or gastro-intestinal tract, guaranteeing a transient presence. The lactococci are also engineered to be dependent on a specific nutrient for their survival. This makes it impossible for them to persist outside the human body and prevents their spread into the environment. These measures make the use of ActoBiotics® safe for both patients and environment.
A lot of ground to cover
Currently, application of ActoBiotics® is mainly focused on anti-inflammatory medication. The production of TNF-inhibitors or anti-inflammatory cytokine IL-10 in the gut by L. lactis, for example, is a strategy being used to treat disorders such as Crohn's disease or ulcerative colitis. ActoBiotics® are also showing great potential to be used in the field of immunology. ActoBiotics® can be used to produce a certain allergen or autoantigen in the gut. Controlled expression of these proteins can re-instate tolerance and reverse allergy or auto-immune reactions. In mouse models of type 1 diabetes, for example, expression of the antigen GAD65 by L. lactis successfully preserved β-cells and reversed disease.
ActoBiotics® technology has attracted the attention of many biopharmaceutical companies interested in collaborations. Because of its flexibility, the platform can be used in numerous disease fields. With this in mind, Intrexon has entered into several strategic alliances for advancing the ActoBiotics® platform. Oral care specialist Oragenics, for example, is collaborating with Intrexon regarding the treatment of oral mucositis, a frequent and painful side effect of cancer therapy, and other diseases and conditions of the oral cavity, throat, and esophagus. One product candidate from the Oragenics collaboration is a mouth rinsing solution containing L. lactis bacteria producing TFF1 (trefoil factor 1), which helps to protect against mucosal damage and aids in its subsequent repair.
Likewise, collaborations with Synthetic Biologics and Ziopharm Oncology have been formed. The former focuses on the intestinal delivery of a therapeutic enzyme to treat the metabolic disorder phenylketonuria. The latter tackles the occasional graft versus host reaction in allogenic hematopoietic stem cell transplantation through the expression of IL-2 to modulate immune function. We are eager to learn which myriad of treatment strategies this platform may bring in the future!
Photo by the National Institute of Allergy and Infectious Disease, https://creativecommons.org/licenses/by/2.0/legalcode