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Edible antibodies to prevent and treat gut diseases

Written by ALB on in the category Insights with the tags , , .


Belgian researchers have developed edible antibodies that can prevent gut bacterial infections. Normally antibodies need to be injected, but the antibodies developed by Dr. Vikram Virdi in the group of Dr. Nico Callewaert can instead be mixed with food and eaten. These antibodies are produced using yeast and have so far been shown to protect piglets from diarrhea-causing enterotoxigenic E. coli, which is a serious issue in pig farming. The edible antibody concept also has enormous potential for applications in human medicine, such as in preventing diarrheal disease outbreaks following natural disasters.

Antibody therapies are on the rise in the health sciences, with an increasing number of treatments appearing every year. The benefits of antibodies are many, including their ability to precisely target specific types of bacteria such as the pathogenic bacteria that cause diarrheal diseases.

The standard treatment for gut infections like enterotoxigenic Escherichia coli (ETEC) is currently broad-spectrum antibiotics, but these kill both the pathogens and the beneficial symbiotic bacteria in our microbiome. Antibodies help us target the pathogenic bugs we wish to eliminate specifically, leaving our symbiotic gut microbes at peace.

Most antibody therapies are currently delivered via injections, which is a great way for systemic delivery; however, if you want antibodies in the gut, why not get them there by eating them?

For the past decade, finding a method of making antibodies ingestible has been the ambition of a Belgian research project. Dr. Vikram Virdi has been at it from the beginning, now working in the team of Prof. Nico Callewaert (VIB-UGent Center for Medical Biotechnology). Earlier on, he performed the research in the team of Prof. Ann Depicker (VIB-UGent Center for Plant Systems Biology). Dr. Henri De Greve (VIB-VUB Center for Structural Biology) generated the antibody’s antigen recognition domains, and Dr. Eric Cox (UGent Faculty of Veterinary Medicine) provided the pig infection model.

The piglet study is an important proof-of-concept that edible antibodies can be used to prevent gut infections in large animals that are good models for human GI tract biology. - Vikram Virdi, VIB-UGent
 

When pigs fly to the rescue

Right from the start they faced a difficult challenge: how do you design protein antibodies that don’t get digested before they’ve done their job? To tackle this tricky conundrum, Virdi conducted his experiments using piglets beset by porcine E. coli.

“Piglets often contract this intestinal bug shortly post-weaning;” Virdi explained. “it has a horrific impact on the young animals, resulting in diarrhea and even death. The cost to the agricultural industry is significant and farmers are running out of options, as treatment with classical antibiotics is increasingly being banned, because it may drive the rise of antibiotic-resistant bacteria. Other alternatives are also under increased safety scrutiny or are less effective.”

“We also chose to use piglets as a model as they have a gut system quite similar to humans, far more similar than mice in fact, and humans also suffer from our own version of diarrhea-causing E. coli infections. The idea was that if we could create edible antibodies for piglets, these would not only be useful for pig farming but could also easily be translated into treatments for human infections.”

This little piggy ate freeze-dried antibodies

The team’s first challenge was designing an antibody that was robust enough to withstand digestion. To do so, they drew on the help of another group of animals: the camelids. Camelids like alpacas and llamas have antibodies that are exceptionally simple and compact. By fusing them to a part of an antibody type that has naturally evolved to be functional in the gut of animals, these camelid antibody fragments could make it through the digestive track of a pig, unscathed.

The precise nature of the antibodies means we could use it not only to treat gastrointestinal bugs like ETEC, but we could also explore this method to modify other GI tract diseases. - Vikram Virdi, VIB-UGent
 

Initially, the team tried to mimic the rather complex normal pig gut antibodies as much as possible. “The recently published breakthrough came when we realized in the Callewaert team that a much simpler form of the antibodies would be needed for large-scale use, which could be made with just a single gene. That was a leap of faith, as no one had tested this before. The simple antibody may very well have been broken down in the gut, but it wasn’t. That gave the project a new lease on life.” Virdi explained.

With the antibody format selected and engineered to target the porcine ETEC, the team at VIB tackled the next step of the process: finding an antibody production method that would be scalable enough, so it could be used in future manufacturing. Virdi recalled:

“For the complex antibodies, we first used a model plant, Arabidopsis, genetically modified to produce the ETEC antibodies in seeds. As we could now work with simplified single-gene coded antibodies, we could use soybeans, a crop that can produce very large quantities of protein-rich seeds. This method worked marvelously, but we realized that current GM regulations would hinder the method from being feasibly commercialized, especially in EU."

"So, we went back to the drawing board in the Callewaert group and came up with an alternate solution, using engineered yeast cells to excrete the antibodies instead. Again a bit of a leap of faith, as now the antibodies are not encapsulated in a plant seed anymore, but just present in the fermentate of the yeast; the ‘beer’ if you will.”

In a final innovation, the team devised ways of freeze-drying or spray-drying the yeast-derived antibodies, meaning that the active substance could be kept stable and at room temperature for years on end. All a farmer needs to do is mix the antibody supplement into the piglets’ regular feed and the pigs will happily slurp it up.

From veterinary treatment to human medicine

The dried antibodies proved extraordinarily effective at preventing ETEC infections in piglets in a pilot study. After being fed the antibody mixture, the pathogenic bacteria subsequently introduced was flushed straight through the pigs’ digestive tracts, as the antibodies stopped ETEC from colonizing.

Edible dried antibody powders, distributed by aid workers along with emergency supplies, could save many lives. - Vikram Virdi, VIB-UGent
 

The implications of this successful project are as important as they are wide-reaching. Not only will this technology be applicable to improve animal performance in livestock farming, but it could be used to reduce the reliance on antibiotics in the veterinary field as well. Moreover, the results also warrant exploration in human medicine. Virdi’s colleagues at the Callewaert lab are already conducting a number of further studies:

“Clinical trials are still a long way further, but the piglet study is an important proof-of-concept that edible antibodies can be used to prevent gut infections in large animals that are good models for human GI tract biology. The precise nature of the antibodies means we could use it not only to treat gastrointestinal bugs like ETEC, but we could also explore this method to modify other GI tract diseases.”

One of the most important aspects of this study, however, is the simple and highly scalable fermentation-and-drying technique the lab developed for the mass-manufactured antibodies. Because the antibodies can be stored without need for refrigeration, remaining bioactive for more than two years at room temperature, the production method opens up the possibility of this kind of treatment being used as humanitarian aid. The team has already received advice from global aid groups. Virdi is ambitious and a firm believer of the life-saving potential of the edible antibodies:

“Imagine if the next time a natural disaster such as an earthquake or flood struck a developing nation and gave rise to a waterborne diarrheal disease outbreak such as cholera or dysentery, people could protect themselves from infection with a simple food supplement. Edible dried antibody powders, distributed by aid workers along with emergency supplies, could save many lives. It will be a key project of the Callewaert lab, at VIB’s Center for Medical Biotechnology, to explore this application in the coming years.”

Click here for the Nature Biotechnology short communicaiton covering Virdi's research.

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