14 candidates, nominated by VIB employees and alumni, the VIB Alumni Board preselected three candidates. A jury of four distinguished emeriti – Marc Van Montagu, Désiré Collen, Joël Vandekerckhove and Hugo Van Heuverswyn – together with guest jury member Maggie De Block, Belgian Federal Minister of Public Health, named Lothar Steidler the winner of the second VIB Alumni Award. Lothar Steidler is currently Chief Technology Officer at ActoBio Therapeutics.
Steidler started his scientific career in the group of Erik Remaut. In the early nineties he combined two research topics of the Walter Fiers Lab: microbial genetic engineering and cytokines. He genetically modified the bacterium Lactococcus lactis to create a safe live vector for expressing and locally delivering potential disease modifying therapeutics. Steidler became a globally known pioneer in this technology and was decades ahead of the current microbiome boom.
“Steidler was never afraid to operate at the frontline of technology in a very competitive international environment with high risks, not only due to several unknown factors in his science, but also because of the vast economic and financial challenges. Therefore, Steidler, who co-founded Actogenix, one of VIB’s spin offs, in 2006, absolutely deserves this award”, says a jury member.
Using genetically modified bacteria as a drug vector is a bold idea. Where did the inspiration come from?
“Sometime during 1992, I was finalizing my PhD; I was looking for new scientific excitement. My ambition was to cure diseases, but not to follow well-trodden paths. I started to experiment with recombinant strains of the bacterium Lactococcus lactis as an expression system for human and murine cytokines. Instead of purifying them for subsequent use as biological medicines, I had the idea to use the bacterium as a vector system to locally deliver the cytokines, first in mice and, ultimately, maybe even into human patients.”
“Lactococcus is an ideal candidate. It is probably the most innocuous microorganism on the planet, used extensively in the production of cheese and other fermented food products. It is consumed in high amounts by nearly every population on earth and by every age group. So the bug has a proven zero profile when it comes to toxicity.”
“The first breakthrough came in 2000 with a publication in Science1. The paper describes the delivery of a therapeutic dose of interleukin-10 by a genetically engineered Lactococcus strain in two mice models for inflammatory bowel disease (IBD). At that time, purified IL-10 was a prime candidate for treating IBD in human clinical trials.”
Most academic scientists would leave it with the Science paper, but you proceeded towards human clinical trials. A risky career choice?
“Law – fortunately - protects the words of poets and authors eternally but new scientific ideas are only protected for a limited amount of time. If you issue a patent, this protection is roughly 20 years. So once you have published an idea, there is a tremendous time pressure to find out whether your invention really works and can be of benefit to society.”
“On the other hand, to push your idea into a marketable product, you have to pass what insiders tend to call the ‘valley of death’: you hardly publish papers, you lack money to pursue your idea(s) and, in my case, I was confronting regulatory authorities with an entirely new concept. Don’t forget that genetically modified plants, at least in Europe, have been going through a very rough phase since the mid-nineties. We came with a genetically engineered bacterium to directly treat diseases. That notion was far from evident.”
But ActoGenix / ActoBio Therapeutics® managed to convince regulatory authorities in the US, Belgium, the Netherlands, Sweden and other countries to allow genetically modified Lactococcus for clinical trials.
“Yes, and we understood it was important to prevent the bacterium from escaping and surviving in the sewer systems to prevent unwanted exposure. So, we built a sort of suicide switch. A pig model proved that this containment strategy worked well.”
“In 2006, a second breakthrough came with the first clinical trial, involving 10 patients with severe Crohn’s disease. Henri Braat, Maikel Peppelenbosch, and Sander van Deventer conducted this trial in a strict containment ward at the Academic Medical Center (AMC) in Amsterdam. The trial showed that the transgenic Lactococcus disappeared from the volunteers’ stools shortly after taking the last capsule.”
“After that initial trial we got approval for deliberate release in the environment. Obviously this is essential if you want to conduct multicenter trials or treat patients with this – or any - technology.”
The AMC Crohn’s disease trial was a landmark study and received wide public attention. For VIB it was also the signal to set up Actogenix. But you had left Ghent and VIB in the meantime.
“I was given a great opportunity to work at the University College of Cork (Ireland) but VIB convinced me to come back to Belgium to help start up Actogenix. Pieter Rottiers, Sabine Neirynck, Karolien Van Huynegem, and Klaas Vandenbroucke (all ex-VIB), had become - and still are - my ‘partners in crime’ during this exciting and adventurous period running up to and culminating in Actogenix, in 2015, when Intrexon Corporation acquired Actogenix, and recently when the unit was rebranded to ActoBio Therapeutics®.”
“The original Lactococcus delivery technology became known as “ActoBiotics®”, a proprietary unique drug delivery platform combining the advantages of highly selective protein-based therapeutic agents with local delivery by the well-characterized, safe, food-grade Lactococcus lactis. Besides interleukins, other potential biological drugs were added to the platform, including trefoil factors, proinsulin, glutamic acid decarboxylase, TNF antibodies and many others. With hundreds of chromosome-modified Lactococcus strains, we have a rich library of therapeutic agents.”
“At ActoBio Therapeutics® the main focus is currently on immunotherapy and tolerance induction/ desensitization, besides interventions in metabolic disease. Our most advanced program is on oral mucositis, a disease resulting in painful inflammation and ulcers in the mouth, throat and esophagus. This type of inflammation is often caused by cancer chemotherapy. In a phase IIb trial on patients with head and neck cancer, ActoBio Therapeutics®, in collaboration with Oragenics Inc., is testing a Lactococcus strain releasing trefoil factor 1. This human protein stabilizes and protects the mucus layer in the mouth. The product is formulated as an oral rinse solution.”
Surprisingly, type 1 diabetes is also on your list of candidate diseases to treat.
“Absolutely. We engineered a Lactococcus strain to deliver proinsulin and the tolerance-enhancing cytokine IL-10. Studies have already demonstrated that this strain, in combination with an anti-CD3 monoclonal antibody, successfully restores normal blood sugar levels in diabetic mice. A clinical trial is now assessing the safety and tolerability of this strain administered in patients with type 1 diabetes mellitus.”
“Besides those clinical programs we have strains in preclinical development for inflammatory bowel disease, chronic rhinosinusitis, food allergies, and celiac disease. On top of this there are early development programs in phenylketonuria, metabolic disease, and autoimmune skin disease.”
Looking back, what do you see as the most important contribution of VIB to your career?
“When I was 15 years old, two of VIB’s founders – Marc Van Montagu and Walter Fiers – immensely inspired me with their interviews on television. They were talking about cutting and gluing genes, transkingdom from one species into another. I was literally gobsmacked and decided then and there that I would become a genetic engineer. Of course, that was way before the creation of VIB, which gave the Flemish biotech landscape as a whole a real boost.”
“The most important contribution of VIB to my career is that its directors and staff believed in our technology and founded Actogenix. Without this company, I might have become a professor in Ireland or something else somewhere else, who knows.”
Finally, as a ‘seasoned genetic engineer’ what is your advice to young researchers?
“Live your dream. If your ambition is to invent and try to cure a disease, well, do so. Don’t be surprised to find that the path is full of obstacles – which, in all honesty, may be great fun to solve, keep that in mind – and that it takes much longer than originally anticipated. Also be critical to yourself: if you end up in a loophole, get out of it. That also happened to me. At some point I was thinking that engineered Lactococci could deliver vaccines. I was not the only one. There was a large European consortium with over a hundred academics, professors and researchers, thinking exactly the same. It may not have been my best idea.”
“And finally, the biggest error that you can make is to think that you are an expert in everything. As a scientist in a company, your job is to profoundly understand the science and the technology, and to be among the best in your field. You will never get to the deepest understanding of the legal aspects, because you are not a lawyer. Or the business aspects, if you are not trained or talented in business administration. As a scientist, you are the inventor. But after all, that is were it all starts.”