Emerging Classes of Next-generation Biotherapeutics

We are entering uncharted territory in biopharmaceutical development. Emerging new classes of treatments are harnessing the natural power of viruses and cells and engineering them to fight human diseases. As our arsenal of conventional therapies begins to fail, a new army of biotherapeutics is on the horizon. Here, we look at two new classes of treatments leading the charge.

The phage therapy that can reverse antibiotic resistance

Searching through sewage to find nature’s bacterial killers may not be the most glamorous of jobs, but it’s an approach that could have huge promise in the fight against antibiotic resistance.

Dr Ben Chan, Associate Research Scientist of Ecology and Evolutionary Biology at Yale University, is on a mission to hunt down naturally occurring phage that can reduce the virulence of some of the deadliest pathogens we face today.

“Bacteria and phages have been fighting it out forever, but bacteria are really good at evolving resistance to these attacks,” he explains. “A promising phage therapy candidate therefore is one that utilizes a virulence factor, or some component involved in either virulence or antibiotic resistance, as its receptor binding site. If the phage is using a virulence factor, it’s likely that the easiest way for the bacteria to become resistant is to make some changes to that receptor, which will almost certainly result in a decrease in virulence.”

The idea is that one of two things will happen: either the phage kills off the bacteria, and the infection goes away, or the bacteria evolve resistance to the phage but in doing so are no longer able to cause an infection or they become sensitive to antibiotics again.

So far, Chan’s group has successfully translated the approach to a small number of patients, including several cases (one published) where they re-sensitized Pseudomonas aeruginosa to antibiotics, allowing resolution of an otherwise intractable vascular graft infection.¹  

These are just the first of many more new phage therapies coming through from the lab, he says. “Right now we’ve got some interesting candidates for therapy. We can flip antibiotic resistance in species other than Pseudomonas, and we’ve got some great virulence targeting phage in a bunch of different species. We can take these clinically invincible-drug resistant pathogens like Pseudomonas and Klebsiella, and we can kill MRSA, VRSA. Phage don’t really care about drug resistance, they’re just great at killing.”

Phages are also cheap to produce, easy to purify, and versatile in terms of formulation.  “They’re pretty tough little things, I think the hardest thing is getting the most phage possible to the site of infection.”  Unlike chemical antibiotics, with phages you have to ensure you get the phage physically to the site of infection. “But I’m really excited about moving a lot of this forward. There’s a lot of momentum behind it, now it’s getting out there that this is something that could work to treat infections. I think people are getting behind it and the next couple of years are going to be really big in the field.”

Engineering bacteria as ‘living diagnostics and therapeutics’

An alternative approach to tackling the problem of multi-drug resistant infections is to make their surroundings inhospitable. That’s just one of the strategies being employed by Professor Jim Collins, Termeer Professor of Medical Engineering & Science at MIT and the Wyss Institute, Harvard University.

“The vision here is to harness synthetic biology, and the innovative tools and platforms being developed in the field, as a means to create novel classes of therapeutics and diagnostics: specifically, the notion of being able to engineer bacteria to function as living diagnostics and living therapeutics.”

As one example, Collins’ team recently used this approach to detect and treat cholera in mice.² They engineered a strain of Lactococcus lactis to detect quorum sensing signals from the pathogen Vibrio cholerae in the gut. Bacteria use these quorum sensing signals to coordinate gene expression in response to the density of their population.

“In response to this detection, L. lactis produce an enzyme that would change your stool a different colour,” explained Collins. “We were also able to utilize L. lactis as a living therapeutic, primarily by having the probiotic produce lactic acid, which changed the pH and made the gut inhospitable for cholera.”

The team is now using this approach to go after other pathogens including Clostridium difficile - the leading cause of infectious diarrhoea in hospitalized patients – as well as other difficult-to-treat infections including MRSA and carbapenem-resistant enterococci. “More broadly, the idea is to identify other natural species that could be used in a competitive fashion to put infectious agents in check,” Collins says.

The approach is not only limited to infectious diseases. Collins is involved in a company, Synlogic, which is using synthetic biology technology to engineer bacteria to treat rare metabolic disorders as well as cancer and other complex diseases such as inflammatory bowel disease. They already have at least two clinical trials under way.

“I think we will see more treatments of this type,” Collins says. “We’re at an exciting time with a new wave of medicines being developed around engineered cell therapies. There’s clearly been considerable interest around CAR-T cells and other mammalian systems and justifiably so.  However, I think engineered bacteria – synthetic biotics -- open up new, exciting possibilities and expand our abilities to treat complex diseases.

References:

1. Chan, BK et al. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol Med Public Health. 2018 (1): 60-66. doi: 10.1093/emph/eoy005
2. Mao, N. et al Probiotic strains detect and suppress cholera in mice. Science Translational Medicine 13 Jun 2018: 10eaao2586 DOI: 10.1126/scitranslmed.aao2586