Bringing Precision Medicine to Antibiotics
Disease-specific antibodies are showing promise for treating bacterial infections, a pharmaceutical researcher said during a recent AAPS webinar.
By David Pittman
The antibiotics field needs a paradigm shift and to embrace a “precision medicine” mindset in the development of new therapies.
Traditional small-molecule drugs are increasingly ineffective against bacterial infections, creating a demand for alternatives, a recent American Association of Pharmaceutical Scientists webinar noted.
Pathogen-specific antibiotics do not have the issues of resistance that today’s broad-spectrum antibiotics carry, making them more reliable for long-term use, Ken Stover, senior director of infectious diseases and vaccines at MedImmune, said on the webinar Monoclonal Antibodies as an Alternative to Antibiotics?
Novel antibody therapies also do not disrupt the helpful microbiome that exists in the body, have longer half-lives, and are generally safer because there are no drug-drug interactions, Stover said. The shift would look “something like how cancer is treated where [doctors] are looking at specific oncogenes and biomarkers to de-termine what drugs to use.”
Adding to the problem, no new types of antibiotics have been discovered since 1984, according to the Pew Charitable Trusts. The drug industry largely moved on to other treatments like those for chronic disease as much of the “low-hanging fruit” was picked off, Stover said.
For these reasons, the time is ripe for a precision medicine paradigm for the antibiotic-development wing of drug development, which has been one of the last to embrace the trend “because they’ve had convenient broad spectrum antibiotics for so long,” Stover said.
Sceptics who point to past failures of antibacterial antibodies as a reason to doubt a new approach should note a few things. Past attempts often aimed at the wrong target, analyses found. They also were narrow in scope, tar-geting a single mechanism or wrong population, Stover said.
MEETING CHALLENGES
There are still many challenges ahead for the paradigm shift to take root. “The science is actually the easy part,” Stover said.
Scientists need more potential monoclonal antibody (mAb) candidates, which takes improved technology to expand mechanisms of action and immune responses. Also, antibody production still needs enhancement.
The science also needs to refine how it works with combination products or drug candidates that attack infec-tions in different ways to ensure against diverse disease types. “It may be difficult to ask a single mAb with a single mechanism of action to do everything you want,” Stover went on to say.
During the webinar, Stover gave multiple examples of using therapies that combine a traditional antibiotic—that might not treat the infection alone or be somewhat resistant—with an antibody. The result was a better outcome in treating infections even when using a small dose of the antibody that would be less than what you would give as a stand-alone product.
The reason, Stover says, is that small-molecule antibiotics cause damage to healthy cells and organs. Antibodies also elicit a natural response that helps fight the infection on top of what the drugs give.
“If you have this background antibody response on board whenever you get an infection, even if that antibody response by itself isn’t protective, it could complement antibiotic therapy and result in a better outcome for the patient,” he said.
If researchers develop two novel therapies for a single product, the Food and Drug Administration requires each be tested individually as well as together under what is referred to as the “combination rule.” So Stover recom-mended using an existing drug when developing combination products.
Resistance on such combination products has not been noticed, Stover said, but they also have tried to force its occurrence in a lab. “Never bet against the microbe,” Stover warned.
Resistance in the clinic, theoretically, is less likely because clinicians are targeting only a single pathogen and a select group of patients. “You won’t have this environmental exposure you have with antibiotics where you can gradually generate resistance in a larger population,” Stover said. “There’s less potential there.”
There is more and more work on this combination-type approach in the field, Stover said.
A more precision medicine-like approach would also be a whole new field for infectious disease doctors, who would need new tools to rapidly diagnose conditions, a complex and difficult jump to make, he added.
The medical field needs to change its thinking about how inexpensive treating a bacterial infection should be. There is a mindset that antibiotics should be cheap and readily available, Stover said. If a precision medicine para-digm shift in infectious disease treatment should occur, doctors will need to not just reach for the easiest-to-find drug.
Delivery is another challenge. Antibodies generally are not delivered orally, creating issues with formulations for pharmaceutical scientists.
Because the drug in most instances is delivered intravenously, new technologies like in vivo expression and viral or DNA delivery are developed “because one can deliver the antibody more rapidly,” Stover said.
Ophthalmologists are seeking to develop an eye drop formulation, but that drug would have to be delivered more frequently since only a small amount of drug is contained in each drop. “That work is actually coming out,” he said. “It may actually work that way as well.”
Cystic fibrosis patients, who are often susceptible to infection, could benefit from an inhaled version, but that might be difficult because of mucus clogging patients’ lungs. Stability issues might also arise because the drug comes out in fine particles after being nebulized. “I wouldn’t be super optimistic that it would be that helpful,” Stover said.
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David Pittman is a science and medical journalist based in Washington, D.C.