Industry Matters: Locus Biosciences enlists CRISPR-enhanced bacteriophages to combat resistant bacteria.

Antibiotic resistance is a real and potentially calamitous problem that would make the 1918 influenza pandemic and Covid-19 pandemic combined pale in comparison. And that isn’t just hyperbole. Simple paper cuts could become deadly. Stomach bugs when traveling? Deadly. That deep cough you caught? Deadly. And each and every type of surgery — even if its just poking a tiny hole — deadly. That’s why its so important to develop effective alternatives to today’s antibiotics.

Locus Biosciences is developing a class of antibiotics that relies on bacteriophages to seek out and destroy harmful bacteria. They are the natural enemies of bacteria so it makes sense. In addition, the targeted nature of the therapy would not wipe out entire colonies of beneficial bacteria we rely on.

Paul Garofolo, Locus Biosciences’ CEO and co-Founder, discussed the science and technology behind their bacteriophage therapy with SCINQ.

Paul Garofolo. (CREDIT: Locus Biosciences)

What real world problems are Locus Biosciences’ products designed to address? 

Through its unique bacteriophage discovery, synthetic biology, and manufacturing platform, Locus is developing two innovative categories of biotherapeutics to address significant unmet medical needs: precision products leveraging CRISPR-Cas3 enhanced bacteriophage to fight deadly infections, including those caused by multi-drug resistant bacteria; and engineered bacteriophage therapies that utilize bacteria resident in specific locations in the body to deliver therapeutic molecules. 

Our lead candidate LBP-EC01 is a CRISPR-Cas3-enhanced bacteriophage precision medicine targeting Escherichia coli (E. coli) bacteria causing urinary tract infections (UTIs). Worldwide, an estimated 150 million people are affected by UTIs each year. Approximately 80% of these are caused by E. coli, often including difficult-to-treat strains that are resistant to commonly used antibiotics. Up to 40% of UTI patients experience a recurrence within months of the first episode. LBP-EC01 met all its endpoints in a Phase 1b trial, and we are working towards initiating a registrational LBP-EC01 Phase 2/3 study in mid-2022.

In addition, Locus is working on products targeting infections caused by Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa), and Staphylococcus aureus (S. aureus) and others targeting Inflammatory Bowel Disease (IBD).

Both the U.S. Centers for Disease Control and Prevention and World Health Organization have identified the pathogens that Locus is targeting with its products as urgent and serious public health threats requiring development of new treatments. A recent article in The Lancet also highlighted E. coli, K. pneumoniae, P. aeruginosa, and S. aureus as four of the six bacterial species associated with the largest number of deaths attributable to bacterial antimicrobial resistance (AMR) worldwide.

Phage therapy has been around for a long time. Why has it taken so long to pin down?

Bacteriophage have been used as antibacterial therapy for more than 100 years, beginning with Felix d’Herelle’s application of Shigella-targeting bacteriophages to cure French troops of dysentery in 1917. However, natural phages are not typically effective enough on their own to treat serious infections in humans. Additionally, phage therapies require the isolation of specific phages to treat each bacterial pathogen, specific diagnosis of the pathogen afflicting each patient, and a sophisticated manufacturing process. As a result, phage therapies lost traction with the medical community in the Western World in the middle of the 20th Century as antibiotics became widely available and became the staple in modern medicine it is today. During this time, however, phage therapy continued to be used effectively in Eastern Europe to treat patients with severe infections.

The ‘one size fits all’ approach to treating bacterial pathogens with broad-spectrum antibiotics set us on an inevitable path to the evolution of even deadlier pathogens that are resistant to the antibiotics that we have developed to treat them. Now, with advances in technology, the rise in AMR, and a dearth of new antibiotics in development, bacteriophage is coming back into focus as the pharmaceutical industry has recognized the critical need for new antimicrobial products and the FDA has provided more guidance on bacteriophage therapies.

What are your crPhage and ePhage platforms? How do they work and make Locus Biosciences’ drug discovery process more efficient?

Through Locus’ discovery platform engine, which includes a sophisticated set of robotics, bioinformatics, artificial intelligence, and machine learning tools, we can scan environmental inputs (e.g., soil, water) to isolate and identify novel bacteriophage and then engineer them to create new products. Utilizing the precision of bacteriophage, we are able to reach into the human body and deliver a payload to a particular species or strain of bacteria. More specifically, we use the crPhage® platform to deliver CRISPR-Cas3 to make phages more effective at killing target bacteria. We also have a series of other engineered phage (ePhage) products in development that deliver alternative payloads with other activity, such as anti-inflammatory molecules. 

The other key to our drug development process is our wholly owned manufacturing facility. As our lead product kills E. coli, a bacterial species commonly used in large molecule product manufacturing, it was imperative to our success that we build our own facility. We commissioned a world-class 12,000-square-foot facility in 2020 which enables the manufacturing of precision medicines, gene therapy vectors, and other advanced biologics to meet or exceed U.S. and international regulatory standards. 

Once crPhage clears out the target bacteria causing the UTI, what’s to prevent it from also decreasing naturally occurring E. coli in our microbiota?

The current standard of care for UTI (broad-spectrum antibiotics) kill E. coli and many other species of bacteria, many of which are important for healthy functioning of the microbiota.  Narrowing the target set to only E. coli is therefore tremendously beneficial to the patient. We have further taken steps to tune our product to target uropathogenic E. coli, those strains that are known to cause UTIs. 

What happens to excess phage once the target bacteria is cleared? Would our immune systems target them causing a fever?

The beauty of engineered bacteriophage as a delivery vector is that once the phage has eliminated the targeted bacteria, the phage will no longer be able to replicate without a host. Over time, any remaining phages are removed from the body by natural excretory processes. Given the immune system’s familiarity with natural or wild-type phage – which are abundantly present in the body – our immune systems typically do not react to the introduction of phages. 

Are mutations in replicating phages a potential problem?

Locus has investigated the genetic stability of our engineered phages under laboratory conditions representing many more rounds of replication than we would expect to occur in a patient and has not seen evidence of mutation on that time scale. Furthermore, any phages that arise with detrimental mutations (i.e., mutations that make them less able to infect and replicate inside their hosts) will be outcompeted by phages that remain unmutated.

There might be some reluctance to the idea of injecting or swallowing viruses into the body, especially in today’s anti-science environment. How can this be addressed?

Viruses have been intentionally delivered into the body to prevent or treat human diseases for over 200 years, dating to Edward Jenner inoculating a 13-year-old boy with vaccinia (cowpox) virus in 1796 to try to immunize him from smallpox. Many other vaccines since then utilize live attenuated or inactivated virus particles. More recently, viruses have been used as delivery vehicles for precision therapies like gene therapy. Public education will be required to support widespread adoption of phage therapy, but we find that the natural abundance of bacteriophage in the environment (upward of 10^31 total bacteriophage on the planet, 10x the number of bacterial cells), and their presence on every surface of our body, throughout our GI tracts and in every bite of food and drink of water we take is easily understood by people.

Furthermore, multiple bacteriophage products have been approved for use in food safety applications and have been given Generally Regarded as Safe (GRAS) designation by the U.S. Food and Drug Administration. See, for example:

Ultimately any pharmaceutical product must demonstrate safety and efficacy in clinical trials.  Notably, results from our Phase 1b trial of LBP-EC01 demonstrated safety and tolerability and support the overall safety profile for Locus’ phage therapy platform. 

Finally, how would the Locus end products be used clinically? Would it be able to be prescribed and taken at home?

Much like the way targeted therapies revolutionized cancer treatment by replacing non-specific approaches like chemotherapy and radiation with precision approaches, we expect our “one bug, one drug” approach will eventually replace broad-spectrum antibiotics with precision therapies. Our products will initially be delivered intravenously, which will be most amenable to an inpatient population. We anticipate that our products will initially be added to standard of care antibiotics as soon as the bacterial pathogen is identified. Over time, as our product set becomes further refined, including delivery by other routes such as nebulization into the lungs and oral pills, we expect to move earlier in the treatment paradigm to eventually become first-line therapy.

We are also developing our technology for applications beyond infectious disease to target bacteria that have a role in causing or exacerbating diseases across multiple therapeutic areas, including immunology, oncology and CNS. We believe phage therapy has an exciting future in battling the global ‘silent pandemic’ in AMR and beyond to deliver life-saving medicines to high-need patient populations faster and less expensively than other drugs. 

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