Pylum Biosciences, based in San Carlos, United States, was founded in 2005 as AvidBiotics. In 2017, the company split: Xyphos Biosciences focuses on switchable CAR-T technology (acquired by Astellas in 2019) and Pylum Biosciences focuses on creating narrow-spectrum precision antibacterials targeting specific infectious diseases as well as bacteria implicated in the pathology of disease, such as cancer and endometriosis.
Bacteria are implicated in diseases beyond traditional infections
Drug-resistant bacterial infections are a major threat to human health. In addition, it is becoming increasingly known that specific deleterious bacteria play a key role in many other diseases, including colon and prostate cancer. The medical community is in dire need of a platform technology specific to the disease-causing bacteria that is readily engineerable as bacteria mutate.
Improving on natural bacteria killers
R-type bacteriocins are bacteriophage-like proteins found in many different bacteria, which kill competing bacteria. To create Avidocins, Pylum engineers the bacteriocin’s phage-like tendrils to target specific receptors on the surface of pathogenic strains of bacteria. The rest of the molecule remains unchanged. Avidocins disrupt the bacterial cell wall, resulting in a single-hit killing of the target bacterium (Fig. 1).
Fig. 1 | Baseplate transition from the pre-contracted to the post-contracted state. a, Illustration of an Avidocin binding to a bacterial cell and firing. b, Ribbon diagram of the conserved baseplate components and sheath proteins in their pre-contracted and post-contracted states. Arrows denote potential movements for subunits in the same colours. OM, outer membrane.
The benefits of the approach are twofold. Firstly, antimicrobial resistance is one of the top global public health threats and in 2019 contributed to more than 4.95 million deaths1. Small-molecule approaches quickly encounter resistance. Avidocins are less likely to trigger resistance, but if it does occur, they can be rapidly re-engineered. Secondly, bacteria are increasingly associated with non-infectious diseases such as cancer. Targeting these species could have profound effects on treatment.
Development of Avidocins can often take as little as three weeks, which is significantly faster than creating new small molecule antibiotics and allows the company to tackle emerging bacterial pathogens. Furthermore, Avidocins leave beneficial bacteria unharmed, reducing off-target effects.
Building precision antibacterials
Clostridioides difficile infection (CDI) is a high priority nosocomial infection. It lengthens hospital stays, raises the risk of mortality, and increases costs for healthcare systems. One-quarter of people who have treatment for a CDI will have another. After three or more infections, half of those patients will have yet another recurrence2. CDI can be treated with antibiotics, but this increases recurrence. The only approved alternative treatments are fecal microbiota transplants, which are marginally effective and haven’t yet gained commercial traction.
Avidocins, currently in preclinical development, act by specifically ablating the C. difficile bacteria. In a mouse model, the C. difficile Avidocin, Av-CD291.2, killed the most common clinical isolates, leaving the gut flora unharmed and, unlike vancomycin,2 did not disrupt colonization resistance.
“Our target is an oral treatment for recurring CDI, an orphan indication,” said Tom Driscoll, CBO, Pylum. “The next step is to seek guidance from the US Food and Drug Administration (FDA) about requirements for toxicology studies. We could be in clinical trials as early as 2025.”
The next target is Fusobacterium nucleatum (FN), which has been linked to many diseases, including adverse pregnancy outcomes, gastrointestinal disorders, cardiovascular disease, rheumatoid arthritis, respiratory tract infections, Lemierre’s syndrome, endometriosis, periodontal disease and Alzheimer’s disease. Research shows involvement in an increasing number of cancers, including colorectal, pancreatic, esophageal, and breast. A study published in Nature showed strong evidence of a causative relationship with FN with colorectal cancer3.
Pylum is developing an Avidocin protein targeting FN for use in combination with routine cancer treatments and could have potential for prevention.
“We have identified engineering targets,” said Driscoll. “The next step will be to determine whether pathogenic strains are susceptible.”
Building a strategy for the future
Pylum’s pipeline is also applicable to animal health, and food safety problems. The current focus, however, is on CDI and FN, as James Knighton, Chair, explained: “We plan to establish clinical proof-of-platform with support from strategic joint ventures with biopharma companies, as well as funding from investors. We are a platform company with a large pipeline of candidates, we offer tremendous value beyond these first candidates.”