PHILADELPHIA – Interest – with perhaps a bit of confusion – abounds in the microbiome space, as evidenced by the fact that there were two panels at this year's BIO International Convention, compared to the single panel last year. But this year showed just how difficult the microbiome is to categorize: One session fell under the chronic/primary care track while the other was listed under the infectious disease track.

(See BIO's new name, in this issue.)

The reason for that confusion is obvious on one level: "Microbiota has an impact on essentially every discipline in medicine," said David Martin, chairman and CEO of Avidbiotics Corp., who moderated the latter panel Tuesday afternoon.

On another level, it makes the distinction even trickier. While many diseases have turned out to be related to infection – hemolytic uremia syndrome, for instance, was found to be a complication of E. coli infection – science has yet to prove causality between specific microbiota in the gut and many other diseases. Many researchers have come to believe microbiota represent, as Jackie Papkoff, vice president of immunology scientific innovation at Johnson & Johnson Innovation, called it, an ecosystem requiring balance. But whether diseases can be traced to specific bacteria or are simply linked to an ecosystem imbalance is a knot it may take years – even decades – to unravel.

"We are where oncology was 100 years ago," Martin said, referring to the discovery of tumor complexity that goes far beyond where in the body a tumor originates. "Hopefully, it won't take us 100 years" to figure out to navigate the microbiome, he added.

What is clear, though, is that the use of broad-spectrum antibiotics to treat bacterial infections has a negative impact on microbiota. Not only do those antibiotics face severe resistance issues – a World Health Organization survey recently showed that bacterial infections are becoming progressively less treatable with current antibiotics – the broad-spectrum activity also can alter the overall "ecosystem" of microbiota, an outcome that could be particularly damaging in young patients. (See BioWorld Today, May 6, 2015.)

"The only way to address this is with narrow-spectrum agents," Martin told BioWorld Today. In 2005, Martin co-founded Avidbiotics, along with Jim Knighton, who serves as the company's president, and Jeffery F. Miller, chairman of the scientific advisory board, to develop proteins capable of targeting specific bacterial strains while leaving surrounding bacteria untouched.

Dubbed Avidocins, they are engineered R-type bacteriocins that target a specific strain, such as Clostridium difficile, for example, which Avidbiotics is advancing as its lead program.

"We're just finishing our preclinical work," Martin said. Data in mice so far show that the narrow-spectrum candidate won't kill anything but C. difficile bacteria and proved effective against strains such as BI/NAP1/027 – "those are the bad actors" that result in the most frequent relapses. But treatment didn't appear to alter the microbiota in the mice at all, he added. "We cannot measure a change."

Martin said he anticipates moving into the clinic sometime next year.

WANTED: A POSTER CHILD

More specific than existing antibiotics, narrow-spectrum drugs also are likely to be more effective than bacteriophage therapy, an approach that is experiencing a resurgence in the wake of the antibiotic resistance crisis.

Bacteriophages marked a "really nice, interesting biologic phenomena," acknowledged Martin, who prior to Avidbiotics, had helmed Gangagen Inc., a privately held firm working on phage preparations for bacterial diseases. But bacteriophages present some disadvantages, including a high risk of resistance, largely because the viruses have to borrow functions from the host cell to complete its task, leaving it susceptible to mutations.

Bacteriocins, on the other hand, only have to rely on one function from the host cell, one that has to be present on the receptor binding site. Best of all, Martin said, "if we're clever and lucky," and the bacterial cell attempts to lose its receptor to escape the bacteriocin, it will also lose its virulence factor. "If we've done it right, the bug is compromised."

Given all that promise, combined with the clear need for new treatments, a narrow-spectrum approach to treating bacterial infections sounds like a simple enough proposition. The tough part is getting people on board, particularly pharma companies.

"Some agencies recognize that [need]," Martin said, such as the FDA and "certain parts of the NIH. A few pharmas recognize it, but in general, they're talking the talk," yet still shying away from drugs that could only reach narrow populations. Of course, drugs targeting small subsets of cancer patients once faced similar pushback; companies eventually came around to see the value.

Part of the value for narrow-spectrum antibiotics will rely on the diagnostic angle. "We need broad-spectrum diagnostics" able to easily and accurately identify specific bacterial infections, Martin said. "The technology is there, [but] the incentive has to be there.

"I think we need a poster child," he added. If Avidbiotics' lead compound shows it can treat humans by targeting the C. difficile bacteria without affecting the rest of the microbiota, that could go a long way to proving the approach, as well as optimizing some of the tools in development.

"The problem is there's been no proof of causality," Martin argued during Tuesday's panel. One way to address that is finding "tools you can use to subtract certain organisms and then validate or not validate" the effect, manipulating the microbiota to determine if that results in any clear changes in phenotype.

"And then if you add back that organism, can you cause that phenotype?" he asked. "If you take it away, can you eliminate that phenotype?"

To that end, the South San Francisco-based firm has a deal with Dupont Nutrition & Health using its Purocin technology, which comprises proteins designed to bind to molecules on the surface of the target bacteria, killing those bacteria and leaving surrounding bacteria unharmed. In the Dupont collaboration, the companies are targeting E. coli 0157:H7 for food protection purposes.

THE OTHER SIDE: ONCOLOGY

While the antibacterial platform at Avidbiotics has been in development the longest, the company has another side to its therapeutic focus: Oncology, specifically immune-oncology, an area that has been moving at breakneck speed in the past year or two thanks to recent developments such as the PD-1 and PD-L1 inhibitors.

"It's much easier to get attention and funding" for that program compared to the antibacterial program, Martin conceded.

Avidbiotics' approach involves targeting specific surface markers on cancer cells, using a bispecific protein that can bind to both the tumor cell and to the NKG2D receptor, which NK cells in the innate immune system and T cells in the adaptive immune system use to detect malignant cells. The trick to the company's approach is using a MICA-derived protein.

MICA is a molecule that "decorates" a stressed cell, essentially letting the immune system know it needs to be destroyed; cancer cells have found ways to eliminate that signal. So Micacide proteins are designed to "redecorate" those cells, Martin explained.

Those programs are in the research stage.