Plant pests are becoming resistant to chemical pesticides, that is, chemical insecticides, herbicides, and fungicides. And simply upping the dose of chemical pesticides is hardly an option, especially since these substances already raise environmental concerns.
Another option is to resort to biological control agents. According to the U.S. Department of Agriculture, the use of biological control agents typically “involves the reduction of pest populations through the use of natural enemies such as parasitoids, predators, pathogens, antagonists, or competitors to suppress pest populations.” The approach has its advantages, but it requires a comprehensive understanding of the relevant pests, nontarget species, and other environmental factors, and it can be slow to take effect. In any case, it has yet to be widely embraced by growers.
There is, however, another kind of biological control agent: the biochemical pesticide. It can be a natural substance, or it can be designed and manufactured. The latter approach is being followed by Biotalys, which applies techniques borrowed from molecular medicine to produce highly specific protein-based biofungicides. Because they are protein based, they don’t persist in the environment. And in field trials, they have proven to be at least as effective at preventing fungal infections as chemical control methods.
Targeting gray mold
Biotalys developed EVOCA, one of the first protein-based biofungicides to be presented to regulators in the United States and the European Union. It targets botrytis, also called gray mold, a fungus that affects grapes, strawberries, cucumbers, and many other crops and ornamental plants.
This protein-based biofungicide was designed with the same methods and specificity that drug developers use to target human pathogens. It targets one or more antigens on fungal cell walls to affect the cells’ function. “We can target any number of sites,” asserts Kevin Helash, CEO, Biotalys. He also suggests that the company’s development platform, the Agrobody Foundry, can generate biofungicides with multiple modes of action, or successive generations of biofungicides that each affect the fungus differently, thus forestalling the risk of disease resistance.
While awaiting approval for EVOCA, Biotalys continues to expand its pipeline. BioFun-6, the next in its lineup, acts against botrytis, anthracnose, and powdery mildew. Greenhouse and small-plot studies began recently, and first results are expected by the end of 2024.
Predictably reliable
Helash says that unlike traditional biological approaches, protein-based biofungicides are predictable and reliable, so they can be used for successive years and achieve similar results. He adds that off-targeting is minimal, and that the biofungicide degrades into amino acids in the soil.
“There’s nothing in terms of on-plant chemical residue on the fruit or in the soil,” he remarks. “It’s a completely harmless and biodegradable product.” That suggests it may be safe for bees and other pollinators.
Chemical pesticides (including fungicides) typically come in packages that display words such as “warning,” “danger,” and “caution.” Will such words be required on EVOCA’s packaging? “We’re not expecting a significant amount of restriction,” Helash replies. He does, however, acknowledge that EVOCA is no silver bullet for disease resistance: “All products with a singular mode of action will develop resistance.”
“What is different,” he continues, “is the potential to combine different modes of action. EVOCA currently has one mode of action. Eventually, it may be possible to combine up to six into one product, so a pathogen can’t get ahead of you. It’s a process of building products over time.”
The case for new pesticides
“There are around 13 fungal modes of action,” Helash points out. “Unfortunately, most of them have developed medium to high resistance.” Consequently, developers of agricultural pesticides are continually working to find new ways to control pathogens. But the task is becoming more difficult because the number of active ingredients available for pesticides is diminishing.
“Some 162 countries have banned 460 pesticide active ingredients,” Helash says, “and the list continues to grow. The United States currently is using 72 pesticides that are banned or will be banned in Europe. That’s quite frightening.”
Although Biotalys appears to have a solution, its novelty for environmental protection agencies is a challenge. “It’s an intense process because this is a new technology to both U.S. and E.U. authorities,” Helash says. “There’s been a lot of dialogue around the technology itself.” Nonetheless, Helash is optimistic that EVOCA could secure U.S. registration in 2024 and E.U. registration in 2025.
Rational pesticide design
In developing its biofungicides, Biotalys has taken a page from the biopharma industry and rational drug design. “We identify the target first—a specific antigen on the fungal cell wall,” Helash says. “Then we go after a mitigant for that specific target” using antibodies derived from the camelid immune system. “Llamas have a unique antibody system that includes a heavy chain antibody that is particularly effective in fighting off diseases,” Helash elaborates. “We are using that heavy-chain antibody system to create the proteins to mitigate pathogens in plants.”
Like chemicals, but safer
The science behind EVOCA was developed in the late 1980s by scientists at the University of Brussels, and advanced by the Flemish Institute of Biotechnology in Ghent, which spun out a life sciences company in 2002 to develop new drugs for human diseases. “Then it decided this platform could be used in the agriculture sectors as well,” Helash says, “so we were spun out in 2013.”
Helash joined Biotalys one year ago. He recalls discussing what the company needed to do to ensure it would deliver value to the marketplace. It needed to make products that were as effective as chemical fungicides, to manufacture its products cost-effectively at a commercial scale, and to provide an acceptable return on investment for stakeholders.
Are these requirements being addressed by EVOCA? “In more than 600 real-world trials, EVOCA has mimicked the performance of synthetic chemistry to control botrytis in our target crop,” Helash says. For grapes, rotation programs performed with EVOCA achieved 87% control of botrytis, whereas a fully chemical program achieved only 60%. Helash adds, “We realized we could create a product based on our platform that could be deployed in agriculture without a sacrifice to the grower in terms of efficacy, return on investment, or extra work to handle and use the product.”
The final hurdle was to find a distribution channel partner to take it to market. Biotalys recently partnered with Novonesis to produce and distribute EVOCA NG (Next Generation) outside the United States.
First use: Commercial growers
EVOCA NG and any subsequent biofungicides will be distributed through Biotalys’s channel partners, first to commercial growers. (However, Helash allows that the consumer market would be a possibility “if a partner were to go in that direction.”) The initial application indications are to prevent botrytis with preharvest treatments. Helash notes that the company is also “looking into the potential of a postharvest market to help further mitigate botrytis or other fungal pathogens in selected crops.”
Six products are in the current pipeline, and Helash plans to add one per year. As Helash points out, there are multiple potential targets and many possible combinations of modes of action for protein-based biofungicides and other pesticides.
