Plant-based biologics: From setbacks to reinvention

Early in the COVID-19 pandemic, Canadian biotechnology company Medicago began clinical trials on Covifenz (CoVLP), a plant-based COVID-19 vaccine produced using plant-based virus-like particles (VLP) of the SARS-CoV-2 spike protein. The effort evaluated the potential of plant molecular farming to provide the speed and scalability needed for pandemic biomanufacturing.

Medicago, which developed and commercialized vaccines and therapeutic proteins using plants as bioreactors, developed Covifenz in partnership with GlaxoSmithKline. The vaccine was authorized by Health Canada in February 2022 for adults ages 18 to 64, making it the world’s first approved plant-derived COVID-19 vaccine.

Yet just a year later, Medicago’s parent company — Mitsubishi Chemical Group — announced it would cease all operations, citing the difficult market environment for COVID-19 vaccines and the company’s challenges in scaling up to commercial production.

In the rapidly evolving field of plant-based biologics, Medicago’s story reflects both the potential and the pitfalls of a technology still finding its footing, but also one that continues to demonstrate promise as new scientific and process innovations take hold.

Issues of scalability

Medicago’s collapse was not an isolated case. One of the field’s enduring hurdles has been translating this scientific promise into commercially sustainable production, says Don Stewart, CEO of PlantForm, a Canadian biopharmaceutical company that uses plants to manufacture antibody and protein drugs.

Stewart points to early U.S. government-backed programs such as DARPA’s “Blue Angel” initiative, which funded several facilities designed to demonstrate that vaccines could be produced in plants within a month in response to a pandemic or biothreat. While the program successfully showcased the technology’s rapid production potential, he notes that the infrastructure design of some of those early facilities proved problematic and limited long-term viability.

“The facilities got set up and, in some cases, they built very large plant-growth spaces,” Stewart says. “The problem with doing that, if you get a contamination it goes into the whole space and for some of the products, they didn’t need that type of volume. But because they built it as one space, not as units, you couldn't subdivide it. You could use a small part of it, but then you couldn’t do something else at the same time.”

While some of those early facilities struggled to remain viable, the Blue Angel initiative and subsequent efforts like Medicago’s marked genuine progress in demonstrating speed and scalability.

“The Blue Angel project demonstrated how you can be given a novel protein that you need to make very quickly, and the nice thing about the plant system from an upstream standpoint is the process that you develop on a small scale is easily scalable,” says Karen McDonald, distinguished professor emerita of chemical engineering at UC Davis.

Glycosylation concerns

Another key scientific barrier in this space has been glycosylation, the process by which sugar chains are attached to proteins. These sugar structures play a vital role in determining how biologics function in the body: how long they circulate, how well they bind to receptors, and whether the immune system recognizes them as “self” or “foreign.”

Plant and human cells, however, decorate their proteins differently. Plant-derived proteins often carry sugar linkages that can appear foreign to the human immune system, raising concerns about immune or allergic reactions and reduced therapeutic activity.

McDonald and Stewart both emphasize that the field has made significant strides in overcoming these challenges.

Researchers are now able to engineer plant hosts to mimic human glycosylation patterns — a process known as glycoengineering — which allows plants to attach sugars more similarly to those made by mammalian cells, according to McDonald.

She added: “And then there’s a whole field that some folks at UC Davis are involved in that we work with from chemistry that are basically figuring out ways to modify the glycosylation in vitro. So, in other words, they produce the protein in a plant, but then they add the sugars that are needed to make it human-like and knock down the enzymes that cause the plant-specific sugars to be added.”

Meanwhile, others are creating aglycosylated proteins — proteins without sugars attached — by mutating the sites where glycosylation would normally occur, according to McDonald.

Stewart says that PlantForm and other companies have addressed this through host engineering as well.

“What we’ve done, and some other companies have done as well, is we’ve changed the way we’ve genetically engineered the host plants so that they make glycosylation that’s the same as mammalian cells,” he says.

The result, Stewart adds, is a growing regulatory comfort level with plant-made drugs, noting that plant-based therapies have been approved by the FDA and Health Canada. PlantForm is advancing a plant-produced biosimilar to pembrolizumab — Merck’s Keytruda — with the Ministry of Health in Brazil (Fiocruz) for market entry in 2028.

Still, as he notes, the role of glycosylation isn’t always to be eliminated. In some cases, it’s a competitive advantage.

Stewart points out an irony in how the field has evolved: one of the most successful plant-based biologics companies succeeded because of its unique glycosylation profile. He cites Protalix, an Israeli-based biopharmaceutical company that uses plant cell cultures rather than whole plants. One of Protalix’s lead products is an enzyme replacement therapy for Gaucher disease that takes advantage of the plant cell’s natural glycosylation patterns, which happen to produce the optimal sugar configuration for that drug.

By contrast, a separate competitor manufactures a similar treatment — Cerezyme — in mammalian cells and must perform two additional enzymatic modification steps to achieve the correct glycan structure. “The Protalix team was clever,” Stewart says, noting that their process uses the plant’s own sugar-adding machinery to generate the right molecular form directly, avoiding extra processing steps and reducing costs.

The importance of transient expression

A major reason for the renewed optimism in plant-based manufacturing is the rise of transient expression systems, which have replaced the older, slower transgenic approaches that once defined the field, according to Stewart.

Historically, researchers relied on stable transgenic plants, which required inserting genes into a plant’s genome — a process that could take years to achieve and often yielded low production rates. In contrast, transient expression introduces genetic instructions temporarily, allowing plants to produce a target protein within days or weeks rather than years.

Stewart explains that most companies now use a strain of tobacco called Nicotiana benthamiana.

“By using transient systems, you get much higher production rates,” he says. “We have one case where we’ve made the same product using a transgenics versus a transient method and we have a thousand times the production rate with the transients.”

PlantForm’s proprietary vivoXPRESS system uses this approach, “infiltrating plant leaf material with an Agrobacterium suspension containing the genetic material for a target therapeutic protein or antibody,” according to the company. The result is a six-week manufacturing processing cycle — from seed-to-high value biopharmaceuticals — that allows rapid, small-footprint production using greenhouse infrastructure rather than traditional stainless-steel bioreactors.

For McDonald, however, the next phase of innovation lies in expanding beyond this single species and format.

“We’re collaborating with a group on campus that’s working on walnut embryos to produce recombinant proteins,” she says. “It’s not just transient expression in Nicotiana benthamiana, which is sort of the workhorse, but it’s now looking at how else could you make these proteins in plant embryos? For example, there’s a lot of work in the aquatic plant duckweed, which grows fast and grows on the surface of liquid.”

Such advances suggest that plant-based biologics are entering a more mature phase — one where flexibility, not speed alone, could define the future of biologic manufacturing.