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Saturday, March 2, 2024

The Llama, the Hamster, and a New Path for Covid Treatment

For decades, mice, monkeys, and roundworms have been the workhorses of science—“model organisms,” in academic parlance—and for good reason. After generations of research, scientists have a solid grasp on their genetics, physiology, and behavior, which makes it possible to study them in unparalleled detail. But some projects require something a bit more unique. To design a new potential Covid treatment, researchers at the Rosalind Franklin Institute at Oxford University took advantage of the biological quirks of an unlikely animal pair: the llama and the Syrian hamster.

Though llamas aren’t exactly common tools for scientific research, their utility is well established: Like humans and other animals, they produce molecules called antibodies to recognize invaders and defeat infections, but their antibodies are unusually small. These “nanobodies” are far easier to manufacture in the lab than human antibodies, which makes them particularly useful for research and, potentially, clinical applications. “It seems to me that anything a human antibody can do, a nanobody could, in theory, do the same thing as well,” says Jiandong Huo, a postdoctoral researcher at Oxford who led this study.

Last year, Huo and his colleagues published a paper showing that they had generated nanobodies that could neutralize SARS-CoV-2, the virus that causes Covid-19. These lab-made nanobodies blocked the virus from infecting cells in the test tube, but the team knew that the llama’s immune system would do even better.

So they embarked on the far more time-consuming task of injecting a llama with the SARS-CoV-2 spike protein and waiting for it to generate its own novel nanobodies against the invader. Their patience was rewarded: These new nanobodies did a much better job of blocking the spike protein from attaching to the ACE2 receptor, the protein through which the virus accesses the cell. “They’re about 1,000 times more potent,” says James Naismith, professor of structural biology at Oxford University and a senior author on both studies.

Studying these nanobodies in the test tube wasn’t enough to prove that they could successfully fight Covid, so Naismith and his colleagues moved from llamas to another animal with some convenient biology. Syrian, or golden, hamsters, which weigh about five times as much as the dwarf hamsters typically kept as pets, have also been used as research animals for a long time, but they are astonishingly well suited to the current moment—unlike most other small animals, they are susceptible to SARS-CoV-2. Through some strange biological happenstance, the hamster ACE2 receptor looks a lot like the human receptor. So when Huo and his colleagues obtained promising nanobodies from the llama, they were able to infect hamsters with the virus and see whether the nanobodies successfully fought it off.

The results, published last Wednesday in the journal Nature Communications, showed that hamsters who received a dose of one of those nanobodies 24 hours after being infected with SARS-CoV-2 returned to their pre-Covid weights just a few days later, a sign that they were beating the virus. Untreated control animals continued to lose weight. The treated hamsters also showed significantly less evidence of lung infection. And because nanobodies are so small and so stable, the researchers didn’t even have to inject the treatment, as is necessary for a human-derived antibody—the nanobodies were sprayed directly into the hamsters’ nostrils.

The 24-hour delay between infection and nasal spray has important implications for the potential use of this nanobody as a Covid treatment, says Ray Owens, professor of molecular biology at Oxford and the studies’ other senior author. Once SARS-CoV-2 has entered the animal’s cells and started producing more copies of itself, the nanobodies have a much harder job to do in treating the disease. “The fact that you can dampen that down and take it out of the system … it gives you a strong indication of the potential for these sorts of agents as therapeutics,” says Owens.

The Oxford team originally identified four different llama nanobodies as promising candidates, but they only tested one in hamsters: C5, which blew last year’s options out of the water. “It’s amongst the best in the field,” says Phillip Pymm, a postdoctoral researcher at the Walter and Eliza Hall Institute of Medical Research who was not involved in this study.

The Oxford researchers aren’t certain why C5 works so well, but they do have a theory. Unlike many other nanobodies, C5 binds to the “all down” configuration of the SARS-CoV-2 spike protein, which is unable to infect cells, and keeps it from moving into an infectious configuration. By essentially locking spike proteins into this inactive state, C5 may provide a particularly high degree of protection. “The C5’s absolutely a stone-dead killer of the virus,” Naismith says. (To make the nanobodies as potent as possible, they used a “trimer”—three copies of it bound together.) And, he says, he and his team have forthcoming work demonstrating that C5 is just as effective against the Delta variant.

Back in May, a team from the University of Pittsburgh demonstrated that their own llama-derived nanobody could also prevent and treat Covid in hamsters when administered through a nasal spray. Like the treated hamsters in the Oxford study, these animals lost minimal weight after infection and had much less virus in their lungs than their untreated counterparts.

For Paul Duprex, a professor of microbiology and molecular genetics at the University of Pittsburgh and one of the senior authors on that study, expanding the menu of nanobodies that could treat Covid represents an important advance. “What we’re really excited about is the use of combinations of different antibodies as a mechanism of overcoming variants,” he says. Imagine a variety of nanobodies administered as a cocktail; if a viral mutation prevents one nanobody from binding, others might be able to compensate.

But despite their unusual biological resemblance to us in one aspect, hamsters are far from human. They are much smaller, for one thing, and Covid progresses in them more quickly. C5 and the other nanobodies still have a long way to go before they can be used to treat people—there’s no guarantee that what works in hamsters will prove successful in humans. “The proof of the pudding is in the eating,” Duprex says. “Let’s see where it goes.” And we won’t know immediately; the human clinical trial process is rigorous and takes time.

Nevertheless, the successful hamster experiments represent a major step forward from the Oxford team’s llama nanobody work last summer. They are already tentatively excited about what nanobodies could mean for the treatment of respiratory illnesses. Since they can be administered intranasally, a person who tests positive for Covid could—in theory—quickly and easily take a treatment at home. Naismith imagines that someone about to enter a high-risk environment, like a nursing home or hospital, could protect themselves from infection by taking a preventative dose.

And sprays have another important advantage—they go directly into the airway. “It actually targets the site of infection in respiratory diseases like Covid,” Pymm says. With nanobodies protecting the throat and lungs, Covid might never be able to gain a hold in someone’s body.

While producing llama nanobodies is slow when the llamas do it, they can be synthesized cheaply and easily in yeast and bacteria—and they don’t require sophisticated storage like human antibodies do. “Nanobodies are more robust, and they can be kept even at warm temperatures,” Huo says, which means that they could perhaps be more easily distributed to low-income regions, where refrigeration may be an issue.

The Oxford team hopes to start moving through human clinical trials soon, but they also hope that, by the time any treatment might be approved, vaccines and other measures will have already ended the pandemic. Even if these nanobodies are never used to treat Covid, Naismith says that what they’ve learned will still be valuable. “We’ll get through the clinical trials and get that accumulated knowledge, so that when the next thing comes—the next respiratory disease—then we know the road map,” he says.

During future pandemics, lab-generated nanobodies could potentially work as a stopgap measure until vaccines can be rolled out. “We can’t go much faster on vaccines than we went—they’re always going to be a few months,” Naismith says. “Nanobodies could be faster than vaccines, at least in that early stage.”

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