The Oxford team initially 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 among the best in the field,” says Phillip Pymm, postdoctoral researcher at the Walter and Eliza Hall Institute for Medical Research who was not involved in this study.
Oxford researchers aren’t sure why C5 works so well, but they have a theory. Unlike many other nanobodies, C5 binds to the “all down” configuration of the SARS-CoV-2 spike protein, which is incapable of infecting cells and prevents it from changing to an infectious configuration. By essentially locking spike proteins in this inactive state, C5 can provide a particularly high degree of protection. “The C5 is absolutely a virus death killer,” says Naismith. (To make the nanobodies as powerful as possible, they used a “trimer” – three copies of it tied together.) And, he says, he and his team have work ahead demonstrating that C5 is just as effective. against the Delta variant.
Last May, a team from the University of Pittsburgh demonstrated that their own llama-derived nanobodies could also prevent and treat Covid in hamsters when administered by nasal spray. Like the hamsters treated in the Oxford study, these animals lost minimal weight after infection and had significantly less virus in their lungs than their untreated counterparts.
For Paul Duprex, professor of microbiology and molecular genetics at the University of Pittsburgh and one of the lead authors of this study, expanding the menu of nanobodies that could treat Covid represents an important step forward. “What really excites us is the use of combinations of different antibodies as a mechanism to overcome the variants,” he says. Imagine a variety of nanobodies administered as a cocktail; if a viral mutation prevents a 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, on the one hand, and Covid is progressing more quickly there. C5 and other nanobodies still have a long way to go before they can be used to treat humans. There is no guarantee that what works in hamsters will prove to be effective in humans. “The proof of the pudding is in the eating,” says Duprex. “Let’s see where this goes. And we won’t know it right away; the human clinical trial process is rigorous and time consuming.
Nonetheless, the successful hamster experiments represent a big step forward from the Oxford team’s work on the llama nanobody last summer. They are already tentatively excited about what nanobodies could mean for the treatment of respiratory diseases. Since they can be given intranasally, a person who tests positive for Covid could – in theory – undergo treatment at home quickly and easily. Naismith imagines that a person about to enter a high-risk environment, such as a nursing home or hospital, could protect themselves from infection by taking a preventative dose.
And the sprays have another big advantage: they go directly into the airways. “It actually targets the site of infection in respiratory diseases like Covid,” Pymm explains. With nanobodies protecting the throat and lungs, Covid might never be able to take over someone’s body.
Although the production of llamas nanobodies is slow when llamas do, they can be inexpensively and easily synthesized in yeasts and bacteria, and they do not require sophisticated storage like human antibodies do. “Nanobodies are more robust and can be stored even in hot temperatures,” says Huo, meaning they could perhaps be more easily distributed in low-income areas, where refrigeration can be an issue.
The Oxford team hope to start human clinical trials soon, but they also hope that by the time any treatment can be approved, vaccines and other measures will have already ended the pandemic. Even though these nanobodies are never used to treat Covid, Naismith says what they learned will always be valuable. “We’ll go through clinical trials and get this accumulated knowledge, so that when the next thing happens – the next respiratory disease – then we’ll know the roadmap,” he says.
In future pandemics, laboratory-generated nanobodies could potentially function as a stopgap until vaccines can be deployed. “We can’t go much faster on the vaccines than we did, they’re always going to take a few months,” says Naismith. “Nanobodies could be faster than vaccines, at least at this early stage. “
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