The Oxford team originally identified four different llama nanobodies as promising candidates, but they only tested one in hamsters: C5, which last year blew options out of the water. “It’s among the best in the field,” says Philip Beam, a postdoctoral researcher at the Walter and Elisa Hall Institute for Medical Research who was not involved in this study.
Oxford researchers aren’t sure why C5 works, but they have a theory. Unlike many other nanobodies, C5 binds to the “bottom” configuration of the SARS-CoV-2 protein, and is unable to infect cells, preventing them from transitioning to an infectious formation. By essentially locking the spiny proteins into this inactive state, C5 may provide an especially high degree of protection. “C5 completely killed the virus,” says Naismith. (To make the nanobodies as robust as possible, they used a “pruner”—three copies of them bonded together), he says, and he and his team have work to come showing that C5 is just as effective against the delta variant.
Last May, a team from the University of Pittsburgh showed that their llama-derived nanobody can also Preventing and treating covid in hamsters when administered through a nasal spray. Like the treated hamsters in the Oxford study, these animals lost little weight after infection and had significantly less virus in their lungs than their untreated counterparts.
For Paul Dobrix, professor of microbiology and molecular genetics at the University of Pittsburgh and one of the senior authors on that study, expanding the list of nanobodies that can treat Covid represents an important advance. “What we are really happy about is using combinations of different antibodies as a mechanism to overcome variants,” he says. Imagine a variety of nanobodies being eaten in the form of a cocktail; If a viral mutation prevents one of the nanobodies from binding, others may be able to compensate.
But despite the unusual biological similarity with us in one aspect, hamsters are far from human. They are much smaller, for one thing, and Covid is developing in them more quickly. C5 and other nanobodies still have a long way to go before they can be used to treat people – there is no guarantee that what works with hamsters will prove to work in humans. “The proof of the dessert lies in the eating,” Dobrix says. “Let’s see where you go.” We won’t know right away. The human clinical trial process is rigorous and time-consuming.
However, the successful hamster experiments represent a major step forward from the Oxford team’s work on the llama nanobody last summer. They are already tentatively excited about what nanobodies could mean in treating respiratory diseases. Because it can be given through the nose, a person who has tested positive for Covid can – in theory – take the treatment at home quickly and easily. Naismith imagines that someone 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 nebulizer has another important advantage – it goes directly into the airway. “It actually targets the site of respiratory illnesses like Covid,” Beam says. With nanobodies protecting the throat and lungs, Covid may never be able to take control of someone’s body.
While production of llama nanobodies is slow when llamas do, they can be cheaply and easily made in yeast and bacteria — and do not require sophisticated storage like human antibodies. “Nanobodies are more robust, and they can be held even at warm temperatures,” Huo says, meaning that they may be more easily distributed in low-income areas, where cooling may be an issue.
The Oxford team hopes to begin human clinical trials soon, but they also hope that by the time any treatment is approved, vaccines and other procedures will have already ended the epidemic. Even if these nanobodies were never used to treat Covid, Naismith says what they’ve learned will still be valuable. “We will pass clinical trials and have that accumulated knowledge, so that when the next thing comes — the next respiratory disease — then we know the roadmap,” he says.
During future epidemics, laboratory-generated nanobodies will likely act as a temporary measure So that vaccines can be offered. “We can’t get ahead on vaccines any faster than we’ve gone – it will always be a few months,” Naismith says. “Nanobodies could be faster than vaccines, at least at that early stage.”
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