Scientists have isolated a special antibody from llamas that could prevent or treat COVID-19 and be delivered via an inhaler, according to a new study.
While humans and almost all vertebrates only make large antibodies, camelids (the family that includes camels, alpacas and llamas) can also produce miniature versions. These special antibodies are smaller and simpler, yet just as effective, so parts can be turned into drugs or ‘nanobodies’ for an inhaler similar to the device used to control asthma.
Using inhalers might sound weird, but it actually makes a lot of sense because it would be faster and more convenient than intravenous injection, notably for people with a fear of blood or needles. And delivering drugs through an inhaler might be especially effective against SARS-CoV-2, the pathogen that causes COVID-19: while injecting a drug into the bloodstream helps distribute it everywhere it may be needed around the body, inhaling a nanobody will provide a more direct route to the main site of infection.
“That can be attractive, particularly for respiratory pathogens because the infection is of course in the airway,” says Dr Jason McLellan, a biochemist at the University of Texas at Austin, who suggests the drug could be used to treat someone who’s already sick. “The nanobody could get in there and prevent severe disease or decrease the number of days of hospitalization.”
McLellan co-led the new study and previously determined the structure of the spike protein that SARS-CoV-2 uses to invade human cells, which works like a lock-pick on a cell-surface ‘receptor’ called ACE2 (the ‘lock’). Antibodies often target the viral lock-pick itself, but the nanobody is like an annoying key-fob that physically blocks a virus from inserting its pick into the lock. “This nanobody is really interesting: it binds to the side and is still able to clash with ACE2 and prevent receptor binding,” says McLellan.
The nanobody, known as VHH-72, was isolated from a llama named Winter after she was given spikes from SARS-CoV-1, the coronavirus behind the 2003 SARS epidemic, which prompted her immune system to generate matching antibodies. The new study shows that the VHH-72 nanobody can also bind and neutralize (or ‘cross-react’) with SARS-CoV-2, which means it could potentially be used as a therapeutic drug for COVID-19.
A nanobody’s ability to reach normally unreachable areas, like those on a coronavirus spike protein, is thanks to the small size and simple structure of the llama antibody. Whereas a conventional antibody is Y-shaped and made from two different types of chains, heavy and light, a camelid ‘single-domain antibody’ consists of only the heavy chains. The part of the camelid antibody that binds another protein, the VHH domain (colored blue in the illustration below), is essentially what forms the nanobody.
Winter the llama’s antibody binds both SARS coronaviruses only weakly, but linking two molecules of VHH-72 together through genetic engineering formed a nanobody that’s better at neutralizing the spike and stopped artificial viruses from invading lab-grown cells. The nanobody is about 60% the size of a conventional antibody with a footprint half as large. “That’s what can be used to access smaller pockets and crevices on the surface of viral proteins that a traditional antibody can’t access because it’s too big,” says McLellan.
The next step is testing whether the nanobody works in animal models, starting with hamsters, which are also susceptible to COVID-19. That would usually be followed by experiments in monkeys (with strict ethical regulations) to see if the drug is safe and effective, but the ongoing pandemic is urgent enough that authorities may waive that requirement and skip straight to clinical trials in humans, to check for issues such as adverse side-effects and to determine the best dosage for an inhaler. If all goes well, McLellan predicts that phase 1 trials could start this summer.
One potential drawback to nanobodies is that, because the unusually tiny proteins aren’t produced by the body, they could themselves trigger defences. “Eventually, the human immune system will recognize them as foreign and make antibodies against them, which may then inhibit their function,” says McLellan, who believes it would be more of a problem if therapy lasted for years. “In this case, where you’re only going to see the nanobody for a week or two, that’s probably not going to be enough time to raise a robust immune response and completely inactivate it.”
Llama Nanobodies: Small, Simple, Stable
The simplicity of a nanobody protein is predicted to provide greater stability, which is what would allow it to be delivered by an inhaler: a nanobody drug must survive being ‘nebulized’ — turning a liquid solution into an aerosol spray.
“Nebulizing an antibody, a fairly complex molecule, in general puts considerable stress on the protein,” says Professor Xavier Saelens, a virologist at Ghent University in Belgium, whose team isolated the VHH-72 nanobody and is leading the hamster experiments. “There’s reason to believe that a more stable nanobody would more easily withstand such stresses, but it needs to be proven.”
A stable nanobody is easier to manufacture and can be stored and stockpiled, ready to be deployed if an outbreak strikes. The drug could be used as a prophylactic for those at higher risk of being infected, like healthcare workers, as nanobodies can circulate in the bloodstream for 1-2 months, offering short-term protection (people would need a booster later as the drug will slowly be broken-down by the body over time).
The nanobody could also be used as a therapeutic drug to treat those who don’t realize that they are carrying and spreading COVID-19. “There’s a period where people are asymptomatic, or fully have almost no symptoms,” says Saelens. “That gives you a window of opportunity which may be convenient for some therapy.”
There are still questions to answer about how nanobodies work. Of the 675 antibody programmes being actively developed for the clinic last year, only 11 involved nanobodies. The FDA approved ‘caplacizumab’ to treat a rare blood clotting disorder and the biotech company which makes that drug, Ablynx, also developed ‘ALX-0171’, a nanobody for Respiratory Syncytial Virus. ALX-0171 was tested as an inhaler in phase 3 trials, which suggests it was effective, but the project is currently on hold. “There’s no product on the market based on llamas or based on nanobodies that’s being inhaled, as far as I know,” says Saelens.
Nanobodies are not new but have only recently gained recognition. Saelens points out that camelid antibodies were discovered by a fellow Belgian scientist, Raymond Hamers at the Free University of Brussels, who found them by chance while studying the blood of a dromedary camel. “If that coincidental finding had been missed or overlooked, we wouldn’t have access to these special antibodies today,” he says. “Curiosity-driven science can lead to applications a long time after the discovery.”
Source : Forbes