Pitt's inhalable 'nanobody' fights off COVID-19 in hamsters at ultralow doses

Existing monoclonal antibodies such as Regeneron’s REGEN-COV cocktail offer potent treatment options for COVID-19. But they require high doses to be effective against the disease, and the high costs and manufacturing challenges also limit their potential for broad clinical application.

Now, scientists at the University of Pittsburgh showed that very low doses of a tiny antibody known as a “nanobody,” administered directly through the nose or by inhalation, could prevent and treat severe COVID-19 in hamsters, according to a new study published in Science Advances.

The treatment, dubbed PiN-21, could offer an affordable, needle-free option for treating early infections of SARS-CoV-2—the novel coronavirus behind COVID—and it may also help high-risk patients, such as seniors, immunocompromised individuals and infants, the team suggests.

“By using an inhalation therapy that can be directly administered to the infection site—the respiratory tract and lungs—we can make treatments more efficient,” study co-senior author Yi Shi, Ph.D., said in a statement.

Shi’s team is currently modifying the nanobodies to work in humans and has generated some positive preliminary data, he told Fierce Biotech Research via email. “We are also working on evaluating the resistance of our nanobodies to the emerging variants of concern and are collecting more preclinical data in a non-human primate model of SARS-CoV-2 infection,” he said.

Nanobodies, originally identified in llamas and other camelids, are only fragments of conventional whole monoclonal antibodies. Shi and colleagues had previously identified over 8,000 nanobodies against the coronavirus. They picked the most potent candidate in lab dishes and engineered it further to better interact with the coronavirus to create PiN-21.

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In the current study, the team tested the drug in Syrian hamsters, a proven animal model for studying COVID-19 therapies.

Hamsters were given a 0.6 mg/kg dose of PiN-21 into the nasal cavities immediately after they were infected with SARS-CoV-2 via the trachea. By contrast, FDA-authorized REGEN-COV is given to humans at a strength of 2,400 mg to treat the disease.

While animals that got a placebo lost up to 16% of body weight after a week of infection, those that got the nanobody treatment didn’t experience any significant weight loss, the team reported. Besides, PiN-21 essentially cleared virus in the lungs after 10 days.

Similar results were observed when hamsters were infected with the virus intranasally and given the drug hours after the infection. The finding suggests the drug could work as a treatment when used early regardless of the original routes of infection.

Nanobodies’ tiny size raised the possibility that they could be efficiently delivered to the lung by aerosolization. The researchers aerosolized the nanobodies using a nebulizer and tested that theory in hamsters.

At an ultralow dose of about 0.2 mg/kg, aerosolized PiN-21 nanobodies reversed weight loss in animals infected with the coronavirus. The control rodents on average lost 5% of body weight after three days after infection, whereas the nanobody-treated animals gained 2%.

PiN-21 also reduced the number of infectious virus particles in the lung tissue by six orders of magnitude, or a million-fold. The scientists also observed a substantial reduction of viral levels in nasal washes and throat swabs, suggesting the treatment may limit human-to-human transmission of the coronavirus, they said in the study.

Animals who received aerosolized PiN-21 nanobodies had milder changes in the lung structure and a lower degree of inflammation than those who received the placebo, the team reported.

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Nanobodies' unique structure and multiple advantages over monoclonal antibodies have attracted the interest of several research groups in their studies against the novel coronavirus. Twist Bioscience previously reported that two of its nanobodies also protected hamsters against COVID.

A collaboration between the University of Bonn, the Karolinska Institutet and Scripps Research Institute recently fused two nanobodies to create new nanobodies that can attack multiple sites of the coronavirus. And a team at the University of California, San Fransisco previously also reported promising early results for an aerosolized form of a nanobody.

Shi and colleagues suggest nanobodies could offer a low-cost alternative to currently available COVID antibody drugs. And its aerosolization delivery may offer the additional benefit of rapid onset of action and improved patient compliance.

“We envision that PiN-21 aerosolization treatment could provide both a convenient and cost-effective solution to alleviate disease onset and reduce virus transmission, especially for mild COVID-19 patients who constitute major populations of infections,” the researchers wrote in the study.