Single-domain antibodies, or “nanobodies,” inspired by llamas, have been proposed as potential treatments for COVID-19. Now, one company’s candidates have shown early promise in animal models.
Two nanobodies developed by Twist Bioscience, dubbed TB202-3 and TB202-63, protected hamsters from weight loss—a key indicator of disease severity—after they were infected with SARS-CoV-2, the virus that causes COVID-19, the California biotech said.
The protection against weight loss was comparable to that produced by plasma from COVID-19 survivors in previous preclinical studies, offering hope that the tiny antibodies could enable new approaches to treatment, prevention and diagnosis of COVID-19, Twist’s CEO Emily Leproust, Ph.D., said in a statement.
With the positive hamster data, Twist Bioscience, a division of Twist Biopharma, is “considering various options, including licensing out the assets for further development,” a company spokesperson said in an email to Fierce BiotechResearch.
Conventional antibodies consist of two immunoglobulin heavy chains and two light chains, with variable heavy and light domains that together give the antibodies their ability to target specific pathogens. By contrast, a nanobody only needs a single variable domain to recognize its target. Nanobodies occur naturally in llamas and other camelids.
Twist chose TB202-63 and TB202-3 from large synthetic antibody libraries, each containing more than 10 billion single-domain antibody sequences. In lab dishes, the two nanobodies neutralized SARS-CoV-2 by binding to the virus’s spike protein receptor-binding domain, which is also the main target of the many other COVID-19 vaccines and monoclonal antibodies in development. During an infection, the spike protein binds to the ACE2 receptors on human cells to gain entry.
In the preclinical studies, investigators at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) injected immunodeficient animals with the Twist nanobodies. At all three dosing levels—1 mg/kg, 5mg/kg and 10 mg/kg—the two nanobodies each protected treated rodents against weight loss. By contrast, animals that were infected with the coronavirus and not treated lost an average 11.7% of body weight.
Because nanobodies are small, they can squeeze into small spaces and bind to antigen areas that would otherwise be inaccessible to human antibodies. Their size also allows for easier manufacturing scale-up.
“[N]anobodies, with their very small size, may offer an advantage over traditional antibodies. For example, they could be delivered intranasally to prevent infection or reduce transmission; or they could be part of a more conventional therapeutic treatment regimen,” Jay Hooper, Ph.D., head of molecular virology at USAMRIID, said in a statement.
Single-domain antibodies are being explored against various diseases, including infectious diseases and cancer. A team led by Scripps Research Institute previously isolated broadly neutralizing single-domain antibodies from llamas that, when linked together into a multidomain antibody, protected mice against almost all influenza A and B viruses.
When the COVID-19 pandemic started, scientists from the University of Texas at Austin, the National Institutes of Health and Ghent University in Belgium quickly pivoted their previous research focused on two related coronaviruses, SARS-CoV-1 and MERS-CoV. They isolated a single-domain antibody from a llama immunized with the coronaviruses’ spike protein. By fusing it to a part of a human antibody, the candidate effectively neutralized SARS-CoV-2 in cell cultures.
Twist believes that its candidates hold potential as “a preventive daily nasal spray that would block aerosolized particles of the SARS-CoV-2 virus from entering the nasal passage and therefore the body,” Leproust said in the statement.
Twist also showed that a traditional antibody called TB181-36, which was discovered in collaboration with Vanderbilt University Medical Center, was also able to protect hamsters against weight loss at 5 mg/kg and 10 mg/kg doses. The company said it intends to move all three candidates forward for further testing either internally or with partners.