Llamas nanobodies may provide protection against COVID-19

  • Researchers found that immune molecules from llamas can neutralize all SARS-CoV-2 strains that cause COVID-19, including Omicron.
  • They noted that these molecules are cheap, easy to produce, and modifiable.
  • Although more research is needed, the molecules show promise as a broadly protective, cost-effective and convenient treatment for future outbreaks.

Coronaviruses are one of the most pressing threats to global health due to their high genetic diversity, frequent mutations, and presence in heavily populated areas.

There is thus an urgent need to develop broad, effective, and complementary interventions for the viruses.

Nanobodies, antibodies with one polypeptide chain instead of two, are naturally produced in llamas and, due to their small size, can target viral antigens with high affinity and selectivity.

Nanobodies may thus be a cost-effective antiviral agent and could serve as a model system to study antibodies.

Recently, researchers developed an ultra-potent nanobody that could provide strong protection against every SARS-CoV-2 variant that causes COVID-19, including Omicron.

“These novel, nano antibodies overcome fundamental problems faced by large molecules such as the human antibodies, “Prof. Elizabeta Mukaetova-Ladinska, a professor of psychiatry of old age at the University of Leicester in the United Kingdom, told Medical News Today.

“[These problems include] poor penetration into tissues including solid tumors and the blood-brain barrier and poor or absent binding to regions on the surface of some molecules which are fully accessible only by molecules of smaller size,” she added.

The study was published in Cell Reports.

Immunizing ‘Wally’ the llama

For the study, the researchers immunized a llama named “Wally” with the SARS-CoV-2 receptor-binding domain (RBD) — the short spike on the virus that attaches to proteins on human cells to enter and infect them.

They then collected a blood sample from Wally and re-immunized him with four additional boosters for two months before collecting a second blood sample.

In lab tests, the second blood sample showed more affinity to SARS-CoV-2 RBD than the first. It also neutralized the Wuhan-Hu-1 strain of SARS-CoV-2 alongside the alpha and Lamba variants of concern.

Researchers also found that blood from the second sample neutralized Beta, Delta, and SARS-CoV more efficiently by 6, 2.3, and 9.3 times than the first sample.

Using proteomics, the researchers next identified 100 nanobodies with a high affinity to SARS-CoV-2.

The researchers tested 17 of these nanobodies on five SARS-CoV-2 variants, including Omnicron and 18 other SARS-related viruses, known as sarbecoviruses.

While all the nanobodies were strongly bound to all variants, seven displayed exceptionally broad activity and were bound to all target sites.

From further tests, the researchers noted that all but one of these 17 nanobodies potently inhibited SARS-CoV-2 and variants of concern in vitro.

Next, the researchers fused two of the most potent and broad-spectrum nanobodies to demonstrate their high bioengineering potential. They called the resulting molecule ‘PiN-31′ and noted its ability to simultaneously bind to two regions of SARS-like viruses’ RBD, alongside its potential to be delivered via nasal spray.

“In a preclinical study, we have shown that our nanobody- PiN-31- can protect both the lung and the upper respiratory tract from infection,” Yi Shi, PhD., Assistant Professor at the Department of Cell Biology and Physiology at the University of Pittsburgh, lead author of the study, told MNT.

“[Our data indicates] that nanobody-based inhalation therapy may minimize transmission and is likely complementary to the existing vaccine,” he explained.

Underlying mechanisms 

When asked to explain in more detail how llama nanobodies are effective against SARS-like viruses, Dr. Shi said:

“These nanobodies strongly target sites (so-called epitopes) on the receptor-binding domain (RBD) that are highly conserved among SARS-like viruses. These epitopes are important for viral fitness, so usually, they can’t mutate. That explains why pan-sarbecovirus nanobodies can protect against a large spectrum of SARS-like viruses, including SARS-CoV-2 variants and SARS-CoV-1,” he said.

“Conserved epitopes are difficult to target by nanobodies because these regions are small, flexible, and flat. However, the pan-sarbecovirus nanobodies that we have discovered seem to be highly evolved to obtain the extraordinary ability of binding,” Dr. Shi added.

The researchers concluded that nanobodies show promise as broadly protective, cost-effective and convenient treatments for future outbreaks.

When asked about the study’s limitations, Dr. Shi noted that they have not yet evaluated the nanobodies’ in-vivo efficacy. He noted that nanobodies should ideally be ‘humanized’ before clinical trials, which his team is working on via their newly-developed software — “Llamanade.”

Treatment implications 

Dr. Shi noted that nanobodies are inexpensive to manufacture compared to monoclonal antibodies as they can be rapidly produced from microbes such as E Coli and yeast cells. They can also be bioengineered to improve functionality.

He added that the nanobodies are stable at room temperature, which means they can avoid cold-chain issues associated with mRNA vaccines and be more equitably distributed worldwide.

Dr. Shi further explained that stable nanobodies can resist aerosolization, meaning they can reach the lungs by inhalation, drastically lowering the required dose and reducing therapy costs.

Dr. Mukaetova-Ladinska noted that nanobodies can also be produced more consistently than monoclonal or polyclonal antibodies as they are reproduced in lab conditions from clonal DNA. Monoclonal antibodies, by comparison, she noted, can undergo genetic drift leading to batch-to-batch variability.

She added, however, that nanobodies may also have wider treatment potential as they can cross the brain-blood barrier and directly interact with neuronal cells. They may also be used to treat conditions such as glioblastoma and Alzheimer’s disease.

Source: Read Full Article