Engineering Nanobodies Can Reduce Mortality from New Variants of COVID-19

Written by: Anusha Srinivasan '24
Edited by: Elizabeth Zhang '23

Recent research into engineering nanobodies from mammals like camels, llamas, and alpacas has revealed a possible new strategy to fight emerging variants of COVID-19. The nanobodies work by making the virus unable to bind to the receptor domain on host cells which permits its entry. Their ability to do this makes these nanobodies effective against three variants of COVID-19: Alpha, Beta, and Gamma[1].

Variants like Alpha, Beta, and Gamma arise from mutations of SARS-CoV-2. These mutations allow the virus to continue to infect vaccinated individuals. There have been some efforts to mitigate spread of variants by altering the construction of booster shots for the vaccines. However, the virus is rapidly mutating. As Assistant Professor Kai Xu of Ohio State University put it, the virus may mutate more rapidly than can be captured by the booster shots. Because of this, other methods to control the spread of mutants of the disease must be utilized[1].
The use of nanobodies to combat variants of COVID-19 has been shown to be promising. Nanobodies are antibodies from immunized camelid mammals (camels, llamas, alpacas) which mimic human antibodies. The nanobodies are produced through two mechanisms. One involves the immunization of llamas, as mentioned earlier. The other requires the use of transgenic mice which contain a camelid mammal gene. Introduction of the camelid mammal gene causes the mice to generate nanobodies which mimic those produced by camelids. The nanobodies were engineered to recognize the receptor binding domain of the virus[1,2]. 
The function of the viral receptor binding domain is pivotal in understanding how nanobodies can interfere with infection by coronaviruses. The receptor binding domain of the coronavirus binds very tightly to a receptor known as the ACE2 receptor to access cells of human lung and nasal cavities. Once it has entered these cells, the coronavirus can effectively replicate and infect neighboring cells[1]. 
Human antibodies in vaccines tend to target the location of the boundary between the ACE2 receptor and the binding domain. This interface, however, is commonly altered in different variants of SARS-CoV-2. It is for this reason that vaccines are likely to become ineffective against emerging variants[1]. 
Nanobodies are particularly effective for a few reasons. Firstly, they are relatively inexpensive to produce. They are also small and soluble, making them easy to administer by inhalation to access key parts of the respiratory tract. While they can be effective therapeutics, only one nanobody-based therapy has so far been approved by the FDA for clinical use. Nanobody-based therapy against the coronavirus is another potentially important clinical application[1,2].
There are two categories of nanobodies that can combat the coronavirus. The nanobodies derived from camelid mammals can recognize and bind to a particular region of the receptor binding domain which is slightly distant from where the ACE2 receptor binds. This region is too small for human antibodies to effectively enter and bind, so the engineered nanobody is an effective method of attaching and blocking entry of SARS-CoV-2. The other group of nanobodies functions in a slightly different way. Scientists engineer the nanobodies to form homotrimers, which are three linked copies of the nanobody. This structure is able to effectively neutralize variants of the virus[1].
In the future, isolating these nanobodies could be a promising tool to ensure the effectiveness of vaccines against more variants of SARS-CoV-2.

References
Engineering nanobodies as lifesavers when SARS-CoV-2 variants attack [Internet]. ScienceDaily. ScienceDaily; 2021 [cited 2021Oct28]. Available from: https://www.sciencedaily.com/releases/2021/06/210622095308.htm

Voss JE. Engineered single-domain antibodies tackle COVID variants [Internet]. Nature News. Nature Publishing Group; 2021 [cited 2021Oct28]. Available from: https://www.nature.com/articles/d41586-021-01721-5?proof=t

​[Image Citation] Rayne Zaayman-Gallant / EMBL. File: The Science Advisory Board. JPG. Retrieved 2021, from https://www.scienceboard.net/Proteomics/5.