Nanobodies

Credit: The Telegraph

Llama’s could help us fight the COVID-19 pandemic by providing antibodies that work effectively against SARS-CoV-2. The llamas produce small antibodies called nanobodies. The nanobodies are not a new discovery but they are becoming more of a realistic treatment for COVID-19.  

What is an antibody? 

An antibody is an immunoglobulin produced by the B cells (plasma cells) of the immune system. They have a specific shape that is complementary to the antigen (protein) on a virus. They will bind to the antigen to neutralise the virus or signal to the body that there is a foreign pathogen in the body that needs destroying. 

Here you can see that there are multiple antigens of different shapes. Some of them don’t fit into the antibody. The antibody has to be a specific shape to bind to a particular antigen to form an antibody-antigen complex.

An antibody is made from 4 polypeptide chains, which are made from a sequence of amino acids. The shape of the antibody is dependant on the amino acid sequence which is why antibodies are able to be different shapes. The hinge on the antibody also allows some flexibility and shape change in the antibody so it can bind more easily to a virus. The problem with antibodies is that they only protect against pathogens that have the same surface protein. If a virus mutates (which it often does), it can evade the defence system of the body. SARS-CoV-2 has mutated already and this may affect the efficacy of the current vaccines scientists have produced. Llamas may offer a solution. 

Here you can see the 4 polypeptide chains (2 heavy, 2 light). The hinge region is supported by disulphides bridges which are strong bonds between polypeptide chains. Credit: Rockland Immunochemicals

How?

Llamas and other camelid animals produce very small antibodies known as nanobodies. Due to their tiny size, they are more specific in targeting a virus.

In the influenza virus (which has a similar structure to SARS-CoV-2) the HA stalk structure is targeted by human antibodies, however, this part of the virus mutates frequently and differs among different strains. The nanobodies are smaller so can bind to the HA tips (rather than the stalk). This part of the virus is essential to the virus’s survival so does not usually change. By using nanobodies in a vaccine someone can be protected against multiple variants and even multiple viruses. The nanobodies could help to create a universal influenza vaccine. Currently, scientists create a new vaccine every year for a new strain of influenza. A universal vaccine could reduce costs, time and number of fatal cases of influenza. 

In the photo on the left you can see the structure of the influenza virus. The haemagglutinin is the HA spike on the membrane of the virus which is responsible for how the virus enters human/host cells. Credit: The Open University

The process of using llamas is quite slow so scientists are using yeast cells. The DNA sequences of the nanobodies found in llamas has been put into yeast cells to produce more nanobodies. The effects are the same but just a faster process that doesn’t require a living animal. The nanobodies target the spike protein on SARS-CoV-2. They bind to them to block them from binding to the ACE2 receptors on our host cells. This would prevent the virus from entering our cells to replicate and damage our cells.

Credit: PromoCell

Scientists need to measure how effective the nanobodies are by how tightly they bind to the spike proteins. Essentially the nanobodies need to compete with the ACE2 receptors and ensure they have a greater affinity to the spike protein.

Here you can see that affinity is determined by how tightly the antibody binds to the antigen. If the nanobody wants to ensure the ACE2 receptors on our cells don’t bind to the spike protein, they need to have a higher affinity to the spike protein.
Credit: Amgen Science

The nanobodies are being researched as a potential prevention and treatment for COVID-19. The antibodies provide passive immunity, which means they don’t provide long term immunity. The antibodies are supplied to the body rather than the body being stimulated to make the antibodies (active immunity). During active immunity, memory cells are produced which will mean the immune system will remember an invading pathogen the next time it invades. However, passive immunity means the body does not know how to make the antibodies so after they have all been “used up” they will need to be replaced by vaccination again (there will be no memory cells). The nanobodies can be given in two ways:

  • It can administered prophylactically (before infection). This would provide temporary immunity for 1-2 months. Over time the antibody concentration will decrease and will need to be replaced (regular vaccines would be needed for the most vulnerable or most exposed, such as health care workers). 
  • It can given as a treatment. This is the main benefit of the antibodies. The treatment for COVID-19 is limited and those with fatal COVID are sent to hospital to recover using ventilators, which can take 2 or more weeks. The antibodies can be given to aid the immune system in recovering from COVID. This can reduce the long term health problems from ‘long COVID’ and reduces the time spent in hospital. This form of treatment could reduce the mortality rate. Some scientists have (unofficially) named their study AeroNabs which are nanobodies in a nasal spray. The spray would be taken after testing positive for COVID-19 to reduce the viral load of a person to reduce the symptoms. 

Watch this video explaining the current research done by scientists:

If successful, these nanobodies would be cheaper and faster to mass produce than traditional antibodies.

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