select search filters
briefings
roundups & rapid reactions
Fiona fox's blog
A study, published in Nature Structural & Molecular Biology, looked llama-derived neutralising nanobodies to SARS-CoV-2 in cell culture.
Prof Herb Sewell FMedSci, Emeritus Professor of Immunology University of Nottingham, said:
“This manuscript represents excellent, high quality science and innovation that has the potential for ready clinical testing/utility.
“The scientists describe elegant and well controlled studies that allow the selection in the laboratory of novel small fragments of antigen binding antibody domains (termed VHH-derived from libraries Llama antibody repertoires these small antigen binding domains are termed nanobodies. Llamas have antibodies that have single “heavy chains” which contrast with human antibodies which have heavy + light chains. Both have heavy chain regions which bind very specifically to antigens; those regions are termed VH(human) or VHH(Llama). Llama VHH are readily accessible and able to be manipulated in the laboratory.
“These nanobodies randomly displayed in phage antibody libraries are selected for their specific binding at high affinity to the target antigen. In this case, the antigen used for selection is the receptor binding domain (RBD) of the SARS-CoV-2, the virus responsible for the ongoing Covid-19 pandemic.
“With this specificity for RBD, the nanobodies were shown to efficiently neutralize (i.e. prevent) the virus binding to its target human ACE2 receptor complexes on cells, which is a requirement for successful infections of humans.
“Two nanobodies showed strong neutralizing anti SARS-CoV-2 activity. To enhance the clinical utility of the nanobodies the researchers genetically engineered them by producing a so-called fusion protein. They linked the Fc region from human antibodies (the non-antigen binding fragment) that allows an increased half-life of the nanobodies and greater functionality when the nanobody-Fc fusion protein is injected into the human body-giving it a greater opportunity to survive and effectively neutralise the virus.
“There is clinical precedent for using such Llama –nanobody-fusion protein (antibody construct) to treat human disease. Caplacizumab is a licensed treatment for human Acquired Thrombotic Thrombocytopenic Purpura.
“These nanobodies which can neutralise SARS-CoV-2 are a very welcome development with the potential for early clinical studies. Should they be shown to work clinically, they could be used for passive immunity treatment of Covid-19 patients or for containment (prevention of infection e.g. in front line staff likely to be exposed to the virus-before there is a vaccine available).
“The authors suggest treatment in late/severe Covid patients. In our view, this is a minor weakness in the paper. Evidence suggests that severe Covid disease occurs when there is marked immune-dys-regulation in vivo. Dys-regulation is initially triggered by the immune-inflammatory response to the virus but the excessive inflammatory response(cytokine storm syndrome-non virus associated) becomes uncontrolled and damaging in late/severe disease.
“If effective, nanobody treatment should be used as soon as possible in the infection/disease pathway, and the follow up studies off the back of this work should take this into account.
“Hopefully, clinical studies are soon in the pipe-line!”
Prof Gary Stephens, Professor of Pharmacology, University of Reading, said:
“The search is on for effective treatments to combat the unprecedented COVID-19 pandemic. Given the lengthy development process for vaccines, one major immediate priority is the development of selective antibodies that can neutralise the SARS-CoV-2 virus responsible for COVID-19. A particularly exciting new advance is the recent development of “nanobody” technology. Nanobodies are smaller, more stable types of antibody taken from the immune systems of camelid species – such as llamas, alpacas and camels. Due to their smaller size, they are more able to target relevant proteins and stop the virus from attaching to a host and spreading.
“This current high-quality work in Nature Structural & Molecular Biology uses a naive llama single-domain antibody library to generate nanobodies which can neutralise the SARS-CoV-2 virus very effectively in the test tube. The nanobody can also augment the neutralizing activity of a larger conventional antibody. A complementary next step is to generate natural antibodies in llamas themselves. At the University of Reading, we are currently working with the Rosalind Franklin Institute, Oxford to generate llama nanobodies that bind to proteins in the SARS-CoV-2 virus including the “spike” glycoprotein that enables the virus to enter human cells. These nanobodies may provide additional capacity to bind SARS-CoV-2 proteins at different sites and neutralise the virus even more effectively.
“An important proof of concept is that the first nanobody drug, caplacizumab which binds to a protein present in human blood and prevents a rare blood clotting disease, was approved for use in 2019. The next step in fighting disease is in passive immunization of COVID-19 patients with such nanobodies and to perform related safety and efficacy tests in animals and humans.”
‘Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2’ by Jiangdong Huo et al. was published in Nature Structural & Molecular Biology on Monday 13 July
https://doi.org/10.1038/s41594-020-0469-6
All our previous output on this subject can be seen at this weblink:
www.sciencemediacentre.org/tag/covid-19
Declared interests
Prof Herb Sewell: No declarations of interest
Prof Gary Stephens: Here at University of Reading we are working with Rosalind Franklin Institute (most directly with Ray Owens, one of the Corresponding Authors on Nature Structural & Molecular Biology) on complementary work with natural llama antibodies. Ray is currently working on generating nanobodies from one of our llamas which was immunized with the SARS-CoV-2 spike protein. So, a declaration of interest in highly related RFI future work, but not this current paper.