This is the second of two posts on the potential use of antibodies in the treatment of COVID-19. See also “Anti-COVID Antibodies I: Basic Principles”.
The current COVID-19 pandemic has prompted an unprecedented global search for treatments and vaccines. As stated in my previous post, antibodies have attractions as potential antiviral treatments, and trials are already underway using convalescent plasma from patients who have recovered from infection with SARS-CoV-2. I have already mentioned the limitations of this approach, however, and the advantages of using highly specific monoclonal antibodies instead.
The Possible Use of Monoclonal Antibodies for COVID-19
In a paper published in Nature in July researchers from Columbia University in New York reported that they had identified a potent cocktail of monoclonal antibodies that could be effective in treating COVID-19. The scientists screened antibodies from 40 COVID-19 patients. They selected five patients for isolation of monoclonal antibodies because their plasma virus-neutralizing levels were among the highest. From these patients they isolated 61 SARS-CoV-2-neutralising monoclonal antibodies, 19 of which were particularly potent, 9 “exquisitely” so.
Tests on cells showed that the antibodies killed off the virus. The Columbia team also tested the potency in vivo of one of the antibodies (mAb 2-15) in a golden Syrian hamster model of SARS-CoV-2 infection. This showed complete elimination of the virus at a relatively modest antibody dose.
Prof David Ho, who led the research team, stated “We specifically isolated very potent antibodies that can be mass produced and then administered.” and “We would assume that these could be used to prevent or treat Sars-Cov-2. We’d be looking to treat early in the course of infection, particularly those at risk of developing severe disease such as the elderly and those with underlying illness.”
He added: “In terms of prevention, these could certainly substitute for vaccines, and again we’d be looking at the most vulnerable, for example, nursing home residents.”
Further work in animal models is required, but the team hope to produced enough of the antibodies to start a phase 1 safety trial in humans later in the year. Drug company laboratories already mass produce antibodies, purifying them from cells that are grown in large fermenters. Ho has estimated that a dose of antibodies might cost $50 (£39) to produce, which seems a remarkably modest sum. Apparently, the antibodies can be modified so that they persist in the bloodstream for 3-6 months.
Another team of scientists at the University of Toronto is also planning clinical trials of monoclonal antibodies against SARS-CoV-2 starting later this year.
Where Do The Llamas Come In, And What Are Nanobodies?
Mammalian, including human, antibodies generally have two chains (heavy and light), but camelids (camels, dromedaries, llamas and alpacas), in addition to two-chain antibodies, also possess a single-heavy-chain antibody variant. The antigen-specific variable portion of this single-chain antibody is termed the VHH domain, and it is commonly referred to as a nanobody, or a single domain antibody. Nanobodies are small (as the name suggests), stable and straightforward to produce. As a result, they serve as an alternative to conventional antibodies in various diagnostic and therapeutic roles. The use of nanobodies in cancer treatment and inflammatory diseases is being evaluated. They have been developed against SARS-CoV-1, and more recently against SARS-CoV-2.
A team from the Rosalind Franklin Institute, Oxford University, Diamond Light Source and Public Health England has produced nanobodies that bind tightly to the SARS-CoV-2 spike protein, preventing the virus entering human cells, and stopping infection. The nanobodies bind to the spike protein in a different way to the conventional monoclonal antibodies that have been developed against the virus. The team were able to combine one of the nanobodies with a human antibody, and they showed that the combination was even more powerful than either agent alone.
Electron microscopy showed that the three nanobodies bind to the virus spike, essentially blocking the areas of the spike that the virus uses to enter human cells. The researchers are now screening antibodies from a llama called Fifi, who was immunised with purified viral proteins. The idea is to come up with a cocktail of potent anti-viral nanobodies.
Another team at the McLellan Lab in Austin Texas are also researching the possible use of llama nanobodies against SARS-CoV-2.
More on Nanobodies
This short YouTube video explains in more detail what nanobodies are, what their advantages are, and how they are likely to find multiple applications in diagnostics and therapeutics: