Accelerating the discovery of elite antibody candidates

Scientists from Hiroshima University have created so-called ‘elite’ antibodies that defeat various coronavirus variants even at an extremely low dose, through a new method that accelerated the months-long process of finding such extraordinary antibody candidates to just 10 days.

Our bodies produce specific antibodies to thwart invading pathogens. Some of these antibodies are the neutralising kind that latches onto the virus’s spike protein, preventing it from hijacking and reprogramming a cell into a virus-making factory. Elite antibodies, known as broadly neutralising antibodies, are rare immune molecules capable of keeping up with disguises used by a virus’s different variants to mask its spike protein.

“Monoclonal antibodies that neutralise the SARS-CoV-2 virus are so far the most promising therapeutic intervention,” said Professor Tomoharu Yasuda, leader of the new study.

“Mutant viruses resistant to current vaccines are a potential but realistic risk in the near future. To prepare to fight against such viruses and to save people from those infectious diseases, we need to hurry in developing effective drugs against broad SARS-CoV-2 mutant strains.”

But these life-saving molecules are laborious to locate: researchers have to screen hundreds to hundreds of millions of B cells from patient blood samples to find the most potent candidates they can enhance and grow in laboratories as therapeutic monoclonal antibodies. By clarifying the typical characteristics of patients likely to carry elite antibodies and optimising the discovery process, Prof Yasuda and colleagues have dramatically cut down the number of cells needed to be screened and sped up the identification of winning antibody candidates.

Eighteen recovered patients were enrolled as blood donors for the study from April 2020 to January 2021. The patients, aged 23–93 years old, experienced COVID-19 at different severities. Blood samples were taken over two weeks after the patients tested positive for COVID-19, based on the germinal centre reaction theory on neutralising antibodies production.

“Getting blood samples from severe COVID-19 patients over four weeks, ideally around eight weeks, after the primary infection obtains effective elite antibodies efficiently,” Prof Yasuda explained.

After analysing the patients’ samples, the researchers found that even though all carried neutralising antibodies, about 40% of those had weak or no activity to beat COVID-19. Their findings also showed that 80% of participants with severe COVID-19 made a high level of elite antibodies, while only 20–30% of those with mild cases did.

The new method successfully obtained five elite antibody candidates out of 51 cells from two donor patients. The team manufactured engineered versions of these antibodies and found that four work against more dangerous strains of SARS-CoV-2 even at a low dose.

All four antibodies quelled the Alpha and Delta variants, which are more infectious than the original strain of the novel coronavirus. Two of them also neutralised the Beta variant known to reduce the effectiveness of some vaccines.

The antibodies showed IC₅₀ potency at 3–20 ng/mL. A widely used measure of medicine effectivity, IC₅₀ determines how much drug is needed to stop a biological process from happening by half. The researchers said that antibody treatments currently progressing in clinical trials worldwide reached IC₅₀ potency at 15–95 ng/mL.

According to them, this technology is the first in Japan to obtain elite antibodies that bind to multiple threatening strains of SARS-CoV-2. Prof Yasuda noted, “Our approach could be useful to develop antibody drugs even in other future pandemics, not only SARS-CoV-2 mutants.”

The team’s novel technique and the four elite antibodies they engineered are now awaiting patent approval. Their next step is to develop a technology that accelerates at a pandemic pace the manufacture of monoclonal antibody therapies effective against future SARS-CoV-2 strains.

Image caption: A member of the Japanese research team observes virus-infected cultured cells under the microscope. Image credit: Tomoharu Yasuda/Hiroshima University.

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