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The ability to screen millions of antibodies could lead to new drug discovery.

Building off decades of previous research and technical breakthroughs, researchers have discovered a new way to rapidly screen millions of human antibodies.

Researchers from the University of Kansas have outlined a new method to screen a person’s diverse set of antibodies, making it easier to discover new antibody drug molecules, while also gaining a better understanding of how an individual’s  immune responds to vaccines and infections.

The new technology enables researchers to screen millions of human B cells to rapidly identify the antiviral antibodies that they contain. To accomplish this, researchers combined past research and advancements, including the development of protein display systems, improvements to antibody discovery and the development of technologies to identify natively paired antibody sequences in a new way to achieve large-scale antibody analysis and screening, resulting in several new and highly potent antibodies in the process.  

“Antibody molecules are encoded by B cells and are assembled from two different genes, called the heavy and light chains,” co-lead author Brandon DeKosky, an assistant professor of chemical & petroleum engineering and pharmaceutical chemistry at the University of Kansas, said in a statement. “The VH and VL portions--derived from the heavy and light chains, respectively--are the sections of an antibody gene that provide specific viral targeting.

“So, the VH and VL portions are the most important region to focus on for antibody screening and discovery.”

The advancements could also lead to better preventative measures and treatments of diseases, including Ebola, HIV, the flu and the Epstein-Barr virus.

“These technologies are providing a new window on human immune protection that we have never been able to see before,” DeKosky said. “They will dramatically accelerate antibody drug development and may also lead to more effective vaccines.”

Antibody proteins specifically target foreign viruses and bacteria and have been the fastest-growing class of approved drugs over several decades.

Previous efforts in antibody discovery often relied on single-cell cloning, which led to dozens of experimental or approved drug therapies. However, the technique is both expensive and limited to sampling only a tiny fraction of the human antibody inventory.

“Because antibodies are derived from two different genes--both of which are highly variable and contained within a single B cell--we need to perform single-cell manipulations en masse to recover the set of complete antibody genes,” DeKosky said. “Traditional single-cell cloning is very expensive and time-consuming.

“The methods described here overcome those limitations and make it possible to screen millions of antibody-producing cells in a single experiment at an academic lab,” he added.

In the past, researchers attempted to use non-natural gene pairing, which resulted in antibodies that were inadequate for an effective drug.

The next step will be to find additional antibodies that could serve as the basis for new drug therapies.

“Our major motivation was to be able to understand human antibody responses in great detail, which is critical for new therapeutic drug discovery and for vaccine design,” DeKosky said. “Promising sources to discover new antibodies include donated blood samples from HIV patients with powerful immune responses against the virus, and also individuals who have received vaccines so that we can understand how those vaccines are working.

“When a potently neutralizing antibody is discovered, it can lead to new vaccine strategies and new therapeutic drug candidates.”

The study was published in Nature Biotechnology

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