Roughly a decade ago, biologists conducting high-stakes experiments noticed a pattern: Many findings couldn’t be replicated in other labs, throwing doubt on data that should have led to treatments for cancers, autoimmune diseases and more.
The culprit? The antibodies, or the proteins whose unique shapes allow them to recognize and bind to other proteins. While the human immune system makes antibodies to target microbes and foreign invaders, researchers for decades have found ways to exploit the natural process of antibody generation and selection to create drugs and research tools.
Not all antibodies are created equal, though. Those developed as therapies to treat diseases need to be well-validated to ensure they bind to the desired target under the right conditions — and that the antibodies’ function can be replicated.
By contrast, reagent antibodies, or those researchers use to study the mechanisms behind disease or as leads to new drugs, typically aren’t tested to the same degree. Companies that distribute reagent antibodies generally cannot always guarantee the antibodies will work in a particular experiment in any scientist’s hands.
Without reliable sources of antibodies, scientists waste time and money validating reagent antibodies on their own. The problem is compounded for researchers using polyclonal antibodies, which are mixtures of antibodies that can recognize the same protein. Unlike monoclonal antibodies, all tuned to the same epitope, researchers can’t replicate identical polyclonal antibodies from batch to batch.
“I talked to a scientist who, every six months, buys six batches of antibodies from a company — they’re all the same antibody, supposedly. But only one batch works. Then, he buys the whole lot from the company,” said Rob Meijers, director of the Antibody Platform at the Institute for Protein Innovation (IPI). “And then he has to repeat that again in six months.”
Worse, many emerging scientists aren’t trained to validate the antibodies that they purchase before using them. At the same time, companies that produce antibodies don’t provide sufficient or accurate data to enable scientists to make informed decisions.
“There are many commercially available antibodies that we don’t know a lot about, and many where the lineage is not well known,” said Joseph Bertelsen, director of IPI’s Antibody Initiative.
That’s partly because of how top antibody sellers grew over time. Companies don’t always make the antibodies they sell. Instead, their inventories have often been built by acquiring smaller companies over time.
Knowledge about antibody behavior has been lost in the acquisitions, said Bertelsen. Many antibodies are also duplicates, compounding the challenges scientists face when sifting through their options and resulting in an overwhelming number of antibody products.
This issue is at the heart of why IPI was founded. Scientists at the Institute are optimizing a pipeline to produce recombinant antibodies, which are made by cloning synthetic genes and inserting them in a host cell for production.
“We want to create a system whereby if an antibody exists in a catalog, then it does what it says it does,” said Stephen Fuchs, director of alliances and partnerships at IPI.
As a nonprofit, IPI is committed to validating its antibodies, ensuring that they bind to the correct targets under the conditions in which they were designed to work. IPI is now one of several ventures characterizing antibodies and publishing the results so scientists have access to reliable data on the antibodies they use. In June 2021, IPI joined the advisory committee of YCharOS, a new company founded to characterize all commercially available antibodies and share their findings with the public.
But, in addition to high-quality antibodies and data, life science needs a culture shift, said Fuchs.
“The real problem is there are literally millions of antibodies being sold in catalogs across the world and a 30- to 40-year history of people doing experiments with those antibodies and getting results that they think are real,” he said. “There’s a real adoption issue.”
To help tackle the challenge, scientists at IPI focus on proteins that are difficult to target, aspiring to create next-generation antibodies that can recognize unique regions of proteins, enabling high-precision studies on protein function.
Experts at the Institute will partner with researchers to design antibodies specifically for their experiments, creating a system in which IPI antibodies will be tested by the researchers using them so they can be improved over time.
“When you start to use the antibodies in that way, you can find new biology,” Fuchs said.
Writer: Halle Marchese, halle.marchese@proteininnovation.org
Sources: Rob Meijers, rob.meijers@proteininnovation.org;
Joseph Bertelsen, joe.bertelsen@proteininnovation.org;
Stephen Fuchs, stephen.fuchs@proteininnovation.org