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AD IMAB (AL L)
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for Merck’s push into the biosimilars arena (C&EN, Jan. 12, page 28). The question now is whether lightning can strike twice for the Dartmouth profesAdimab believes its yeast-based ANTIBODY DISCOVERY SYSTEM sor. If Adimab’s technology works, it could significantly abbreviate the time-consumcould change how biotherapeutics are found ing process of developing a therapeutic anLISA M. JARVIS, C&EN NORTHEAST NEWS BUREAU tibody. More important, it could take much of the guesswork out of antibody discovery by enabling researchers to pick the best anWEARING STYLISH GLASSES and a tibodies out, in a few weeks—there is no tibody for a target early on in development. jacket without a tie, Dartmouth College entechnology that can do that.” Adimab has attracted funding from several gineering professor Tillman U. Gerngross Gerngross’ name might sound familiar: prominent life sciences venture-capital looks the part of an Ivy League academic. He was one of the masterminds behind firms. More recently, two big drug compaBut after talking to him for a few minutes GlycoFi, the biotech firm that managed nies became sufficiently convinced of the about Adimab, the company he recently to coax yeast into adding technology’s value to test-drive it. formed with Massachusetts Institute of complex sugars to a proInvestors often worry that compaTechnology chemical engineering profestein. Merck & Co. snapped LIGHTING THE WAY nies spun out of academia are based Adimab’s yeast cells on too tenuous a link between an insor K. Dane Wittrup, it becomes clear that up the company in 2006 are decorated with he would be just as at home in a boardroom for a cool $400 million, teresting idea and commercial reality, antibodies, as in a lecture hall. The two professors have and GlycoFi’s yeast manu- human but Adimab was started to fill a gap in then exposed developed a yeast-based antibody discovfacturing platform subsethe market. to fluorescently tagged antigens. ery and optimization platform that, if it quently became the basis After Merck bought GlycoFi, Gernworks as easily as Gerngross suggests, gross gained an insider’s perspective could represent an important new on the importance of unencumbered technology for the biopharmaceutical access to antibody discovery techindustry. nology. Big pharma companies were In a nutshell, Adimab has managed striving to create biopharmaceutical to create a fully synthetic human imbusinesses but found that they “remune system in yeast. With roughly ally had no good options” among 10 billion yeast cells, each popuantibody technology providers, Gernlated by a unique human antibody, gross says. the company’s discovery platform boasts a diversity that rivals existing IF A DRUG COMPANY wanted to fragment-based antibody discovery develop an antibody, its choices at systems but with the advantages of the time were to use in vivo technolwhole antibodies. ogy, offered by companies such as Add a fluorescently tagged antigen Medarex and Abgenix, or phage-disto Adimab’s yeast-antibody library, play technology, used by firms such and yeast cells that make an antibody as Cambridge Antibody Technology. that binds to the antigen light up. The in vivo method involves injecting Then the library is run through a cell an antigen into a genetically engisorter that weeds out the nonbinding neered mouse, which then produces cells and identifies which antibodies an antibody. With phage-display express well and bind to the antigen technology, genetic engineering is most tightly. Next, the whole process used to create a library of antibody is reversed by subjecting the hits to fragments displayed on the surface a growth medium that causes the of Escherichia coli; researchers then yeast to secrete the antibodies, which introduce an antigen to the library are then collected and purified. The and extract the members it latches result is a collection of potential drug onto. These fragments have to be candidates, each one a human immuengineered into full antibodies before noglobulin G (IgG) antibody like the they become drug candidates. ones created by human B cells. In both cases, it can take six “We have come up with a way months to more than a year before an where you walk in the door with an antibody is delivered to a customer. antigen and, a few weeks later, you But Gerngross sees more significant walk away with fully human antibodscientific and commercial limitations. ies against your target,” Gerngross The biggest issue, he says, is that the says. “Antigen in, hundreds of antechnology companies are limited in WWW.CEN-ONLINE.ORG
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what they can offer new customers. They made broad deals with drug companies to develop antibodies, shutting other firms out from large areas of research. “The gatekeeping process prevented you from working on a particular target,” Gerngross says. Furthermore, the few companies with viable antibody discovery technology have been swallowed up by their partners. In 2006, Amgen paid $2.2 billion for Abgenix, and AstraZeneca laid out $1.6 billion for the 80% of Cambridge Antibody Technology it did not already own. There are also scientific issues associated with older antibody discovery technologies. Although Abgenix refined in vivo technology to enable a mouse to produce a fully human antibody, the diversity of the antibodies a mouse can make is limited, notes Carolyn Bertozzi, a chemistry professor at University of California, Berkeley, who studies cell-surface interactions. Meanwhile, the success of phage-display technology rests on the notion that the antibody fragments (Fabs) displayed on E. coli will function in the same way as the entire antibody. But, Bertozzi points out, “there’s actually a pretty huge canyon between identifying that little Fab region and actually having a functional antibody that’s fully humanized and therefore tolerated by the human body.” GERNGROSS AND his partners spent about a year figuring out
how to navigate the crowded intellectual property around antibodies and another year honing their discovery platform and business strategy. They are convinced that Adimab’s approach offers significant scientific and commercial advantages over older technologies. For example, under traditional methods, a company’s researchers might know they have found an antibody fragment that binds to an antigen, but they won’t know what response is elicited from that action once that fragment is formatted back into a full antibody. According to Gerngross, it has become clear that hitting the right spot, or epitope, on a given antigen matters. “You can hit a receptor and shut it down, or you could hyperactivate it. The therapeutic outcome of an antibody binding an antigen can be drastically different,” he says. When Adimab tested out its technology on commercially relevant antigens, it discovered hundreds of fully human antibodies with binding affinity for each one. In theory, having an entire suite of antibodies lets a company choose the best drug at the outset and box out the competition. “We feel we can so exhaustively scan an antigen that, if there’s a new target, you can find all the possibilities,” Gerngross says. “By virtue of protecting all those solutions, you almost virtually protect the target.” Researchers at Merck and Roche seem to think the approach can work. Although Adimab has barely launched its technology, both companies have already signed on to screen antigens using its yeast library. Adimab gets undisclosed milestone payments and royalties if any of the resulting antibodies are developed. Bertozzi agrees that the ability to quickly produce a human antibody is enticing to drug company scientists. “Nothing beats the IgG,” she says. A human IgG can circulate in the body for weeks— an asset because all antibody drugs are currently injected, and the less frequent the dosing the better. But until the technology is proven—until there’s more clarity on how the technology was developed, a deal with significant dollars attached, or a drug in the clinic—some may regard Adimab’s offering as too good to be true. “People said the same thing about GlycoFi,” Bertozzi notes. “There was so much skepticism behind that whole approach—nobody thought it would work.” ■
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