Biotechnology: CrossMAb technology

Therapeutic antibodies have improved treatments of complex diseases such as cancer, viral infections and inflammatory diseases over the past three decades, due to their unique ability to specifically home in on surface proteins.

Now, a new generation of biologically engineered antibody drugs is on the horizon. In contrast, to the first generation of therapeutic antibodies, engineered bispecific antibodies combine the binding specificity of two antibodies in only one molecule. Roche has invented the CrossMAb technology to produce bispecific antibodies.

“That would be an advantage, because bispecific antibodies are aimed to do things that monospecific antibodies are not able to do. For instance, with a bispecific antibody we could physically link a cancer cell to an immune cell which potentially may destroy the cancer, a concept being tested in cancer immunotherapy. Furthermore, with bispecific antibodies we potentially could switch on processes like cell suicide that requires binding to more than one receptor protein on the surface of a cancer cell“, explains Hubert Kettenberger from Roche Pharma Research Early Development (pRED).

Moreover, blocking two target proteins with one molecule instead of two may be more efficient; this may change the development timeline. Unsurprisingly, engineering of bispecific antibodies has become a clear industry trend in the past decade.

Kettenberger is a team member of pRED’s large molecule research unit who presented the CrossMAB technology to produce bispecific antibodies in 2011, positioning Roche at the forefront of the field. The company’s CrossMAb bispecific antibody formats are different from the about 50 more or less artificial formats of bispecific antibodies engineered over the past two decades. “We produce our CrossMAbs with the same biology used by nature and the same manufacturing process in mammalian cells established 30 years ago for monoclonal antibodies”, says Kettenberger. “Our CrossMAbs have no chemical linkers or connectors, that wouldn’t be part of a natural antibody.”

Additionally, they seem to show the same laboratory stability as monoclonal antibodies and they can be easily produced in similar quantities.

The idea to combine the halves of two different Y-shaped antibody molecules dates back to the 1980ties dubbed “quadroma technology“ back then. However, producing the desired bispecific antibody was like a molecular lottery because there are 16 different possibilities to combine each antibody’s two heavy chains with its two light chains resulting in 10 different antibodies, because normally all heavy chains can pair with each other and every light chain can bind unspecifically to two regions at the top of the heavy chains. ”We invented the CrossMAb technology to ensure correct assembly while preventing formation of unwanted side products“, says Christian Klein, one of the CrossMAb inventors at Roche pRED. According to Klein, the correct pairing of heavy chains from different antibodies was already achieved by a technology invented at Genentech back in 1997. A “knob“ and a “hole“ built into the two heavy chains of different antibodies promoted correct pairing. However, using the knob-into-hole technology was just half of the molecular puzzle the CrossMAb inventors had to solve. The problem was to find a trick to prevent unspecific binding of the light antibody chains to its heavy counterparts to prevent unwanted side products. The bio-engineers solved it like LEGO® players: by exchanging the molecular bricks between heavy and light chain, only specific interaction can take place in the short arm of the Y-shaped antibody.

“The CrossMAb format has potentially huge advantages over existing platforms“, says Jörg Regula, a researcher from Roche pRED. According to Roche pRED colleague Peter Brünker, engineered formats, like the bispecifics are getting more complex. In fact, Roche has CrossMAb antibodies under development, that even have four separate binding sites. “There has been a large shift in the industry towards engineered antibody formats“, says Klein. Roche is well-prepared to face the new challenges.

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