In a study challenging a long-held doctrine of antibody binding -- which states that a single antibody corresponds to just one antigen, fitting it like a lock fits a key -- researchers have created a designer version of an antibody that can bind two completely different targets.

Two-in-one antibodies Image: Allison Bruce & Jenny Bostrom

The findings, reported in this week's Science, raise the possibility that antibodies with dual specificity could occur naturally, the authors say.

The results are "tremendously exciting," said Jefferson Foote, a geneticist who engineers antibodies at Arrowsmith Technologies in Seattle, Wash., and who was not involved in the study.

Biochemist Germaine Fuh of Genentech, and her colleagues set out to design multi-binding antibodies, just to see if it would be possible. They started by creating a library of mutants of Herceptin, Genentech's monoclonal antibody treatment for breast cancer, which turns off the receptor protein Human Epidermal Growth Factor Receptor 2 (HER2).

To maintain the mutant molecules' binding ability, the researchers selectively tweaked a portion of the protein called the light chain, which past studies showed could be modified without disrupting antibody function. They then tested the mutated Herceptin molecules against an array of different antigens. One of the designer molecules could bind to either HER2 or vascular endothelial growth factor (VEGF), a protein critical to angiogenesis and implicated in cancer.

"It's very novel," Carlos Barbas, a molecular biologist at the Scripps Research Institute in La Jolla, Calif, who was not involved in the study, said of the findings.

Past work showed that some antibodies can bind two different haptens, or small molecule antigen fragments, said Foote. However, the amount of surface area involved in binding is much smaller on haptens. Since haptens are small, only a tiny portion has to match up, "but for a large protein antigen, you're talking about the whole surface of the key being able to kind of adapt itself to two very different locks" Fuh said.

Other work, too, had shown that very similar, or homologous, antigens could also bind to the same antibody. Many researchers, however, argued that those cases were anomalies that didn't represent how most antibodies work, Foote said. The current study shows dual specificity in canonical antibodies that are also important therapeutic targets. "They didn't just find it in some academic model that was very strange, they found this kind of cross-reactivity with the two most important drugs in the 21st century," Foote said.

The new development--essentially "two antibodies wrapped in one"--could boost the therapeutic effects of anti-cancer monoclonal antibody treatments, Barbas said. For instance, the breast cancer drug Herceptin targets HER2, while the colon cancer drug Avastin blocks VEGF. Combining two functions in one antibody could lead to a cheaper, more effective medicine. One limitation, though, is that the existing antibodies still have one binding site, preventing both antigens from binding at the same time.


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