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Double-duty antibodies

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 antibodiesImage: Allison Bruce & Jenny BostromThe findings, reported in this week's Science, raise the possibility that antibodies with dual specificity could occur naturally, the authors say. The result

By | March 19, 2009

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.
**__Related stories:__***Reinventing the antibody
[April 2008]*linkurl:Antibodies Go recombinant;http://www.the-scientist.com/article/display/53131/
[May 2007]*linkurl:Another kind of antigen;http://www.the-scientist.com/article/display/15621/
[18th July 2005]
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Comments

Avatar of: Zhaohua Lu

Zhaohua Lu

Posts: 1

March 20, 2009

I am wondering how this dual-antibodies were made. From the imagine, the two binding sites of an antibody binds to two different antigens.One may bind to HER2, another may bind to VEGF. From the text, it was done by "tweaked" light chain. Unless the "tweak" is selective for one light chain, otherwise, how come another binding site wont be affected?\nAnother question remaining in my mind is the therapeutics. Is there any synergistic or combining effect of this dual antibody could be proposed to treat cancers?\n
Avatar of: anonymous poster

anonymous poster

Posts: 85

March 20, 2009

I find this result (one antibody, two antigens) hardly surprising. The comment quoted in the article about antibodies being known to sometimes bind two completely different haptens, but that proteins are a different story, is just plain dumb -- antibodies don't bind whole proteins, they bind specific (haptenic!) antigenic sites that represent rather small parts of the 3-D structure of the whole protein. What I would like to know is if the same binding site on the Ab is involved in binding to both of the protein antigens (suggesting some shared structural motif or feature in the two proteins, not at all unlikely), or if separate regions in the binding site of the Ab are involved (probably a less likely scenario, but certainly not impossible).\n\nSo, an interesting result, but not at all unexpected or surprising.

March 23, 2009

Engineered antibodies binding two different antigens, one "arm" each, wow, there was a Canadian company offering this, hmmm...15 years ago or so, if I remember well.\nI don't see anything new in this "double-duty" that justifies a half-line of interest!\nOr did I miss something?
Avatar of: Chandrika B-rao

Chandrika B-rao

Posts: 2

April 21, 2009

Way back in the early 1990s, we talked of [Jerne's] immune networks, multifunctional antibodies, those that work like "glues", binding to almost every antigen, and those that are essentially "stand-alones", binding to just one or a few antigens. So much of wet-lab work done at Institut Pasteur & elsewhere with real antibodies and antigens ... Ideas of "shape space", "mirror shape space", "affinity space" fuelled discussions on multifunctional antibodies and how to place them in such spaces... This is not to detract from the original work reported here, but just to point out that it only provides new proof of what immunologists (theoretical and wet-lab) have known for a long time.
Avatar of: SHANNON BEATTY

SHANNON BEATTY

Posts: 2

April 21, 2009

The illustration that accompanies this article depicts two molecular scenarios: one, of a "monospecific" IgG molecule with both antigen-binding sites occupied by apparently identical antigen moieties (either small and green or large and purple) and two, of a "bispecific" IgG molecule with its pair of antigen-binding sites occupied by two apparently different antigen moieties (one small and green, the other large and purple). A description of the precise nature(s) of the epitope(s) bound on the green moiety and on the purple moiety is not contained in the text, making a distinction between true bispecificity and cross-reactivity impossible. For two target molecules in the growth-hormone family, one might anticipate some degree of structural, and therefore antigenic, similarity. I simply do not see anything new presented here.

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