Researchers have challenged an old immunological dogma — that an antibody can bind to only a single target or antigen — by engineering an antibody to bind tightly to two distinct proteins.
The antibody, described in Science1, blocks two proteins: vascular endothelial growth factor (VEGF) and human epidermal growth factor receptor 2 (HER2). VEGF is thought to promote growth in tumours, and HER2 is highly expressed by some aggressive breast tumours.
Separate antibodies that target each protein individually are already used to treat some cancers: trastuzumab tackles HER2, whereas bevacizumab binds to VEGF.
Although researchers frequently come across antibodies that weakly bind to multiple targets, until now no antibodies have been found, or engineered, that specifically bind to two very different antigens.
The results are surprising, says Paul Parren, a senior vice-president of biotechnology company Genmab, which focuses on antibody therapies, based in Utrecht, the Netherlands. "You just didn't think about antibodies that way before. It makes you wonder if such molecules might also exist in nature."
Two-in-one
To create the antibody, Germaine Fuh at Genentech, a biotechnology company in South San Francisco, California, and her colleagues mutated an antibody for HER2 and then screened for mutants that bound to both HER2 and VEGF.
A similar approach is sometimes used to modify antibodies so that they bind a different antigen, and in 2006, researchers reported that they had used the technique to create antibodies that bound to two similar forms of botulinum toxin2. But Fuh's team is the first to use the technique to create antibodies that bind two unrelated proteins. "This could open the door to dual-targeting types of therapy," she says.
The structures of the bound proteins show that they attach to distinct, but overlapping, sites on the antibody. The antibody also slowed tumour growth in mice, but the mouse models used were designed to respond to either one antibody or the other and researchers do not yet know if targeting VEGF and HER2 simultaneously would enhance the cancer-fighting effect in human cancers.
Dosing difficulties
Fuh notes that antibodies which can target two proteins could dramatically reduce the cost of developing a combination therapy, which would normally require clinical trials with each antibody individually as well as in combination. A dual-targeting antibody, however, would be treated as a single drug.
Although it is possible that such antibodies could reduce costs, they could also present practical challenges in the clinic, says Parren. "How do you find the optimal dose for something that binds to two targets?" he says. This could be particularly important if one activity of the antibody is more toxic than the other. Fuh acknowledges that dosing difficulties could be a tricky to overcome, but says that the antibodies could also be engineered to bind their two targets with different efficiencies.
Combining two therapeutic antibodies is not always beneficial, even when both are at their optimal doses. Two studies published in February analysed antibody combinations in the treatment of colorectal cancer, and found that the combinations increased toxicity and reduced survival rates3,4. "Hopefully these cases are just exceptions, but they shows that preclinical research doesn't always tell you what's going to happen in the patient," says Parren. "If you've developed a two-in-one antibody, you will be less flexible at that point."
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