Lampreys are notorious for sucking blood, but they also produce antibody-like proteins with a taste for sugar. Dubbed lambodies, these proteins bind polysaccharides more tightly and specifically than most conventional antibodies, researchers have found (ACS Chem. Biol., DOI: 10.1021/cb300399s). The discovery provides a new source of reagents for detecting sugars linked to disease, such as those on tumor cells.
Compared to healthy cells, cancer cells display and secrete proteins and lipids with telltale differences in the sugars that decorate the molecules. Researchers want to exploit these differences by using specific polysaccharides, or glycans, as biomarkers for detecting and targeting drugs to cancer cells. But current reagents for binding specific glycans have limitations. Most conventional antibodies produced by immunizing animals with glycoproteins bind the sugar molecules weakly. Lectins, natural glycan-binding proteins found in human and other cell types, bind glycans more tightly but lack specificity.
Zeev Pancer, an immunologist at the University of Maryland’s Institute of Marine and Environmental Technology, thought lambodies might provide a solution to this problem. His team discovered the proteins in 2004 while studying the differences between the immune response of jawless lampreys, which are directly descended from the most primitive vertebrates, and that of jawed vertebrates. They found that the lambodies can bind antigens as strongly as conventional antibodies. So they wondered if they could find lambodies that had a high binding affinity for glycans.
To do so, Pancer, who also works at the University of Maryland School of Medicine, and his colleagues created a library of 100 million yeast clones that each expressed a different lambody on their surface. Using a cell-sorting technique, they then screened the library for cells that could bind one of several glycans linked to disease, including one for HIV and two found on most types of cancer cells.
They identified lambodies with affinities up to 100 times greater than that of conventional antibodies for these biomarkers. The lambodies also were highly selective for the biomarkers when the team tested them against hundreds of other glycans on a microarray.
Pancer speculates that lambodies are such tight and specific glycan binders because the protein structure that interacts with the glycan has a highly variable sequence and a rigid structure. The rigid structure may help immobilize the flexible glycan, while the high sequence variability increases binding specificity.
The group is working to develop a lambody-based diagnostic biosensor to detect glycan biomarkers of cancer in patients’ blood, urine, or saliva.
Pauline Rudd, professor of glycobiology at University College Dublin, calls the lambodies “gold dust,” because they’ll be valuable to the cancer biomarker field. She points out another advantage lambodies have over conventional antibodies: They’re smaller, potentially allowing them to penetrate deep into cancer tissue for drug delivery, she says.