High-Affinity Lamprey Antibodies
A number of alternatives to immunoglobulin-based antibodies have been proposed such as lipocalins, fibronectins, ankyrins, and src-homology domains, but Zeev Pancer, Ph.D., assistant professor at the Center for Marine Biotechnology, University of Maryland Biotechnology Institute, proposes another possibility—the lamprey antibody. The jawless lampreys and hagfish are at the base of the vertebrate branch of the evolutionary ladder and have been around for a long time.
The lamprey’s immune system is based on somatic rearrangements of diverse leucine-rich repeats within incomplete vlr genes. The N- and C- terminal ends of the vlr gene are constant, and these repeating units form the lymphocyte receptors, which are the primary recognition sites of the lamprey’s immune system. These somatic rearrangements have the potential to generate over 1014 unique variable lymphocyte receptors (VLRs), a figure that is comparable to the level of diversity inherent within the mammalian immune system.
“The evolutionary history of these organisms is fascinating,” says Dr. Pancer. “The lampreys are part of the deuterosome lineage that includes modern vertebrates, but their immune systems have diverged dramatically, so their molecular structures are quite different.”
In a manner similar to the mammalian immune system, lamprey secrete VLRs in their plasma. The animals respond to repeated injections of antigen by mobilizing a hearty immune response of low-affinity antibodies followed by high-affinity antibody idiotypes. Several investigators have already developed monoclonal antibodies using the lamprey system, and they were found to bind antigen with high avidity.
Dr. Pancer argues that the lamprey system offers a unique opportunity to generate antibodies that could recognize mammalian antigens invisible to immunoglobulin-based antibodies due to self-tolerance. Moreover, the VLRs are modular, single-chain polypeptides, which makes them highly amenable to molecular engineering. Dr. Pancer cautions that lamprey antibodies may not be good therapeutic candidates since their sequences could be immunoreactive to mammals, but they could serve a variety of important functions in the diagnostic sphere, including protein chips, flow cytometry, immunohistochemistry, and ELISAs.
Furthermore, there is a spirited search under way today for better affinity purification tools, and the lamprey antibodies could fill the bill. So while the lamprey system is very old, it is hardly out of date.