Nanobodies

Nanobodies (aka single domain antibodies or V_HH antibodies) are a type of antibodies derived from camelids, and are much smaller than traditional antibodies. Standard antibodies are giants by molecular standards, since each one is a conglomerate of two heavy protein chains and two light chains, intricately folded and garnished with elaborate sugars. Nanobodies, however, are relatively simple proteins about a tenth the size of human antibodies and just a few nanometers in length. After the discovery that camelidae (camels and llamas) possess fully functional antibodies that lack light chains, the nanobody technology was developed to exploit these smaller heavy-chain-only constructs. Nanobodies are being researched for multiple pharmaceutical applications and have potential for use in cancer and Alzheimer's Disease treatments.

Traditional therapeutic monoclonal antibodies (MAbs) must be stored at near freezing temperatures to prevent their destruction. Antibodies are not suited for oral administration because they are digested quickly in the gut, and are not usually useful for treating diseases of the brain because they do not easily permeate the blood-brain barrier. Additionally, therapeutic antibodies are not well suited to target large tumors because they are held to the periphery of solid tumors. Many illnesses are thus unreachable by monoclonals, and patients who use MAb therapies must receive them by injection or infusion at a clinic. For certain conditions in which the traditional MAbs do not work well, and even for some in which they currently do, simpler, smaller proteins like nanobodies might perform better, be easier to make, easier to handle, easier to admister, and be more affordable. (2)

In 1989 a group of biologists led by Raymond Hamers at the Free University (Brussels, Belgium) investigated an odd observation handed in as part of a student project on parasite immunodefense in dromedary camels (the one-humped Arabian variety) and water buffalo. One of the tests for antibodies in the dromedary blood seemed to show an error: in addition to normal four-chain antibodies it indicated the presence of simpler antibodies composed solely of a pair of heavy chains.

After several years of investigation, Hamers and his colleagues published their discovery in Nature in 1993. In dromedaries — and also in two-humped Asian camels and South American llamas — about half the antibodies circulating in the blood lack a light chain. Equally surprising, they found that these "incomplete" antibodies are able to grasp their targets just as firmly as normal antibodies do, with affinities for their targets virtually equal to a full antibody 10 times their size.

These shortened proteins were also more chemically agile, able to engage targets — including the active sites of enzymes and clefts in cell membranes — too small to admit an antibody.

Because nanobodies are so much smaller than antibodies and are not hydrophobes (as are standard human antibodies), they are more resistant to heat and pH, and may retain their activity as they pass through the gastrointestinal tract, raising the prospect of oral nanobody pills to treat inflammatory bowel disease, colon cancer and other disorders of the gut.