Conventional antibodies are familiar largish protein molecules that aid us in maintaining health. But camels have a unique antibody as well as the normal kind circulating in their bloodstreams. Dromedary, Bactrian camel, llama, alpaca, guanaco, and vicua all have both kinds.
What makes camel antibodies so special is not that they are somewhat smaller than conventional antibodies, but that their key component the variable portion that binds to other proteins works fine all by itself. That means you can produce even smaller proteins, dubbed nanobodies by Muyldermans, that can do almost everything normal antibodies do and some things they cannot yet are just a tenth of their size. New Scientist
Because they are so much smaller than normal human antibodies, nanobodies can get to or be delivered to parts of the body and cells that their larger cousins cannot reach. This has important implications for the future of human and animal health. And for plants, too.
In themselves, nanobodies are amazing, but their true wonder may be their mere puniness and property of attachment. They can adhere to toxins and other molecules for delivery across the placenta, the brain barrier, and to the gut without becoming too large.
They're also tougher than regular antibodies. Suitable for swallowing to treat intestinal diseases, capable of being absorbed without being digested.
They're easier and cheaper to make than normal antibodies, which must be manufactured in mammalian cells, so nanobodies can be used to deliver drug molecules in products like anti-dandruff shampoo.
They can be introduced into plants and animals to enable metabolic studies or to produce metabolic altering effects, even miniature chemical "labs."
Conventional drugs fight disease but are large molecules that carry with them all sorts of side effects. Antibodies fight disease without those undesirable side effects, but they're still very large molecules. Nanobodies are little giants: proteins so much smaller than large and complex everyday antibodies that function the same way -- at times, maybe even better.
But, you may ask, can't human antibodies be reduced in size? After all they're two heavy chains and two light chains. And
only the ends of them contain the variable regions that bind to other proteins. So why not chop off the variable regions, or domains, and use these as "single-domain antibodies"?
I don't want to have to kiss a camel! Because the proteins that form human single-domain antibodies "are naturally sticky, and have a tendency to clump together and to bind to proteins other than the target, making them useless." Pucker up and get ready to plant a big wet one on the split lip of your hairy friend: camelid antibodies have no stickiness problem with the single-domain antibodies nanobodies derived from them. Lacking light chains, the variable domain at the end of the chain has evolved in camels to "work alone," rather than stuck onto a light chain.
Just how hard is it to make nanobodies? Not very. First you steal a camel. Then you inject him/her with the antigen you want an antibody to. Say, a virus. Then you go away for a few days. Come back, preferably with a carrot to sweeten the deal, catch your camel, now steal some blood and plant that kiss. Take your camel's blood to the lab and check out the WBCs that are making antibodies that bind to your target. Extract the DNA that codes for your particular variable domain and Joe's your favorite Camel. Crank up the nutrient vats because the "big advantage of single-domain antibodies is that these proteins are simple enough to fold correctly when they are made in genetically engineered bacteria or yeast." In most cases, that's all that's needed. Some nanobodies may need to be tweaked if they're to be injected into humans so that they're not recognized as foreign invasive bodies, but they're already beneficial "kissing cousins" -- heck, near twins -- to the variable domain of human antibodies. All right. The idea of kissing a camel isn't so bad anymore.
What's that about their toughness? Thanks to extra internal bonds that reinforce their structure, ""You can use them in very harsh conditions where normal antibodies collapse, get digested or don't fold," says Serge Muyldermans of the Flemish Institute of Biotechnology. Thus, they're easier to store and transport. Plus, some nanobodies can survive the trip through the gut which means nanobody pills may one day treat colon cancers and inflammatory disease of the bowel, or diarrhoea in children caused by rotovirus. "Children could be dosed with live bacteria that churn out these nanobodies, making the treatment cheap."
Americans may find it odd to discover that smaller is better, but that's just the case with nanobodies.
They are small enough to wheedle their way into the active sites of enzymes, deep clefts in receptors on the surface of viruses and bacteria, or into the heart of dense tumours. It looks as if they might even penetrate the blood-brain barrier effectively enough for drug designers to think about adapting them to treat conditions like Alzheimer's disease.
Smallness has a disadvantage, though. They're pissed away so fast as to be of little therapeutic use in many cases.
But we can fix that. By linking them to other proteins, one manufactures useful hybrids. By linking two nanobodies of the same kind together, they can become more effective "bullets" that bind to a target better. By linking two different nanobodies together, you "create a protein capable of bringing together the target and a killer cell from the patient's immune system (the same function is carried out by the "tail" of full-sized antibodies)." To treat cancer, nanobodies can be linked to an "effector molecule" that kills cells, such as a toxin, an enzyme, or a radioactive substance.
Currently, nanobodies are showing much promise in the development of anti-coagulents for use in patients at risk of heart attacks or strokes that have, following initial trials, shown no unwanted action.
. . .two linked nanobodies that bind to a protein called von Willebrand factor, which is only involved in clotting where the blood is moving fast. This means it should keep fast-flowing blood in arteries free of dangerous clots without affecting clotting elsewhere.
Nanobodies applications in areas other than fighting disease are endless:
Genetic engineering organisms to produce nanobodies inside themselves; "Intrabodies that targeted and inhibited specific proteins would reveal the role of these proteins in laying down the nervous system."
Manufacturing fluorescent nanobodies, chromabodies, can be used to light up specific proteins inside living cells.
Nanobodies that target specific enzymes have been shown to alter metabolic pathways in potatoes, which might "make it possible to endow crops with immunity to specific pests or to create vegetables that combat gut infections when eaten."
And even
Nanobodies that bind to different parts of a surface on a crystal lattice. . .could be used to align different enzymes into a carefully coordinated sequence,
in essence, "creating a miniature chemistry laboratory capable of performing a series of incredibly efficient reactions."
Fair-minded people can probably agree that kissing a camel is a small price to pay for the promise nanobodies hold. So, how do you feel about kissing a shark? A ray? Yep, these creatures sport similarly slender antibodies for targeting invading viruses and bacteria. They're called sharkbodies.