Unusual antibodies could lead to new drugs

Making the Most of Mini-Antibodies

Sharks, llamas, camels and their relatives have unusual, diminutive antibodies that are “only about half the size of the conventional versions,” according to Mitch Leslie in a recent issue of Science.

Researchers have known about the tiny proteins since the late 1980s, when scientists at the Free University of Brussels (VUB) discovered them. According to biochemist Hidde Ploegh of Boston Children's Hospital, "Since 2012, the field has really taken off."

The molecules and even tinier fragments of them, referred to as nanobodies, are easier for researchers to make as compared with conventional antibodies. They are also said to be more durable and more soluble. They can function inside cells and stretch deeply into tissues that regular antibodies might not be able to penetrate, making them valuable research tools.

Ploegh and his associates have used the antibodies to track a key immune protein in the body, neutralize plant viruses, and label cancer cells. They hope to use them to bind to and stabilize fragile proteins to enable researchers to understand their architecture.

Evolutionary immunologist Martin Flajnik, also of UMD's School of Medicine, has used the mini-antibodies to determine crystal structures. A llama nanobody was critical to structure studies that won a recent Nobel Prize.

Now the miniature antibodies are expected to be used in medical endeavors with real patients. Sometime in 2018, the first nanobody treatment, which will come from a llama small antibody, may garner approval in some countries to be used in people with a rare clotting disease. Over 40 similar therapies are being developed for diseases including lupus, lung infections and cancer. While conventional antibodies work for diagnosis and treatment of many diseases, molecular biologist Nick Devoogdt, also of VUB, believes that the smaller version will become the antibodies of choice in uses "where conventional antibodies are less optimal."

Small antibodies were discovered when students at VUB did not want to analyze human blood for a lab exam because of the potential for contracting a disease and the lack of desire to kill a mouse to obtain its blood, according to Serge Muyldermans, a molecular biologist at the university. They found frozen dromedary camel serum that had been collected to study parasites in the camels.

When the students finished their assignment, they noticed that, along with normal antibodies, there were an undersize version of the molecules. Thinking the students had done something wrong, scientists at the university investigated further. Using blood from zoo animals in the same evolutionary family, including a Bactrian camel and a llama, they found that “all had the same diminutive antibodies,” Muyldermans said.

In a 1993 Nature paper, the scientists said that a major difference between the small antibodies and full-size antibodies is that a conventional antibody consists of “four protein strands—two heavy chains that form the backbone of the Y-shaped molecule and two light chains that cling to the outside of the prongs,” while “the mini-antibodies retain roughly the same shape but are missing the light chains.”

According to Muyldermans,”Small antibodies must have an important role, because they emerged independently in as many as three different lineages: sharks, camels and probably another group of sharklike fishes. “At the moment, we have no clue why the molecules evolved, but we have put them to work in a variety of medical and research applications.”