single-domain antibody

A handful of animals make a pared-down version of these pathogen-fighting proteins of our immune system. Scientists hope to harness them as treatments for ills from cancer to Covid, for tracking cells in the body, and more. Every four months, pathologist Aaron LeBeau scoops into a net one of the five nurse sharks he keeps in his University of Wisconsin lab. Then he carefully administers a shot to the animal, much like a pediatrician giving a kid a vaccine. The shot will immunize the shark against a human cancer, perhaps, or an infectious disease, such as Covid-19. A couple of weeks later, after the animal’s immune system has had time to react, LeBeau collects a small vial of shark blood. Halfway across the country, immunologist Hidde Ploegh goes through the same steps, but with alpacas that live on a farm in western Massachusetts. The scientists are after the same thing: tiny antibodies, made only by certain animals, that may have big implications for human health. “They can get into little nooks and crannies of different proteins that human antibodies cannot access,” LeBeau says. A group of biology students were the first to discover these unusual antibodies — quite by chance — back in 1989. The students of Free University in Brussels needed some blood for an exam in which they were tasked with separating an antibody into its two main parts: two heavy protein chains, which form a Y shape, and two light protein chains, which flank the prongs at the top of the Y. Strangely, the students found only heavy chain proteins in the blood even though antibodies were supposed to also have light chains. As Muyldermans tells it, everyone thought that the camel antibodies had degraded — or that the students had done something wrong — so Hamers went to the Antwerp Zoo to collect fresh camel blood. But the students had not screwed up: Camels make antibodies with only heavy protein chains. The potential applications of camelids’ small antibodies dawned on Hamers during those early years, says Muyldermans, who details their myriad uses in the 2021 Annual Review of Animal Biosciences . Like antibodies from people or mice, the camelid antibodies could be further pared down into even smaller, yet still effective, fragments — just the tips of the Y. These fragments, called variable domains, are the business end of any antibody — they act as the antibody’s “sensor” and can stick to parts of pathogens or toxins, whatever substance is recognized as foreign and a possible threat. Full-size antibodies, like those of humans (left), typically have heavy protein chains (dark blue) and light protein chains (light blue). In addition to these standard antibodies, sharks and camels and their relatives make antibodies with only heavy chains (middle and right). The fragments at the antibody tips (shown in circles), called variable domains, stick to parts of pathogens or toxins, whatever substance is recognized as foreign to the body. The variable domains of sharks (VNARs, middle) and camels (VHHs, or nanobodies, right) have an extra-long fingerlike extension, called the CDR3 loop, that can reach into nooks and crannies inaccessible to a standard antibody fragment (ScFv, left). Scientists have since learned a lot about the advantages of these mini antibodies. Some is practical: Unlike full-size antibodies, the fragments are stable at room temperature so there’s no need to keep them in a freezer or ship them cold. The mini antibodies of sharks can even be boiled with no effect on their function, LeBeau says. And while full-size antibodies require mammalian cells to be grown in a flask, which can be complicated and expensive to maintain, the fragments can be manufactured in large quantities using bacteria, saving time and money. These mini antibodies also tend to self-assemble properly, keeping their correct shapes, making them a promising alternative to full-size antibodies, which have more pieces and thus can misfold. Such misfolding may expose parts th