The human body doesn’t like outsiders. When a foreign pathogen or substance, say an unwanted virus, finds its way into our blood streams we produce antibodies that the neutralize the threat. These “Y”-shaped proteins are made by a class of white blood cells called plasma cells and bind to molecules on the invaders called antigens, triggering another set of white blood cells to literally ingest the interloper. For years now doctors have used antibodies and other protein-based therapies (aka biologics) to treat a range of illnesses, cancers, infections and autoimmune diseases among them.But antibodies have their drawbacks: for one they’re bulky and hence usually have to be administered intravenously as they’re often too big to be absorbed in the gastrointestinal tract. With this in mind, chemist David Spiegel and his colleagues at Yale University are out to develop compounds with the benefits of antibodies—hopefully minus the needle.*In work recently published in the Journal of the American Chemical Society Spiegel and his team have successfully developed the first synthetic molecules that behave like antibodies. Like the real thing, these so-called “synthetic antibody mimics”—or “SyAMs”—bind to both diseased cells and disease-fighting immune cells. Specifically the compounds were found to zero in on and bind to a specific antigen on prostate cancer cells. The SyAMs also bind to and activate certain immune cells that then devour the malignancy.Spiegel’s SyAMs are produced in a way that is similar to conventional drugs, by using chemical reactions to piece together various structural features often not found in nature. As he explains, the therapeutic potential of synthetic antibodylike compounds is vast: “Because antibodies are proteins they’re difficult and expensive to produce on a large scale, can cause unwanted immune reactions and tend to aggregate and denature with long-term storage.” Spiegel speculates that SyAMs will be easier and cheaper to produce and less likely to incite aberrant immune activity. SyAMs are also one twentieth the size of antibodies—more akin to the size of most medications—and can therefore perhaps be administered orally. This could be a major boon to patients with cancers and autoimmune diseases like multiple sclerosis who have to regularly get themselves to infusion centers for monoclonal antibody therapy.The idea of producing “artificial antibodies” traces back to the work of late 19th-century German physician Paul Ehrlich who first proposed that the immune system can neutralize toxins or pathogens by forming “antitoxins.” Based on the idea he and his colleagues began developing drugs meant to function like these antitoxins, including one to treat Trypanosoma parasite infections. During the 1930s and 1940s—as understanding of antibody–antigen interactions grew—famed chemist, activist and vitamin C evangelist Linus Pauling started tinkering with the idea that proteins could be transformed into antibodies by exposing them to certain antigens.Artificial antibody research split subsequently in two directions: one camp pursued creating protein antibodies resulting in what are called monoclonal antibodies. Monoclonals are produced by natural means in a lab and are now commonly used therapeutically. The other camp, in which Spiegel falls, set out to produce smaller, nonprotein compounds with antibodylike properties.Beyond attacking prostate cancer, Spiegel’s group has also developed SyAM-based approaches targeting HIV, various other cancers and bacterial triggers of autoimmune disease. And although SyAM research remains in the petri dish, a mouse model is in the works and human studies are not far off. A number of other labs are also researching ways to fight disease by manipulating antibodies and synthesizing molecules that act on the immune system, including Peter Schultz at the Scripps Research Institute in La Jolla, Calif. “He’s probably our biggest competitor and I’m his biggest fan,” Spiegel says.
Laura Kiessling at the University of Wisconsin–Madison, who studies ways to draw natural antibodies to tumor cells, comments on the benefits of Spiegel’s approach: “It can be tailored to selectively recruit specific types of immune cells to kill tumor cells. The smaller size of the compounds could also be an asset in eliminating tumors, but the benefits would need to be looked at in vivo,” Kiessling says.
As Spiegel confesses, his route to the chemistry lab was an unusual one. He went to medical school to become a psychiatrist but along the way also picked up an interest in chemistry and—in decidedly un-psychiatristlike fashion—tacked on a PhD in organic synthesis (the development of new organic compounds and reactions in the lab). “The relevance of this research to clinical medicine was not always clear to my classmates and colleagues—or sometimes to myself,” he recalls, “but I realized that organic chemistry has been critically associated with drug development from the beginning.”
Spiegel points out that most U.S. Food and Drug Administration–approved drugs are in fact small organic molecules. “My thought was that by working to understand diseases at the cellular and molecular level, I could not only learn how to make new drugs,” he notes, “but also perhaps develop new paradigms for how drugs could function.” Spiegel’s decision to join his chemical and clinical interests, it seems, was a wise one.