Until about twenty years ago, there were limited treatment options for rheumatoid arthritis (RA). The first drugs prescribed for RA worked well in only about a third of all patients. Today, “biologic” drugs provide more treatment options that work in various ways. But even these newer drugs pose challenges, because in a small percentage of patients, who have an immune response to the drug, they may lose their effectiveness over time. That response—called “immunogenicity”—can make the drugs less effective. The challenge for researchers now is to develop biologic drugs that don’t provoke that kind of immune response, so that more patients can be treated with these medicines.
There’s no cure for rheumatoid arthritis, a chronic disease that causes joint pain, fatigue, and bone erosion, but drug treatments can ease the symptoms and may prevent patients from becoming more debilitated. The usual first-line treatments for RA are generic drugs called “conventional synthetic disease-modifying anti-rheumatic drugs,” nicknamed csDMARDs. One of these is a fairly common cancer drug called methotrexate, but there are several others. Typically, csDMARDS are effective in only about 30-40 percent of patients.
A type of drug, called “biologic DMARDS,” came along, introduced to the market in 1989. These biologics work differently, providing another treatment option to patients with RA.
Researchers figured out that when people have RA, their immune cells release proteins called “cytokines” that cause inflammation. When the inflammatory cytokines were discovered, they became a target for treating the disease.
Many biologic medicines are “monoclonal antibodies”, which can fight disease-causing proteins like these inflammatory cytokines. In the case of rheumatoid arthritis, the monoclonal antibodies are engineered to block the cytokines that cause inflammation in people's bodies.
Biologic drugs are proteins, and proteins are known to potentially initiate an untoward immune response. In the broadest sense, immunogenicity is the body’s response to a foreign protein that’s put into it, trying to fight it off. Sometimes, such as in the case of vaccines, we actively want to provoke immune response. Vaccines work by stimulating the immune system to produce antibodies against a foreign agent, a weakened version of a disease germ, creating antibodies to that disease, so that the body can protect itself from that disease ever after.
But with biologic drugs, immunogenicity is a bad thing. There are people whose bodies fight against the monoclonal antibodies, potentially rendering them ineffective, or even provoking an allergic response or adverse side effects. Currently, it is difficult or impossible for physicians to predict which patients are going to end up with an immunogenic response, which makes it tricky to monitor them and prescribe the right treatment. Immunogenicity of biologics that treat RA can range from 1-15 percent, the goal is always to overcome the problem of immunogenicity.
One way that researchers have tried to reduce immunogenicity is by “humanizing” the mouse antibodies, genetically engineering them by taking out mouse sections of the antibody and grafting human sections into the antibody. In general, it’s more likely that people will react against mouse antibodies than those that are more fully human because they are less compatible with us, so we’re more apt to reject them. Some of the antibodies are engineered so that they are completely human. However, regardless if the antibodies are humanized or fully human, immunogenicity remains.
“So far, there doesn’t seem to be that much of a difference between humanized and fully human drugs,” says my colleague Benjamin Kramer, an allergist and immunologist who is the former Vice President in US Medical Affairs for Immunology and Ophthalmology at Genentech. There are other avenues to explore before the problem of immunogenicity is tackled. “There’s still a lot we need to learn about immune system responses and immunogenicity,” he says.