Ever since he can remember, even as a boy growing up on a small farm in Michigan, Ken Martin has battled betrayal by his own body. Now 50 years old, Martin was born with hemophilia, and he bleeds almost uncontrollably from a cut. If an internal vein or artery is injured, the blood it carries pools in an intensely painful balloon under Martin's skin. When that happens in his knees, as it frequently does, he must hobble on crutches or stay in a wheelchair until the bleeding slowly stops.

Worse, Martin's body has dealt him a double whammy. People have hemophilia because they lack a gene that makes an essential blood-clotting protein, and many of them get regular infusions of the missing molecule, which is called Factor VIII. But if Martin gets an injection of Factor VIII, his immune system launches a swarm of disease-fighting antibodies against the clotting protein, sweeping it away as if it were an infectious microbe. “I've never benefited from any regimen containing Factor VIII,” says Martin, who is married with two boys and, despite the ailment, has had a successful career as a design engineer in the auto industry. Martin deals with his bleeds by elevating and icing the swollen area and resting—and with “a lot of patience,” he says. There are about 20,000 people in the U.S. with hemophilia, and around 30 percent of those with Martin's type experience similar antibody attacks.

The problem of antidrug antibodies reaches far beyond blood-clotting disorders. ADAs, as they are called, threaten some of the newest drugs for treating cancer, heart disease and various autoimmune illnesses, such as rheumatoid arthritis. These medications, referred to as biologics, mimic naturally occurring proteins. That often makes them more effective than traditional drugs: the pills we swallow that contain small synthesized chemicals. But because our immune systems are built to detect foreign proteins, some patients react to biologics as if they were invading bacteria, and this sets off an antibody onslaught rarely seen with pills or tablets. The result is that biologic medicine can be blocked or destroyed before it can do any good.

Early biologic developers believed that because many of the drugs were based on human genes and proteins, the human immune system would not treat them as foreign. This turned out to be overly optimistic. When there are reactions, they are frequently big enough to ruin the drug. Awareness of this response has turned into alarm as biologics have become a major part of our medical arsenal. They have grown from 11 percent of the total global drug market in 2002 to between 19 and 20 percent in 2017, according to the IMS Institute for Healthcare Informatics, a research firm, and pharma companies keep making more. “With the explosion of biologic products on the market and in research pipelines, we've become very concerned about the effectiveness and safety of these drugs,” says Amy Rosenberg, director of a U.S. Food and Drug Administration division that regulates therapeutic proteins.

An antibody response is the likely reason that AbbVie's Humira, a biologic that treats inflammatory bowel disease, psoriasis and rheumatoid arthritis, fails to work in one fifth of patients or more in some studies.* Drugmaker Pfizer had to pull a promising anticholesterol medicine, a biologic named bococizumab, after testing it in more than 25,000 people. The drug lost its ability to help patients over time, and in six trials almost half the people who received medication developed ADAs. The antibodies were the probable reason for the drug failure, says Paul Ridker, a cardiologist at Brigham and Women's Hospital, who oversaw the tests.

In October 2016 researchers at the Netherlands Cancer Institute in Amsterdam reported that more than half the biological anticancer drugs being tested in 81 clinical trials worldwide were generating antibodies, although they could not determine if the activity always crippled the drug. Swiss drug company F. Hoffmann–La Roche recently stopped developing a protein that successfully treated breast and lung tumors after it triggered ADAs in initial human studies.

When these drugs failed, they cost patients dearly and also set back pharma companies hundreds of millions of dollars. So there is widespread worry. In 2016 Rosenberg's agency called on drugmakers to improve ADA-testing technologies, to look for the antibodies before and during clinical trials, and to report the incidence of such reactions and their effect on drug efficacy and patient safety. “It's important to get evidence we didn't ask for before,” Rosenberg says.

Researchers themselves are asking for tolerance—but not for crippled drugs. They are devising ways to get greater tolerance from the immune system for biologic molecules. In one approach gaining wide interest, immunologists are testing new ways to “teach” the immune system to accept these new biologics, to perceive them as normal instead of as an unwanted intruder. Other biotech companies are building tolerance into the therapeutic molecules themselves, developing substances that lack the features that raise an immune alarm. One, in fact, is using antibodies themselves to develop medicine with a minimal antibody response.

Telling Friend from Foe

Selecta Biosciences, a biotech firm based outside Boston, is trying to foster tolerance based on new insights into how the immune system distinguishes pathogens it should destroy from human cells it must leave undisturbed. Selecta's most advanced therapy prevented ADA reactions that hinder a medicine for severe gout, a disabling form of arthritis, in a clinical trial. The technique is also showing promise in enhancing the effectiveness of treatments for cancer and genetic illnesses that have been inhibited by ADAs, the company says.

“We have found a way to manipulate the immune system in a very specific way,” says Takashi Kei Kishimoto, Selecta's chief scientist. “It's something immunologists have been trying to do for a very long time.”

Selecta's technology has its origins in the Harvard Medical School laboratory of Ulrich Von Andrian, who has spent years unraveling how the body's disease defenders signal the presence of a marauding infectious agent. After tracking how immune system cells move through the body to an infection site, he focused on dendritic cells, which appear to act like the commanding officers of the immune system's army. They are responsible for signaling an offensive against a marauding pathogen. When a dendritic cell encounters a virus or some other dangerous germ, it carries a unique fragment of the interloper, called an antigen, into one of a number of lymph nodes distributed throughout the body. “I wanted to study what goes on in the lymph nodes to understand the rules of this immune surveillance,” Von Andrian says.

Credit: Mesa Schumacher

Beginning in 1994, Von Andrian employed increasingly powerful imaging techniques to track cellular traffic in and out of the lymph compartments in studies of mice. He and his colleagues were able to see the dendritic cells, like relay racers exchanging a baton, pass along the antigen identity of a threatening pathogen to other immune system constituents called T cells. Once activated, the T cells launched a barrage of disease-fighting mechanisms, including antibodies, against the unwelcome invader.

About 10 years ago Von Andrian's team was able to track the way that dendritic cells not only start immune system wars but also stop them. The researchers were looking at how rapamycin, a drug that can suppress immune activity, does so through the action of dendritic cells. They combined rapamycin with antigen from cells of healthy tissue, and the pairing was taken up, as usual, by dendritic cells. But this time the cells became “tolerogenic” instead of actively campaigning against marauders. They induced T cells that were not activated but actually heightened tolerance by preventing the formation of antibodies. These T cells could also suppress other immune system activity that can lead to tissue-damaging inflammation.

Because of this dual dendritic nature, Von Andrian thought that if he could figure out a reliable way to spark the cells' protective action, that process could suppress the hyperactive immune responses underlying autoimmune diseases such as rheumatoid arthritis, multiple sclerosis or type 1 diabetes. These ailments all result from the immune system mistakenly assaulting healthy tissue, much in the way ADAs fight off biologics.

Although Von Andrian did not know it at the time, a possible method to communicate with dendritic cells—to switch an immune response on or off—was being developed by researchers at the nearby Massachusetts Institute of Technology. In the lab of bioengineer Robert Langer, scientists were designing nanometer-scale biodegradable particles, about as small as a virus, that could be constructed to ferry anticancer agents through the bloodstream to the site of a tumor. Those particles became the seeds of Selecta technology.

Von Andrian—who had been asked by some of the scientists to consult about a venture to commercialize the particles—realized that the nanoparticles, composed of a soluble polymer called poly(lactic-co-glycolic) acid, most likely could be constructed to contain an antigen signature and ferry it to dendritic cells inside lymph nodes. But it was Kishimoto who hit on a new way this ferrying action could be used. “It struck me that [nanoparticles] could be used to prevent ADAs,” he recalls.

A Vaccine Approach

The scientists had already formed Selecta and were working on synthetic vaccine particles, or SVPs. Kishimoto's idea was to insert a combination of rapamycin and the antigen of a particular biologic into the SVP. Once injected under the skin or into a muscle, the particles would eventually enter lymph nodes. There they would spur dendritic cells to generate a surge of tolerance, in the form of regulatory T cells that prevented the creation of antibodies against whatever drug that the company researchers combined with the nanoparticle.

Selecta tested the concept by tackling the hemophilia antibody problem. Researchers administered nanoparticles containing rapamycin and a Factor VIII antigen to mice that lacked the blood-clotting factor. And they gave the mice Factor VIII. The treatment cut down the number of Factor VIII antibodies after 10 weekly treatments, according to a 2015 paper in the Proceedings of the National Academy of Sciences USA. (At present, the company is partnering with investigators who are developing a gene therapy for clotting that will be delivered with a nanoparticle.)

Satisfied that the SVP approach was worthwhile, Selecta is now aiming it at gout, a particularly painful type of arthritis that if untreated can eat away at bone and joint tissue. About eight million people in the U.S. have the condition, which is caused when uric acid builds to very high levels in the blood and forms crystals. It can damage blood vessels and kidneys, and severe cases can be fatal.

There is a biologic gout treatment, a synthetic version of a crystal-degrading enzyme called uricase that is found in many mammals. People, however, do not make uricase. As a result, the human immune system perceives the enzyme as foreign. Just more than 40 percent of those treated with uricase generate ADAs that neutralize the drug's action.

The SVP therapy works similarly to the Factor VIII experiment. The nanoparticles contain the synthetic uricase, along with rapamycin, and head for dendritic cells to make peace. An early study in gout patients reported in the summer of 2017 that the treatment, administered once a month, reduced blood levels of uric acid to almost zero without inducing antibodies. “It's an exciting approach,” says David W. Scott, an immunologist at Uniformed Services University. “It's especially important because it works by activating the immune system's own immune-suppressing process.”

With a colleague, Scott is working on a way to avoid ADAs by genetically engineering regulatory T cells to protect a protein-based drug. In one experiment reported last year, these lab-designed T cells prevented antibodies against Factor VIII in healthy donor blood samples as well as in hemophilia-bred mice. A commercial product, though, is probably years off, Scott says.

Rejecting Rejection

If an antagonistic immune response cannot be tamed, another idea about tolerance is to design biologic molecules that do not set the response off in the first place. Hemophilia, again, is a target disease for this approach. Alnylam Pharmaceuticals in Cambridge, Mass., is developing a hemophilia medicine based on RNA interference, or RNAi, a discovery that garnered a Nobel Prize in medicine in 2006. The scientists who found it, Craig Mello of the University of Massachusetts Medical School and Andrew Fire of the Stanford University School of Medicine, learned that by injecting small molecules of double-stranded RNA, they could interfere with the longer RNA molecules that a cell sends to carry production orders to its protein factories. As a result, the cell stopped making certain proteins.

One of Alnylam's first drugs is Fitusiran, a lab-made chemical that mimics the action of an RNAi molecule. What Fitusiran interferes with is a protein that shuts off another key blood-clotting protein called thrombin. Knocking out the first protein means more thrombin is available in the body, which means more clotting and less hemophilia-driven bleeding. In July 2017 in the New England Journal of Medicine, Alnylam scientists reported that a once-monthly injection of the drug reduced bleeding events during a 20-month trial in 25 patients with hemophilia.

The immunological value of RNAi as a drug is that unlike proteins, RNA-based medicines generally do not elicit antidrug antibodies, says Akin Akinc, who runs Alnylam's Fitusiran project. And if a larger study proves successful, the therapy may be available by 2020. Alnylam is also making an RNAi molecule that hits the same target as Pfizer's troubled anticholesterol drug—the one abandoned because of frequent ADA responses—but does not trigger an antibody attack.

Antibodies can do more than attack invaders, and their other abilities hold different solutions to the drug problems they create. For instance, they can bind two proteins together. Scientists at Japanese drug company Chugai began taking advantage of this in another attempt to treat hemophilia, in this case to sidestep Factor VIII and all its problems. Factor VIII gets a lot of attention in hemophilia treatment design because it is an essential link in a chemical chain reaction called the coagulation cascade. It makes two other proteins—Factors IX and X—bind together, a key step in forming a clot. But of course, it also can attract destructive antibodies.

The researchers designed a synthetic humanlike antibody that acts like a chemical bridge, tying together Factors IX and X and thereby eliminating the need for Factor VIII. In this incarnation as a drug, the antibody is called emicizumab. In two clinical trials reported last year, it was administered once weekly to prevent bleeding episodes in hemophilia patients who had generated antibodies to Factor VIII. In adults, the drug reduced bleeding events by 87 percent. Antibodies against emicizumab did arise in a small number of patients, but those ADAs apparently did not interfere with the drug's effectiveness, says Gallia Levy of biotech company Genentech, which began developing the drug with Chugai after Roche bought both companies. The therapy is not perfect: some patients developed unintended clots, and one died from a bleeding event unrelated to the medicine. Even so, the FDA gave the drug a priority review and approved it in November 2017.

“It's a potential game changer,” says Michael Callaghan, a hematologist at DMC Harper University Hospital and Children's Hospital of Michigan, who treats several patients enrolled in emicizumab trials. (Callaghan receives a fee from Genentech to discuss the drug with other doctors.) One of his patients is Ken Martin. “Mr. Martin has had a very long and challenging struggle,” Callaghan says. “For him the drug has been life-altering.”

Martin agrees. For several years he has kept a log documenting his bleeds. Before joining an emicizumab trial in July 2016, Martin says he had an average of 46 bleeding episodes a year. Since starting the drug, he has had only three. He still hurts, though. The years of blood pooling in his joints, along with inflammation, have left him with severe arthritis in his knees, ankles, elbows and shoulders. He hopes that if patients prone to ADAs start the drug when they are younger, they might avoid such problems. That has not yet been tested. But even at this late stage, Martin is happy to have found a remedy his body can live with. “I'm pretty fortunate,” he says.

Editor’s Note: The affiliation of Amy Rosenberg was clarified on December 22, 2017, to state that she directs one division of the U.S. FDA that regulates therapeutic proteins, not the only division.

*Editor's Note (1/10/17): This sentence from the print article was edited after posting. In the original the bowel condition was incorrectly referred to as “irritable bowel disease.”