The immune system is our best protection. Sometimes, when the body struggles with disease, our immunity begins to fight off drugs that save lives. Until recently, doctors were powerless in this situation, and patients – no chance.
This miracle treatment should have saved Becca Boscarino’s son, but it was close to hastening his death. Doctors diagnosed Magglio with Pompe’s disease, a rare and fatal genetic disorder of metabolism leading to the accumulation of glycogen in the body. If left untreated, it would probably kill the baby before his first birthday. Only one drug, given by injection, can help. Meanwhile, after the fifth dose, little Magglio turned blue, stopped breathing and developed anaphylactic shock. What happened? Doctors finally determined that the child’s body began to produce antibodies aimed at the drug.
Unusual reaction
Few doctors and patients have heard of this problem, and the phenomenon has not been sufficiently well researched. But experts say what happened to Magglio also happened to many other people taking other medications.
The human immune system produces antibodies, blood proteins designed to attack molecules that the body deems foreign, such as viruses and bacteria. Occasionally, however, antibodies may also develop in response to other unknown substances, including drugs given to patients. Antibodies directed at a specific drug would stick to the drug molecules and neutralize its action. However, it is impossible to predict which patient will respond in this way to treatment, or which drug may trigger such a response in a large number of patients.
“Once a drug is approved and released for distribution, it’s rare for a doctor to order a patient to measure antibodies,” said Mary Crow, a rheumatologist at Hospital for Special Surgery in New York. “There is no commercially available test for such a measurement,” he adds.
Threatening Drugs?
In an article published in March in the New England Journal of Medicine, [pharmaceutical company] Pfizer reported that in the final phase of clinical trials on a new drug for lowering cholesterol, a large group of 30. over time, patients no longer respond to treatment as desired. Cholesterol, which initially decreased under the influence of the drug, rose again later. As it turned out, the patients’ bodies began to produce antibodies against the drug over time. Pfizer had no choice but to stop research and withdraw from a project in which it had already invested billions of dollars.
An adverse reaction of the immune system in response to treatment is a problem that is very difficult to circumvent. Drugs containing proteins stimulate the production of antibodies. Steve Danehy, a Pfizer spokesman, said that even 87 percent of among patients taking monoclonal antibodies drugs, the production of drug neutralizing antibodies may occur (also the mentioned experimental drug of Pfizer was of the monoclonal antibody species).
Patients and their doctors often have no idea what is happening: the only obvious thing is that the drug is no longer working. Then the sick are enrolled in his counterpart in the hope that he will help them. However, such a strategy can only be used if there is an alternative. Unfortunately, this alternative is not available for some diseases.
For a small group of extremely severe gout patients, antibodies are “a really huge problem,” said Robert Terkeltaub, a gout specialist at the University of California, San Diego. Only one drug would be able to help these people, but most of them start producing antibodies, blocking treatment.
For patients like Magglio Boscarino, finding a way to suppress the immune response would be a matter of life or death. After the boy was born, everything seemed to be fine with him, but soon he fell ill: he seemed to have a very cold. Since his condition did not improve, the doctors recommended that the child’s chest be x-rayed and found that the little patient had a very enlarged heart. At the end of six months, Magglio was weak and had abnormal muscle tone. Then the boy was diagnosed with Pompe disease and started to be treated with injections of an enzyme that the child’s body could not produce by itself.
At first, Magglio’s condition improved. Within a few months, the little one learned to sit up and use his hands. However, with the fifth dose of the drug, a tragedy occurred: the child suffered anaphylactic shock and stopped breathing. He was then given oxygen and epinephrine, after which little Magglio recovered. Doctors have not yet realized that it was the drug that caused such a violent reaction in the body, so two weeks later the boy was given another injection, which led to the same dangerous consequences.
Only then did it become clear what the problem was. However, because Pompe’s disease progressed and could soon kill the boy, the doctors kept the treatment as usual, hoping that the child’s body would eventually tolerate the next doses of the drug. Magglio took the injections for a year and a half, but his condition worsened. After some time, he could no longer breathe on his own and underwent a tracheotomy. He was unable to sit. At the age of two, he developed heart failure. “He was dying,” recalls Becka Boscarino. – That was awful.
Cheat immunity
Magglio was not the only child going through this ordeal. Most patients with Pompe disease treated by the only means available soon begin to develop antibodies to block the action of the medicine. “We tried everything, but these babies had no chance,” says Priya Kishnani, professor of paediatrics at Duke University.
Kishnani realized that she had to somehow trick the children’s immune system into stopping it neutralizing the protein injected. The doctor came up with the idea of giving little patients rituximab, a chemotherapy drug that destroys cells that would eventually develop into antibody producers. In addition, Kishnani tried to use methotrexate in children to destroy large amounts of white blood cells and injections of antibodies obtained from donated serums to enable small organisms to fight infections. For toddlers like Magglio, who were already producing antibodies to block the action of the life-saving drug, she added another drug, bortezomib, designed to eliminate the cells responsible for the formation of antibodies.
Once the patients’ immune systems were under control, their treatment began to pay off again. “It was stunning,” remembers Kishnani. – We were able to save these children.
Find out how drugs that improve the immune system in children work
Chance
Putting it in perspective, the same approach could be applied to many patients who are being treated for various other diseases. “I have the impression that Pompe’s case has opened up new perspectives for us,” commented Kishnani. “The more we talked about it, the more we became aware of the role of antibodies.
Scientists have already started clinical trials targeting patients with the very serious form of gout, in whom antibodies are blocking the treatment. In one case, researchers modify the dose of the drug and the frequency of its administration. In another, employees at Selecta Biosciences are testing a drug that blocks the production of antibodies when taken with a gout drug.
At Brigham and Women’s Hospital in Boston, cardiologist Paul Ridker, who leads Pfizer’s research, took a different tactic: the scientist intends to see if it is possible to predict in which patients the body will start producing antibodies in response to Pfizer’s drug, and possibly other drugs that the immune system will treat it as a foreign body. “We are probably facing the best opportunity in history to understand why these antibodies develop,” says Ridker. – It would be very valuable for the development of future drugs if we could say: “This one patient among 20 others should not be treated like this”.
It would also mean that discontinued drugs could be further developed with well-tolerated patients in mind.
Magglio has undergone treatment to weaken his immune system at Dr. Kishnani’s lab and looks to be recovering. “The good news is my son is still alive,” admits the mother. – She’s like a rag doll. He moves his lips but makes no noise and uses his eyes to control the computer, which his voice replaces.
Magglio has been breathing with the help of a respirator since he was nine months old. However, he has developed his own way of communicating with the use of language, says mom. After all, she goes to school – fourth grade elementary school – and even plays for a baseball team for children with disabilities. His mother helps him in sports. “He’s a huge fan of the Yankees,” adds Boscarino.