What It Means to Develop Antibodies to Biologics

Anti-drug antibodies could mean that a biologic may become less effective

Antibodies

 

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One complication of treatment with biologic medications is the formation of anti-drug antibodies. These antibodies can have an effect on not only how well the drug works to treat disease, but it can render the drug no longer useful. Biologics may be given to treat many different diseases and conditions, especially inflammatory diseases. If you are a candidate for treatment with a biologic medication, it is useful to understand what this complication is and what strategies are being used to try to prevent developing anti-drug antibodies and monitor antibody levels.

What Is a Biologic?

A biologic is a type of medication that is created inside a living cell. The living cell can be from a human, an animal, or a microorganism. They are manufactured in a controlled, engineered environment, which is very different than chemically-derived medications (often called small molecules). Biologic medications are used to treat many conditions, including inflammatory bowel disease (IBD), rheumatoid arthritis, psoriasis, ankylosing spondylitis, and hidradenitis suppurativa. Biologics are usually given either by injection or by intravenous infusion, which is done at an infusion center, a doctor’s office, or a hospital.

The biologic medications are engineered to target inflammation and are complicated in terms of their makeup. This is in contrast to the small molecule medications, which includes most of the drugs people take. One example of a small molecule is aspirin. Aspirin is created through a chemical process and it can be made the same every time. There is no variability, and copies of aspirin can be made easily, which means that there can be generic versions of small molecule drugs that are identical to the original version.

Biologics are large molecules, with a higher molecular weight. They tend to be unstable and in many cases need to be kept refrigerated until they are used. The manufacturing process for a biologic medication is complex. A change in this process could have the result of changing the chemical makeup of the biologic. Such a change in the biologic could affect that drug's ability to be effective in treating a disease or condition.

It’s not possible to make exact copies of a biologic, so creating “generic” that is the same as the original isn’t possible. It is possible, however, to make a biologic that is similar to the original. These are called “biosimilars.” Because of the challenges involved in their development, manufacture, and distribution, biologics tend to be of a higher cost than the small molecule drugs.

Biologics and Immune Response

Biologics also have the potential to cause what is called an immune response. This response is an unintended effect and can not only be harmful but in some cases can also be life-threatening.

When the body mounts an immune response to a biologic, this could lead to the development of anti-drug antibodies. The anti-drug antibodies could mean that the drug might become less effective. Being less effective has implications for treatment because there may be a need for a co-therapy, an increase in the drug dosage or frequency, or a change to a different drug altogether.

Almost all biologic medications can result in the creation of anti-drug antibodies, though the risk is going to be different for each individual drug. This is true for biologics whether they are derived from human, animal, or microorganism sources.

During an immune response to a biologic, certain cells in the body may be activated which in turn trigger antibodies to be created. The antibodies to the biologic drug can lead to complications as well as to the drug not working as well to treat disease. The human immune system is complex. It’s not clear why some people develop these antibodies and others do not, although it may be due to genetic differences.

One way that the anti-drug antibodies can be a problem is in shortening the half-life of the drug. A half-life of a drug is the time it takes for 50% of it to leave the body. If the half-life is reduced, the drug doesn’t stay as long in the body. When the drug is cleared from the body more quickly, its effectiveness might be reduced.

A potential way of addressing a shorter half-life is to give the drug more often. That will work in some cases, but there is a limit on how often a drug can be given. One reason is because of the potential for there to be too much of the drug in one’s system. Another reason is because of limitations like cost, as biologics tend to be more expensive to manufacture and to administer.

Because of this potential for an immune response, researchers are trying to understand better why it happens, and how to treat it or avoid it in the first place. In some cases, other medications are given to try to avoid the immune response. Other strategies include slowing down the rate at which the drug is given during an infusion and in doing regular blood tests to monitor the presence and/or level of anti-drug antibodies (called therapeutic drug monitoring).

The Potential for Anti-Drug Antibodies

Not every biologic medication is associated with the same chance of creating antibodies. In one small study comparing three popular biologic medications, it was found that anti-drug antibodies were present in 42% of those receiving Remicade (infliximab), 33% of those receiving Humira (adalimumab), and in none of those patients receiving Enbrel (etanercept).

A review of 443 studies was done to find out how often antibodies were present in patients who had rheumatoid arthritis and were treated with biologics. This review showed that antibodies were found in 0% to 85% of patients treated with Remicade, 0% to 54% of patients treated with Humira, 21 to 52% of patients treated with Remsima (which is also marketed as Inflectra, which are both biosimilars of Remicade), 0% to 1% of patients treated with Cosentyx (secukinumab), 1 to 11% of patients treated with Stelara (ustekinumab), 0% to 13% of patients treated with Enbrel (etanercept), and 0% to 19% of patients treated with Simponi (golimumab).

Risks With Stopping and Restarting a Biologic

In some cases, a patient might stop receiving a biologic drug for a while. This is sometimes called a “drug holiday” though it’s not always done because of feeling better. In some cases, the disease entering remission is a reason that people stop taking their medication. In other cases, it may be not by patient choice but because of a loss of health insurance or for financial reasons. Loss of response to the biologic is also a reason for stopping a drug and switching to another type of therapy.

There may be some concerns about starting a drug again after stopping it for a while. For those who stop receiving a drug not because of a drug holiday but because of anti-drug antibodies or an infusion reaction, it might not always be possible to start that same drug again because there’s a risk of an adverse reaction or of the drug simply not working. If antibodies weren’t the reason that the drug was stopped, it might be possible to start that same drug again. Using monitoring to look for antibodies when restarting a drug will be important to ensure that a patient is tolerating the re-introduction of the biologic well.

There has been some research on loss of response and re-starting a biologic after it stopped working the first time. In one study on patients with inflammatory bowel disease (IBD), Remicade was started after a drug holiday of about 15 months. The reasons for stopping in the first place were infusion reactions, pregnancy, loss of response, or an infusion reaction. The researchers found that while some patients did have infusion reactions, 70% of patients were still responding one year after starting Remicade again along with an immunomodulator (such as 6-MP or azathioprine).

Therapeutic Drug Monitoring

One way of tracking the formation of anti-drug antibodies is through therapeutic drug monitoring. With a blood test, it can be determined how much of a drug is in one’s system and if there are any anti-drug antibodies.

The level of anti-drug antibodies is important. A low concentration of antibodies might not be considered clinically relevant. This means that the level of antibodies in the blood isn’t high enough to make any changes to either the dosage of the drug or to how often it is given. In some cases, if there are low amounts of antibodies but the drug also appears to be working not as well to control inflammation, it could be decided to add another drug, such as an immunomodulator. 

A high level of antibodies, however, could mean, for instance, that there is a loss of response. A loss of response with a biologic medication could mean that it is not as effective as it once was in controlling inflammation or symptoms.

Drug monitoring tests can help in watching the antibody levels in order to be proactive about a loss of response. If antibodies are high and the drug level is low, this could mean that the drug isn’t going to be as effective, even if the dose is increased. In that case, it might be decided to switch to another drug.

The Role of Steroids in Preventing Antibodies

In some cases, steroids (like prednisone) are given before an injection or an infusion of a biologic medication. The idea behind giving this medication is to suppress the formation of antibodies. However, it might not work exactly in that way.

One study was done with 53 patients who were receiving Remicade to treat Crohn’s disease. The study participants were randomized to receive either hydrocortisone by IV or a placebo prior to receiving the Remicade. What happened was that 19 of the 53 developed antibodies (which was 36%). The level of antibodies was lower in those people with Crohn’s disease who had received the hydrocortisone versus those that had received the placebo. However, the researchers concluded that the hydrocortisone did not stop infusion reactions or the formation of antibodies. Steroids are still given as a pre-med for many people but its actual utility remains unclear.

How Developing Antibodies Affects Future Treatment

In some cases, developing antibodies to one biologic medication could mean that there is a higher risk of developing antibodies to another biologic. This has been studied in the class of biologics that are anti-tumor necrosis factor drugs.

For instance, it was shown that patients with IBD who developed antibodies to Remicade were more likely to also develop antibodies to Humira when switched to that drug. The researchers stress that this is important knowledge which can help physicians and patients make informed decisions when it comes to drug antibodies and in switching medications.

A Word From Verywell

Drug antibodies are an important aspect of receiving treatment with a biologic medication. There are still a lot of unknowns about antibodies. However, there are guidelines that are used in order to ensure that patients can be monitored for them and then make changes in a treatment plan when needed. Understanding drug antibodies and how to address them isn’t easy, even for physician specialists. It is key, though, to learn about the risk of antibodies, how monitoring for them will take place, and what might change if they develop. While there is some evidence that can help when deciding what to do if anti-drug antibodies become a problem, shared decision-making between patients and providers is an important part of the process.

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