What It Means to Develop Antibodies to Biologics

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

One of the complications of treatment with biologic medications is the formation of anti-drug antibodies. These antibodies can affect how well the drug works to treat disease, and can even render the drug no longer useful. Biologics may be prescribed for the treatment of many different diseases and conditions, especially inflammatory diseases. If you are a candidate for treatment with a biologic medication, it is useful to know how anti-drug antibodies are monitored and prevented, as well as the effects they may have on your treatment.



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What Is a Biologic?

A biologic is a type of medication that is created inside a living cell, which can be from a human, an animal, or a microorganism. They are manufactured in a controlled, engineered environment. 

Biologic medications are engineered to treat inflammation and they are used to treat many conditions, including inflammatory bowel disease (IBD), rheumatoid arthritis, psoriasis, ankylosing spondylitis, and hidradenitis suppurativa. These treatments 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 production and chemical composition of biologics are more complex than that of most medications. Biologics are large molecules, with a high 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 requires highly controlled conditions. Because of the challenges involved in their development, manufacture, and distribution, they tend to be very expensive.

It’s not possible to make exact copies of a biologic, so creating “generic” that is exactly the same as the original isn’t possible. It is possible to make a biologic that is similar to the original. These are called “biosimilars.” 

Biologics and Immune Response

Because biologics are created using living cells, they can trigger an unintended immune response in which the body forms anti-drug antibodies that actually "fight" the drug.

Almost all biologic medications can lead to the development of anti-drug antibodies, though the risk is different for each individual drug. This is true for biologics whether they are derived from human, animal, or microorganism sources. The anti-drug antibodies could make the drug less effective.

Effects and Management of Anti-Drug Antibodies

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

Solutions for this problem include the addition of a co-therapy, an increase in the drug dosage or frequency, or a change to a different drug altogether.

There are pros and cons to each solution. For example, if you take your biologic drug more often, there's a potential for there to be too much of the drug in your system. And the cost is a limitation, as biologics tend to be expensive to manufacture and administer.

The Potential for Anti-Drug Antibodies

It’s not clear why some people develop these antibodies and others do not, although it may be due to genetic differences.

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 prevent the immune response. Other strategies include slowing down the rate at which the drug is given during an infusion and doing regular blood tests to monitor the presence and/or level of anti-drug antibodies (called therapeutic drug monitoring).

Research on Prevalence

Not every biologic medication is associated with the same chance of creating antibodies, and it's possible that certain immune diseases could result in different anti-drug antibody responses.

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).

And 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, you might stop receiving a biologic drug for a while. This is sometimes called a “drug holiday.”

Reasons for a drug holiday:

  • The disease entering remission
  • Before and after elective surgery
  • During an infection
  • During pregnancy
  • Loss of health insurance or other financial reasons

Loss of response to the biologic is also a reason for stopping a drug and switching to another type of therapy.

It might be possible to start the same drug again after a drug holiday, but there may be some considerations. Your doctor might monitor you to look for antibodies during the drug re-introduction.

There has been some research on 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 were infusion reactions, pregnancy, or loss of response. The researchers found that while some patients who restarted did have infusion reactions, 70% of patients were still having a beneficial response one year after starting Remicade again along with an immunomodulator (such as 6-MP or azathioprine).

If you stopped taking a drug 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.

Therapeutic Drug Monitoring

With therapeutic drug monitoring, the drug level is considered when deciding whether to continue or stop these medications. The level of anti-drug antibodies is also an important factor.

A blood test can measure how much of a drug is in your system and if you have any anti-drug antibodies.

  • A low concentration of antibodies might not be considered clinically relevant. If someone has a low level of antibodies with a therapeutic amount of drug, the drug might be continued without making any changes to either the dosage of the drug or how often it is given.
  • In some cases, if there are low amounts of antibodies but the drug doesn't appear to be working as well to control inflammation, another drug, such as an immunomodulator, might be added. 
  • A high level of antibodies could mean that you've had a loss of response to the drug and that it is not as effective as it once was in controlling inflammation or symptoms.
  • 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

The addition of methotrexate is considered key to preventing the development of anti-drug antibodies, particularly with Humira and Remicade.

In some cases, steroids (like prednisone) are given before an injection or an infusion of a biologic medication. Steroids are given as a pre-medication for many people.

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.

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.

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

A Word From Verywell

There are many considerations to keep in mind when you have an autoimmune disease. Make sure you tell your doctor about any symptoms you're experiencing—they could be due to your disease or they could be side effects of treatment. If you develop anti-drug antibodies to the biologics you're taking, you might need to have a modification of your therapeutic plan. There are still a lot of unknowns about anti-drug antibodies. Currently, there are guidelines for monitoring and for making changes in treatment when needed, and you can ask your medical team to help you understand the reasons for any adjustments.

11 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
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Additional Reading

By Amber J. Tresca
Amber J. Tresca is a freelance writer and speaker who covers digestive conditions, including IBD. She was diagnosed with ulcerative colitis at age 16.