Immunogenicity in Biosimilars: Why Immune Responses May Differ from Reference Biologics

When you hear "biosimilar," you might think it’s just like a generic drug-cheaper, same active ingredient, same effect. But that’s not true. Biosimilars aren’t copies of biologics like generics are of small-molecule drugs. They’re made from living cells, not chemicals. And because of that, tiny differences in how they’re built can trigger your immune system in ways the original drug doesn’t. That’s immunogenicity-and it’s the biggest reason some patients react differently to biosimilars than to the reference biologic they’ve been on for years.

What Immunogenicity Really Means

Immunogenicity is when your body sees a drug as a threat and makes antibodies against it. These are called anti-drug antibodies, or ADAs. For some biologics, up to 70% of patients develop them over time. That sounds scary, but not all ADAs are dangerous. Some just stick to the drug and don’t do anything. Others, called neutralizing antibodies, actually block the drug from working. That’s when problems start-loss of effectiveness, flare-ups of your disease, or even serious reactions like anaphylaxis.

The key point: biosimilars aren’t required to be identical to the original. They’re required to be "highly similar" with no clinically meaningful differences. That’s a big gray area. Two batches of the same reference drug made years apart can differ slightly. So when a biosimilar manufacturer uses a different cell line, fermentation process, or purification method, even minor changes in sugar attachments (glycosylation) or protein folding can create new spots on the drug that your immune system hasn’t seen before.

Why Biosimilars Might Trigger a Stronger Response

It’s not about being "worse." It’s about being different in ways that matter to your immune system. Here’s how:

• Manufacturing differences: Most biologics are made in Chinese hamster ovary (CHO) cells. But some biosimilars use human cell lines. CHO cells add sugars differently than human cells. Even a 5% change in sialic acid or galactose on the protein surface can make it look more "foreign" to your immune cells.
• Aggregates and impurities: If a biosimilar has more than 5% protein clumps (aggregates), immunogenicity risk jumps 3.2 times. Host cell proteins left over from manufacturing-above 100 parts per million-correlate with 87% higher ADA rates. These aren’t always caught in standard tests.
• Stabilizers and excipients: One biosimilar version of rituximab uses polysorbate 80. The original uses polysorbate 20. That small change can affect how the protein behaves in your bloodstream, increasing the chance of clumping-and triggering immune responses.

These aren’t mistakes. They’re trade-offs. Biosimilar makers have to balance cost, stability, and shelf life. But your immune system doesn’t care about cost. It only cares if something looks like a threat.

How Your Body Affects the Outcome

It’s not just the drug. It’s you.

• Disease state: People with rheumatoid arthritis have 2.3 times higher risk of developing ADAs than healthy people. Their immune systems are already on high alert.
• Genetics: If you carry the HLA-DRB1*04:01 gene variant, your risk of developing antibodies to certain biologics goes up nearly fivefold. Most doctors don’t test for this-but it’s a major reason why some patients react and others don’t.
• Other meds: Taking methotrexate with a TNF inhibitor cuts ADA risk by 65%. It’s not just helping your joints-it’s calming your immune system down enough to ignore the drug.
• How you get the drug: Subcutaneous injections (shots under the skin) are 30-50% more likely to trigger an immune response than IV infusions. Why? Because your skin is packed with immune cells ready to react.

That’s why two people on the same biosimilar can have totally different outcomes. One stays stable. The other loses response and needs to switch back. It’s not the drug’s fault. It’s the combination of the drug’s subtle changes and your unique biology.

What the Studies Actually Show

You’ve probably heard that biosimilars are just as safe. That’s mostly true. But the data is messy.

In the NOR-SWITCH trial, 481 patients switched from originator infliximab to its biosimilar CT-P13. ADA rates went from 8.5% to 11.2%. Not a huge jump. But it was there. And in the Danish registry, adalimumab biosimilar Amgevita had a 23.4% ADA rate compared to 18.7% for Humira. The difference was statistically significant. Yet, clinical outcomes? Still comparable. So the immune system noticed the difference-but it didn’t always break your treatment.

On the flip side, a 2021 study of 1,247 rheumatoid arthritis patients found no difference in ADA rates between originator infliximab and CT-P13. Same drug, same disease, same method. No difference.

Why the contradiction? Because every study uses different tests. Some labs use highly sensitive electrochemiluminescence (ECL) assays. Others use older ELISA methods. One can detect 13.1% ADA. The other might only catch 5%. If a biosimilar study uses a less sensitive test than the reference drug’s original trial, it looks safer-even if it’s not.

And then there’s real life. On Reddit, one patient reported severe injection site reactions after switching to a biosimilar etanercept. Another said they’d been on three different biosimilars over three years with zero issues. Anecdotally, it’s all over the map. That’s because immunogenicity isn’t predictable. It’s personal.

How Regulators Handle the Risk

The FDA and EMA don’t ignore immunogenicity. They demand head-to-head comparisons under identical conditions. That means the same patient population, same dosing schedule, same assay method. No shortcuts.

Testing happens in three layers:

1. Screening: Does the patient have any antibodies at all?
2. Confirmation: Are those antibodies really targeting the drug, or just random noise?
3. Characterization: Are they neutralizing? Do they bind to the same spot as antibodies to the original drug?

For neutralizing antibodies, regulators prefer cell-based assays-even though they’re less precise-because they show real biological impact. A ligand-binding test might say "positive." But a cell assay can tell you if the drug can still bind to its target and block inflammation.

Still, there’s a gap. Most clinical trials last 6 months. But immunogenicity can take years to develop. That’s why real-world data is so important. And why regulators now require post-marketing surveillance studies.

What This Means for Patients

If you’re on a biologic and your doctor suggests switching to a biosimilar, here’s what you should ask:

• Is there data showing this biosimilar was tested head-to-head with my current drug using the same assay?
• What’s the rate of ADA development in studies? Was it measured the same way?
• Am I on methotrexate? If not, should I be?
• What signs should I watch for? Fatigue, joint pain returning, injection site redness, or flu-like symptoms after dosing?

Most patients switch without issue. But if you’ve had a good response for years, don’t assume switching is risk-free. Your immune system remembers. And if it reacts, you might need to go back to the original-sometimes after months of lost control over your disease.

The Future: Better Detection, Fewer Surprises

By 2027, advanced mass spectrometry will let manufacturers map the exact sugar structures on biologics with 99.5% accuracy. That means fewer surprises. New tools combining proteomics, glycomics, and immunomics are already being tested in clinical trials to predict who’s at risk before they even get the drug.

But until then, immunogenicity remains a quiet risk. Not because biosimilars are unsafe. But because biology is messy. And your immune system? It’s the ultimate detector of difference-even when the difference is too small to see.

That’s why the promise of biosimilars isn’t just about cost. It’s about trust. Trust that the tiny differences won’t break your treatment. Trust that your doctor knows when to watch. And trust that if something changes, you’ll be heard.