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

When you hear the word biosimilar, you might think it’s just like a generic drug-cheaper, same effect, no big deal. But that’s not true. Biosimilars aren’t chemically identical copies like your generic aspirin. They’re complex, living molecules made in living cells. And because of that, tiny differences in how they’re made can trigger your immune system in ways the original biologic doesn’t. That’s immunogenicity-and it’s not just a technical footnote. It’s the biggest reason some patients react differently to biosimilars than to the brand-name drug they’ve been on for years.

What Makes Biosimilars Different From Generics?

Generics are simple. They’re small molecules, made in a lab with exact chemical formulas. If you make 1,000 tablets, they’re all the same. Biosimilars? They’re proteins. Big, tangled, three-dimensional structures. They’re grown in cell cultures-usually Chinese hamster ovary cells or human cell lines. Even with the same DNA blueprint, the cells can tweak the final product in ways we can’t always control. Think of it like baking the same cake recipe in two different ovens. One might brown a little more. One might be a bit drier. Those differences seem tiny, but your immune system? It notices.

The FDA says biosimilars must have no clinically meaningful differences from the reference product. That sounds reassuring-until you realize what that really means. It doesn’t mean identical. It means the differences don’t change how well the drug works or how safe it is for most people. But for some? Those tiny changes matter.

How Your Body Reacts: Anti-Drug Antibodies

When your immune system sees a protein it doesn’t recognize as fully "self," it can start making antibodies against it. These are called anti-drug antibodies, or ADAs. They’re not always bad. Sometimes they just stick to the drug and do nothing. Other times, they block it from working. That’s when things get dangerous.

For drugs like adalimumab or infliximab-used for rheumatoid arthritis, Crohn’s, and psoriasis-up to 70% of patients can develop ADAs over time, even with the original biologic. But with biosimilars, the rate can shift. In one Danish study, the biosimilar Amgevita triggered ADAs in 23.4% of patients, compared to 18.7% for Humira. That’s a real difference. And while most patients still responded well to treatment, some saw their symptoms flare up. Others developed injection site reactions they never had before.

Why? It’s not just the protein itself. It’s what’s stuck to it. Sugars. Fats. Tiny bits of leftover cell material. These are called post-translational modifications. A difference in sialylation or galactosylation-changes that affect just 15-20% of the protein molecules-can make your immune system treat the biosimilar like an invader.

The Manufacturing Wildcard

The cell line used. The growth medium. The purification steps. Even the type of buffer in the vial. All of it matters.

One biosimilar version of rituximab uses polysorbate 80 as a stabilizer. The original uses polysorbate 20. Sounds like a small detail? It’s not. These surfactants can cause proteins to clump together. And protein aggregates? They’re a known trigger for immune responses. Studies show that if more than 5% of the drug is in aggregate form, the risk of ADAs jumps by over three times.

Then there are host cell proteins-leftover bits from the cells that made the drug. If levels go above 100 parts per million, ADA rates go up 87%. That’s not a typo. That’s a massive spike. And here’s the kicker: biosimilar manufacturers aren’t required to match the reference product’s impurity profile exactly. They just need to prove their product is safe. That leaves room for variation.

How You’re Made Matters Too

It’s not just about the drug. It’s about you.

Your genes play a huge role. If you carry the HLA-DRB1*04:01 allele, your risk of developing ADAs to certain biologics goes up nearly fivefold. Your immune system is already primed to react. If you have rheumatoid arthritis? You’re 2.3 times more likely to make antibodies than a healthy person. Your body is already in inflammatory overdrive.

Age, gender, and other medications matter too. People on methotrexate? Their ADA rates drop by 65%. That’s why doctors often prescribe it alongside biologics-it’s not just for joint pain. It’s a shield.

And the way you get the drug? Subcutaneous shots carry a 30-50% higher immunogenicity risk than IV infusions. Why? Because your skin is packed with immune cells. Every time you inject, you’re handing your immune system a direct sample of the drug. That’s why some patients report severe redness or swelling after switching to a biosimilar version of etanercept-something they never saw with the original.

Are the Studies Reliable?

Here’s the problem: not all immunogenicity tests are created equal.

Some labs use electrochemiluminescence (ECL) assays. Others use ELISA. ECL is more sensitive-it can detect ADAs in 13.1% of patients where ELISA only catches 5%. If one study uses ECL and another uses ELISA, you can’t compare them. That’s why the EMA insists that biosimilar trials must use the exact same testing method as the reference product trial. Otherwise, you’re not comparing drugs-you’re comparing tools.

Even the way you test for neutralizing antibodies is messy. Cell-based assays are more biologically relevant-they show if the antibody actually blocks the drug’s function. But they’re less precise. Their results can vary by 25-30%. Ligand-binding assays are more consistent, but they don’t tell you if the antibody is actually hurting the drug’s effect.

That’s why some studies show no difference in ADA rates between biosimilars and originals-like the NOR-SWITCH trial-and others do. It’s not always the drug. It’s the test.

What Does Real-World Data Show?

The data is mixed, but leaning toward reassurance.

A 2021 study of over 1,200 rheumatoid arthritis patients found no difference in ADA rates between infliximab and its biosimilar CT-P13. The NOR-SWITCH trial, which followed patients who switched from originator to biosimilar, saw a small uptick in ADAs-but no drop in effectiveness. No increase in side effects. No hospitalizations.

But then there’s the Danish registry. Amgevita showed higher ADA rates than Humira. And in Reddit threads, patients describe sudden rashes, fatigue, or flares after switching. One user wrote: "I felt like I was back to square one after the switch. My joints hurt worse than before. I went back to Humira-and boom, I felt normal again." Doctors are divided. A 2022 survey of 347 rheumatologists found 68% think immunogenicity fears are overblown. But 22% say they’ve seen real, clinically meaningful differences in practice.

That’s the gap. The science says "no meaningful difference." The patients say "I felt it." And both might be right.

What’s Next for Biosimilars?

The future isn’t about eliminating differences-it’s about detecting them before they hurt people.

New tools are coming. Advanced mass spectrometry can now map protein structures with 99.5% accuracy. Glycomics can analyze sugar patterns on the drug’s surface. Immunomics can predict which patients are genetically prone to reacting.

Some labs, like those at UCSF, are already combining these methods in clinical trials to build personalized risk profiles. Imagine knowing before your first injection: "Based on your genes and immune history, you have a 32% chance of developing ADAs to this biosimilar. We recommend sticking with the original." That’s not science fiction. It’s the next step.

For now, the message is simple: biosimilars are safe for most. But they’re not identical. And if you’ve been stable on a biologic for years, switching isn’t always harmless. If you notice new side effects after switching-rashes, fatigue, flares, injection site reactions-don’t brush it off. Talk to your doctor. Your immune system might be trying to tell you something.

What Should You Do?

If you’re considering a biosimilar:

• Ask your doctor if your current biologic has been tested for immunogenicity in clinical trials with the biosimilar version.
• Find out what testing method will be used to monitor ADAs-if any.
• If you’re on methotrexate or another immunosuppressant, ask if it’s still recommended with the biosimilar.
• Track your symptoms. Keep a journal. Note when you feel worse, better, or different after a dose.
• If you’ve had a good response for over a year, switching might not be worth the risk.

If you’ve already switched and feel off:

• Don’t assume it’s "all in your head."
• Ask for an ADA test. Not all clinics offer it-but many can send your blood out.
• Consider switching back. Many patients do-and feel better.

The goal isn’t to scare you away from biosimilars. They’ve saved billions in healthcare costs. They’ve made life-saving treatments accessible. But they’re not generics. They’re complex. And your immune system? It knows the difference.