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 generics. They’re made from living cells, and even tiny differences in how they’re grown or processed can change how your body reacts to them. One of the biggest concerns doctors and patients worry about? Immunogenicity - the chance your immune system will see the drug as a threat and start attacking it.

What Exactly Is Immunogenicity?

Immunogenicity means your body produces antibodies against a drug. These are called anti-drug antibodies, or ADAs. It’s not rare. Some biologic drugs trigger ADAs in up to 70% of patients. That doesn’t always mean trouble - sometimes the antibodies just float around harmlessly. But when they’re neutralizing antibodies, they can block the drug from working. In worst-case scenarios, they can cause serious reactions like anaphylaxis. That’s what happened with cetuximab, where a sugar molecule on the drug triggered IgE-mediated allergic shock in some patients.

The scary part? Even fully human proteins - ones that look exactly like your own - can cause this. Why? Because the way they’re folded, or the tiny spots on their surface (called epitopes), can be new to your immune system. Think of it like recognizing a face. Even if someone looks exactly like your friend, if they’re wearing a different hat or have a new scar, your brain might think, “Wait, that’s not them.” Your immune system does the same thing.

Why Do Biosimilars Sometimes Trigger Different Reactions?

Biosimilars are designed to be “highly similar” to the original biologic, but they’re not exact clones. The original drug is made in one factory, using one cell line, one process. The biosimilar is made in another factory, maybe with a different type of hamster or human cell, different temperature controls, different purification steps. All of that can change how the protein is modified after it’s made - something called post-translational modification.

These changes might sound small, but they matter. For example:

• One biosimilar might have more sialic acid on its surface - that’s a sugar that helps hide the protein from your immune system.
• Another might have slightly more galactose, which can make the protein stickier and more likely to clump.
• Or it might contain tiny bits of leftover host cell proteins from the manufacturing process - even 100 parts per million can spike ADA rates by 87%.

Protein aggregates - clumps of the drug that shouldn’t be there - are another big trigger. If more than 5% of the product is aggregated, immunogenicity risk jumps 3.2 times. That’s why regulators demand ultra-tight controls. But even with strict standards, small differences creep in.

How You Get the Drug Matters Too

It’s not just about the drug. It’s also about how it gets into your body. Subcutaneous injections - the kind you give yourself in the thigh or belly - are way more likely to cause an immune response than IV infusions. Why? Because the skin and fat tissue are packed with immune cells. When you inject a protein there, your body sees it as an invader right away. Studies show subcutaneous delivery increases immunogenicity risk by 30-50% compared to IV.

Frequency matters too. If you’re getting a shot every week, your immune system has more chances to notice the drug. Continuous dosing - like getting an infusion every 8 weeks - gives your body time to get used to it. Intermittent dosing? That’s like waking your immune system up every few weeks and saying, “Hey, remember this weird thing?” It’s more likely to fight back.

Your Body’s Role in the Reaction

You’re not a blank slate. Your immune system has its own history. If you have rheumatoid arthritis, your risk of developing ADAs is 2.3 times higher than a healthy person’s. Why? Because your immune system is already on high alert. It’s primed to react.

Genetics play a role too. People with a specific gene variant - HLA-DRB1*04:01 - are 4.7 times more likely to develop antibodies against certain biologics. It’s not something you can test for routinely, but it helps explain why some people react and others don’t.

And then there’s what else you’re taking. Methotrexate, a common arthritis drug, cuts ADA rates by 65% when used with TNF inhibitors. It’s like putting a brake on your immune system so it doesn’t overreact to the biologic. That’s why many patients get both drugs together - not just for better results, but to keep the immune system quiet.

What Do the Studies Really Show?

Real-world data gives mixed signals. Some studies say there’s no difference. Others say there’s a small but real gap.

The NOR-SWITCH trial in 2016 followed 481 patients who switched from originator infliximab to its biosimilar. The biosimilar group had slightly more ADAs - 11.2% vs. 8.5%. But here’s the catch: those extra antibodies didn’t lead to worse outcomes. Patients didn’t lose response, didn’t have more side effects.

Then there’s the Danish registry study on adalimumab. They found 18.7% of patients on Humira developed ADAs, but 23.4% on the biosimilar Amgevita did. The difference was statistically significant - p=0.03. Yet, both groups had similar clinical results. So the immune system reacted more often to the biosimilar, but it didn’t break the drug’s effectiveness.

A 2021 study of 1,247 rheumatoid arthritis patients on infliximab or its biosimilar CT-P13 found almost identical ADA rates: 12.3% vs. 11.8%. No difference.

And then there are the patient stories. One person on Reddit reported severe injection site reactions after switching from originator etanercept to its biosimilar. Another said they’d been on both rituximab versions for three years and couldn’t tell the difference. Neither story proves anything, but they remind us: people aren’t data points.

How Do We Even Measure This?

Here’s the messy part: measuring immunogenicity is hard. Different labs use different tests. Some use electrochemiluminescence (ECL) assays - super sensitive. Others use older ELISA methods. One study found ECL detected ADA rates as high as 13.1%, while other methods saw only 5%. That’s not a real difference in patients - that’s a difference in tools.

Regulators know this. The EMA says you must compare biosimilars and reference products using the exact same assay, side by side. The FDA requires parallel or crossover trials with identical testing methods. But not all studies follow this. And when they don’t, you get confusing results.

Neutralizing antibody tests are even trickier. Cell-based assays are more realistic - they show if the antibody actually blocks the drug’s function - but they’re less precise. Their variability can be 25-30%. Ligand-binding assays are more accurate, but they might miss functional effects. So regulators ask for both.

What’s Changing Now?

The field is moving fast. Five years ago, we couldn’t see the tiny differences in sugar chains on proteins. Now, advanced mass spectrometry can analyze glycosylation patterns with 99.5% accuracy. By 2027, manufacturers will be able to design biosimilars that match the original protein’s sugar profile almost perfectly.

Some companies are already using multi-omics approaches - combining proteomics (protein structure), glycomics (sugar patterns), and immunomics (how immune cells respond) to predict immunogenicity before a drug even hits the market. Universities like UCSF are running trials using these tools, and early results look promising.

Still, the FDA warns: even tiny changes - less than 5% - in the Fc region of a protein can alter how immune cells interact with it. That’s enough to trigger a response in sensitive people.

Should You Be Worried?

If you’re on a biologic and your doctor suggests switching to a biosimilar, the answer is usually: no, don’t worry. The vast majority of patients switch without issue. In Europe, 85% of infliximab prescriptions are now for biosimilars. In the U.S., adoption is slower, but growing. The real barrier isn’t safety - it’s cost, patents, and insurance rules.

The data shows: biosimilars are safe. They work. Immunogenicity rates are similar, and when differences occur, they rarely affect outcomes.

But that doesn’t mean we ignore the risk. It means we monitor. If you start having new side effects after a switch - rashes, fever, worsening joint pain, or injection site reactions - tell your doctor. It might be nothing. Or it might be your immune system reacting.

The goal isn’t to avoid biosimilars. It’s to use them wisely. With better testing, better manufacturing, and better understanding of patient factors, we’re getting closer to a future where switching is seamless. Where the only difference between a biosimilar and its originator is the price tag.