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 pill-cheaper, same effect, no big deal. But biologics aren’t pills. They’re complex proteins made in living cells, and their biosimilars aren’t exact copies. They’re incredibly close, but not identical. And that tiny difference? It can sometimes trigger your immune system in ways the original drug never did.

Why Your Body Might React Differently

Biologics like Humira or Enbrel are made using living cells-usually Chinese hamster ovary cells. These cells tweak the protein after it’s made, adding sugar molecules (glycans), changing how the protein folds, or adding tiny chemical tags. That’s called post-translational modification. Even small shifts in those changes-like more or less sialic acid, or different galactose patterns-can turn a harmless protein into something your immune system sees as foreign.

That’s immunogenicity. It’s not rare. Up to 70% of patients on some monoclonal antibodies develop anti-drug antibodies (ADAs). These aren’t always bad. Some just stick to the drug and clear it faster. But when they block the drug’s active site or cause inflammation, that’s when things get dangerous. Think anaphylaxis with cetuximab, or reduced effectiveness in rheumatoid arthritis patients who suddenly stop responding to their TNF blocker.

Biosimilars are built to match the original. But if the manufacturer uses a different cell line, or a different purification process, those sugar tags might look slightly different. One study found that protein aggregates-tiny clumps of misfolded protein-over 5% of the total product increased ADA risk by more than three times. Host cell proteins left behind from manufacturing? More than 100 parts per million? That’s linked to an 87% higher chance of your body attacking the drug.

How You’re Treated Matters Just as Much

It’s not just about the drug. It’s about how you get it.

Subcutaneous injections-like those for adalimumab or etanercept-carry a 30-50% higher immunogenicity risk than intravenous infusions. Why? Because the drug sits under your skin for hours, slowly leaking into immune-rich tissue. Your dendritic cells have time to grab it, process it, and show it to your T cells. IV delivery? It goes straight into your bloodstream. Less exposure. Less chance for your immune system to notice.

Dosing frequency plays a role too. If you’re getting a shot every week, your immune system gets constant reminders. Intermittent dosing? That’s like waving a flag in front of your immune cells every few months. It’s more likely to react. And the longer you’re on the drug? The more likely your immune system will break tolerance. After six months, ADA rates start climbing steadily.

Then there’s what else you’re taking. Methotrexate, a common RA drug, cuts ADA formation by 65% for TNF inhibitors. Why? It suppresses the immune cells that make antibodies. Patients on combo therapy rarely develop ADAs. Those on monotherapy? Much higher rates.

Your Genetics and Health Play a Part

Not everyone reacts the same. Your genes matter.

People with the HLA-DRB1*04:01 allele are nearly five times more likely to develop ADAs against certain biologics. That’s not a guess-it’s backed by multiple studies. If you’re of European descent and have rheumatoid arthritis, your odds of having this gene are higher. That’s one reason why immunogenicity rates vary across populations.

Your disease state matters too. Healthy volunteers show low ADA rates. Patients with active rheumatoid arthritis? Their immune systems are already revved up. Studies show they’re 2.3 times more likely to develop ADAs than healthy people given the same drug. Inflammation breaks immune tolerance. It’s like your body is already on high alert-and the drug is just another thing to attack.

Even your immune status changes things. If you’re on chemotherapy or have HIV, your ADA rates drop. Why? Because your immune system is too weak to mount a strong response. That’s not a good thing-it just means the drug might stay active longer, but you’re also more vulnerable to infections.

Are Biosimilars Really Different? The Evidence

Let’s cut through the noise. Do biosimilars cause more immunogenicity?

The data is messy-but mostly reassuring.

The NOR-SWITCH trial, which followed 481 patients switching from originator infliximab to its biosimilar CT-P13, saw a small uptick in ADA rates: 8.5% vs. 11.2%. But no one had worse outcomes. No more flares, no more hospitalizations. The same was true in a large 2021 rheumatoid arthritis study of 1,247 patients: 12.3% on the original, 11.8% on the biosimilar. No difference.

But then there’s the Danish registry. For adalimumab, Humira had a 18.7% ADA rate. Amgevita, the biosimilar? 23.4%. Statistically significant. But here’s the kicker: patients on both drugs still responded just as well to treatment. No drop in remission rates. No increase in side effects.

Real-world Reddit threads tell another story. One patient reported severe injection site reactions after switching from Enbrel to its biosimilar. Another switched from Rituxan to Rixathon and saw zero difference after three years. Both are real. Neither is the whole picture.

The American College of Rheumatology surveyed 347 rheumatologists. Two-thirds said immunogenicity concerns are overblown. One in five say they’ve seen real differences in practice. That’s not a contradiction. It’s reality. For most, it’s fine. For a few, it’s not.

How Regulators Check for Differences

The FDA and EMA don’t just approve biosimilars based on a few lab tests. They demand a full picture.

First, analytical studies. Thousands of comparisons: protein structure, glycosylation patterns, charge variants, aggregation levels. Then functional tests: does it bind to the same receptors? Does it trigger the same cell death in cancer cells? Then animal studies. Then human trials.

The immunogenicity part? It’s the hardest. You can’t just compare one assay. You need the same test, done the same way, on the same patients. That’s why head-to-head trials are required. If one study uses electrochemiluminescence (ECL) and another uses ELISA, you’re comparing apples to oranges. ECL can detect ADAs in 13% of patients. ELISA? Maybe 5%. That’s not a drug difference-that’s a method difference.

Neutralizing antibodies? Those need cell-based assays. They’re less precise-25-30% variation-but they show if the antibody actually blocks the drug’s function. That’s what matters clinically.

And formulation? That’s sneaky. Rixathon uses polysorbate 80. Rituxan uses polysorbate 20. One might cause more protein clumping. That’s not a biosimilar flaw-it’s a formulation choice. But regulators now require manufacturers to prove those stabilizers don’t increase immunogenicity risk.

What’s Next? Better Tools, Better Safety

The future is in precision.

By 2027, advanced mass spectrometry will be able to map glycosylation patterns at 99.5% accuracy. That means we’ll know if a biosimilar’s sugar tags are truly identical to the original-not just "similar enough." Some labs are already combining proteomics, glycomics, and immunomics. They’re not just looking at the drug. They’re looking at how your immune cells respond to it. At UCSF, clinical trials are using these multi-omics tools to predict who’s at risk before they even start treatment.

The goal isn’t to make every biosimilar perfect. It’s to know which ones are safe for which patients. For most people, biosimilars work just fine. For a small group? We’re getting better at spotting who might react-and why.

Bottom Line

Biosimilars aren’t generics. They’re not copies. They’re near-identical twins with tiny differences. Those differences can, in rare cases, trigger immune responses that the original drug didn’t. But for the vast majority, they’re just as safe and effective.

The key takeaway? Don’t assume all biosimilars are the same. Don’t assume your body will react the same way to every version of the same drug. If you switch and notice new side effects-rash, fatigue, joint pain, or loss of effectiveness-talk to your doctor. It might not be your disease flaring. It might be your immune system reacting to a new version of the drug.

The science is evolving. The data is growing. And for now, the evidence says: biosimilars are a win for affordability, and mostly, a win for safety too.