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

When you hear the word biosimilar, you might think it’s just a cheaper copy of a brand-name biologic drug. But here’s the thing: unlike generic pills, which are exact chemical copies, biosimilars are made from living cells. And because they’re grown, not synthesized, tiny differences can creep in - differences that might affect how your immune system reacts.

Why Biosimilars Aren’t Like Generic Pills

Generic drugs are simple. If the original pill has 500 mg of acetaminophen, the generic has the same molecule, in the same form, made the same way. No surprises. Biosimilars? They’re not that simple. Take adalimumab - the active ingredient in Humira. It’s a monoclonal antibody, a protein made by genetically engineered cells. Even if two companies use the same DNA sequence, the cells they grow it in (Chinese hamster ovary vs. human cell lines), the nutrients they feed them, the temperature, the purification steps - all of it adds up. These small variations change how the protein folds, how sugars attach to it (glycosylation), or whether tiny clumps form. And your immune system? It notices.

What Is Immunogenicity, Really?

Immunogenicity means your body sees the drug as foreign and mounts a defense. It’s not always bad - your immune system does this every day to fight viruses. But when it happens to a drug you’re taking for rheumatoid arthritis or Crohn’s disease, it can turn into a problem. Your body starts making anti-drug antibodies (ADAs). These can stick to the drug and block it from working. Worse, some ADAs are neutralizing - they don’t just bind, they shut down the drug completely. In rare cases, like with cetuximab, they trigger a full-blown allergic reaction because of a sugar molecule (galactose-α-1,3-galactose) left over from the manufacturing process.

How Do Biosimilars Compare to the Original?

Regulators like the FDA and EMA say biosimilars must show no clinically meaningful difference from the reference product. That means the same effectiveness, the same safety profile, including immunogenicity. But here’s the catch: detecting tiny differences in immune response is hard. Two studies can use different tests and get different results. One might use a highly sensitive electrochemiluminescence (ECL) assay and find 13% of patients developed ADAs. Another using a less sensitive ELISA test might find only 5%. That’s not a real difference - it’s a measurement problem.

Real-world data tells a more nuanced story. The NOR-SWITCH trial in 2016 followed 481 patients switching from originator infliximab to its biosimilar CT-P13. The biosimilar group had a slightly higher ADA rate - 11.2% versus 8.5%. But no one had worse symptoms. A 2021 study of 1,247 rheumatoid arthritis patients found no difference in ADA rates between reference infliximab and CT-P13. Then there’s the Danish registry: for adalimumab, Humira had a 18.7% ADA rate, while Amgevita (its biosimilar) hit 23.4%. Statistically different? Yes. Clinically worse? No. Patients still responded well to treatment.

What Makes One Person More Likely to React?

It’s not just the drug. It’s you. Your genes, your disease, even what else you’re taking matter a lot. If you have rheumatoid arthritis, your immune system is already on high alert - you’re 2.3 times more likely to make ADAs than a healthy person. If you’re on methotrexate along with your biologic, your ADA risk drops by 65%. That’s why many doctors start patients on combo therapy - not just to boost effectiveness, but to lower immune reactions.

Your genetics play a role too. Certain versions of the HLA-DRB1*04:01 gene make you 4.7 times more likely to develop ADAs to some monoclonal antibodies. And if you’re immunocompromised - say, from chemotherapy or HIV - your body might not react at all. That’s not a good thing. It means the drug might work, but you’re not building the immune memory that could help if the drug ever stops working.

How you get the drug matters too. Injecting under the skin (subcutaneous) is more likely to trigger an immune response than an IV drip. Why? Because the skin is packed with immune cells. If you’re getting your drug weekly or monthly instead of every few weeks, your immune system has more chances to notice it. Chronic use beyond six months? That’s when tolerance often breaks down.

Manufacturing Is the Wild Card

Even if two biosimilars are made from the same cell line, one might have 6% protein aggregates, another only 3%. A 5% increase in aggregates? That triples your risk of immunogenicity. Host cell proteins - leftover bits from the manufacturing cells - are another culprit. If levels go above 100 parts per million, ADA rates jump 87%. And don’t forget the stabilizers. Rituxan uses polysorbate 20. Rixathon, its biosimilar, uses polysorbate 80. Sounds minor? Maybe. But these surfactants can affect how the protein behaves, how stable it is, and whether it clumps. And clumps? They’re like little flags waving at your immune system saying, “Hey, look at me - I’m foreign.”

How Do We Know It’s Safe?

Regulators don’t just accept claims. They demand proof. Before a biosimilar gets approved, companies must run head-to-head clinical trials using identical testing methods. The FDA requires a tiered approach: first screen for any antibodies, then confirm they’re real and specific, then check if they neutralize the drug. Neutralizing antibodies are the big red flag. Cell-based assays are preferred for these because they show actual biological effect - even if they’re less precise than lab-based tests.

The “totality of evidence” rule means regulators look at everything: how similar the molecules are at the atomic level, how they behave in lab tests, animal studies, and finally, human trials. If all lines point to similarity, they approve it. But they’re watching. Post-marketing surveillance tracks real-world outcomes. In Europe, 85% of infliximab prescriptions are now for biosimilars. In the U.S., it’s 45%. Why the gap? Legal battles and insurance hurdles, not safety fears.

What Do Patients and Doctors Really See?

On Reddit’s r/rheumatology, one patient wrote about severe injection site reactions after switching from originator etanercept to its biosimilar. Another said they switched to a biosimilar rituximab and felt no difference after three years. Neither story is rare. Doctors aren’t blind to this. A 2022 survey of 347 rheumatologists showed 68% think immunogenicity concerns are overblown. But 22% say they’ve seen real differences - mostly in patients who had bad reactions after switching, not from the start.

The takeaway? For most people, switching to a biosimilar is safe. But for a small group - maybe 1 in 20 - something changes. That’s why many experts now recommend switching only under supervision, with monitoring. If you’re stable on your original drug, switching isn’t always necessary. If you’re having side effects or losing response, it’s worth investigating - but don’t assume it’s the biosimilar’s fault. It could be your disease, your other meds, or even stress.

The Future: Smarter Testing, Fewer Surprises

The next wave of biosimilars will be smarter. Advanced mass spectrometry can now map protein structures with 99.5% accuracy. That means we’ll soon know not just if two proteins are similar, but exactly how they differ - and whether those differences matter. Some labs are already combining proteomics, glycomics, and immunomics to build risk profiles for individual patients. Imagine a test that tells you, based on your genes and immune history, whether you’re likely to react to a specific biosimilar. That’s not science fiction. It’s happening now in trials at UCSF and other centers.

For now, the message is clear: biosimilars are safe for most. They’ve saved billions in healthcare costs. But immunogenicity isn’t a myth. It’s a real, measurable, sometimes unpredictable variable. The goal isn’t to eliminate all differences - that’s impossible with living systems. The goal is to understand them, measure them accurately, and match the right drug to the right patient.