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 version of a biologic drug-like a generic pill but for injections. But that’s not quite right. Unlike generic drugs, which are exact chemical copies of their brand-name counterparts, biosimilars are made from living cells. That means tiny differences in how they’re grown, processed, or stabilized can change how your body reacts to them. One of the biggest concerns doctors and patients have is immunogenicity: the chance that your immune system will see the drug as a threat and start attacking it.
What Immunogenicity Really Means
Immunogenicity isn’t just about getting a rash or feeling a little sore at the injection site. It’s when your body produces anti-drug antibodies (ADAs)-proteins your immune system makes to neutralize what it thinks is an invader. These ADAs can bind to the drug and block it from working. In worst-case scenarios, they can cause serious reactions like anaphylaxis or make the drug completely useless over time. Take cetuximab, a cancer drug. Some patients developed life-threatening allergic reactions because the drug carried a sugar molecule-galactose-α-1,3-galactose-that’s not found in humans but is common in certain animal cell lines used to make it. That’s not a flaw in the drug itself; it’s a side effect of how it was made. And that’s exactly why biosimilars can’t be treated like generics.Biosimilars Aren’t Copies-They’re Close Relatives
Biologics are made using living cells, usually Chinese hamster ovary (CHO) cells or human cell lines. These cells are like tiny factories. Even if two factories use the same recipe, slight differences in temperature, nutrients, or pH can change how the final product folds, adds sugars, or clusters together. These changes are called post-translational modifications. A single sugar group added or missing can alter how the drug interacts with your immune cells. The FDA says biosimilars must have “no clinically meaningful differences” from the original. But “clinically meaningful” doesn’t mean “identical.” It means the end result works the same way in patients. That’s why regulators require thousands of lab tests-analytical, functional, and animal studies-before even thinking about human trials. Still, the most important test happens in people: the immunogenicity comparison.Why Some Patients React Differently
It’s not just the drug. Your body plays a huge role too.- How you get the drug: Injecting under the skin (subcutaneous) triggers immune responses more often than IV infusions. Subcutaneous delivery exposes the drug to immune cells in the skin and lymph nodes, which are basically the body’s alert centers. Studies show this route increases ADA risk by 30-50%.
- How often you take it: If you’re getting doses every few weeks, your immune system has time to notice and react. Continuous therapy-like weekly infusions-can actually train your body to tolerate the drug.
- Your health: People with autoimmune diseases like rheumatoid arthritis already have overactive immune systems. Their risk of developing ADAs is more than double that of healthy people.
- Your genes: Certain versions of the HLA-DRB1 gene make some people much more likely to respond to specific drugs. One variant increases ADA risk by nearly five times.
- What else you’re taking: Methotrexate, a common rheumatoid arthritis drug, cuts ADA formation by 65% when used with TNF inhibitors. It’s not just helping your joints-it’s calming your immune system’s overreaction.
Manufacturing Differences That Matter
Two biosimilars made from the same reference drug can still differ in ways that affect immunity.- Protein aggregates: If more than 5% of the drug forms clumps (aggregates), immunogenicity risk jumps 3.2 times. These clumps look like invaders to your immune system.
- Host cell proteins: Leftover proteins from the manufacturing cells can trigger immune responses. If levels go above 100 parts per million, ADA rates go up 87%.
- Stabilizers: Rituxan uses polysorbate 20. Rixathon, its biosimilar, uses polysorbate 80. These aren’t just random additives-they can change how the protein behaves in your body. One might cause more aggregation than the other.
- Glycosylation: The pattern of sugars attached to the protein (especially in the Fc region) affects how it interacts with immune cells. Even a 3% difference can change whether the drug triggers inflammation or suppresses it.
What the Data Shows-Real Patients, Real Results
The big question: Do biosimilars really cause more immune reactions? Studies give mixed answers. In a 2021 trial with over 1,200 rheumatoid arthritis patients, the biosimilar CT-P13 and the original infliximab had almost identical ADA rates: 11.8% vs. 12.3%. No difference. No clinical impact. But in another study of adalimumab biosimilars, patients on Amgevita had a 23.4% ADA rate compared to 18.7% on Humira. Statistically significant. But here’s the twist: both groups had the same clinical outcomes. The immune response didn’t hurt their disease control. Then there’s the NOR-SWITCH trial, where patients were switched from originator to biosimilar. The biosimilar group had slightly higher ADA rates (11.2% vs. 8.5%), but again, no drop in effectiveness or rise in side effects. Patient stories online are all over the place. One person on Reddit reported severe injection reactions after switching to a biosimilar etanercept. Another, on the same forum, said they’d switched between six different biosimilars over three years with zero issues. The American College of Rheumatology surveyed 347 rheumatologists. Two-thirds said immunogenicity concerns are overblown. But one in five said they’ve seen real, clinically relevant differences in their patients.
How Scientists Measure Immune Responses
This is where things get tricky. Not all tests are created equal. The FDA requires a tiered approach:- Screening: A highly sensitive test (like electrochemiluminescence) finds any antibodies that might be present.
- Confirmation: A second test checks if those antibodies are actually targeting the drug and not something else.
- Characterization: Does the antibody neutralize the drug? Is it just binding, or is it blocking it?
The Future: Better Tools, Fewer Surprises
The field is moving fast. New tools are making it easier to spot tiny differences before a drug even reaches patients. Mass spectrometry is now so precise it can map every sugar group on a protein with 99.5% accuracy. That means manufacturers can tweak their processes to match the original down to the last molecule. By 2027, experts predict we’ll be able to eliminate immunogenicity risks caused by structural differences entirely. Meanwhile, researchers are combining proteomics (protein analysis), glycomics (sugar analysis), and immunomics (immune response mapping) to predict who’s at risk before they even get the drug. Clinical trials are already testing this in patients with conditions like Crohn’s disease and lupus. The goal isn’t to stop biosimilars. It’s to make them safer, more predictable, and more trustworthy.What This Means for Patients
If you’re considering switching from a biologic to a biosimilar, here’s what you need to know:- Most people won’t notice a difference. For the vast majority, biosimilars work just as well.
- If you’ve had a good response to your current drug, there’s no urgent need to switch.
- If you do switch, watch for new symptoms: unusual fatigue, joint pain returning, rashes, or swelling at the injection site.
- Don’t panic if your doctor orders an ADA test. It’s routine-not a sign something’s wrong.
- Ask about your treatment plan. Are you on methotrexate? Are you getting the drug IV or by injection? These factors matter more than the brand name.
Are biosimilars safe if they cause immune responses?
Yes, for most people. Even when anti-drug antibodies form, they don’t always affect how well the drug works. Many patients develop low-level ADAs without any loss of effectiveness or new side effects. The key is monitoring-if your symptoms change or your disease flares, your doctor can test for neutralizing antibodies and adjust your treatment. The goal isn’t to avoid all immune responses-it’s to avoid clinically meaningful ones.
Can I switch back to the original biologic if I have a reaction to a biosimilar?
Yes, and many patients do. Switching back is common in clinical practice, especially if you develop new symptoms like injection site reactions, increased fatigue, or a return of disease activity. Studies show that patients who switch back usually regain their original response. There’s no evidence that switching multiple times increases long-term risk. The bigger issue is cost-originator biologics are often much more expensive, so insurance may require you to try the biosimilar first.
Why are biosimilars cheaper if they’re so complex to make?
They’re cheaper because manufacturers don’t have to repeat the full clinical trials the original company did. Instead, they prove similarity through detailed lab tests and targeted studies. That cuts development time from 10-12 years to 5-7 years and saves billions in R&D costs. The manufacturing process is still expensive-biologics cost $100-$500 per dose to make-but without the need to fund massive Phase III trials, the price can drop by 30-70%.
Do all biosimilars have the same risk of immunogenicity?
No. Each biosimilar is its own product. Even two biosimilars of the same reference drug can have different immunogenicity profiles because of manufacturing differences. For example, one might use a different cell line, purification method, or stabilizer. That’s why regulators require each biosimilar to be tested individually. You can’t assume that because one biosimilar is safe, another one is too.
Is immunogenicity worse with long-term use?
Yes, over time. Immune tolerance doesn’t happen overnight. Many patients don’t develop antibodies until after 6-12 months of treatment. That’s why long-term studies are so important. Short-term trials might show no difference, but real-world data over 2-5 years reveals patterns that clinical trials miss. That’s why registries like the Danish Biologics Registry track patients for years-they’re the ones catching what early studies overlook.
