By Nitisha Pyndiah, PhD

One of the most challenging parts of your drug development is making sure that your drug does not elicit a detrimental immune response in the patient also known as immunogenicity. This immunogenic response can impact the efficacy and safety of the therapeutic product. There are ways to mitigate those immunogenicity risks and phase three clinical trials aim at directly looking at the response in patients and, according to FDA, resolve any ‘residual uncertainty’. But before reaching Phase 3, you should know enough about your product to avoid unforeseen events.

You will have to respond to regulatory bodies’ requirements, safeguard the safety of the patient and avoid loss of investment in your product development. Characterizing your biological product is crucial, understanding these complex products allows predicting whether a product is more, or less likely to induce immunogenicity in a patient based on previous studies and literature.

It is therefore of major importance to always keep in mind the immunogenicity risk during the development and have the appropriate tools to test and analyze this potential response.

We can help you navigate safely through your product development and mitigate the risk of immunogenicity to allow your product to benefit patients faster.

Let’s answer some of the most commonly asked questions about immunogenicity.

What to consider regarding immunogenicity when you are developing your product? 

A detrimental immune response to the therapeutic agent can be triggered in a patient through three ways:

  • The patient

Including genetic predisposition, the presence of already present antidrug antibodies from previous treatments, Fc receptors for IgG (FcγR)

The patient may develop anaphylactic reactions due to hypersensitivity to the therapeutic product, product neutralizing antibodies that may compromise the treatment, the immune response may alter pharmacokinetics/pharmacodynamics, the produced antidrug antibodies (ADA) may cross-react with endogenous proteins and trigger serious adverse reactions.

  • The therapeutic product

If is often thought that mainly protein drugs can elicit immunogenicity, but other biopharmaceuticals also can lead to an anti-drug antibody (ADA) response.

Drug-related factors that can affect immunogenicity include: Structure (amino acid sequence, tertiary structure), Post-translational modifications (glycosylation), Mode of action, Aggregates, Contaminants including process and product-related impurities.

  • The route of administration

Availability of immune cells and proteins at the site of entry will affect immunogenicity risk, indeed, it is broadly perceived that the subcutaneous route of administration poses a higher immunogenicity risk due to increased interactions of the therapeutic product with immune cells such as dendritic cells present at the site of injection, but it is still controversial whether this route is more immunogenic. This route is often preferred for the convenience offered to patients when it comes to home administration.

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Mitigating immunogenicity risks is made on a case by case basis and relies on the characteristics of your therapeutic product. Want to learn more about how to mitigate the risks of immunogenicity? Contact us now. We can conduct an immunogenicity risk assessment for you.

What is the mechanism of immunogenicity? 

Immunogenicity involves both innate immunity and adaptive immunity. Innate immunity proteins and cells activate and enhance the response to the therapeutic agent. We describe here, in a simplified manner, the complex mechanism of immunogenicity.

Immunogenicity involves several mechanisms, including a wide range of cells and molecules that have recognized the therapeutic agent as an antigen. (see figure below for mechanism)

Want to learn more about the mechanism and if your product may place patients at risk? Contact us now.

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How to assess immunogenicity?

The most common way and technically reasonable approach to evaluating immunogenicity are through antibodies that the patient generates against the therapeutic product. These antibodies are called anti-drug antibodies (ADA) and can be tested using several methods and assays can allow elucidating the effect and impact of the ADAs produced.

We can guide you in testing appropriately immunogenicity, understanding the requirements and help you save costs by making important decisions early in your product development as well as planning a smooth program. Contact us now.

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Immunogenicity risk assessments are expected by the regulatory authorities. EMA expects an Integrated Summary of Immunogenicity in your Marketing Application. FDA accepts this summary in your BLA.


Do you need to conduct an immunogenicity risk assessment? Do you need an Integrated Summary of Immunogenicity for the regulatory authorities? Are you in the process of developing a biological product? Do you need help preparing your IND or BLA? Contact us today to learn more about our services and how we can help you.


Nitisha Pyndiah - Biotech Consulting Services

Nitisha Pyndiah, PhD, is a Consultant where she provides advice for the development of biological, biotechnological, and biosimilar products.

Nitisha provides expertise in the areas of virology, molecular biology, microbiology, immunology, immunogenicity, quality control, GLP and GMP. She prepares and evaluates CMC sections, including FDA meeting documents; and conducts scientific and regulatory gap analyses. She supports technical, strategic, and operational regulatory affairs for recombinant proteins, monoclonal antibodies, and vaccines.