Immunogenicity of Biotherapeutics

How can developers of biotherapeutics improve prediction and mitigation of immunogenicity risk?

The immunogenicity of biological drugs can potentially be a significant obstacle to development of successful new therapies. Unwanted immunogenicity can manifest itself through anti-drug antibody (ADA) responses. ADA responses can lead to allergic reactions, reduction or neutralization of the activity of the drug and in some cases cross-reactive immune responses, which could lead to serious adverse events.

Unwanted immunogenicity is also a factor to consider for those developing food additives, animal feed components, and consumer goods such as washing powder and cosmetics.

Many biological drugs that are currently in the clinic or already licenced show appreciable immunogenicity. What lessons can be learned from prior experience to improve the design and development of second-generation products, biosimilars and biobetters?

Drugs designed as fully humanized, for example the current generation of fully human monoclonal antibodies including Omalizumab and Alemtuzumab, might be expected to avoid unwanted immunogenicity by design.  However,  single nucleotide polymorphisms (SNPs) in related human proteins could cause a patient to recognize the ‘humanized’ molecule as foreign.

Immunogenicity risk varies considerably among different products, patient populations and treatment regimens. It is caused or influenced by a multitude of factors, which can be subdivided into intrinsic and extrinsic factors. Extrinsic factors include route of drug administration and immune history of a patient; intrinsic antigenicity refers to the ability of a protein to provoke an immune response based on its epitope content.  Both T and B cell epitopes in a biologic can cause cellular and humoral anti-drug immune responses.

For immunotherapeutic vaccines, understanding the epitopes eliciting a response to tumor or disease associated antigens is critical to designing the most effective treatment.  The assays that can be performed to understand this ‘desired’ immunogenicity are exactly the same as those designed to understand unwanted immunogenicity.

Evaluating the Relative Antigenicity of a Protein

Evaluating T Cell Epitopes

Antibody responses that are of high affinity and sufficient titer require the help of CD4+ T cell immune responses for their maturation. Contrary to the complex three-dimensional B cell epitopes that often depend on secondary and tertiary protein structure, CD4+ T cell epitopes are relatively short linear peptide stretches, typically 11-20 amino acids long. Identifying all potential CD4+ T cell epitopes in the protein content of a drug is therefore a powerful rational approach for assessing and comparing antigenicity of drug leads. The information on such epitopes can be used to identify the best lead from a group of candidates for a new drug. It also raises the possibility that T cell epitopes can be removed in order to avoid unwanted immunogenicity, by mutating key amino acid residues that do not affect drug potency.

The immunogenicity assays from ProImmune that can help you manage immunogenicity risk are outlined in the table below,   Each of our assays has the potential to be used in your immunogenicity risk management program either alone or in combination with other assays.

Our assays allow you to identify the presented epitopes from your protein, characterize the binding of these peptides to MHC in vitro, and measure the proliferative response of CD4+ T cells to peptide epitopes or to your fully formulated biologic.


Evaluating B Cell Epitopes

ADA responses will be directed towards B cell epitopes on a drug, and these epitopes can be mapped through a  combination of predictive conformational modelling and linear interaction mapping.

Taken together, these assays help to establish the most in-depth profile of  the helper T cell immune response to one or more drug leads. If desired, these leads can then be re-engineered to remove unwanted helper T cell epitopes. The best lead from this process can then be tested to validate that its ability to cause T cell proliferation has been reduced.

Working with ProImmune

Strategies recommended for immunogenicity evaluation and monitoring are specialized and take time to establish in-house. ProImmune is your expert partner of choice for outsourcing these aspects of your study, leaving you to focus energy on your core competencies.

ProImmune’s REVEAL® Immunogenicity System services are customizable and delivered in a straight forward manner. ProImmune is independently owned and free of any restrictions or tie-ins as a service provider. We do not develop our own therapeutic pipeline and we have not entered into any strategic alliances that would restrict our capacity to work in specific target areas. In practise this means that our customers do not have to worry about potential conflicts of interest or complex payment structures.

Our services can be tailored to your specific project requirements, providing a flexible and cost effective solution as part of your drug development process.

To help you decide whether ProImmune is the right partner for you, review customer testimonials, and see a list of some of our clients


How are Industry Leaders Addressing Immunogenicity?

Genentech, Pfizer, Syngenta, Apitope, AbbVie, Roche and the FDA were among the organizations who have sent speakers and delegates to our past Mastering Immunogenicity Conferences.  The conference brings together regulators and research scientists from academia and industry to discuss methods and technologies for immunogenicity risk management.

Watch videos of the Mastering Immunogenicity conference talks

Download presentations from the Mastering Immunogenicity conference

Scientists at Baxter have published their work studying adverse responses to recombinant Factor VIII treatment using ProImmune’s Immunogenicity Risk Management Services

Drawing on the discussion sessions at the meeting and also on our own expertise, we have written a white paper:

Managing Immunogenicity Risk Through Assay-based Rational Drug Design and Selection

In January 2011 we published a review article in Drug Discovery and Development on Managing Biopharmaceutical Immunogenicity Risk summarizing the technologies available.


More information can be found in the ProImmune Immunogenicity Knowledge Base

After the ProImmune Mastering Immunogenicity Meeting, we put together a range of resources requested by conference attendees, for all of our customers to access,

Immunogenicity Knowledge Base


Join the ‘Mastering Immunogenicity’ LinkedIn Group for topical discussions and updates:Join our Mastering Immunogenicity LinkedIn Group


back to top