Immunogenicity of Biotherapeutics


How can immunogenicity risk be better understood and managed throughout the development process?

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

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.

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 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 our customer testimonials, and see a list of some of our clients.


How are Industry Leaders Addressing Immunogenicity?

FDA, Genentech, TEVA, Pfizer, Janssen, FDA, Roche, Celgene, AbbVie, Roche, GSK, and Sanofi are just a few of the organizations who have sent speakers and delegates to our past Mastering Immunity 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

Join the Mastering Immunogenicity LinkedIn Group for topical discussions and updates.