Current Edition

Pre-existing Immunogenicity: How Will Cell and Gene Therapies Change Our Testing Approach?

When bringing a therapeutic to market, determining its potential to elicit an immune response and understanding the molecular and cellular interactions involved is essential. In some patients, it is possible that a previous exposure event to certain antigens associated with the therapeutic can prime the immune system for re-infection. The resulting pre-existing immunogenicity may affect both the safety and efficacy of the drug in these patients.

As we move into a new era where cell and gene therapies (C&GTs) are frequently gaining approval for use, it is important to consider how best to approach preexisting immunogenicity assessment for these relatively new modalities. With the C> space expanding so quickly, developers must exhibit flexibility in their bioanalytical decisions and methods – ready to weather regulatory requirements as they evolve.

In this article, Chief Scientific Officer at BioAgilytix, Jim McNally, Ph.D., explores why bioanalysts should prepare for the impending wave of C&GTs entering the development pipeline and the considerations they must make in their pre-existing immunogenicity assessments.

How Pre-existing Immunogenicity Can Determine Therapy Success

When developing any biologic therapy, it is essential to understand the prevalence and potential impact of patients’ pre-existing immunogenicity. Previous exposure of an individual to environmental antigens can trigger an immune response that may be cross-reactive to a biological therapy– from monoclonal antibodies (mAbs) to cell and gene therapies (C&GTs). For a sub-class of gene therapies, those that use adeno-associated viruses (AAVs) as the vector, it has been well established that there is a significant incidence of pre-existing immunogenicity since AAV is present in the environment and anywhere from 40-70% of the global population has been exposed and has antibodies against the AAV (Boutin, et al. 2010). There are three key areas where the presence of pre-existing immunity can influence the success of a gene therapy product: safety, efficacy, and commercialisation.


The risk associated with pre-existing anti-drug antibodies (ADA) has been a concern for biotherapeutics and only increased since AAVs became one of the main vectors for gene therapy delivery. However, for biotherapeutics, the impact of these pre-existing antibodies on safety has been limited and infrequent based on an industry survey (Xue, et al. 2013). In most cases, these pre-existing antibodies have little known impact on the biotherapeutic at all. But, due to the high incidence of antiAAV antibody positive individuals, there is a reasonable concern around safety issues and an immunogenicity risk assessment suggests that this should be monitored closely in individuals receiving an AAV-based gene therapy. For some AAV-based gene therapy programs, this concern has led to a decision to exclude anti-AAV positive patients from clinical trials to avoid the risk of a safety event. However, excluding these patients from clinical trials in the absence of a safety risk can be counter-productive for the development of the gene therapy program, as a significant portion of the patient population would be eliminated from the potential benefit of the gene therapy.