Keynote: Getting Up Close and Personal: Can Understanding the Pharmacogenetic Determinants of Immunogenicity Help in the Design of Safer Biologics?

Immunogenicity is an essential consideration during the development and licensure of any therapeutic protein because it affects the safety and/or efficacy of the product. It is desirable to develop predictive tools for assessing immunogenicity risk for several reasons: (i) The use of these tools early in the drug-development cycle, can prevent expensive drug failures during. (ii) Most protein drugs address very serious unmet clinical needs and thus are often approved even if immunogenic in some patients. Immunogenicity assessment tools permit better management of immunogenicity in the clinic. (iii) Understanding the pharmacogenetics of immunogenicity allows identifying individuals and/or populations at higher risk of developing immune responses to protein drugs and novel modalities. (iv) Mechanistic understandings of immunogenicity and identification of biomarkers allow the re-engineering of proteins used in therapeutic applications to modulate immunogenicity. Here, specific examples of the application of immunogenicity assessment tools in assessing the immunogenicity of protein therapeutics are provided. These include comparing recombinant Factor VIIa (FVIIa) and its engineered variant Vatreptacog Alfa (VA) which has only 3 amino acid substitutions. This is a useful model system because while FVIIa used therapeutically rarely elicit an immune response, 11% of patients treated with VA in a clinical trial developed anti-drug antibodies. A diverse array of in silico, in vitro and ex vivo methods can be used to assess immunogenicity. The selection, use and interpretation of results from these immunogenicity assessment tools will be discussed in the context of association with clinical immunogenicity. Finally, the limitations of learnings from decades of studies on immune response to therapeutic proteins will be discussed in the context novel modalities (Gene Therapy, CRISPR-Cas) will be discussed.