Anne De Groot, M.D., is professor and director at the University of Rhode Island Institute for Immunology and Informatics.
Sometimes handlebar mustaches are in, and sometimes, they are very, very out! The world of fashion is well known for its “emerging trends” and well, it seems that trends are also common in preclinical development of protein therapeutics. Ten years ago, anti-drug antibody (ADA) responses to protein therapeutics were the focus of each and every meeting, while aficionados of T cells (with and without handlebar mustaches) made time to talk about their favorite topic over lunch. At that time, few but the bravest would bring up the concept of doing T cell epitope- focused immunoinformatics analysis of biologic proteins in the preclinical phase of drug development. The T cell-driven immune response, as a contributor to protein immunogenicity, was definitely a “fringe” concept.
That was then, and this is now. As a group, biologics developers have broadened their horizons over the past 10 years, to consider the implications of T cell epitopes in the evaluation of protein therapeutic immunogenicity. Now, such concepts as inducing tolerance, screening for T cell epitope content, or even removing T cell epitopes to lower protein immunogenicity (deimmunization) that might once have been considered avant garde are considered de rigeur. Protein drug developers are now taking a broader view of preclinical immunogenicity screening, leading to changes in the way biotherapeutics are developed and advances in our ability to reduce protein immunogenicity that will have a significant impact on human health.
We are well past handlebar mustaches and bushy side-burns. Now, the ability of immunoinformatics tools to predict and reduce immunogenicity of a potential protein therapeutic is well recognized, and drug developers that are plugged in to current trends are demonstrating the tremendous benefits of applying these tools at every stage of drug development. Although immunoinformatics tools clearly are not the only tools in the preclinical repertoire, they are now well accepted for their ability to analyze, predict, and modify the immunogenicity of therapeutic proteins. Use of immunoinformatics tools expands the available strategies for mitigating therapeutic protein immunogenicity and opens multiple windows for intervention during the drug development process.
I will be presenting our work on immunogenicity screening, deimmunization, and tolerance induction at the 2013 AAPS National Biotechnology Conference. At that time, I’ll review the importance of T cell responses to immunogenicity and will provide evidence that Tregitope sequences derived from human IgG can reproduce immunomodulatory effects of IVIG in vitro and in vivo. In vitro, Tregitopes activate CD4+CD25+FoxP3+ natural regulatory T cells (nTreg). In vitro and in vivo, Tregitopes cause Tregs to produce IL-10 and to expand, and iTreg are induced.
I look forward to discussing the application of immunology research to protein therapeutics and how applying up-to-date trends in immunology, informatics, and T cell epitope screening tools to biologics development will improve our ability to treat, and cure, human disease. And I’m sure I’ll see some of my favorite handlebar mustaches too!