Advances in the last 10 years, and a look into the next…
Historically, advances in immunology have been closely associated with studies of infectious diseases. However, in the past 10 years, immunology has moved from identifying and characterizing individual molecules and cell types to understanding the roles of each, and the regulatory networks that govern interactions between immune cells. This increased understanding has led to the elucidation of new therapeutic targets and the development of novel assays in multiple species, such as an increase in the biomarker evaluation to assess immunopharmacology and immunotoxicology.
In the last decade, the plasticity of the immune system was revealed. It became clear that an individual immune cell type did not have just one function. Rather, they comprise multiple subsets with distinct functional specializations. Numerous components of the immune system and the environment interact together to shape the response against pathogens, cancer cells or even one’s own cells. Indeed, the studies on regulatory T cells, peripheral tolerance and immune suppression shed some light on the mechanisms involved in the manipulation of the immune system by internal or external factors such as the microbial and viral environment. It was previously known that microbial recognition was brought about by the innate immune system; however, all of the components involved in this recognition and how this was linked to the adaptive immune response was not clear. We have now identified many sensor and messenger molecules, such as the Toll-like receptors and cytokines, as well as other pattern- or damage-recognition receptors responsible for this link. This has allowed the further understanding of a complex world of innate immune recognition, signal transduction, cross-regulation and inflammatory gene regulation with broad therapeutic implications.
One example of a drug class that has benefitted from these discoveries is anti-inflammatory agents. There are several drugs currently on the market or in development that work on the basis of reducing production or activity of pro-inflammatory molecules. Many of these have been proven successful in the treatment of conditions like rheumatoid arthritis. Although generally well-tolerated and safe, one drawback of these therapies is decreased host immune defense against infection and possibly cancer. In many cases, the benefits of these therapies outweigh these potential risks. It is important, however, to keep in mind that ideally newer drugs in development should have minimal risk of organ toxicity and not compromise immune defense against infection and cancer. This is especially important for drugs aimed at treating the inflammatory component of conditions associated with aging, such as atherosclerosis, joint disease and neurodegeneration.
We now appreciate that in addition to protection against pathogens, the immune system is involved in allergies, immune surveillance of cancer cells and chronic inflammation. Modern immunology, using newly developed technologies, has greatly advanced our understanding of individual players and their functions in the immune system. But what does the future hold for immunology research?
We believe genetic studies in healthy humans and in those suffering from certain conditions will help identify functional pathways disrupted in different disease states and aid in the development of more targeted therapeutics. In addition, the identification of biomarkers that are predictive of successful therapy (rather than a reliance on clinical endpoints) should help expedite immunotherapeutic trials. We have seen an increase in the number and variety of biomarkers tested in the last few years. Many of those were used in clinical trials to determine if a new drug was efficient, whereas others were able to detect early toxicity. On the immunotherapeutic drug development side, we should see the emergence of additional biomarkers, immunopharmacology guidance, requirements for more sensitive assays, more predictive immunogenicity testing, further growth of specialty assays and models (e.g., autoimmunity and hypersensitivity for which predictive model often do not exist) and increased use of clinical immunotoxicity to detect early potential toxicity on the immune system.
Certainly, the next 10 years will be just as interesting as the last ten, with the further development of immunomodulators and biotherapeutics such as mAb fragments, bispecific mAbs, biosimilars/biobetters and antibody drug conjugates. Notably, we are expecting a white paper on ADC preclinical testing, which is just one example demonstrating what will further drive immunology experience and guidelines as well as appropriate risk assessment.
Marie-Soleil Piche is a Principal Scientist in Charles River’s immunology group. She develops immunotoxicology assays to evaluate the effects of drugs on the immune system as well as pharmacodynamic assays for mode of action investigations. Prior to joining Charles River in 2009, Marie-Soleil studied at McGill University in immunology and obtained her PhD at the Montreal University Research Center where she published results on the role of autoantibodies in the protection against autoimmune-induced thrombosis.
Lynne LeSauteur is the Director of Immunology at Charles River. Her group consists of 70 staff specialized in the evaluation of drug impact on the immune system, including development, GLP validation and sample analysis from preclinical and clinical studies to assess immunotoxicity, immunomodulation and immunogenicity. Prior to joining Charles River in 2000, Lynne obtained her PhD from McGill University, Department of Pharmacology and Therapeutics and conducted a post-doctoral position at the Montreal Neurological Institute, which resulted in Lynne’s publications and patents describing the design and mechanism of monoclonal antibody based agonistic and antagonistic receptor ligands.