Summary of a workshop on nonclinical and clinical immunotoxicity assessment of immunomodulatory drugs

Drug Safety, Schering-Plough Research Institute, Summit and Lafayette, New Jersey 07901, USA.
Journal of Immunotoxicology (Impact Factor: 2.05). 04/2009; 6(1):1-10. DOI: 10.1080/15476910802656440
Source: PubMed


The number of anti-inflammatory and immunomodulatory drugs being developed in the pharmaceutical industry has increased considerably in the past decade. This increase in research and development has been paralleled by questions from both regulatory agencies and industry on how best to assess decreased host resistance to infections or adverse immunostimulation caused by immunomodulatory agents such as anti-cytokine antibodies (e.g., the tumor necrosis factor-alpha inhibitors), anti-adhesion molecule antibodies (e.g., anti-alpha-4 integrin inhibitors) and immunostimulatory molecules (e.g., anti-CD28 antibodies). Although several methods have been developed for nonclinical assessment of immunotoxicity, highly publicized adverse events have brought to light significant gaps in the application of nonclinical immunotoxicity testing in assessing potential risk in humans. Confounding this problem is inconsistent application of immunotoxicology methods for risk assessment within the scientific community, limited understanding of appropriate immunotoxicity testing strategy for immunomodulators and inconsistent testing requests by regulatory agencies. To address these concerns, The Immunotoxicology Technical Committee (ITC) of the International Life Science Institute (ILSI) Health and Environmental Sciences Institute (HESI) organized a workshop on Immunomodulators and Clinical Immunotoxicology in May 2007. The Workshop was convened to identify key gaps in nonclinical and clinical immunotoxicity testing of anti-inflammatory and immunomodulatory agents and to begin to develop consistent approaches for immunotoxicity testing and risk assessment. This paper summarizes the outcome of the HESI ITC Immunomodulators and Clinical Immunotoxicology Workshop. Topics not discussed at the Workshop were outside the scope of this report. Although more work is needed to develop consistent approaches for immunotoxicity assessment of immunomodulators, this Workshop provided the foundation for future discussion.

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    • "There is general agreement that the case-by-case approach is the most appropriate since it provides the flexibility needed to do the best science appropriate for the specific drug being developed. With the increasing number and diversity of immunomodulatory drugs in development along with inconsistencies in immunotoxicity testing practice between companies and requests for immunotoxicity testing by regulatory agencies, a workshop was held to discuss this topic in May 2007 (summarized in Piccotti et al. 2009). The primary goal of the meeting was to discuss testing strategies and identify key gaps in nonclinical and clinical immunotoxicity testing for anti-inflammatory and immunomodulatory drugs. "
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    ABSTRACT: The ICH S8 immunotoxicity testing guideline for human pharmaceuticals was published in 2006 and was intended to provide guidance for assessing the immunotoxicity potential of low-molecular-weight drugs that are not intended to alter the immune system. For drugs intended to modulate the immune system, immunotoxicity testing strategies are generally developed on a case-by-case approach since the targets, intended patient population, and mechanisms of action of the test compound will determine the type of testing needed. Some of the general principles of ICH S8, however, may be applied to immunotoxicity testing strategies for immunomodulatory drugs. A weight-of-evidence approach using factors discussed in ICH S8 in concert with an assessment of the potential value of additional immunotoxicity testing should be considered. For most situations, immunotoxicity studies with immunomodulatory compounds evaluate off-target effects on the immune system and exaggerated pharmacology. The potential use of data from these studies and considerations such as translatability to humans are discussed.
    Full-text · Article · Jan 2012 · Toxicologic Pathology
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    • "The impact on immune status and function in preclinical studies in animals is an important component of safety assessment of immunomodulatory agents. Although the benefits of immunomodulatory therapeutics have dramatically improved the lives of many patients, unexpected side effects have occurred resulting in adverse responses including increased risk of infection due to immunosuppression and cytokine release syndrome (Hansel et al. 2010; Piccotti et al. 2009). These toxicities underscore the necessity to develop assays that detect the immunotoxic potential of pharmaceuticals in a species predictive of human responses (National Research Council 1992). "
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    ABSTRACT: Regulatory T cells (Tregs) are a rare subset of lymphocytes that inhibit the activation and effector functions of T cells and are important regulators of immune responses. Although Tregs are well characterized in humans and rodents, little is known about their immunophenotyping (IP) profile in cynomolgus macaques (Macaca fascicularis), which is an important species for pharmacological and toxicological evaluation of potential immune modulators because of their similar physiologic, genetic, and metabolic response patterns to humans. The authors have developed an immunophenotyping panel using a high-throughput 96-well microtiter plate-based assay to detect circulating Tregs (CD3(+)CD4(+)CD25(hi)FoxP3(+)) and have determined the normal range for the number of Tregs in naive healthy cynomolgus macaques to be 56.4 to 179.7 cells/µL (mean ± SEM = 113.6 ± 5.1 cells/µL; n = 25). Furthermore, the authors compared the resulting FoxP3(+) Treg profiles with a CD127(lo) cell-surface panel (CD3(+)CD4(+)CD25(hi) CD127(lo)) and found a close correlation between the absolute numbers of CD3(+)CD4(+)CD25(hi)FoxP3(+) and CD3(+)CD4(+)CD25(hi)CD127(lo) cells (mean ± SD = 120 ± 8.0 cells/µL). Quantification of circulating Tregs in cynomolgus macaques in this high-throughput assay may help to identify drug candidates that affect this rare, but critical, immunoregulatory cell population.
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    ABSTRACT: In the drive to develop drugs with well-characterized and clinically monitorable safety profiles, there is incentive to expand the repertoire of safety biomarkers for toxicities without routine markers or premonitory detection. Biomarkers in blood are pursued because of specimen accessibility, opportunity for serial monitoring, quantitative measurement, and the availability of assay platforms. Cytokines, chemokines, and growth factors (here referred to collectively as cytokines) show robust modulation in proximal events of inflammation, immune response, and repair. These are key general processes in many toxicities; therefore, cytokines are commonly identified during biomarker discovery studies. In addition, multiplexed cytokine immunoassays are easily applied to biomarker discovery and routine toxicity studies to measure blood cytokines. However, cytokines pose several challenges as safety biomarkers because of a short serum half-life; low to undetectable baseline levels; lack of tissue-specific or toxicity-specific expression; complexities related to cytokine expression with multiorgan involvement; and species, strain, and interindividual differences. Additional challenges to their application are caused by analytical, methodological, and study design-related variables. A final consideration is the strength of the relationship between changes in cytokine levels and the development of phenotypic or functional manifestations of toxicity. These factors should inform the integrated judgment-based qualification of novel biomarkers in preclinical, and potentially clinical, risk assessment. The dearth of robust, predictive cytokine biomarkers for specific toxicities is an indication of the significant complexity of these challenges. This review will consider the current state of the science and recommendations for appropriate application of cytokines in preclinical safety assessment.
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