Book Review

This book presents a summary of the current scientific and regulatory thinking involving the evaluation of immunotoxic potential pharmaceuticals, with particular attention to biopharmaceuticals. It is well organized and informative and provides a comprehensive insight into a complex area of inquiry that is still evolving. Although the book is a multi-authored, specialist book, it could be used as a text for a graduate class in regulatory or clinical immunotoxicology. It is appropriate for use at either a beginner or intermediate level because it covers both the basic preclinical studies involved in immunotoxicological assessment and the rationale for the selected tests while providing interesting clinical vignettes to prompt thoughtful review of the future of immunotoxicology and case-by-case evaluation of immunotoxicological potential. The chapters are short and easy to comprehend, and the print is of high quality. Some chapters include easy-to-understand graphics to represent complex processes. The book would be improved by the inclusion of more graphics of this type, but those that are available are quite useful. One distraction is the presentation of histological figures in the text as black and white photographs with color plates in the middle of the book. However, once the reader realizes this is the case, the process of flipping back and forth is manageable.

The book provides an interesting combination of preclinical testing guidance within the arena of immunotoxicology and clinical examples of immunotoxicological events. The book contains an introduction and 11 parts, with subsections within the parts provided by chapter authors. The introduction describes the immune system and the origins of immunotoxicology, Part I explains the current regulatory expectations within immunotoxicological evaluations, and Part XI provides an overview of the status of immunotoxicology followed by predictions as to the future of the discipline. Between these bookends are 9 well-organized parts representing different aspects of the field.

Part II describes the concept of a weight of evidence review to assess the immunotoxicological potential of a pharmaceutical. This is a relatively new concept as a method of identifying potential immunotoxicological hazards. The first subsection involves guidance as to careful evaluation of clinical pathology as a means to provide an early indication of immune modulation. This subsection describes the end points in standard toxicological testing, particularly hematology, that might provide this early evidence and means to interpret changes. The author cautions that one must be cognizant as to whether effects of an agent on clinical parameters are due to direct or indirect effects, such as stress. Subsection 4 reviews specific scenarios in which alterations in hematological parameters may be seen, in particular drug-induced hemolytic anemia. The second subpart reviews best practices for routine pathological evaluation of the immune system. The author points out that enhanced pathological review of immune organs combined with specialized techniques can provide insight into the immunotoxicological potential of a pharmaceutical. This is further emphasized in the third subsection involving immunohistochemistry to evaluate histopathological preparations from standardized toxicity testing. One deficit in this section is the brevity of the chapters. Given that this type of investigation (ie, weight of evidence based on enhanced and careful review of hematology, clinical chemistries, and histopathology from currently conducted repeat-dose studies) is often the only routine evaluation that most pharmaceuticals will receive, this section should have been expanded.

Part III reviews nonclinical immune function tests that are routinely used to assess the immunotoxic potential of a pharmaceutical or biopharmaceutical. The reviewed tests include T-cell-dependent antibody response (TDAR, subsection 1), natural killer cell activity and innate immunity (subsection 2), cell-mediated immunity and delayed type hypersensitivity (subsection 3), and immune phenotyping (subsection 4). These chapters represent the major tiers recommended for the assessment of immune function in a screening setting. The TDAR has been adapted by many for use in groups of satellite animals in routine repeat-dose studies. This response was found to be the first-line immune function test for evaluating the immunotoxic potential for new drug candidates because it is sensitive and involves the participation of 3 types of cells within the immune system for optimal generation. Part III is key because it provides the necessary background for anyone desiring to determine basic immune function. Basic methods, potential pitfalls, and criteria to evaluate and interpret data are included. One deficiency in this section is the relative lack of depth as to the historic rationale for choosing these assays. Also, with the exception of the subsection on TDAR, few explanatory graphics are provided to help the novice follow the discussion.

Part IV contains 2 subsections that focus on the evaluation of immune function ex vivo. The first subsection involves components of the immune system that are key in developing intact immune response, such as TDAR and cell-mediated immunity, lymphocyte proliferation, and cytokine production. The chapter emphasizes the rationale for studying these parameters and the methods to use for such study. The second subsection further discusses the application of flow cytometry to immune parameters beyond basic immune phenotyping. The text provides an overview of fundamental considerations, such as equipment selection and sample preparation, as well as exciting new techniques that have the potential to enhance the use of flow cytometry in immunotoxicology. Again, these subsections are directed toward helping the reader understand the utility and place of the technologies described. As before, additional explanatory graphics would be of benefit. Part V has 2 subsections as well and involves the in vivo evaluation of immunotoxic potential. The first subsection includes an excellent overview of a very complex and important area of immunotoxicology, host resistance assays. When immunomodulation occurs, there is the potential for increased susceptibility to infection and tumor progression. This subsection provides insight into models to evaluate potential increased susceptibility in standardized animal models that involve the use of functional tests of immunity rather than rely on the more variable and less sensitive end point of mortality. The second subsection describes models to evaluate the potential of a pharmaceutical to stimulate autoimmunity. Autoimmune diseases involve a broad range of disorders that are often defined clinically by symptoms and whose cause is unknown. There has been difficulty in defining models that can be used to screen the potential of a new drug to contribute to autoimmunity, and this is well delineated by the author. The author provides suggestions for approaching this area, and it will be interesting to see whether these strategies bear fruit.

Part VI is a turning point at which the book goes from discussing methods and processes to examining specific issues within immunotoxicology, for example, differentiating between desired immune modulation and potential immunotoxicity (subsection 1). This chapter provides examples from clinical trials of biopharmaceuticals that have consequences beyond their intended immune modulation. This emphasizes the need for the prelinical evaluation of biopharmaceuticals. Subsection 2 provides insight into the complex area of the assessment of biopharmaceuticals in the preclinical setting. The expertise and experience of the author are evident by the thoughtful insight into the use of nonhuman primates, humanized mice, and transgenic/knockout animals to answer critical questions before beginning clinical development. One important consideration in the preclinical evaluation of a biopharmaceutical is the possible formation of antibodies to the new drug. This is carefully reviewed in subsection 3.

Part VII provides an overview of considerations in vaccine development including pharmacological immunogenicity (the deliberate generation of an immune response to the administered agent) and adverse reactions to vaccine administration (subsection 1) and adjuvants (subsection 2). Included in subsection 1 is a discussion of unique animal models for vaccine development.

Part VIII covers testing for drug-induced hypersensitivity. Hypersensitivity involves a reaction to a drug, either allergic or nonallergic. Subsection 1 discusses systemic hypersensitivity and methods to evaluate this activity in a preclinical setting. Chemical flags that might indicate a potential for haptenization are discussed as potential means of identifying a drug with the potential to induce hypersensitivity. The second subsection describes nonclinical models to assess respiratory hypersensitivity. Allergic reactions and risk factors are carefully reviewed as well as methods for screening for agents that might induce respiratory hypersensitivity.

Part IX describes a field that is rapidly changing with regard to regulatory oversight: developmental immunotoxicology. Subsection 1 is an excellent review of the unique nature of the developing immune system and compares the differences, regarding stage of development, between the human and mouse immune system during gestation and in the early postnatal period. The review, comprehensive in comparison with other subsections, provides insight into testing that can be done with the fetus and guidelines as to which tests are appropriate for a given stage of development. Subsection 2 describes the evaluation of developmental immunotoxicity in nonhuman primates. The author reviews the prenatal and postnatal development of the immune system in nonhuman primates and discusses end points and design factors.

Part X describes new methods for assessing immunomodulation, immunotoxicity, and immunogenicity. The first subsection discusses alternative models, knockout mice, mice with genetic defects leading to immune deficiency, transgenic models, and conditional knocks. As discussed by the author, these models have the potential to allow hazard identification in susceptible populations but should not be used for risk assessment. Subsection 2 discusses animal models for preclinical comparative immunogenicity testing. The focus of this chapter is biopharmaceuticals, which is defined by the author as any therapeutic biological entity that is not used for a vaccine. It is very challenging to use preclinical models to assess immunogenic potential, and interspecies differences are defined as a major roadblock. Strategies to probe the antigenic and immunogenic potential of a novel biopharmaceutical are addressed. In the last subsection (subsection 3), the involvement of T-cell epitopes in the generation of immunogenicity (not just antibody responses through B cells) is described. The focus to date has been assessment of antibodies to the drug (subsection 2), and this subsection describes the potential for T-cell-based anti-drug responses. Although this is a new field for consideration regarding the immunotoxicity potential of a drug and does not currently have well-described screening tools, it is an very important problem to consider when evaluating the immunotoxicity potential of a biopharmaceutical.

This book comprehensively examines the role of the assessment of immunotoxic potential during preclinical development. Most of the chapters are short, which provides a broad overview of a number of subjects but does not allow for in-depth examination. The treatise is well organized and easy to comprehend, but more visual displays and graphics could improve the reader’s understanding of many of the subjects.