Immunosafety Resources
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Applied and Basic Immunology
Book: Immunotoxicity Biomarkers Reference
Biomarkers in Toxicology (Second Edition), 2019, Pages 413-425, Chapter 24)
Book: Introduction to Immunotoxicology
An Introduction to Interdisciplinary Toxicology, From Molecules to Man, 2020, Pages 233-244, Chapter 18)
Book: Immune Target sites References
Information Resources in Toxicology (Fifth Edition), Volume 1: Background, Resources, and Tools, 2020, Pages 555
This is a good chapter that presents a selection of journal articles among the most relevant review articles on immunotoxicology published since 2000
Immunosafety Regulatory Focus
European Medicines Agency (EMA) Guidelines
The scope of this guidance as described in the document “mainly apply to the development of an unwanted immune response against a purified therapeutic protein in patients and to a systematic evaluation of it. The guideline applies to proteins and polypeptides, their derivatives, and products of which they are components, e.g. conjugates. These proteins and polypeptides are mainly produced by recombinant or non-recombinant expression systems. Throughout this guideline, the term “therapeutic protein” is used. This guideline does not apply to coagulation factors, vaccines, or heterogenous immunoglobulin preparations, such as human immunoglobulins purified from plasma.
The scope of this guidance as describe in the document “ addresses the general principles for the non-clinical and clinical development and assessment of the marketing authorisation applications of biosimilars containing biotechnology-derived proteins as active substance(s). Nevertheless, the principles explained in this document could apply to other biological products, on a case by case basis. This guideline does not address the comparability exercise for changes introduced in the manufacturing process of a given product (i.e. changes during development and post-authorisation).
The scope of this guidance as describe in the document “apply to the development and systematic evaluation of an unwanted immune response against a therapeutic or in vivo diagnostic mAb in recipients. The guideline applies to mAbs, their derivatives, and products of which they are components, e.g., conjugates, Fc linked fusion proteins. This guideline considers the major quality and clinical aspects that are important for adequately addressing the problems with detection of and risk related to the development of an unwanted immune response to the particular mAb in the particular clinical indication sought. This guideline is aimed at products at final development stage (e.g. marketing authorization application stage). However, many of the principles are relevant to earlier phases of development.
US Food and Drug Administration (FDA) Guidelines
Link: https://www.fda.gov/media/72028/download
Application/topics covered: Introduces immunogenicity and immunotoxicity studies as preclinical safety evaluation
Link: https://www.fda.gov/media/72621/download
Application/topics covered: Immunotox for medical devices, definition of immunotoxic effects (hypersensitivity, immunosuppression, chronic inflammation, autoimmunity); Table 3 includes test indicators, modules for evaluating immune response
Link: https://www.fda.gov/media/72228/download
Application/topics covered: Recommendations (and descriptions of potential ways to evaluate effects) of INDs that may have effects of immunosuppression, on immune function, on immune cell phenotype, of immunogenicity, hypersensitivity, autoimmunity, and adverse immunostimulation
Link: https://www.fda.gov/media/72047/download
Application/topics covered: Factors to consider in evaluating potential immunotoxicity (with appendix including standard toxicology studies), weight-of-evidence approach, additional immunotoxicity studies (e.g., TDAR, immunophenotyping, NK killing assay, host resistance studies, macrophage/neutrophil function, assays to measure cell-mediated immunity)
Link: https://www.fda.gov/media/78034/download
Application/topics covered: Provides an update/clarification on S6 on study design, immunogenicity, reproductive/developmental toxicity and carcinogenic potential
Link: https://www.fda.gov/media/85017/download
Application/topics covered: Focus on the immune implications of therapeutic proteins and how to potentially monitor; appendix includes, diagnosis of anaphylaxis, cytokine release syndrome, non-acute immune responses, antibody responses to therapeutic protein products, utility of animal studies, comparative immunogenicity studies
Link: https://www.fda.gov/media/135312/download
Application/topics covered: Assessing potential for products to reduce/increase immune system activity, also developmental/juvenile studies; covers evaluation of functional, histomorphologic, cellular aspects in nonclinical studies for new drugs, therapeutic proteins, and recombinant/plasma-derived blood proteins