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Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies
Open accessAbstract
Most therapeutic monoclonal antibodies (mAbs) licensed for human use or in clinical development are indicated for treatment of patients with cancer and inflammatory/autoimmune disease and as such, are designed to directly interact with the immune system. A major hurdle for the development and early clinical investigation of many of these immunomodulatory mAbs is their inherent risk for adverse immune-mediated drug reactions in humans such as infusion reactions, cytokine storms, immunosuppression and autoimmunity. A thorough understanding of the immunopharmacology of a mAb in humans and animals is required to both anticipate the clinical risk of adverse immunotoxicological events and to select a safe starting dose for first-in-human (FIH) clinical studies. This review summarizes the most common adverse immunotoxicological events occurring in humans with immunomodulatory mAbs and outlines non-clinical strategies to define their immunopharmacology and assess their immunotoxic potential, as well as reduce the risk of immunotoxicity through rational mAb design. Tests to assess the relative risk of mAb candidates for cytokine release syndrome, innate immune system (dendritic cell) activation and immunogenicity in humans are also described. The importance of selecting a relevant and sensitive toxicity species for human safety assessment in which the immunopharmacology of the mAb is similar to that expected in humans is highlighted, as is the importance of understanding the limitations of the species selected for human safety assessment and supplementation of in vivo safety assessment with appropriate in vitro human assays. A tiered approach to assess effects on immune status, immune function and risk of infection and cancer, governed by the mechanism of action and structural features of the mAb, is described. Finally, the use of immunopharmacology and immunotoxicity data in determining a minimum anticipated biologic effect Level (MABEL) and in the selection of safe human starting dose is discussed.
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“This isotype is considered to come with the smallest risk of toxicity because of its poor ability to recruit immune effector functions via Fc receptors or through complement activation (reviewed in ref. [31]).”
From The rise and fall of the CD 28 superagonist TGN 1412 and its return as TAB 08: a personal account (2016) · cites this paper as [31]
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Metadata
- Authors
- Brennan, F. R., Morton, L. D., Spindeldreher, S., Kiessling, A., Allenspach, R., Hey, A., Müller, P., Frings, W., & Sims, J.
- Affiliations
- Novartis (Switzerland) (CH)
- Corresponding author
- Brennan, Frank R.
- Venue
- mAbs
- Publisher
- Informa UK Limited
- Published
- 2010-05
- Volume
- 2
- Issue
- 3
- Pages
- 233-255
- ISSN
- 1942-0862 (ISSN-L)
- 1942-0870
- PMC
- PMC2881251
- OpenAlex
- W2044692977
- Cited by
- 250
- References
- 115
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 21 · 2023: 13 · 2022: 14 · 2021: 9 · 2020: 13 · 2019: 15 · 2018: 18 · 2017: 23 · 2016: 16 · 2015: 19 · 2014: 19 · 2013: 22 · 2012: 14
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- mAbs (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Keywords
- immunotoxicity, immunopharmacology, cytokine release syndrome, dendritic cell activation, immunogenicity, first-in-human dose selection, immune-related adverse events
- MeSH terms
- Animals, Antibodies, Monoclonal, Autoimmune Diseases, Clinical Trials as Topic, Dendritic Cells, Drug Evaluation, Preclinical, Humans, Immune System, Neoplasms, Cytokines, Guidelines as Topic, Drug-Related Side Effects and Adverse Reactions
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