Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment
Open accessAbstract
Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.
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Non-human primates are frequently the sole species with pharmacological relevance, raising ethical and economic concerns.
“Non-human primates are often the only pharmacologically relevant species, whose use has ethical and economic implications7.”
From Human disease models in drug development (2023) · cites this paper as [7]
The Discussion (page not specified) says that, for many monoclonal antibodies, non-human primates are the only pharmacologically relevant species. The Introduction calls for ethically justified use and reduced NHP use, but the passages do not address economic implications. (LLM, conf=0.86)
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“However, use of NHPs should not be the default, but rather justified by proper rational and science-based decision-making that should both support their ethical use and better inform the safety of clinical studies.(3) There are multiple approaches to reduce the NHP use in PKPD development of biologics by using alterna…”
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“In addition to these quantitative approaches to understanding the value of nonclinical safety testing, Brennan et al gathered a set of case studies to examine the value of studies in nonhuman primates for risk assessment of monoclonal antibodies.(31) Eighteen cases were collected via a survey and found that the nonhum…”
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“Inflammation(1) NHP + rat (8) None Pharmacology NHP (26) None Yes CNS(2) NHP + rat (13) None — * (Rat) — Yes CNS NHP + Tg mouse (5) None Timing NHP + Tg mouse (26) None —”
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BackgroundCross-species cellular mapping and humanization of Fcγ receptors to advance antibody modeling
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- Authors
- Brennan, F. R., Cavagnaro, J., McKeever, K., Ryan, P. C., Schutten, M. M., Vahle, J., Weinbauer, G. F., Marrer-Berger, E., & Black, L. E.
- Affiliations
- UCB Pharma (United Kingdom) (GB)
- Access Bio, Boyce, Verginia, United States
- Ultragenyx Pharmaceutical (United States) (US)
- Toxicology, Medimmune LLC, One Medimmune Way, Gaithersburg, Maryland, United States
- Genentech (US)
- Eli Lilly (United States) (US)
- Covance (Germany) (DE)
- Novartis Pharma, Preclinical Safety, F Hoffmann-La Roche Ltd., Grenzacherstrasse 124, Basel, Basel-Stadt, Switzerland CH-4070
- Charles River Laboratories (United States) (US)
- Corresponding author
- Brennan, Frank R.
- ORCID
- Venue
- mAbs
- Publisher
- Informa UK Limited
- Published
- 2017-10-26
- Volume
- 10
- Issue
- 1
- Pages
- 1-17
- ISSN
- 1942-0862 (ISSN-L)
- 1942-0870
- PMC
- PMC5800363
- OpenAlex
- W2762769547
- Cited by
- 70
- References
- 72
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 7 · 2023: 4 · 2022: 10 · 2021: 7 · 2020: 15 · 2019: 6 · 2018: 4 · 2017: 2
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- mAbs (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Centre for the Replacement Refinement and Reduction of Animals in Research
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- monoclonal antibodies, non-human primates, preclinical safety, human risk assessment, drug safety, pharmacological activity, novel scaffolds, clinical trial design, adverse events, translational toxicology
- MeSH terms
- Animals, Antibodies, Monoclonal, Consumer Product Safety, Drug Evaluation, Preclinical, Humans, Primates, Risk Factors, Species Specificity, Risk Assessment, Models, Animal
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