Scoping review
Animal Model Limitations in Antibody Therapeutics Safety Assessment and the Potential of NAMs as Human-Relevant Alternatives: A Scoping Review
Rationale
Antibody therapeutics have advanced treatment across diverse medical disciplines, including oncology, autoimmune conditions, and infectious diseases (Kothari et al., 2024; reviewed in Beilmann et al., 2025). Yet the same specificity that underlies their clinical value also complicates their safety and efficacy assessment, as animal models traditionally used in their nonclinical assessment often impose translational limitations due to species-specific differences (Brennan & Kiessling, 2016; Cauvin et al., 2015).
While animal studies have historically contributed valuable insights into the nonclinical assessment of many therapeutics, documented cases of translational failure raise concerns about the reliability of animal models for antibody therapies. For example, in the TGN1412 case, animal models failed to predict a severe, though non-lethal, systemic inflammatory response in humans (Suntharalingam et al., 2006), and in the MEDI-565 (MT111) case, no animal models expressed the necessary targets for assessing its efficacy (Ryan et al., 2012). Within this context, new approach methodologies (NAMs) have been suggested as options to overcome such translational limitations (Beilmann et al., 2025; Ryan et al., 2012).
Worthy of note, the FDA’s Roadmap to Reducing Animal Testing in Preclinical Safety Studies (FDA, 2025) has further accelerated the shift toward human-relevant NAMs for the nonclinical assessment of antibody therapeutics, reinforcing the need to understand the limitations of current animal models and the potential of NAMs to address them.
Objectives
Aligned with current scientific and regulatory developments, this project aims to conduct a scoping review to map (i) where animal models have failed to predict safety and efficacy in nonclinical studies of antibody therapeutics, and (ii) where NAMs have been successfully used in the nonclinical assessment of antibody therapeutics. Specifically, the review aims to map evidence on species-specific translational limitations of in vivo methods, map evidence on successful cases where NAMs overcame these limitations, and identify priority areas for future research to support the development of human-relevant testing alternatives.
Methodology
This scoping review will be conducted and reported in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist (Tricco et al., 2018). A protocol has been developed a priori, in line with Peters et al. (2020), and will be made publicly available on a dedicated platform ahead of the review’s execution. An adapted PCC (Population, Concept, Context) framework guided the formulation of the research question and eligibility criteria. Any amendments to the protocol will be clearly documented, justified, and reported in the resulting publication.
A preliminary literature search using a set of seed articles supported moving forward with a full scoping review on this topic. The formal search strategy will draw on multiple biomedical databases, with records screened independently by two investigators against predefined eligibility criteria.
Status and outcomes
This project is ongoing. If successful, it will produce a structured scoping review mapping documented animal-to-human translational failures in the nonclinical assessment of antibody therapeutics, alongside successful examples where NAMs have provided reliable alternatives for safety and/or efficacy assessment. This is intended to provide a basis for a gap analysis evaluating the relevance and potential applicability of NAMs in this field. Findings will be submitted to a peer reviewed journal in toxicology, regulatory science, or translational medicine, and shared through this platform and our LinkedIn page.
Open to collaborations: Yes. If you are interested in contributing to this project, get in touch.
References
Beilmann, M., Adkins, K., Boonen, H. C. M., Hewitt, P., Hu, W., Mader, R., Moore, S., Rana, P., Steger-Hartmann, T., Villenave, R., & van Vleet, T. (2025). Application of new approach methodologies for nonclinical safety assessment of drug candidates. In Nature Reviews Drug Discovery (Vol. 24, Number 9, pp. 705–725). Nature Research. https://doi.org/10.1038/s41573-025-01182-9
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Cauvin, A. J., Peters, C., & Brennan, F. (2015). Advantages and Limitations of Commonly Used Nonhuman Primate Species in Research and Development of Biopharmaceuticals. In The Nonhuman Primate in Nonclinical Drug Development and Safety Assessment (pp. 379–395). Elsevier Inc. https://doi.org/10.1016/B978-0-12-417144-2.00019-6
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Ryan, P. C., Hammond, S. A., Ren, S., Lutterbuese, P., Amann, M., Oberst, M. D., Mulgrew, K., Criste, R., Fuhrmann, S., Lee, N., Gross, R., Liang, M., Schneider, A., Dixit, R., Baeuerle, P. C., Rattel, B., Coats, S., Roskos, L., Jallal, B., & Richman, L. (2012). In Vitro MABEL Approach for Nonclinical Safety Assessment of MEDI-565 (MT111). ALTEX Proc. 1/12, Proc of WC8 Montreal. 2012:85-87.
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Tricco, A. C., Lillie, E., Zarin, W., O’Brien, K. K., Colquhoun, H., Levac, D., Moher, D., Peters, M. D. J., Horsley, T., Weeks, L., Hempel, S., Akl, E. A., Chang, C., McGowan, J., Stewart, L., Hartling, L., Aldcroft, A., Wilson, M. G., Garritty, C., … Straus, S. E. (2018). PRISMA extension for scoping reviews (PRISMA-ScR): Checklist and explanation. In Annals of Internal Medicine (Vol. 169, Number 7, pp. 467–473). American College of Physicians. https://doi.org/10.7326/M18-0850