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Species selection considerations for preclinical toxicology studies for biotherapeutics
1Executive Director of Toxicology Amgen, Inc., One Amgen Center Dr, MS 29-2-A, Thousand Oaks, CA 91320-1799, USA. bussierj@amgen.com
Background:
Preclinical efficacy and safety studies, especially chronic studies, can be difficult to perform when the candidate therapeutic agent is a human protein due to the specificity of these molecules for the human target. The main issues are: i) the human protein or target may not be pharmacologically active in rodents or dogs, the standard toxicology species; or ii) the therapeutic agent may be so immunogenic in these species, that longer duration studies are not possible due to the formation of neutralizing antibodies. Thus, preclinical safety testing of biotherapeutics poses a particular challenge in selecting a relevant animal species for use in toxicology studies.
Objective:
This article will discuss the considerations that are unique to safety assessment of biotherapeutics and will provide alternatives to the standard toxicity testing which is conducted for small molecules.
Methods:
This article is based on published information with regards to species selection considerations as well as information from the FDA website on several marketed compounds. In addition, discussions of this topic that have occurred in public forums as well as the experience of the author are considered.
Conclusion:
The most important consideration in species selection for a biotherapeutic is that the drug is pharmacologically active in the preclinical species. This is a key consideration as biotherapeutics are highly targeted and rarely, if ever, demonstrate off-target toxicity. Because of this species specificity, nonhuman primates are often the only relevant species that can be used to assess the safety of a biotherapeutic. Other alternatives such as use of a homologous protein in rodents or the use of transgenic or knockout mice can also be used to assess safety although the caveats to these approaches must be considered.
Insights
Selecting the right animal model is crucial for biotherapeutic safety testing. Human proteins may not work in standard species, necessitating alternative methods like nonhuman primates or genetically modified rodents for accurate preclinical assessment.
Area of Science:
- Biopharmaceutical Development
- Toxicology
- Immunology
Background:
- Preclinical safety studies for human protein therapeutics face challenges due to species-specific target activity and potential immunogenicity.
- Standard toxicology species like rodents and dogs may not accurately reflect human responses to biotherapeutics.
- Developing safe and effective biotherapeutics requires overcoming these preclinical testing hurdles.
Purpose of the Study:
- To discuss unique considerations for biotherapeutic safety assessment.
- To explore alternatives to standard toxicity testing for biotherapeutics.
- To provide guidance on selecting appropriate animal models for biotherapeutic preclinical studies.
Main Methods:
- Review of published literature on species selection for biotherapeutics.
- Analysis of information from the U.S. Food and Drug Administration (FDA) website.
- Consideration of expert discussions and author experience in the field.
Main Results:
- Pharmacological activity in the chosen preclinical species is paramount for biotherapeutic safety assessment.
- Biotherapeutics are highly targeted, with off-target toxicity being rare.
- Species specificity significantly impacts the relevance of standard toxicology models.
Conclusions:
- Nonhuman primates are frequently the most relevant species for biotherapeutic safety evaluation due to target specificity.
- Alternative approaches include using homologous proteins in rodents or employing transgenic/knockout mice.
- Careful consideration of the limitations and caveats of each alternative method is essential.
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