Translational accuracy begins with species selection: Matching models to human biology.
Selecting the appropriate nonclinical species is a critical decision in drug development. The choice directly affects the predictive value, safety assessment, and clinical translation of new therapeutics. Because no animal species fully replicates human biology, the optimal model depends on a combination of organ-specific physiological similarity, molecular target homology, target expression profile, and pharmacodynamic/pharmacokinetic (PD/PK) behavior.
For small molecules, species selection is often driven by ADME characteristics, metabolic pathways, and similarity in the primary organ system targeted by the therapy. For biologics, the decision becomes even more constrained: molecular target homology to humans, receptor sequence identity, ligand-binding affinity, and FcRn biology are frequently decisive, as they determine both pharmacological activity and systemic exposure.
Many investigational drugs fail in translation because preclinical findings reflect species-specific biology rather than true human pharmacology. Therefore, the alignment between drug mechanisms, human target biology, and species physiology must be carefully evaluated prior to selection of the correct species for any drug development program.
This includes:
- Organ-system homology: Structural and functional similarity of major systems, including cardiovascular, pulmonary, hepatic, renal, CNS, GI tract, immune, endocrine, skin, bone, reproductive, and ocular systems. In particular, the system(s) that would be the target for the drug under development.
- Molecular target homology: Degree of amino acid sequence identity and receptor–ligand compatibility between human targets and their orthologs in each species.
- Target expression profile: Comparable distribution and density of the therapeutic target across tissues.
- Pharmacology: Similar receptor binding/internalization, activity, and biological response.
The following table quantifies these cross-species differences using a numerical homology scoring system across 11 major organ systems, along with total and average scores that summarize the overall translational relevance of each species. The table is based on an objective AI generated evaluation based on the following input: “Compare NHP, Göttingen Minipigs and dog with human in relation to different organ systems and rate the homology for each organ from 1-10 and provide a rational for the rating – make one table.”
Across all evaluated organ systems, Non-Human Primates (NHP) show the highest overall homology to humans, particularly in immune biology, reproductive physiology, CNS structure, cardiovascular electrophysiology, and drug metabolism. This makes NHPs the most translationally predictive species, especially for biologics, CNS drugs, immunotherapies, reproductive toxicity, and complex human-like physiological responses. Their limitations lie mainly in ethical constraints, cost, and logistics, rather than biological relevance, although in some cases, e.g. skin, the minipig is superior to the NHP.
Göttingen Minipigs emerge as the strongest non-primate alternative, offering high similarity in skin, cardiovascular, GI, renal, and metabolic systems with anatomy and physiology often closer to humans than dogs. Their gyrencephalic brain, human-like dermal structure, cardiovascular perfusion, and predictive PK/PD and toxicology properties make them particularly valuable in dermal, cardiovascular, metabolic, and general toxicology studies. However, their immune system, FcRn biology, and reproductive physiology diverge more from humans than NHPs. The newly derived Humanized IgG1/IgG4 Göttingen Minipigs enable safety and efficacy testing of human recombinant antibodies and reduce the need for studies in NHPs, providing a new tool to mitigate clinical development risk. The sensitivity with which Humanized IgG1/IgG4 Göttingen Minipigs respond to immunogenic human mAbs while tolerating non-immunogenic human mAbs makes them an ideal model for safety assessments of therapeutic human mAbs and prediction of possible side effects.
Dogs show moderate but consistently lower homology than NHPs and minipigs compared to humans across most organ systems. Strengths include cardiovascular hemodynamics, renal function, but notable divergences in GI physiology, metabolism (CYPs), skin structure, immune responses, and reproductive biology reduce their human predictive power in several domains. As a result, dogs remain useful in some safety pharmacology and historical regulatory settings, but scientific homology increasingly favours minipigs in many areas.
In conclusion, with the push away from using NHPs in biomedical research unless absolutely necessary, the minipig, with its close similarity to humans in several areas, is an ideal non-human model with superiority to dogs in many ways.
Acknowledgements
Thank you to Andrew Makin, Andrew Makin Preclinical Consulting; and Susanne Mohr and Björn Jacobsen, F. Hoffmann-La Roche for providing edits and validating the contents of this whitepaper.
Download whitepaper on translation species selection.
