Safety pharmacology cross-reactivity studies

Some biotechnologically derived pharmaceuticals will cross-react with species that can be evaluated toxicologically, while others cross-react only with nonhuman primates such as the chimpanzee, a protected species. In this case, a well-designed safety, or Phase 0 study at doses higher than the proposed clinical dose may provide valuable safety information. However, a lack of cross-reactivity with any nonhuman species does not necessarily make preclinical safety evaluation impossible, not does it limit toxicity testing to species in which the protein lacks relevant pharmacological activity. Some alternative possibilities are summarized in Table 12.9. 

Pulmonary Assessment in ICH S7A Safety Pharmacology Studies for Human the Conscious Rat Pharmaceuticals Tissue Cross-Reactivity (TCR) 2-4 4-8 25,000 5,000... 

From a practical perspective, species cross-reactivity should be considered an important criterion for lead candidate selection. In the absence of cross-reactivity, there are limited options for assessing the potential safety risks during nonclinical development, which in turn impacts the conduct of the clinical trials (Muller et al., 2009). Ideally, a lead candidate with both rodent and nonrodent cross-reactivity would be identified, as this enables the molecule to be evaluated in pharmacology studies and if needed early rodent toxicology studies. However, if not possible, all available protein engineering efforts should be undertaken to identify a lead with NHP CToss-reactivity (Doria-Rose and Joyce, 2015). 

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