Evaluating Cytokine Data In Nonhuman Primate Safety Assessment Studies: A Correlation To Toxicity Outcomes

By Cassandra Johnson, Narine Lalayeva, and Julie Forget

Cytokines are small proteins involved in cell signaling, categorized as either pro-inflammatory or anti-inflammatory, and have become increasingly important as potential biomarkers in safety assessment studies, especially with the growing development of biologics and immune-modulating drugs. However, evaluating cytokine levels can be challenging due to their short half-life and the variability of stimuli, which makes it difficult to establish a clear correlation to toxicity responses within animals in the same dose group. Additionally, toxicity responses observed in clinical observations, body weights, clinical pathology, and anatomic pathology findings often exhibit high variability within the same dose group. To explore this issue, previous studies were reviewed to determine whether animals exhibiting a larger or more sustained elevation of inflammatory cytokines had worse prognoses compared to other animals within the same group.

For example, in one study, a single high-dose animal with the highest circulating levels of IL-6 and MCP-1 (following a Day 29 dose) was euthanized due to moribund conditions on Day 31. In another study, an animal within a dose group, which showed prolonged elevations of MCP-1, IL-6, and IFN-γ, experienced altered clinical pathology parameters, decreased body weight, and abnormal clinical observations compared to the other animals in the same group. For instance, one animal showed a transient increase in BUN and creatinine levels three days after a persistent elevation in inflammatory cytokines. However, in some studies, correlating cytokine levels with other parameters can be challenging, especially when multiple clinical conditions occur within the same dose group. In a third study reviewed, clinical observations of excessive scratching, decreased activity, inappetence, unresponsiveness, and shivering were observed in the high-dose group, with one animal displaying microscopic lesions in the kidney, lung, bone marrow, and spleen, along with the highest circulating levels of IL-6 but not MCP-1.

In conclusion, cytokine data should be interpreted within the context of other study findings. The correlation between cytokine levels and other parameters is likely influenced by the pharmacological action of the test article, the specific cytokines being evaluated, and the timing of cytokine measurements in relation to dosing.