Pharmacokinetics and Pharmacodynamics of Recombinant Human Interleukin 12 in Dog and Rabbit Models of Toxicity.

Interleukin 12 (IL-12) is a potent pro-inflammatory Th1 cytokine with transient antitumor effects when given systemically. Local administration has recently shown more promising results, particularly when lower doses are delivered directly to tumor microenvironments, promoting anti-tumor T-cell immunity. In addition, IL-12 holds promise as a mucosal adjuvant. Renewed attention has led to novel delivery strategies that will necessitate pivotal non-clinical toxicology studies. Because recombinant human IL-12 (rhIL-12) is not functional in rodents, non-human primates (NHPs) have traditionally been used for these studies. However, their high cost and ethical concerns incentivize the search for alternative models. To this end, we examined the pharmacodynamics and pharmacokinetics of microencapsulated rhIL-12 in beagle dogs, which displayed expected transient IFNγ increases and hematopoietic and systemic effects similar to those seen in humans. Although New Zealand White (NZW) rabbits were hypothesized to be responsive to rhIL-12, no evidence of activity was observed, despite significant exposure in a study using microencapsulated rhIL-12. These results support beagle dogs as a useful alternative to NHPs for rhIL-12 toxicology studies, while ruling out NZW rabbits as a suitable model. Moreover, sex-based pharmacokinetic differences were observed, which might explain enhanced efficacy with microencapsulated rhIL-12 in several animal models.