Benjamin D Green, Peter C Soema, Heleen Kraan, Laura Hammer, Edith Mathiowitz, Dominick L Auci
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引用次数: 0
Abstract
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.
期刊介绍:
Journal of Applied Toxicology publishes peer-reviewed original reviews and hypothesis-driven research articles on mechanistic, fundamental and applied research relating to the toxicity of drugs and chemicals at the molecular, cellular, tissue, target organ and whole body level in vivo (by all relevant routes of exposure) and in vitro / ex vivo. All aspects of toxicology are covered (including but not limited to nanotoxicology, genomics and proteomics, teratogenesis, carcinogenesis, mutagenesis, reproductive and endocrine toxicology, toxicopathology, target organ toxicity, systems toxicity (eg immunotoxicity), neurobehavioral toxicology, mechanistic studies, biochemical and molecular toxicology, novel biomarkers, pharmacokinetics/PBPK, risk assessment and environmental health studies) and emphasis is given to papers of clear application to human health, and/or advance mechanistic understanding and/or provide significant contributions and impact to their field.