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

IF 2.7 4区 医学 Q3 TOXICOLOGY
Benjamin D Green, Peter C Soema, Heleen Kraan, Laura Hammer, Edith Mathiowitz, Dominick L Auci
{"title":"Pharmacokinetics and Pharmacodynamics of Recombinant Human Interleukin 12 in Dog and Rabbit Models of Toxicity.","authors":"Benjamin D Green, Peter C Soema, Heleen Kraan, Laura Hammer, Edith Mathiowitz, Dominick L Auci","doi":"10.1002/jat.4824","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7000,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Applied Toxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/jat.4824","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"TOXICOLOGY","Score":null,"Total":0}
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.

重组人白细胞介素12在狗和兔毒性模型中的药动学和药效学。
白细胞介素12 (IL-12)是一种有效的促炎性Th1细胞因子,在全身给予时具有短暂的抗肿瘤作用。局部给药最近显示出更有希望的结果,特别是当低剂量直接给药到肿瘤微环境时,促进抗肿瘤t细胞免疫。此外,IL-12有望作为粘膜佐剂。重新关注导致了新的递送策略,这将需要关键的非临床毒理学研究。由于重组人IL-12 (rhIL-12)在啮齿类动物中没有功能,因此传统上使用非人类灵长类动物(NHPs)进行这些研究。然而,它们的高成本和道德问题促使人们寻找替代模式。为此,我们研究了微胶囊化的rhIL-12在比格犬体内的药效学和药代动力学,结果表明,微胶囊化的rhIL-12在短时间内会增加IFNγ,并对造血和全身产生类似于人类的影响。虽然假设新西兰白兔(NZW)对rhIL-12有反应,但没有观察到活性的证据,尽管在使用微胶囊化的rhIL-12的研究中大量暴露。这些结果支持beagle犬作为一种有效的替代NHPs用于rhIL-12毒理学研究,同时排除了NZW兔作为合适模型的可能性。此外,观察到基于性别的药代动力学差异,这可能解释了微胶囊化rhIL-12在几种动物模型中的疗效增强。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
7.00
自引率
6.10%
发文量
145
审稿时长
1 months
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信