Institute of Oncology Ljubljana, 1000, Ljubljana, Slovenia.
Faculty of Health Sciences, University of Ljubljana, 1000, Ljubljana, Slovenia.
Sci Rep. 2024 Sep 27;14(1):22288. doi: 10.1038/s41598-024-73314-x.
Immunotherapeutic drugs are promising medicines for cancer treatment. A potential candidate for immunotherapy is interleukin-12 (IL-12), a cytokine well known for its ability to mediate antitumor activity. We developed a plasmid encoding human IL-12 devoid of an antibiotic resistance gene (phIL12). For the approval of phase I clinical trials in basal cell carcinoma (BCC), the regulatory agency requires non-clinical in vivo testing of the pharmacodynamic, pharmacokinetic and toxicological properties of the plasmid. As human IL-12 is not biologically active in mice, a mouse ortholog of the plasmid phIL12 (pmIL12) was evaluated. The evaluation demonstrated the antitumor effectiveness of the protein accompanied by immune cell infiltration. The plasmid was distributed throughout the body, and the amount of plasmid diminished over time in all organs except the skin around the tumor. The therapy did not cause any detectable systemic toxicity. The results of the non-clinical evaluation demonstrated the safety and efficacy of the pmIL12/phIL12 GET, and on the basis of these results, approval was obtained for the initiation of a phase I clinical study in BCC.
免疫治疗药物是癌症治疗中很有前途的药物。一种有潜力的免疫治疗候选药物是白细胞介素 12（IL-12），这种细胞因子以介导抗肿瘤活性的能力而闻名。我们开发了一种不含抗生素抗性基因的人白细胞介素 12 质粒（phIL12）。为了获得基底细胞癌（BCC）I 期临床试验的批准，监管机构要求对质粒的药效学、药代动力学和毒理学特性进行非临床体内测试。由于人白细胞介素 12 在小鼠中没有生物活性，因此评估了质粒的小鼠同源物（pmIL12）。评估结果表明，该蛋白具有抗肿瘤作用，并伴有免疫细胞浸润。质粒分布在全身，除肿瘤周围皮肤外，所有器官中的质粒数量随时间减少。该疗法不会引起任何可检测到的全身毒性。非临床评估的结果证明了 pmIL12/phIL12 GET 的安全性和有效性，基于这些结果，获得了批准，可以开始在 BCC 中进行 I 期临床研究。
