Non-Clinical Safety Evaluation of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells in Cynomolgus Monkeys

Abstract

Xin-Mei Hu,1,* Can-Can Wang,1,* Yu Xiao,1 Yu Liu,1 Hong-Ri Huang,2 Peng Jiang,1 Ying-Kai Wang,1 Yun-Jin Lin,1 Liang-Cheng Li,3 Zhong-Quan Qi1 1Medical College, Guangxi University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Research and Development, Guangxi Taimei Rensheng Biotechnology Co., Ltd, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhong-Quan Qi, Guangxi University, Da-Xue-Dong Road No. 100, Xixiangtang District, Nanning, Guangxi Zhuang Autonomous Region, 530004, People’s Republic of China, Tel [phone], Email [email protected] Liang-Cheng Li, Xiamen University, No. 4221-115, Rm 355, Xiang’an District, Xiang’an, Xiamen Fujian Province, 361102, People’s Republic of China, Tel [phone], Email [email protected]: In recent years, exosomes have been proved to be used to treat many diseases. However, due to the lack of uniform quality control standards for exosomes, the safety of exosomes is still a problem to be solved, especially now more and more exosomes are used in clinical trials, and its non-clinical safety evaluation is particularly important. However, there is no safety evaluation standard for exosomes at present. Therefore, this study will refer to the evaluation criteria of therapeutic biological products, adopt non-human primates to evaluate the non-clinical safety of human umbilical cord mesenchymal stem cell exosomes from the general pharmacology and immunotoxicity, aiming at establishing a safety evaluation system of exosomes and providing reference for the clinical application of exosomes in the future.Methods: 3.85 × 1012 exosomes derived from human umbilical cord mesenchymal stem cells were injected into cynomolgus monkeys intravenously. The changes of general clinical conditions, hematology, immunoglobulin, Th1/Th2 cytokines, T lymphocytes and B lymphocytes, and immune organs were observed before and within 14 days after injection.Results: The results showed that exosomes did not have obvious pathological effects on the general clinical conditions, blood, coagulation function, organ coefficient, immunoglobulin, Th1/Th2 cytokines, lymphocytes, major organs, and major immune organs (spleen, thymus, bone marrow) of cynomolgus monkeys. However, the number of granulocyte-macrophage colonies in exosomes group was significantly higher than that in control group.Conclusion: To sum up, the general pharmacological results and immunotoxicity results showed that the injection of 3.85 × 1012 exosomes may have no obvious adverse reactions to cynomolgus monkeys. This dose of exosomes is relatively safe for treatment, which provides basis research for non-clinical safety evaluation of exosomes and provides reliable research basis for future clinical application of exosomes.Keywords: exosomes, cynomolgus monkeys, safety, immunotoxicity

Keywords

• exosomes
• cynomolgus monkeys
• safety
• immunotoxicity