PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients
Jintrolong® is a long-acting PEGylated recombinant human growth hormone (PEG-rhGH) developed for weekly injection in patients with pediatric growth hormone deficiency (PGHD). Although PEG modification of therapeutic proteins is generally considered safe, concerns persist about the potential for adve...
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| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.821588/full |
| _version_ | 1828264704767688704 |
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| author | Wei Wu Juan Zhou Chuandong Wu Qian Zhou Xiaoyu Li Yanlin Zhang Conglin Zuo Jun Yin Ling Hou Shuyang Wang Hongyang Gao Tianhong Luo Lei Jin Enhong Zhong Yingwu Wang Xiaoping Luo |
| author_facet | Wei Wu Juan Zhou Chuandong Wu Qian Zhou Xiaoyu Li Yanlin Zhang Conglin Zuo Jun Yin Ling Hou Shuyang Wang Hongyang Gao Tianhong Luo Lei Jin Enhong Zhong Yingwu Wang Xiaoping Luo |
| author_sort | Wei Wu |
| collection | DOAJ |
| description | Jintrolong® is a long-acting PEGylated recombinant human growth hormone (PEG-rhGH) developed for weekly injection in patients with pediatric growth hormone deficiency (PGHD). Although PEG modification of therapeutic proteins is generally considered safe, concerns persist about the potential for adverse vacuolation in tissues with long-term exposure to PEG-included therapies, particularly in children. We assessed the safety of Jintrolong® in cynomolgus monkeys with an examination of vacuolation in the brain choroid plexus (CP) and reported long-term clinical safety data obtained from children with PGHD. The toxicity of Jintrolong® was assessed following the 52-week administration with doses at 0.3, 1, or 3 mg/kg/week. The levels of vacuolation of CP in animals were dose-dependent and at least partially reversible after a 104- or 157-week recovery period. Vacuolation in the CP epithelium did not lead to obvious subcellular structural or cell functional abnormalities. Compared with the clinical dose of 0.2 mg/kg/week Jintrolong® in PGHD patients, exposure in monkeys under NOAEL 3 mg/kg/week exhibited safety margins greater than 120.5, the predicted minimum dose to induce vacuolation in monkeys is equivalent to 1.29 mg/kg/week in humans, which is 6.45-fold higher than the clinical dose. The safety data acquired in clinical trials for Jintrolong® were also analyzed, which included phase III (360 patients), phase IV (3,000 patients) of 26-week treatment, and a follow-up study with treatment lasting for 3 years. There was no statistically significant difference in the incidence of adverse reactions between the Jintrolong® group and the daily rhGH control group (no PEG), and no new adverse effects (AE) were observed in the Jintrolong® group at the clinical therapeutic dose of 0.2 mg/kg/week. |
| first_indexed | 2024-04-13T04:28:45Z |
| format | Article |
| id | doaj.art-97e8687a3d664d16bf328b4525f3edab |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-13T04:28:45Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-97e8687a3d664d16bf328b4525f3edab2022-12-22T03:02:23ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-07-011310.3389/fendo.2022.821588821588PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency PatientsWei Wu0Juan Zhou1Chuandong Wu2Qian Zhou3Xiaoyu Li4Yanlin Zhang5Conglin Zuo6Jun Yin7Ling Hou8Shuyang Wang9Hongyang Gao10Tianhong Luo11Lei Jin12Enhong Zhong13Yingwu Wang14Xiaoping Luo15Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaCenter for Nonclinical Research and Translational Medicine, Changchun GeneScience Pharmaceuticals Co., Ltd., Changchun, ChinaDepartment of Toxicology, JOINN Laboratories (Suzhou) Co., Ltd., Suzhou, ChinaCenter for Nonclinical Research and Translational Medicine, Changchun GeneScience Pharmaceuticals Co., Ltd., Changchun, ChinaCenter for Nonclinical Research and Translational Medicine, Changchun GeneScience Pharmaceuticals Co., Ltd., Changchun, ChinaDepartment of Toxicology, JOINN Laboratories (Suzhou) Co., Ltd., Suzhou, ChinaDepartment of Toxicology, JOINN Laboratories (Suzhou) Co., Ltd., Suzhou, ChinaDepartment of Toxicology, JOINN Laboratories (Suzhou) Co., Ltd., Suzhou, ChinaDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaDepartment of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaElectron Microscope Core Laboratory, Shanghai Medical College, Fudan University, Shanghai, ChinaCenter for Nonclinical Research and Translational Medicine, Changchun GeneScience Pharmaceuticals Co., Ltd., Changchun, ChinaCenter for Nonclinical Research and Translational Medicine, Changchun GeneScience Pharmaceuticals Co., Ltd., Changchun, ChinaCenter for Nonclinical Research and Translational Medicine, Changchun GeneScience Pharmaceuticals Co., Ltd., Changchun, ChinaSchool of Life Science, Jilin University, Changchun, ChinaDepartment of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaJintrolong® is a long-acting PEGylated recombinant human growth hormone (PEG-rhGH) developed for weekly injection in patients with pediatric growth hormone deficiency (PGHD). Although PEG modification of therapeutic proteins is generally considered safe, concerns persist about the potential for adverse vacuolation in tissues with long-term exposure to PEG-included therapies, particularly in children. We assessed the safety of Jintrolong® in cynomolgus monkeys with an examination of vacuolation in the brain choroid plexus (CP) and reported long-term clinical safety data obtained from children with PGHD. The toxicity of Jintrolong® was assessed following the 52-week administration with doses at 0.3, 1, or 3 mg/kg/week. The levels of vacuolation of CP in animals were dose-dependent and at least partially reversible after a 104- or 157-week recovery period. Vacuolation in the CP epithelium did not lead to obvious subcellular structural or cell functional abnormalities. Compared with the clinical dose of 0.2 mg/kg/week Jintrolong® in PGHD patients, exposure in monkeys under NOAEL 3 mg/kg/week exhibited safety margins greater than 120.5, the predicted minimum dose to induce vacuolation in monkeys is equivalent to 1.29 mg/kg/week in humans, which is 6.45-fold higher than the clinical dose. The safety data acquired in clinical trials for Jintrolong® were also analyzed, which included phase III (360 patients), phase IV (3,000 patients) of 26-week treatment, and a follow-up study with treatment lasting for 3 years. There was no statistically significant difference in the incidence of adverse reactions between the Jintrolong® group and the daily rhGH control group (no PEG), and no new adverse effects (AE) were observed in the Jintrolong® group at the clinical therapeutic dose of 0.2 mg/kg/week.https://www.frontiersin.org/articles/10.3389/fendo.2022.821588/fullPEG-rhGHGHDchoroid plexus (CP)vacuolationMRITEM |
| spellingShingle | Wei Wu Juan Zhou Chuandong Wu Qian Zhou Xiaoyu Li Yanlin Zhang Conglin Zuo Jun Yin Ling Hou Shuyang Wang Hongyang Gao Tianhong Luo Lei Jin Enhong Zhong Yingwu Wang Xiaoping Luo PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients Frontiers in Endocrinology PEG-rhGH GHD choroid plexus (CP) vacuolation MRI TEM |
| title | PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients |
| title_full | PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients |
| title_fullStr | PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients |
| title_full_unstemmed | PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients |
| title_short | PEGylated Recombinant Human Growth Hormone Jintrolong® Exhibits Good Long-Term Safety in Cynomolgus Monkeys and Human Pediatric Growth Hormone Deficiency Patients |
| title_sort | pegylated recombinant human growth hormone jintrolong r exhibits good long term safety in cynomolgus monkeys and human pediatric growth hormone deficiency patients |
| topic | PEG-rhGH GHD choroid plexus (CP) vacuolation MRI TEM |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.821588/full |
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