化工进展 ›› 2021, Vol. 40 ›› Issue (6): 3401-3410.DOI: 10.16085/j.issn.1000-6613.2020-1448
李瑶1(), 巨晓洁1,2(), 汪伟1,2, 刘壮1,2, 谢锐1,2, 褚良银1,2
收稿日期:
2020-07-27
修回日期:
2020-09-01
出版日期:
2021-06-06
发布日期:
2021-06-22
通讯作者:
巨晓洁
作者简介:
李瑶(1996—),女,硕士研究生。E-mail:基金资助:
LI Yao1(), JU Xiaojie1,2(), WANG Wei1,2, LIU Zhuang1,2, XIE Rui1,2, CHU Liangyin1,2
Received:
2020-07-27
Revised:
2020-09-01
Online:
2021-06-06
Published:
2021-06-22
Contact:
JU Xiaojie
摘要:
重组人生长激素(rhGH)是治疗各种生长激素缺乏症及并发症的首选药物,但临床上需长期频繁注射给药,实现rhGH长效化和改变给药途径可显著提高患者依从性,具有重要的研究价值。本文针对近年来rhGH长效化制剂和非注射给药途径的类型、有效性及开发现状进行了综述,主要介绍了利用化学修饰、构建融合蛋白、构建缓释微球等rhGH长效化方法以及经皮给药、肺部给药、鼻腔黏膜给药等rhGH非注射给药途径的研究现状和最新进展,分析了各类rhGH给药系统在应用方面的潜在问题,以期使读者对该领域的研究状况有更全面、更清楚的了解;并指出了该研究领域未来的发展方向,提出了将rhGH长效化与非注射给药途径合理结合应是将来实现rhGH高效递送的重要研究方向,以期为进一步开发安全有效的rhGH新型给药系统提供参考。
中图分类号:
李瑶, 巨晓洁, 汪伟, 刘壮, 谢锐, 褚良银. 重组人生长激素给药系统的研究进展[J]. 化工进展, 2021, 40(6): 3401-3410.
LI Yao, JU Xiaojie, WANG Wei, LIU Zhuang, XIE Rui, CHU Liangyin. Research progress of recombinant human growth hormone delivery systems[J]. Chemical Industry and Engineering Progress, 2021, 40(6): 3401-3410.
产品名称 | 生产企业 | rhGH修饰策略 | 给药频率 | 研发状态 |
---|---|---|---|---|
NNC126-0083[ | Novo Nordisk | 将43000 PEG分子附着于rhGH分子谷氨酰胺141上 | 7天1次 | 研发终止 |
PHA-794428[ | Pfizer | 将40000分支型PEG修饰在rhGH分子的N末端上 | 7天1次 | 研发终止 |
BBT-031[ | Bolder BioTechnology | 位点特异性PEG化rhGH | 7天1次 | 临床前研究 |
ARX201[ | Ambrx | 在rhGH的氨基酸35处,对乙酰基苯丙氨酸取代天然酪氨酸后与30kg/mol的PEG连接 | 7天1次 | 研发终止 |
Jintrolong?[ | GeneScience | 将40000支链亲水PEG残基连接到氨基末端 | 7天1次 | 在中国上市 |
表1 PEG修饰rhGH研究
产品名称 | 生产企业 | rhGH修饰策略 | 给药频率 | 研发状态 |
---|---|---|---|---|
NNC126-0083[ | Novo Nordisk | 将43000 PEG分子附着于rhGH分子谷氨酰胺141上 | 7天1次 | 研发终止 |
PHA-794428[ | Pfizer | 将40000分支型PEG修饰在rhGH分子的N末端上 | 7天1次 | 研发终止 |
BBT-031[ | Bolder BioTechnology | 位点特异性PEG化rhGH | 7天1次 | 临床前研究 |
ARX201[ | Ambrx | 在rhGH的氨基酸35处,对乙酰基苯丙氨酸取代天然酪氨酸后与30kg/mol的PEG连接 | 7天1次 | 研发终止 |
Jintrolong?[ | GeneScience | 将40000支链亲水PEG残基连接到氨基末端 | 7天1次 | 在中国上市 |
名称 | 生产企业 | rhGH融合方式 | 给药频率 | 开发现状 |
---|---|---|---|---|
AG-B1512[ | Ahn-Gook | 与抗人血清白蛋白Fab抗体基因融合进行多肽连接 | 14或28天1次 | 临床前研究 |
GX-H9[ | Genexine | 与IgD和IgG4的杂合免疫球蛋白Fc部分融合 | 7~14天1次 | 临床二期完成 |
Albutropin(TV1106)[ | Teva | 人血清白蛋白融合到rhGH的N末端 | 7天1次 | 研发终止 |
Somavaratan(VRS-317)[ | Versartis | 与天然产生的亲水氨基酸XTEN序列融合 | 7~30天1次 | 研发终止 |
LAPS-rhGH(HM10560A)[ | Hanmi | 与同二聚体苷基化IgG4 Fc片段融合 | 7~14天1次 | 临床前研究 |
JR-142[ | JCR | 工程rhGH与改良的人血清白蛋白C端在N端融合 | 7天1次 | 临床前研究 |
ALT-P1(CJ-40002)[ | Alteogen | rhGH与重组α1-抗胰蛋白酶融合 | 未知 | 研发终止 |
ProFuse GH[ | Asterion | rhGH与其受体胞外域结合蛋白片段融合 | 1月1次 | 临床前研究 |
Somatrogon(MOD-4023)[ | OPKO and Pfizer | 与HCG的3个羧基末端B亚单位融合 | 7天1次 | 临床三期 |
表2 rhGH融合蛋白研究
名称 | 生产企业 | rhGH融合方式 | 给药频率 | 开发现状 |
---|---|---|---|---|
AG-B1512[ | Ahn-Gook | 与抗人血清白蛋白Fab抗体基因融合进行多肽连接 | 14或28天1次 | 临床前研究 |
GX-H9[ | Genexine | 与IgD和IgG4的杂合免疫球蛋白Fc部分融合 | 7~14天1次 | 临床二期完成 |
Albutropin(TV1106)[ | Teva | 人血清白蛋白融合到rhGH的N末端 | 7天1次 | 研发终止 |
Somavaratan(VRS-317)[ | Versartis | 与天然产生的亲水氨基酸XTEN序列融合 | 7~30天1次 | 研发终止 |
LAPS-rhGH(HM10560A)[ | Hanmi | 与同二聚体苷基化IgG4 Fc片段融合 | 7~14天1次 | 临床前研究 |
JR-142[ | JCR | 工程rhGH与改良的人血清白蛋白C端在N端融合 | 7天1次 | 临床前研究 |
ALT-P1(CJ-40002)[ | Alteogen | rhGH与重组α1-抗胰蛋白酶融合 | 未知 | 研发终止 |
ProFuse GH[ | Asterion | rhGH与其受体胞外域结合蛋白片段融合 | 1月1次 | 临床前研究 |
Somatrogon(MOD-4023)[ | OPKO and Pfizer | 与HCG的3个羧基末端B亚单位融合 | 7天1次 | 临床三期 |
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