重组人生长激素给药系统的研究进展

doi:10.16085/j.issn.1000-6613.2020-1448

摘要/Abstract

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。

关键词: 重组人生长激素, 长效化制剂, 非注射给药途径

Abstract:

Recombinant human growth hormone (rhGH) is the first choice to treat various growth hormone deficiencies and complications. But the rhGH requires long-term and frequent injection clinically. Long-acting rhGH preparations and non-injection administration routes can significantly increase patient compliance. In this paper, the types, effectiveness and development status of long-acting rhGH preparations and non-injection administration routes were reviewed. The research status and latest progress of rhGH long-acting methods (such as chemical modification, construction of fusion proteins, construction of sustained-release microspheres) and non-injection routes of rhGH (such as transdermal, pulmonary, nasal administrations) were introduced. The potential application problems of these rhGH delivery systems were analyzed, so that readers can have a more comprehensive and clear understanding of the research status in this field. The future development direction of this field was also proposed, that the rational combination of long-acting and non-injection administration would be an important research direction to achieve high-efficiency delivery of rhGH in the future. This paper provides a reference for the further development of a new safe and effective rhGH drug delivery system.

Key words: recombinant human growth hormone(rhGH), long-acting preparation, non-injection administration route

中图分类号:

TQ469

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.

图/表 5

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产品名称	生产企业	rhGH修饰策略	给药频率	研发状态
NNC126-0083^［24］	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^［29］	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^［30］	Bolder BioTechnology	位点特异性PEG化rhGH	7天1次	临床前研究
ARX201^［31］	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?^［27］	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

产品名称	生产企业	rhGH修饰策略	给药频率	研发状态
NNC126-0083^［24］	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^［29］	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^［30］	Bolder BioTechnology	位点特异性PEG化rhGH	7天1次	临床前研究
ARX201^［31］	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?^［27］	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^［34］	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^［35］	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）^［36］	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）^［37］	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）^［38］	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^［39］	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）^［40］	Alteogen	rhGH与重组α1-抗胰蛋白酶融合	未知	研发终止
ProFuse GH^［41］	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）^［42］	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

名称	生产企业	rhGH融合方式	给药频率	开发现状
AG-B1512^［34］	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^［35］	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）^［36］	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）^［37］	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）^［38］	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^［39］	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）^［40］	Alteogen	rhGH与重组α1-抗胰蛋白酶融合	未知	研发终止
ProFuse GH^［41］	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）^［42］	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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