靶向治疗蛋白与肽的工程化设计优化及应用进展

doi:10.16085/j.issn.1000-6613.2024-2127

摘要/Abstract

摘要：

靶向性治疗蛋白和肽在精准医学中发挥着越来越重要的作用，尤其在癌症、免疫性疾病等治疗领域，展示了显著的潜力。与传统的小分子药物相比，靶向性蛋白和肽具有更高的特异性和较低的副作用，能够精准靶向疾病相关的分子。然而，它们的临床应用仍然面临一系列挑战，如稳定性差、免疫原性高、药代动力学差等问题。为了克服这些挑战，工程化设计优化已经成为提升其药效、安全性和临床应用前景的关键。本文首先介绍了靶向性治疗蛋白和肽的工程化设计的步骤；简述了肽类药物、蛋白质药物的优化设计方法；探索了相关药物递送策略，列举部分药物实例；分析了靶向性治疗蛋白和肽的临床应用现状、面临的挑战和发展前景；最后指出随着技术的不断发展，靶向性治疗蛋白和肽将在精准医学中发挥更重要的作用，为多种复杂疾病提供更高效的治疗方案。

关键词: 靶向性治疗, 蛋白质, 单克隆抗体, 生物分子工程, 精准医学

Abstract:

Targeted therapeutic proteins and peptides are playing an increasingly important role in precision medicine, especially in the treatment of cancer and immune diseases, showing significant potential. Compared with traditional small molecule drugs, targeted proteins and peptides have higher specificity and lower side effects, and can accurately target disease-related molecules. However, their clinical application still faces a series of challenges, such as poor stability, high immunogenicity, and poor pharmacokinetics. In order to overcome these challenges, engineering design optimization has become the key to improving their efficacy, safety and clinical application prospects. This article firstly introduces the steps of engineering design of targeted therapeutic proteins and peptides, briefly describes the optimization design methods of peptide drugs and protein drugs, explores related drug delivery strategies and lists some drug examples, and analyzes the current clinical application status, challenges and development prospects of targeted therapy proteins and peptides. Finally, it is pointed out that with the continuous development of technology, targeted therapeutic proteins and peptides will play a more important role in precision medicine and provide more efficient treatments for a variety of complex diseases.

Key words: targeted therapy, protein, monoclonal antibody, biomolecular engineering, precision medicine

中图分类号:

Q816

江奇逸, 邓鑫月, 袁艳婷, 张雅倩, 杨敏, 李伟娜, 范代娣. 靶向治疗蛋白与肽的工程化设计优化及应用进展[J]. 化工进展, 2025, 44(5): 2407-2420.

JIANG Qiyi, DENG Xinyue, YUAN Yanting, ZHANG Yaqian, YANG Min, LI Weina, FAN Daidi. Advances in engineering design, optimization and application of targeted therapeutic proteins and peptides[J]. Chemical Industry and Engineering Progress, 2025, 44(5): 2407-2420.

图/表 13

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靶标	相关疾病	靶向药物名称	作用机制	参考文献
HER2受体	HER2阳性乳腺癌、胃癌	赫赛汀（曲妥珠单抗）	阻断HER2受体，抑制肿瘤细胞增殖并促进免疫系统攻击肿瘤细胞	[36]
PD-1/PD-L1受体	黑色素瘤、非小细胞肺癌、肾癌	帕博利珠单抗、纳武单抗	解除免疫抑制，增强T细胞抗肿瘤活性	[37-38]
VEGF受体	结直肠癌、肾癌、湿性黄斑变性	贝伐珠单抗	阻断VEGF，抑制肿瘤血管生成	[39]
TNF-α	类风湿性关节炎、银屑病、克罗恩病	阿达木单抗、依那西普	阻断TNF-α，减轻免疫反应和炎症	[16,40]
CD20	B细胞淋巴瘤、慢性淋巴细胞白血病（CLL）	利妥昔单抗	与CD20结合，激活免疫系统清除肿瘤细胞	[41]
EGFR	非小细胞肺癌、头颈癌、结直肠癌	西妥昔单抗、吉非替尼	阻断EGFR受体，抑制肿瘤细胞增殖与侵袭	[42-43]
CD19	急性淋巴细胞白血病（ALL）、大B细胞淋巴瘤	替萨根微核素、axi-cel	通过基因改造T细胞，识别并攻击CD19阳性肿瘤细胞	[44-45]
C5补体成分	阵发性睡眠性血红蛋白尿症（PNH）	依库珠单抗	抑制C5，减少补体系统对红细胞的攻击，防止溶血	[46]

靶标	相关疾病	靶向药物名称	作用机制	参考文献
HER2受体	HER2阳性乳腺癌、胃癌	赫赛汀（曲妥珠单抗）	阻断HER2受体，抑制肿瘤细胞增殖并促进免疫系统攻击肿瘤细胞	[36]
PD-1/PD-L1受体	黑色素瘤、非小细胞肺癌、肾癌	帕博利珠单抗、纳武单抗	解除免疫抑制，增强T细胞抗肿瘤活性	[37-38]
VEGF受体	结直肠癌、肾癌、湿性黄斑变性	贝伐珠单抗	阻断VEGF，抑制肿瘤血管生成	[39]
TNF-α	类风湿性关节炎、银屑病、克罗恩病	阿达木单抗、依那西普	阻断TNF-α，减轻免疫反应和炎症	[16,40]
CD20	B细胞淋巴瘤、慢性淋巴细胞白血病（CLL）	利妥昔单抗	与CD20结合，激活免疫系统清除肿瘤细胞	[41]
EGFR	非小细胞肺癌、头颈癌、结直肠癌	西妥昔单抗、吉非替尼	阻断EGFR受体，抑制肿瘤细胞增殖与侵袭	[42-43]
CD19	急性淋巴细胞白血病（ALL）、大B细胞淋巴瘤	替萨根微核素、axi-cel	通过基因改造T细胞，识别并攻击CD19阳性肿瘤细胞	[44-45]
C5补体成分	阵发性睡眠性血红蛋白尿症（PNH）	依库珠单抗	抑制C5，减少补体系统对红细胞的攻击，防止溶血	[46]

合成方法	概述	优点	局限性	参考文献
固相合成法（SPPS）	在固相载体上逐步合成肽链，通过肽键连接氨基酸	高效，自动化程度高，适用于短肽合成，获得高纯度肽	对于长肽或大规模生产成本高，可能出现肽链折叠问题	[64]
液相合成法（LPPS）	在溶液中进行肽合成，通过酰胺化反应形成肽链	适合特殊反应和大规模合成	合成周期长，纯化难度较大	[65]
重组DNA技术	通过将目标蛋白或肽的基因导入宿主细胞进行表达，生成目的蛋白	能够高效表达大量蛋白，适合复杂蛋白和大规模生产	对于某些复杂蛋白或肽，可能需要特殊的后期修饰（如糖基化）	[66]
化学合成与后期修饰	在化学合成的基础上进行后期修饰（如PEG化、脂化等），提高药物活性和稳定性	改善肽或蛋白的稳定性、溶解度和免疫原性	后期修饰增加合成难度和成本	[67]

合成方法	概述	优点	局限性	参考文献
固相合成法（SPPS）	在固相载体上逐步合成肽链，通过肽键连接氨基酸	高效，自动化程度高，适用于短肽合成，获得高纯度肽	对于长肽或大规模生产成本高，可能出现肽链折叠问题	[64]
液相合成法（LPPS）	在溶液中进行肽合成，通过酰胺化反应形成肽链	适合特殊反应和大规模合成	合成周期长，纯化难度较大	[65]
重组DNA技术	通过将目标蛋白或肽的基因导入宿主细胞进行表达，生成目的蛋白	能够高效表达大量蛋白，适合复杂蛋白和大规模生产	对于某些复杂蛋白或肽，可能需要特殊的后期修饰（如糖基化）	[66]
化学合成与后期修饰	在化学合成的基础上进行后期修饰（如PEG化、脂化等），提高药物活性和稳定性	改善肽或蛋白的稳定性、溶解度和免疫原性	后期修饰增加合成难度和成本	[67]

药物类别	融合蛋白功能域	作用机制	应用领域	融合药物及应用疾病	参考文献
Fc融合蛋白	Fc段（人类IgG Fc）	延长半衰期，增加稳定性，增强免疫系统识别和靶向性	疫苗、免疫治疗、抗体药物偶联物	依那西普：融合TNF-α受体与Fc段，用于治疗类风湿性关节炎	[16]
抗体药物偶联物（ADCs）	Fc段与细胞毒性药物结合	精准递送细胞毒性药物到靶细胞，减少对正常细胞的影响	癌症治疗	曲妥珠单抗：HER2靶向药物，用于HER2阳性乳腺癌治疗	[36]
免疫检查点抑制剂融合蛋白	Fc段与免疫抑制因子结合	解除免疫抑制，增强T细胞抗肿瘤活性	癌症免疫治疗	阿特朱单抗：结合PD-L1抗体与Fc段，用于治疗非小细胞肺癌和其他癌症	[82]
抗体-酶融合蛋白	Fc段与酶（如酶活性蛋白）	通过Fc段增加酶的稳定性和靶向递送，提升治疗效果	代谢性疾病、癌症治疗	α葡糖糖苷酶：用于治疗庞贝病的酶替代疗法	[83]
细胞因子融合蛋白	Fc段与细胞因子（如IL-2、GM-CSF等）	提高细胞因子的稳定性，增强免疫反应和细胞活性	免疫治疗、癌症、炎症性疾病	非格司亭：与Fc融合的G-CSF，用于治疗化疗引起的白细胞减少症	[84]
抗体-抗体融合蛋白	Fc段与另一个抗体（如抗肿瘤抗体）	通过增强免疫系统的联合作用，提高对肿瘤细胞的免疫反应	癌症治疗、免疫疗法	博纳吐单抗：融合抗CD19与CD3抗体，用于治疗急性淋巴细胞白血病	[85]
Fc融合蛋白疫苗	Fc段与抗原结合	通过Fc段促进抗原呈递，增强免疫反应，提高疫苗效果	疫苗开发	Cervarix：HPV疫苗，采用Fc融合蛋白增加免疫反应	[86]