德曲妥珠单抗的专利布局分析

Analysis on the patent layout of trastuzumab deruxtecan

摘要

德曲妥珠单抗在人表皮生长因子受体2(HER2)相关肿瘤治疗中具有广阔的应用前景,对其专利信息的分析有助于此类药物的研发和创新。通过专利检索与文献研究,德曲妥珠单抗中曲妥珠单抗的分子专利期限已届满。连接子、毒素药物的相关专利仍然有效。德曲妥珠单抗的相关专利全部有效,专利布局结构合理,采取“结构-工艺-适应证-联合用药”的递进式申请策略,持续延长专利生命。从专利分析角度,为创新主体提供新药研发思路:① 充分利用专利期限届满的抗体药物。② 保留连接子中的马来酰亚胺基己酸-甘氨酸-甘氨酸-苯丙氨酸-甘氨酸(GGFG)四肽,实质性改进其他部分的分子结构。以瑞康曲妥珠单抗为例,通过创造性的结构修饰,有希望突破德曲妥珠单抗的专利壁垒。

Abstract

Trastuzumab Deruxtecan has broad application prospects in the treatment of HER2-related tumors. The analysis of patent information can facilitate the research and innovation of this class of drugs. Through patent search and literature review, the molecular patents for the trastuzumab component have expired. The related patents for the linker and the cytotoxic drug remain valid. All the related patents of trastuzumab deruxtecan are valid, and its patent layout structure is reasonable. A progressive application strategy of “structure-process-indication-combination therapy” has been adopted to continuously extend the patent life. From the perspective of patent analysis, this provides new drug research pathways for innovative entities. First, make full use of the antibody drugs whose patent terms have expired; second, retain the GGFG tetrapeptide in the linker and substantially improve the molecular structure of other parts. Taking trastuzumab rezetecan as an example, through creative structural modifications, this strategy is expected to break through the patent barriers of trastuzumab deruxtecan.

关键词

德曲妥珠单抗 / 甘氨酸-甘氨酸-苯丙氨酸-甘氨酸四肽 / 抗体药物偶联物 / 专利布局 / 新药研发

Key words

trastuzumab deruxtecan / GGFG / antibody drug conjugate / patent layout / new drug research

[1] JANG JY, KIM D, LEE NK, et al. Antibody-drug conjugates powered by deruxtecan: innovations and challenges in oncology[J]. Int J Mol Sci, 2025, 26(13): 6523.
[2] INDINI A, RIJAVEC E, GROSSI F. Trastuzumab deruxtecan: changing the destiny of HER2 expressing solid tumors[J]. Int J Mol Sci, 2021, 22(9): 4774.
[3] MERIC-BERNSTAM F, MAKKER V, OAKNIN A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial[J]. J Clin Oncol, 2024, 42(1): 47-58.
[4] YAGISAWA M, TANIGUCHI H, SATOH T, et al. Trastuzumab deruxtecan in advanced solid tumors with human epidermal growth factor receptor 2 amplification identified by plasma cell-free DNA testing: a multicenter, single-arm, phase II basket trial[J]. J Clin Oncol, 2024, 42(32): 3817-3825.
[5] MODI S, JACOT W, YAMASHITA T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer[J]. N Engl J Med, 2022, 387(1): 9-20.
[6] TSAO LC, WANG JS, MA XR, et al. Effective extracellular payload release and immunomodulatory interactions govern the therapeutic effect of trastuzumab deruxtecan (T-DXd)[J]. Nat Commun, 2025, 16(1): 3167.
[7] ALROSAN AZ, DMOUR I, RATAAN AO, et al. Comparative pharmacological analysis of fam-trastuzumab deruxtecan-nxki and sacituzumab govitecan-hziy: Two recently developed chemotherapies in the crucial battle against breast cancer[J]. Toxicol Rep, 2025, 14: 102054.
[8] XIAO T, ALI SJ, MATA DGMM, et al. Antibody-drug conjugates in breast cancer: ascent to destiny and beyond-a 2023 review[J]. Curr Oncol, 2023, 30(7): 6447-6461.
[9] ZHOU L, LU YL, LIU W, et al. Drug conjugates for the treatment of lung cancer: from drug discovery to clinical practice[J]. Exp Hematol Oncol, 2024, 13(1): 26.
[10] CECI C, LACAL PM, GRAZIANI G. Antibody-drug conjugates: Resurgent anticancer agents with multi-targeted therapeutic potential[J]. Pharmacol Ther, 2022, 236: 108106.
[11] LIUBOMIRSKI Y, TIRAM G, SCOMPARIN A, et al. Potent antitumor activity of anti-HER2 antibody-topoisomerase I inhibitor conjugate based on self-immolative dendritic dimeric-linker[J]. J Control Release, 2024, 367: 148-157.
[12] 李栋. 抗体药物偶联物差异化研发策略[J]. 中国肿瘤生物治疗杂志, 2025, 32(3): 331-337.
[13] 郭敏娜, 张孟容, 肖洋, 等. 基于IncoPat数据库的黄精专利可视化分析[J]. 中医药管理杂志, 2025, 33(1): 236-243.
[14] 马艳林. 基于专利数据的前蛋白转化酶枯草溶菌素9抑制剂研发现状分析[J]. 中国新药杂志, 2025, 34(21): 2284-2292.
[15] JOUBERT N, BECK A, DUMONTET C, et al. Antibody-drug conjugates: the last decade[J]. Pharmaceuticals (Basel), 2020, 13(9): 245.
[16] WANG YM, XIE F, LIU LQ, et al. Development of applicable thiol-linked antibody-drug conjugates with improved stability and therapeutic index[J]. Drug Deliv, 2022, 29(1): 754-766.
[17] 孙树蕾, 刘昕昕, 胡志伟, 等. 喜树碱结构修饰研究进展[J]. 生物医学转化, 2024, 5(1): 53-65.
[18] 刘飒. 曲妥珠单抗靶向治疗在乳腺癌患者中的应用观察[J]. 实用中西医结合临床, 2025, 25(7): 57-59.
[19] 汪浩浩, 陈庆杰, 罗长江. 曲妥珠单抗在HER2阳性胃癌中耐药机制研究进展[J]. 中国肿瘤生物治疗杂志, 2024, 31(7): 728-732.
[20] 何明星, 张露, 谭燕. 靶向治疗HER2阳性乳腺癌患者的新型抗体药物偶联物: T-DM1与T-DXd[J]. 中南药学, 2024, 22(7): 1877-1882.
[21] 郭宗儒. 德曲妥珠单抗的研制[J]. 药学学报, 2023, 58(1): 229-234.
[22] DUMONTET C, REICHERT JM, SENTER PD, et al. Antibody-drug conjugates come of age in oncology[J]. Nat Rev Drug Discov, 2023, 22(8): 641-661.
[23] 李倩, 武勇凯, 韦薇, 等. 《抗体偶联药物药学研究与评价技术指导原则》解读[J]. 中国新药杂志, 2025, 34(6): 561-565.
[24] 杨超. 基于专利数据的SHP2抑制剂布局策略研究[J]. 中国医药工业杂志, 2026, 57(4): 481-486.
[25] LONG R, ZUO HR, TANG GY, et al. Antibody-drug conjugates in cancer therapy: applications and future advances[J]. Front Immunol, 2025, 16: 1516419.
[26] 段海明, 吴昊, 刘娟, 等. 抗体药物偶联物DS-8201a在晚期乳腺癌中的研究进展[J]. 中国肿瘤临床, 2021, 48(12): 640-643.
[27] CHEN R, REN ZW, BAI L, et al. Novel antibody-drug conjugates based on DXd-ADC technology[J]. Bioorg Chem, 2024, 151: 107697.
[28] 王鑫瑄, 王静萱. 抗体偶联药物治疗乳腺癌的研究进展[J]. 现代肿瘤医学, 2021, 29(12): 2187-2191.
[29] 朱逸晖, 李婷, 胡夕春. Trastuzumab deruxtecan的临床研究进展及展望——HER2耐药患者的新希望[J]. 中国癌症杂志, 2021, 31(8): 754-761.
[30] LI ZM, WANG Y, SUN YP, et al. Trastuzumab rezetecan, a HER2-directed antibody-drug conjugate, in patients with advanced HER2-mutant non-small-cell lung cancer (HORIZON-Lung): phase 2 results from a multicentre, single-arm study[J]. The Lancet Oncology, 2025, 26(4): 437-446.
[31] 刘巧, 刘晓, 温学美, 等. 重组胰蛋白酶和TPCK胰蛋白酶用于曲妥珠单抗肽图分析的对比研究[J]. 中国医药工业杂志, 2025, 56(10): 1282-1292.