抗体-药物偶联物（ADC）的应用前景--上篇

抗体-药物偶联物（ADC）通过稳定的连接体将细胞毒性小分子化学药物连接到单抗上，使用单抗作为载体将小分子化学药物运输到目标肿瘤细胞，利用靶抗原介导的细胞内吞作用使ADC进入肿瘤内部，之后释放出小分子药物从而达到杀死肿瘤细胞的目的[1]。为新辅助治疗后非pCR的HER2阳性患者带来希望的T-DM1就是具有代表性的ADC，同时也是首个在中国获批的ADC。 

• ADC与传统化疗药物相比有哪些优势？

  

• T-DM1作为第一个具有HER2靶向功能的ADC，有哪些特点？

T-DM1使用曲妥珠单抗（T）作为载体，将微管抑制药物DM1（美坦新衍生物）靶向递送到HER2性肿瘤细胞，他具有两大特点：

1. 曲妥珠单抗本身就具有抗肿瘤活性，而目前其他获批的ADC所用的抗体基本只作为药物的载体，单独抗肿瘤效果非常有限^[2]

2. DM1的抗肿瘤效价百倍于普通化疗药物^[3-5]

3. T-DM1具有优秀的ADC机制:

   

• T-DM1在治疗HER2阳性乳腺癌中有哪些优势？

  

T-DM1单药用于HER2阳性I期乳腺癌辅助治疗也显示出良好的效果，ATEMPT研究初步报告显示3年无疾病生存率为97.7%（曲妥珠单抗联合紫杉醇组为92.8%），3年无复发间期率为99.1%[11]。

另一在乳腺癌领域取得重大研发突破的ADC为DS-8201。DESTINY-Breast01研究发现，患者无疾病生存期达16.4个月，缓解持续时间14.8个月[12]。基于该结果，DS-8201在美国获得加速批准，用于既往针对转移性疾病接受过≥2线以抗HER2为基础的方案的不可切除或转移性HER2阳性乳腺癌，但该适应证在全球其他地区尚未获批。战“疫”当前，T-DM1与您携手共进。

         参考文献

1.       抗体偶联药物质量控制和临床前评价专家共识.中国药事, 2018, 32(7): 991-1004.

2.       Birrer M J, Moore K N, Betella I, et al. Antibody-drug conjugate-based therapeutics: State of the Science. J Natl Cancer Inst. 2019,111(6):538-549.

3.       王彦明,郝伯钧,李静,等. 美登素类抗体药物偶联物研究进展.国际药学研究杂志，2016,43(3): 410-419.

4.       Barok M, Tanner M, Köninki K, Isola J. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett 2011; 306 (2):171-179.

5.       Junttila TT, Li G, Parsons K, et al. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Breast Cancer Res Treat 2011; 128 (2):347–356

6.       Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014 ,15(6):640-7.

7.       Shao Z, Pang D, Yang H, et al. Abstract P6-17-17: Pertuzumab, trastuzumab, and docetaxel for HER2-positive early or locally advanced breast cancer in the neoadjuvant setting: Efficacy and safety analysis of a randomized phase III study in Asian patients (PEONY). Cancer Research 2019,79(4 Supplement):P6-17-17.

8.       Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016,17(6):791-800.

9.       van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(12):1630-1640.

10.    von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med. 2019,380(7):617-628.

11.    Tolaney SM, Hu J, Dang C, et al. TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-05.

12.    Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2020;382(7):610-621.