抗体偶联药物的研究进展
Research Progress of Antibody-Drug Conjugate
DOI: 10.12677/ACM.2021.119603, PDF,   
作者: 李 玲, 杨 雪, 袁胜利:青岛大学附属青岛市市立医院肿瘤科,山东 青岛;刘根利:大连医科大学附属青岛市市立医院肿瘤科,山东 青岛
关键词: 抗体偶联药物组成部分疗效临床试验Antibody-Drug Conjugate Components Effectiveness Clinical Trial
摘要: 抗体偶联药物(antibody-drug conjugate, ADC)是一类由靶点特异的单克隆抗体(mAb)及具有强效细胞毒性的小分子药物(payload)通过生物活性连接子(linker)偶联而成的新型生物药物。ADC可以将高效的细胞毒药物直接递送到肿瘤细胞,同时对正常组织的毒性降至最低,这种对靶点的准确识别性及非癌细胞不受影响性,极大提高了药效并减少了毒副反应。迄今为止,全球已开展的ADC临床研究已接近200项,其中获美国食品药品监督管理局(FDA)批准的ADC有10个。在本文中,综述了ADC的发展过程、组成部分以及获批的10个ADC的临床试验及未来发展方向。
Abstract: Antibody-drug conjugate (ADC) is a type of new biologic drug couple target-specific monoclonal antibody (mAb) and small cytotoxic drug with strong cytotoxicity (payload) by a biologically active linker (linker). ADC can deliver high-efficiency cytotoxic drugs directly to tumor cells while minimizing the toxicity to normal tissues. This specificity is unaffected to the non-tumor cell, which greatly improves the efficacy and reduces toxicity. So far, nearly 200 ADC clinical studies have been carried out worldwide, of which 10 ADCs have been approved by the Food and Drug Administration (FDA). In this article, the development process and components of ADC are reviewed, as well as the clinical trials and future development directions of 10 ADCs approved.
文章引用:李玲, 杨雪, 刘根利, 袁胜利. 抗体偶联药物的研究进展[J]. 临床医学进展, 2021, 11(9): 4135-4143. https://doi.org/10.12677/ACM.2021.119603

参考文献

[1] Strebhardt, K. and Ullrich, A. (2008) Paul Ehrlich’s Magic Bullet Concept: 100 Years of Progress. Nature Reviews Cancer, 8, 473-480. [Google Scholar] [CrossRef] [PubMed]
[2] Ford, C.H., Newman, C.E., Johnson, J.R., et al. (1983) Localisation and Toxicity Study of a Vindesine-Anti-CEA Conjugate in Patients with Advanced Cancer. British Journal of Cancer, 47, 35-42. [Google Scholar] [CrossRef] [PubMed]
[3] Dimitrov, D.S. and Marks, J.D. (2009) Therapeutic Antibodies: Current State and Future Trends Is a Paradigm Change Coming Soon. Methods in Molecular Biology, 525, 1-27. [Google Scholar] [CrossRef] [PubMed]
[4] Trail, P.A., Willner, D., Lasch, S.J., et al. (1993) Cure of Xenografted Human Carcinomas by BR96-Doxorubicin Immunoconjugates. Science, 261, 212-215. [Google Scholar] [CrossRef] [PubMed]
[5] Damelin, M., Zhong, W., Myers, J., et al. (2015) Evolving Strategies for Target Selection for Antibody-Drug Conjugates. Pharmaceutical Research, 32, 3494-3507. [Google Scholar] [CrossRef] [PubMed]
[6] Damle, N.K. and Frost, P. (2003) Antibody-Targeted Chemotherapy with Immunoconjugates of Calicheamicin. Current Opinion in Pharmacology, 3, 386-390. [Google Scholar] [CrossRef
[7] Donaghy, H. (2016) Effects of Antibody, Drug and Linker on the Preclinical and Clinical Toxicities of Antibody-Drug Conjugates. MAbs, 8, 659-671. [Google Scholar] [CrossRef] [PubMed]
[8] Carter, P.J. (2006) Potent Antibody Therapeutics by Design. Nature Reviews Immunology, 6, 343-357. [Google Scholar] [CrossRef] [PubMed]
[9] Nasiri, H., Valedkarimi, Z. and Aghebati-Maleki, L. (2018) Antibody-Drug Conjugates: Promising and Efficient Tools for Targeted Cancer Therapy. Journal of Cellular Physiology, 233, 6441-6457. [Google Scholar] [CrossRef] [PubMed]
[10] Francisco, J.A., Cerveny, C.G., Meyer, D.L., et al. (2003) cAC10-vcMMAE, an Anti-CD30-Monomethyl Auristatin E Conjugate with Potent and Selective Antitumor Activity. Blood, 102, 1458-1465. [Google Scholar] [CrossRef] [PubMed]
[11] Alley, S.C., Benjamin, D.R., Jeffrey, S.C., et al. (2008) Contribution of Linker Stability to the Activities of Anticancer Immunoconjugates. Bioconjugate Chemistry, 19, 759-765. [Google Scholar] [CrossRef] [PubMed]
[12] Beck, A., Goetsch, L. and Dumontet, C. (2017) Strategies and Challenges for the Next Generation of Antibody-Drug Conjugates. Nature Reviews Drug Discovery, 16, 315-337. [Google Scholar] [CrossRef] [PubMed]
[13] Tsuchikama, K. and An, Z. (2018) Antibody-Drug Conjugates: Recent Advances in Conjugation and Linker Chemistries. Protein & Cell, 9, 33-46. [Google Scholar] [CrossRef] [PubMed]
[14] Ducry, L. and Stump, B. (2010) Antibody-Drug Conjugates: Linking Cytotoxic Payloads to Monoclonal Antibodies. Bioconjugate Chemistry, 21, 5-13. [Google Scholar] [CrossRef] [PubMed]
[15] European Medicines Agency (2018) Mylotarg: Summary of Product Characteristics.
https://www.ema.europa.eu/en/medicines/human/EPAR/mylotarg-0
[16] Bross, P.F., Beitz, J., Chen, G., et al. (2001) Approval Summary: Gemtuzumab Ozogamicin in Relapsed Acute Myeloid Leukemia. Clinical Cancer Research, 7, 1490-1496.
[17] Petersdorf, S.H., Kopecky, K.J., Slovak, M., et al. (2013) A Phase 3 Study of Gemtuzumab Ozogamicin during Induction and Postconsolidation Therapy in Younger Patients with Acute Myeloid Leukemia. Blood, 121, 4854-4860. [Google Scholar] [CrossRef] [PubMed]
[18] Amadori, S., Suciu, S., Selleslag, D., et al. (2016) Gemtuzumab Ozogamicin versus Best Supportive Care in Older Patients with Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTCGIMEMA AML-19 Trial. Journal of Clinical Oncology, 34, 972-979.
[19] Castaigne, S., Pautas, C., Terré, C., et al. (2012) Effect of Gemtuzumab Ozogamicin on Survival of Adult Patients with De-Novo Acute Myeloid Leukaemia (ALFA-0701): A Randomised, Open-Label, Phase 3 Study. The Lancet, 379, 1508-1516. [Google Scholar] [CrossRef
[20] Taksin, A., Legrand, O., Raffoux, E., et al. (2007) High Efficacy and Safety Profile of Fractionated Doses of Mylotarg as Induction Therapy in Patients with Relapsed Acute Myeloblastic Leukemia: A Prospective Study of the Alfa Group. Leukemia, 21, 66. [Google Scholar] [CrossRef] [PubMed]
[21] Brodersen, L.E., Gerbing, R.B., Pardo, M.L., et al. (2020) Morphologic Remission Status Is Limited Compared to ΔN Flow Cytometry: A Children’s Oncology Group AAML0531 Report. Blood Advances, 4, 5050-5061. [Google Scholar] [CrossRef] [PubMed]
[22] Katz, J., Janik, J.E. and Younes, A. (2011) Brentuximab Vedotin (SGN-35). Clinical Cancer Research, 17, 6428-6436. [Google Scholar] [CrossRef
[23] Senter, P.D. and Sievers, E.L. (2012) The Discovery and Development of Brentuximab Vedotin for Use in Relapsed Hodgkin Lymphoma and Systemic Anaplastic Large Cell Lymphoma. Nature Biotechnology, 30, 631-637. [Google Scholar] [CrossRef] [PubMed]
[24] Pro, B., Advani, R., Brice, P., et al. (2012) Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study. Journal of Clinical Oncology, 30, 2190-2196. [Google Scholar] [CrossRef
[25] Younes, A., Gopal, A.K., Smith, S.E., et al. (2012) Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients with Relapsed or Refractory Hodgkin’s Lymphoma. Journal of Clinical Oncology, 30, 2183-2189. [Google Scholar] [CrossRef
[26] Prince, H.M., Kim, Y.H., Horwitz, S.M., et al. (2017) Brentuximab Vedotin or Physician’s Choice in CD30-Positive Cutaneous T-Cell Lymphoma (ALCANZA): An International, Open-Label, Randomised, Phase 3, Multicentre Trial. The Lancet, 390, 555-566. [Google Scholar] [CrossRef
[27] Connors, J.M., Jurczak, W., Straus, D.J., et al. (2018) Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. The New England Journal of Medicine, 378, 331-344. [Google Scholar] [CrossRef
[28] Horwitz, S., O’Connor, O.A., Pro, B., et al. (2019) Brentuximab Vedotin with Chemotherapy for CD30-Positive Peripheral T-Cell Lymphoma (ECHELON-2): A Global, Double-Blind, Randomised, Phase 3 Trial. The Lancet, 393, 229-240. [Google Scholar] [CrossRef
[29] Amiri-Kordestani, L., Blumenthal, G.M., Xu, Q.C., et al. (2014) FDA Approval: Ado-Trastuzumab Emtansine for the Treatment of Patients with HER2-Positive Metastatic Breast Cancer. Clinical Cancer Research, 20, 4436-4441. [Google Scholar] [CrossRef
[30] Verma, S., Miles, D., Gianni, L., et al. (2012) Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. The New England Journal of Medicine, 367, 1783-1791. [Google Scholar] [CrossRef
[31] Krop, I.E., Kim, S.-B., Martin, A.G., Lorusso, P.M., Ferrero, J.-M., Badovinac-Crnjevic, T., Hoersch, S., Smitt, M. and Wildiers, H. (2017) Trastuzumab Emtansine versus Treatment of Physician’s Choice in Patients with Previously Treated HER2-Positive Metastatic Breast Cancer (TH3RESA): Final Overall Survival Results from a Randomised Open-Label Phase 3 Trial. The Lancet Oncology, 18, 743-754. [Google Scholar] [CrossRef
[32] Von Minckwitz, G., Huang, C.S., et al. (2019) Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. The New England Journal of Medicine, 380, 617-628.
[33] Wynne, J., Wright, D. and Stock, W. (2019) Inotuzumab: From Preclinical Development to Success in B-Cell Acute Lymphoblastic Leukemia. Blood Advances, 3, 96-104. [Google Scholar] [CrossRef] [PubMed]
[34] Kantarjian, H.M., DeAngelo, D.J., Advani, A.S., et al. (2017) Hepatic Adverse Event Profile of Inotuzumab Ozogamicin in Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukaemia: Results from the Open-Label, Randomised, Phase 3 INO-VATE Study. The Lancet Haematology, 4, e387-e398. [Google Scholar] [CrossRef
[35] Pfeifer, M., Zheng, B., Erdmann, T., et al. (2015) Anti-CD22 and Anti-CD79B Antibody Drug Conjugates Are Active in Different Molecular Diffuse Large B-Cell Lymphoma Subtypes. Leukemia, 29, 1578-1586. [Google Scholar] [CrossRef] [PubMed]
[36] Sehn, L.H., Herrera, A.F., Flowers, C.R., et al. (2020) Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Journal of Clinical Oncology, 38, 155-165. [Google Scholar] [CrossRef
[37] Rosenberg, J.E., O’Donnell, P.H., Balar, A.V., et al. (2019) Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma after Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. Journal of Clinical Oncology, 37, 2592. [Google Scholar] [CrossRef
[38] Modi, S., Saura, C., Yamashita, T., et al. (2020) Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. The New England Journal of Medicine, 382, 610-621. [Google Scholar] [CrossRef
[39] Shitara, K., Bang, Y.J., Iwasa, S., et al. (2020) Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. The New England Journal of Medicine, 382, 2419-2430. [Google Scholar] [CrossRef
[40] Siena, S., Di Bartolomeo, M., Raghav, K., et al. (2021) Trastuzumab Deruxtecan (DS-8201) in Patients with HER2-Expressing Metastatic Colorectal Cancer (DESTINY-CRC01): A Multicentre, Open-Label, Phase 2 Trial. The Lancet Oncology, 22, 779-789. [Google Scholar] [CrossRef
[41] Starodub, A.N., Ocean, A.J., Shah, M.A., et al. (2015) First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors. Clinical Cancer Research, 21, 3870-3878. [Google Scholar] [CrossRef
[42] Bardia, A., Mayer, I.A., et al. (2019) Sacituzumab Govitecanhziy in Refractory Metastatic Triple-Negative Breast Cancer. The New England Journal of Medicine, 380, 741-751. [Google Scholar] [CrossRef
[43] Bardia, A., Hurvitz, S.A., Tolaney, S.M., et al. (2021) Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. The New England Journal of Medicine, 384, 1529-1541.
[44] Tagawa, S.T., Balar, A.V., Petrylak, D.P., et al. (2021) TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients with Metastatic Urothelial Carcinoma Progressing after Platinum-Based Chemotherapy and Checkpoint Inhibitors. Journal of Clinical Oncology, 39, 2474-2485. [Google Scholar] [CrossRef
[45] Lonial, S., Lee, H.C., Badros, A., et al. (2020) Belantamab Mafodotin for Relapsed or Refractory Multiple Myeloma (DREAMM-2): A Two-Arm, Randomised, Open-Label, Phase 2 Study. The Lancet Oncology, 21, 207-221.
[46] Caimi, P.F., Ai, W., Alderuccio, J.P., et al. (2021) Loncastuximab Tesirine in Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS-2): A Multicentre, Open-Label, Single-Arm, Phase 2 Trial. The Lancet Oncology, 22, 790-800. [Google Scholar] [CrossRef