2019年的奥瑞克、斯雷门和谢波德 ● ● ● 图1 80年代的奥瑞克(Axel Ullrich)| 图源:[18] 图2 HER2和赫赛汀的开发历史。莱文森(Arthur Levinson)和奥瑞克(Axel Ullrich)用v-erbB基因探针在基因库中找到了HER2(1985)。HER2与MIT的温伯格团队找到的neu(1979 – 1984)实际上是同一基因。斯雷门(Dennis Slamon)和奥瑞克发现HER2基因在20 - 30%的乳腺癌中有扩增(1987)。奥瑞克、谢波德(Mike Shepard)和基因泰克同事开发了靶向HER2的单抗药——赫赛汀。现在上市的另外几种抗癌药也源于赫赛汀 | 图源:[4] 让奥瑞克羡慕的是,由于斯雷门是临床肿瘤医生,他可以直接接触到很多来自患者的肿瘤组织。这是奥瑞克所不具备的。奥瑞克一直想知道,他克隆的几个原癌基因,包括EGFR和HER2,在真正的患者肿瘤中是否有突变或扩增,在癌症中是否起重要作用? 图3 80年代的斯雷门(Dennis Slamon)| 图源:[18] 但当他们再想往前推进时,却遇到了层层阻力。奥瑞克和斯万森开了无数的会,劝说他允许把这个单抗从科研阶段转换到开发阶段。但由于基因泰克在开发癌症药物上有过失败的经历(干扰素),又由于单抗药还没有成功的先例,斯万森和其他高管不肯批准。那个时候,基因泰克已从一个十几人的初创企业成长为有1700名员工的大公司,任何开发项目的上马都需要复杂、耗时的程序。奥瑞克坚持无果后,于1988年离开了基因泰克,回到德国,到普朗克(Max Planck)研究所任职。 图4 80年代的谢波德(Mike Shepard)| 图源:[18] 图5 曲妥珠单抗(Trastuzumab)的作用机理。它结合肿瘤细胞表面的HER2,阻断其下游信号传导(抑制其形成二聚体或裂解),并介导免疫细胞攻击肿瘤细胞(ADCC)| Image credit: National Cancer Institute 图6 2019年的奥瑞克、斯雷门和谢波德 | 图源:[17] 参考资料(上下滑动可浏览) 1. Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI, et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature. 1984;312(5994):513-6. 2. Lu RM, Hwang YC, Liu IJ, Lee CC, Tsai HZ, Li HJ, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020;27(1):1. 3. Harries M, Smith I. The development and clinical use of trastuzumab (Herceptin). Endocr Relat Cancer. 2002;9(2):75-85. 4. Sawyers CL. Herceptin: A First Assault on Oncogenes that Launched a Revolution. Cell. 2019;179(1):8-12. 5. Shepard HM, Lewis GD, Sarup JC, Fendly BM, Maneval D, Mordenti J, et al. Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. J Clin Immunol. 1991;11(3):117-27. 6. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707-12. 7. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-82. 8. Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985;230(4730):1132-9. 9. Genentech Goes Public 2016 [Available from: https://www./stories/genentech-goes-public. 10. Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature. 1984;309(5967):418-25. 11. Bazell R. Her-2: the Making of Herceptin, a Revolutinary Treatment for Breast Cancer: Random House; 1998. 12. Ullrich A. Axel Ullrich, 'Molecular Biologist at UCSF and Genentech,' an Oral History Conducted in 1994 and 2003 by Sally Hughes. In: Hughes S, editor.: Regional Oral History Office, The Bancroft Library, University of California, Berkeley; 2006. 13. King RT. Genentech Drug is Viewed to Be Successful Against Breast Cancer. The Wall Street Journal. 1998. 14. King RT. Genentech Notes Promising Results for Breast-Cancer Drug, Herceptin. The Wall Street Journal. 1997. 15. King RT. Genentech's Herceptin Gains Approval from FDA for Breast-Cancer Treatment. The Wall Street Journal. 1998. 16. www.indiainfoline.com/article/general-editors-choice/iifl-pharma-opportunities-series-trastuzumab-the-wonder-drug-118112000581_1.html 17. https:///winners/herceptin-a-targeted-antibody-therapy-for-breast-cancer/ 18. https:///QFXVprOlu84 制版编辑 | 卢卡斯 |
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