拉斯克奖背后的故事:T细胞B细胞发现与抗癌药赫赛汀的诞生

2019-09-10 包雨朦 澎湃新闻

有诺奖风向标之称的拉斯克奖(Lasker Awards)于9月10日揭晓。拉斯克奖是生物医学领域的重要奖项,设有三个奖项:基础医学研究奖、临床医学研究奖以及拉斯克-布伦伯格公共服务奖。今年的基础医学研究奖颁给了埃默里大学的Max D.Cooper、澳大利亚生物学家Jacques Miller;基因泰克公司的前科学家H.Michael Shepard、加州大学洛杉矶分校的Dennis J.Sla

有诺奖风向标之称的拉斯克奖(Lasker Awards)于9月10日揭晓。

拉斯克奖是生物医学领域的重要奖项,设有三个奖项:基础医学研究奖、临床医学研究奖以及拉斯克-布伦伯格公共服务奖。

今年的基础医学研究奖颁给了埃默里大学的Max D.Cooper、澳大利亚生物学家Jacques Miller;基因泰克公司的前科学家H.Michael Shepard、加州大学洛杉矶分校的Dennis J.Slamon、德国马克斯-普朗克研究所的Axel Ullrich获得临床医学研究奖;国际组织全球疫苗免疫联盟(Gavi)获得拉斯克-布伦伯格公共服务奖。

资料显示,每个拉斯克奖项的奖金为25万美元。拉斯克奖在生命科学、医学领域享有盛誉,被誉为诺贝尔奖“风向标”。在该奖项的所有获得者中,有近90人同时也获得了诺贝尔奖。中国首位自然科学诺贝尔奖得主、2015年诺贝尔生理学或医学奖获得者屠呦呦,也曾于2011年荣获拉斯克奖。

T细胞与B细胞的发现

获得基础医学奖的Max D.Cooper和Jacques Miller的主要贡献在于发现两种不同类型的淋巴细胞——B细胞和T细胞,从而推动了现代免疫学的进程。

在给予他们的颁奖词中这样写道:“这是具有里程碑意义的成就,提供了适应性免疫系统的组织原理。这项开拓性的工作推动了基础科学和医学的巨大进步。”

1961年在伊丽莎·霍尔医学研究所Jacques Miller在实验中发现,切除胸腺之后的小鼠不会对来自另一品系的小鼠的皮肤产生排异反应,由此证明了排异反应相关的免疫细胞形成于胸腺,这也是最早关于T细胞形成的记录。

但他的实验并没有得到广泛的接受。当时的科学家已经意识到淋巴细胞是抗体的唯一来源,而胸腺中参与人体排异反应的淋巴细胞与产生抗体的淋巴细胞有何关系却不为人所知。在这个背景下,身为儿科医生和免疫学家的Max D.Cooper继续展开一系列的临床观察,为两种淋巴细胞的存在提供了早期线索。在此基础上,科学家们继续实验终于证明了能够产生抗体的淋巴细胞和来源于胸腺、产生排异反应的淋巴细胞是两种完全不同的东西。

1965年1月,《自然》期刊发表了Max D.Cooper等人的论文,标志着淋巴B细胞首次被人类发现,这一划时代的发现解开了免疫学的重要谜团,并且为众多药物和疫苗的研发奠定了基础。

事实上,过去50年来免疫领域的所有基本发现都可以追溯到Max D.Cooper和Jacques Miller的开创性工作。他们历史性的发现还推动了治疗新策略的产生——利用免疫细胞及其产物来对抗癌症、自身免疫病、免疫缺陷病等众多疾病。

具体来说,例如近三十年来在药物研发领域炙手可热的单克隆抗体技术也正是在上述研究的基础上诞生的。目前在临床上,单抗技术已经成为最有效的诊断和治疗工具。1974年单抗技术的两位发明人获得了诺贝尔生理学奖。可以说,以T细胞和B细胞的发现为起点,一系列里程碑式的科研成果就此建立起来。

赫赛汀的诞生

今年的拉斯克临床医学研究奖授予了对赫赛汀(曲妥珠单抗)的新药研发做出重要贡献的三位科学家。他们是来自基因泰克公司(Genentech)的H.Michael Shepard,加州大学洛杉矶分校(UCLA)的Dennis J.Slamon和马克斯-普朗克研究所(Max planck institute)的Axel Ullrich。

赫赛汀是人类历史上第一个靶向致癌蛋白HER-2的单克隆抗体药物,它的出现引发了全球抗体药物研发的热潮,在进入市场之后又创造了一个个销售神话,上市多年之后依然能够保持每年超过60亿美元的销售收入。

但赫赛汀的发明过程却是一波三折,还一度被抛弃,是Dennis J.Slamon等科学家的强大毅力才争取到了最后上市的机会。

故事要从上个世纪80年代说起,基因泰克公司因设计出了先进的基因重组药物生产技术而正处于快速发展期,但是公司缺少新药。1996年在一场学术会议上,一位基础科学家Axel Ullrich讲述了NEU基因的发现过程,并分离出了HER-2靶点。当时科学界还没有意识到NEU基因究竟有何作用,但这一发现深深吸引了台下的Dennis J.Slamon。

Dennis J.Slamon彼时正在研究病毒与癌症的关系,他知道杀灭病毒不会治愈癌症,而需要杀灭致癌基因,听到NEU的故事之后,他凭借直觉将二者联系在了一起。Dennis J.Slamon与Axel Ullrich一拍即合,共同协作研究HER-2基因与肿瘤的关系。

就在研究进行的过程中,一些其他的制药公司试图利用癌细胞生长机制研发的抗癌药惨遭失败,基因泰克担心Dennis J.Slamon的研究也会如此,于是宣布撤回癌症研究方面的大部分经费。一方面是研究迟迟没有突破性进展,另一方面又被斩断了研究经费的来源,心力交瘁的Axel Ullrich选择离开该项目,留下Dennis J.Slamon孤军奋战。

Dennis J.Slamon之后说服基因泰克组建了一个小的创业团队,以推动HER-2项目,在这个时期,免疫学家H.Michael Shepard加入了这个不为公司重视的创业团队。终于,1990年的夏天,他们终于做成了HER-2人源化抗体,起名为Herceptin(赫赛汀),这一名字融合了HER靶点、拦截和抑制剂三个英文单词。

然而,赫赛汀诞生的故事到这里还不能划上圆满的句号。进入临床试验之后,一位参与临床试验的乳腺癌患者死亡,这一事件经过媒体的报道和放大之后引发了舆论抗议。1994年12月,一群义愤填膺的来自乳腺癌防治协会的妇女闯入基因泰克园区为临床中死去的患者“送葬”。之后,基因泰克公司花了数年的时间继续临床实践,才平息了这场史上最大的公关危机。

1998年,赫赛汀获得美国食品药品管理局的批准,正式上市。基因泰克凭借赫赛汀在单抗道路上高歌猛进,2014年赫赛汀全球销售额达到了巅峰的68亿美元。曾经在很多年的时间里,赫赛汀都是全球销售额排名前三的药品,给无数乳腺癌患者带去了生机。赫赛汀的发现故事也被改变成了电影《生存证明》,2008年在美国上映。

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    2019-09-12 sunylz
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    2019-09-12 wrj0122
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    2019-09-11 深海的鱼

    学习学习学习

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