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Nat Commun:让抗体穿透细胞,解决癌症靶点“不可成药”难题

2017-05-16 佚名 药明康德

RAS是一个常见的致癌基因,在大约30%的癌症患者中存在RAS基因突变。突变的RAS蛋白会被持续激活,导致细胞生长和增殖异常,从而引发癌症。针对RAS这个靶点的药物研究已经有数十年之久了,但是科学家们始终找不到一个既有效又安全的方法,RAS基本上被归入了“不可成药”的靶点。最近,来自韩国亚洲大学(Ajou University)和Orum Therapeutics公司的科学家们开发出了一个新型单抗

RAS是一个常见的致癌基因,在大约30%的癌症患者中存在RAS基因突变。突变的RAS蛋白会被持续激活,导致细胞生长和增殖异常,从而引发癌症。针对RAS这个靶点的药物研究已经有数十年之久了,但是科学家们始终找不到一个既有效又安全的方法,RAS基本上被归入了“不可成药”的靶点。

最近,来自韩国亚洲大学(Ajou University)和Orum Therapeutics公司的科学家们开发出了一个新型单抗药物RT11-i,它可以穿过细胞膜进入细胞,并选择性地抑制活跃的RAS蛋白,从而切断其产生的促进癌症生长的信号传递。这一研究发表在了最近的《自然》子刊《Nature Communications》上。

RAS蛋白在细胞生存、生长和分化过程中起到重要作用,突变引起的RAS持续激活对于肿瘤发生和扩张有很大影响。带有RAS突变的肿瘤往往更具侵袭性,并且更有可能对现有药物产生抗药性。小分子制剂直接抑制致癌RAS突变蛋白已被证明是极具挑战性,迄今为止没有临床批准任何试剂,这主要是由于小分子难以识别RAS表面的药物口袋。

目前广泛研究和应用的抗体药物主要是全长IgG抗体。这些抗体主要靶向细胞表面的蛋白。这是因为抗体通常由于其大尺寸和亲水性而不能穿过活细胞的细胞膜。细胞穿透抗体可以通过受体介导的内吞作用进入活细胞的胞质溶胶。这种独特的功能使得这些下一代治疗性抗体直接靶向以前被认为是不可治疗的许多人类疾病相关的细胞溶质蛋白。

此次,韩国科学家设计的这种靶向细胞中RAS蛋白的单克隆抗体RT11-i就是这样一种细胞穿透抗体。它渗透细胞后,选择性地结合激活的RAS蛋白,阻止其与下游效应蛋白结合,从而抑制肿瘤生长。在小鼠RAS突变结直肠癌模型中的实验研究发现,RT11-i能够聚集在肿瘤组织中,治疗两周后,小鼠的肿瘤减小了42-63%。在进一步的实验中,对EGFR抑制剂有抗药性的结直肠癌模型小鼠接受了EGFR抑制剂cetuximab和RT11-i共同治疗后,肿瘤变得重新对cetuximab敏感并且体积明显缩小,小鼠的寿命也相应的得到延长。

                                                    
                            ▲细胞穿透抗体研发平台(图片来源:Orum公司官网)

Orum Therapeutics的共同创始人和首席执行官Sung Joo Lee博士表示:“作为一种抗癌药物,我们的细胞穿透抗体易于生产,全身给药耐受性良好,并且具有理想药理学性质。我们认为这有望成为治疗难治性胰腺癌、结直肠癌和肺癌的重要一线疗法。”

成功抑制RAS活性对许多类型的癌症都有重要意义。在死亡率很高的胰腺癌中,RAS突变率高达95%。其它常见癌症中,结直肠癌中RAS突变率为45%,肺癌中RAS突变率为35%。我们希望这个新药能够尽快进入临床试验阶段,早日造福癌症患者。

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    2018-04-06 liye789132251
  2. [GetPortalCommentsPageByObjectIdResponse(id=1882036, encodeId=4106188203612, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Apr 06 21:14:00 CST 2018, time=2018-04-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2087021, encodeId=c2e6208e02164, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Sun Nov 19 09:14:00 CST 2017, time=2017-11-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=199239, encodeId=7eeb199239b6, content=这个问题,总会解决的,放心, beContent=null, objectType=article, channel=null, level=null, likeNumber=104, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04f22055142, createdName=131****2916, createdTime=Wed May 17 14:10:16 CST 2017, time=2017-05-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=199198, encodeId=fc5619919822, content=看到了希望,RAS突变位点,想克服你真难, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NdicLmdJEK9VoiaDianY6fzHNN9iaGv80m39pMHU3eSnNN0kn1o0rdQ7Bz2f03Qibcf1ia7rKvxIt4UVlErF2d4gCmDC5/0, createdBy=98e31740255, createdName=cqykthl, createdTime=Wed May 17 12:01:06 CST 2017, time=2017-05-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=198783, encodeId=fcba198e83d1, content=这个如果真能成功,那是挺不错的, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04f22055142, createdName=131****2916, createdTime=Tue May 16 12:36:18 CST 2017, time=2017-05-16, status=1, ipAttribution=)]
    2017-11-19 liuli5079
  3. [GetPortalCommentsPageByObjectIdResponse(id=1882036, encodeId=4106188203612, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Apr 06 21:14:00 CST 2018, time=2018-04-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2087021, encodeId=c2e6208e02164, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Sun Nov 19 09:14:00 CST 2017, time=2017-11-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=199239, encodeId=7eeb199239b6, content=这个问题,总会解决的,放心, beContent=null, objectType=article, channel=null, level=null, likeNumber=104, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04f22055142, createdName=131****2916, createdTime=Wed May 17 14:10:16 CST 2017, time=2017-05-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=199198, encodeId=fc5619919822, content=看到了希望,RAS突变位点,想克服你真难, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NdicLmdJEK9VoiaDianY6fzHNN9iaGv80m39pMHU3eSnNN0kn1o0rdQ7Bz2f03Qibcf1ia7rKvxIt4UVlErF2d4gCmDC5/0, createdBy=98e31740255, createdName=cqykthl, createdTime=Wed May 17 12:01:06 CST 2017, time=2017-05-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=198783, encodeId=fcba198e83d1, content=这个如果真能成功,那是挺不错的, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04f22055142, createdName=131****2916, createdTime=Tue May 16 12:36:18 CST 2017, time=2017-05-16, status=1, ipAttribution=)]
    2017-05-17 131****2916

    这个问题,总会解决的,放心

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1882036, encodeId=4106188203612, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Apr 06 21:14:00 CST 2018, time=2018-04-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2087021, encodeId=c2e6208e02164, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Sun Nov 19 09:14:00 CST 2017, time=2017-11-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=199239, encodeId=7eeb199239b6, content=这个问题,总会解决的,放心, beContent=null, objectType=article, channel=null, level=null, likeNumber=104, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04f22055142, createdName=131****2916, createdTime=Wed May 17 14:10:16 CST 2017, time=2017-05-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=199198, encodeId=fc5619919822, content=看到了希望,RAS突变位点,想克服你真难, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NdicLmdJEK9VoiaDianY6fzHNN9iaGv80m39pMHU3eSnNN0kn1o0rdQ7Bz2f03Qibcf1ia7rKvxIt4UVlErF2d4gCmDC5/0, createdBy=98e31740255, createdName=cqykthl, createdTime=Wed May 17 12:01:06 CST 2017, time=2017-05-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=198783, encodeId=fcba198e83d1, content=这个如果真能成功,那是挺不错的, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04f22055142, createdName=131****2916, createdTime=Tue May 16 12:36:18 CST 2017, time=2017-05-16, status=1, ipAttribution=)]
    2017-05-17 cqykthl

    看到了希望,RAS突变位点,想克服你真难

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1882036, encodeId=4106188203612, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Apr 06 21:14:00 CST 2018, time=2018-04-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2087021, encodeId=c2e6208e02164, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Sun Nov 19 09:14:00 CST 2017, time=2017-11-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=199239, encodeId=7eeb199239b6, content=这个问题,总会解决的,放心, beContent=null, objectType=article, channel=null, level=null, likeNumber=104, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04f22055142, createdName=131****2916, createdTime=Wed May 17 14:10:16 CST 2017, time=2017-05-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=199198, encodeId=fc5619919822, content=看到了希望,RAS突变位点,想克服你真难, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NdicLmdJEK9VoiaDianY6fzHNN9iaGv80m39pMHU3eSnNN0kn1o0rdQ7Bz2f03Qibcf1ia7rKvxIt4UVlErF2d4gCmDC5/0, createdBy=98e31740255, createdName=cqykthl, createdTime=Wed May 17 12:01:06 CST 2017, time=2017-05-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=198783, encodeId=fcba198e83d1, content=这个如果真能成功,那是挺不错的, beContent=null, objectType=article, channel=null, level=null, likeNumber=82, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=04f22055142, createdName=131****2916, createdTime=Tue May 16 12:36:18 CST 2017, time=2017-05-16, status=1, ipAttribution=)]
    2017-05-16 131****2916

    这个如果真能成功,那是挺不错的

    0

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今天,《自然 医学》杂志上刊登了一个有关癌症的里程碑式临床研究[1]!美国最好的癌症中心之一,纪念斯隆凯特琳癌症研究中心(Memorial Sloan Kettering Cancer Center,简称MSK)的研究人员利用他们独有的肿瘤检测技术MSK-IMPACT对超过10000名晚期癌症患者进行了基因测序,这是目前转移性癌症患者中最大规模的肿瘤测序研究。

Nat Genet:启动子突变也会影响胰腺癌发生

在过去的十年时间里,科学家们通过对外显子进行测序在发现癌症驱动基因方面取得了显著进展。如果癌症是因基因突变累积而导致的疾病,我们就需要知道不同癌症类型中究竟存在哪些基因改变。在一项发表在国际学术期刊Nature Genetics上的研究中,来自冷泉港实验室的一支研究团队对癌细胞中除外显子之外其余98%的DNA进行了研究。他们收集了308名胰腺

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