JITC:突破性进展!开发出一种有望使免疫疗法适用于所有癌症患者的小分子PD-1/PD-L1抑制剂

2022-08-17 科研转化 科研转化

除了药物可及性方面的考虑之外,实验显示,这种小分子药物改善了实体瘤肿块内免疫细胞的激活。

在一项新的研究中,来自以色列特拉维夫大学和葡萄牙里斯本大学的研究人员发现并合成了一种小分子,而且相对于一种成功用于治疗一系列癌症的抗体,它可以成为一种更容易获得、更有效的替代物。相关研究结果近期发表在Journal for ImmunoTherapy of Cancer期刊上,论文标题为“Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment”。论文通讯作者为特拉维夫大学萨克雷医学院癌症生物学研究中心主任Ronit Sachi-Fainaro教授、里斯本大学药学院药物研究所的Helena Florindo教授和Rita Guedes教授。

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Satchi-Fainaro教授说,“2018年,诺贝尔医学奖被授予给James Allison和Tasuku Honjo,以表彰他们对免疫疗法---通过激活免疫系统来治疗癌症---研究的贡献。Honjo发现称为T细胞的免疫细胞表达蛋白PD-1,癌细胞表达的蛋白PD-L1与 PD-1结合后可使T细胞自身的活性受到抑制。事实上,PD-1和PD-L1之间的相互作用使得癌细胞能够抑制T细胞,阻止它们攻击癌细胞。Honjo开发了中和PD-1或PD-L1的抗体,从而解除了对T细胞的抑制,使得它们有效地对抗癌症。”

针对PD-1/PD-L1蛋白的抗体已经被批准用于临床,并被认为是抗击癌症的巨大希望。这种免疫疗法可以大大改善患者的治疗效果,而且没有化疗等治疗方法所带来的严重副作用。但这种抗体的生产成本很高,因此并非所有患者都能获得。此外,这种治疗方法并不影响实体瘤的所有部分,因为这类抗体太大,无法穿透并到达实体瘤中不容易接近和暴露的区域。如今,在这项新的研究中,这些作者利用生物信息学和数据分析工具,找到了这类抗体的一种更小、更智能的替代物。

图片

在计算机上虚拟筛选潜在的PD-1/PD-L1抑制剂。图片来自Journal for ImmunoTherapy of Cancer, 2022, doi:10.1136/jitc-2022-004695

Satchi-Fainaro教授说,“博士后研究员Rita Acúrcio博士从数以千计的分子结构开始,通过使用计算机辅助药物设计(CADD)模型和数据库,我们缩小了候选名单,直到我们找到最佳结构。在第二阶段,我们证实了这种小分子能像抗体一样有效地控制肿瘤生长---它能在经过改造后携带人类T细胞的动物身上抑制PD-L1。换句话说,我们开发出一种小分子,可以抑制PD-1/PD-L1的结合,提醒免疫系统需要攻击癌症。此外,与抗体药物相比,这种新分子有一些主要优势。首先是成本:由于抗体是一种生物制品而非合成分子,它需要复杂的基础设施和相当多的资金来生产,每个患者每年的成本约为20万美元。相比之下,我们用简单的设备在短时间内合成了这种小分子,而且成本很低。这种小分子的另一个优势是,患者可能将能够在家里口服,而不需要在医院进行静脉注射。”

除了药物可及性方面的考虑之外,这些作者的实验显示,这种小分子药物改善了实体瘤肿块内免疫细胞的激活。

Satchi-Fainaro教授解释说,“实体瘤的表面是异质性的。如果在实体瘤的某一特定区域有较少的血管,抗体将无法进入它的内部。另一方面,这种小分子会扩散,因此不完全依赖于肿瘤的血管或其高渗透性。我相信,在未来,这种小分子将在市场上销售,并使免疫疗法成为癌症患者可以负担得起的疗法。”

参考资料:

Rita C. Acúrcio et al. Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment. Journal for ImmunoTherapy of Cancer, 2022, doi:10.1136/jitc-2022-004695.

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    2023-03-21 jklm09
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    2023-08-01 宋威
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    2022-08-19 smartjoy
  5. [GetPortalCommentsPageByObjectIdResponse(id=1853031, encodeId=b8381853031bd, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=64, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Tue Mar 21 10:21:14 CST 2023, time=2023-03-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1914736, encodeId=a2571914e3636, content=<a href='/topic/show?id=84d7469559b' target=_blank style='color:#2F92EE;'>#小分子#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=46955, encryptionId=84d7469559b, topicName=小分子)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6105386, createdName=宋威, createdTime=Tue Aug 01 21:21:14 CST 2023, time=2023-08-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1656483, encodeId=e79016564837e, content=<a href='/topic/show?id=14001392e65' target=_blank style='color:#2F92EE;'>#PD-L1抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13927, encryptionId=14001392e65, topicName=PD-L1抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=d5eb24855327, createdName=LSJ119, createdTime=Mon Mar 06 17:21:14 CST 2023, time=2023-03-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1255169, encodeId=bc3f125516969, content=<a href='/topic/show?id=be71139214f' target=_blank style='color:#2F92EE;'>#PD-L1#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13921, encryptionId=be71139214f, topicName=PD-L1)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=e76f39, createdName=smartjoy, createdTime=Fri Aug 19 01:21:14 CST 2022, time=2022-08-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1289772, encodeId=09e31289e7239, content=<a href='/topic/show?id=cbb8e1356f7' target=_blank style='color:#2F92EE;'>#癌症患者#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=71356, encryptionId=cbb8e1356f7, topicName=癌症患者)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=10ba218, createdName=zgwhgch, createdTime=Fri Aug 19 01:21:14 CST 2022, time=2022-08-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1388141, encodeId=416c1388141e8, content=<a href='/topic/show?id=779d1389e7e' target=_blank style='color:#2F92EE;'>#PD-1/PD-L1抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13897, encryptionId=779d1389e7e, topicName=PD-1/PD-L1抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/WQ1WyMBGic8d2fKdCe6Cm3vaRh4X8YnlumYndC46iagNCBl9Df8RtoCaQchnFtZldHUctGJjsgsyutUlu8vPq6yQ/132, createdBy=97862500016, createdName=ms3117646317107274, createdTime=Fri Aug 19 01:21:14 CST 2022, time=2022-08-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1239242, encodeId=509f1239242af, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=99206163724, createdName=ms9000000236829232, createdTime=Wed Aug 17 11:09:51 CST 2022, time=2022-08-17, status=1, ipAttribution=)]
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    2022-08-17 ms9000000236829232

    学习了

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