Nature Medicine:利用胞葬作用,更好更安全地治疗阿尔茨海默病

2022-08-09 王聪 “生物世界”公众号

在阿尔茨海默病小鼠模型中,αAβ-Gas6不仅能更好地清除Aβ,而且还规避了与常规抗体治疗相关的神经毒性炎症副作用。

2021年6月7日,FDA宣布加速审批渤健(Biogen)的单抗药物aducanumab(商品名Aduhelm)上市,用于治疗阿尔茨海默症源性轻度认知障碍(MCI)及轻度阿尔茨海默症。这是自2003年以来,FDA批准的首个阿尔茨海默症治疗新药。

Aduhelm 是一种针对β淀粉样蛋白(Aβ)的单克隆抗体,临床试验显示其能够清除大脑中的β-淀粉样蛋白(Aβ),但并没有足够的证据表明其能够减缓或阻止阿尔茨海默病的疾病进展。因此,该药物在获得FDA批准后,立即引发了巨大争议。

该单抗药物售价昂贵,高达5.6万美元/年,然而,实际治疗效果并不明确,更重要的是,该单抗药物在治疗过程中还存在明显的副作用,JAMA Neurology 期刊发表的大型3期临床试验显示,超过三分之一的患者在治疗后出现脑水肿。

2022年8月4日,韩国科学技术院(KAIST)的研究人员在国际顶尖医学期刊 Nature Medicine 发表了题为:Anti-inflammatory clearance of amyloid-β by a chimeric Gas6 fusion protein 的研究论文。

该研究开发了一种新型融合蛋白药物——αAβ-Gas6,它通过与基于Aβ单抗完全不同的机制有效地清除大脑中的β淀粉样蛋白(Aβ)。在阿尔茨海默病小鼠模型中,αAβ-Gas6不仅能更好地清除Aβ,而且还规避了与常规抗体治疗相关的神经毒性炎症副作用。

2021年11月22日,JAMA Neurology 期刊发表了题为:Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease 的论文。

该论文报告了两项Aduhelm治疗阿尔茨海默病的大型3期临床试验,并重点关注了治疗期间患者的淀粉样蛋白相关成像异常(ARIA)问题。

试验结果表明,在10mg/kg剂量组的1029名患者中,425名患者(41.3%)经历了淀粉样蛋白相关成像异常(ARIA)问题,362名患者(35.2%)出现ARIA脑水肿,197名患者(19.1%)出现了ARIA微出血,151名患者(14.7%)出现了ARIA表层铁沉积。在这些出现副作用的患者中,有14人情况严重。

这两项大型3期临床试验表明,超过40%的患者在接受Aduhelm治疗后出现了淀粉样蛋白相关成像异常(ARIA)问题。

这些炎症副作用可能导致神经元死亡和小胶质细胞的突触消除,甚至可能加剧阿尔茨海默病患者的认知障碍。因此,目前基于Aβ抗体的免疫疗法由于炎症副作用的存在,对阿尔茨海默病患者而言可能是弊大于利的。

通过免疫疗法清除Aβ仍是阿尔茨海默病最有希望的治疗方法之一。尽管已有研究显示几种针对Aβ的单克隆抗体可以显着降低阿尔茨海默病患者大脑中的Aβ负担,但它们对改善患者认知功能的作用仍微不足道。 此外,很大一部分接受Aβ抗体治疗的患者会出现与抗体介导的大脑内Fc受体激活相关的脑水肿和微出血。

在这项最新研究中,研究团队开发了一种新型Aβ吞噬诱导剂——αAβ–Gas6,由靶向Aβ的单克隆抗体的单链可变片段与Gas6的截短受体结合域融合而成。该融合蛋白通过TAM受体依赖性吞噬作用选择性地消除Aβ,而不诱导NF-kB介导的炎症反应或反应性神经胶质增生。

αAβ–Gas6结构

研究团队表示,通过Aβ抗体靶向激活FC受体会诱导小胶质细胞介导的Aβ吞噬作用,但同时也会产生炎症信号,从而不可避免地损害大脑组织。而这项最新研究表明,αAβ-Gas6可能是一种新型阿尔茨海默病免疫治疗剂,可以克服传统抗体治疗带来的副作用。

具体来说,该研究利用了细胞的胞葬作用(efferocytosis),这是吞噬细胞将程序性死亡的凋亡细胞移除的过程。Gas6是一种可溶性衔接蛋白,可通过TAM吞噬受体介导胞葬作用。利用这一特性,研究团队设计了αAβ–Gas6融合蛋白,从而将这种胞葬作用从对死亡细胞的特异性靶向重新定位到对Aβ斑块的清除。

此外,与Aβ抗体治疗相比,αAβ–Gas6可以通过激活小胶质细胞和星形胶质细胞的吞噬作用来诱导对Aβ的协同清除,从而在阿尔茨海默病小鼠模型和脑淀粉样血管病小鼠模型中产生更好的行为结果,显着减少突触消除和微出血。

据悉,研究团队基于这项研究成果创立了一家名为 Illimis Therapeutics 的公司,研究团队计划通过该公司进一步开发各种Gas6融合蛋白,用于清除Aβ、Tau等,用来治疗包括阿尔茨海默病在内的多种神经系统疾病以及受有毒蛋白影响的自身免疫疾病的治疗,该方法有望成为一种新型治疗平台。

原始出处:

Jung, H., Lee, S.Y., Lim, S. et al. Anti-inflammatory clearance of amyloid-β by a chimeric Gas6 fusion protein. Nat Med (2022). https://doi.org/10.1038/s41591-022-01926-9.

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createdName=jeanqiuqiu, createdTime=Mon Sep 12 07:45:57 CST 2022, time=2022-09-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817231, encodeId=c018181e23120, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Sat Oct 22 04:45:57 CST 2022, time=2022-10-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1238477, encodeId=241412384e77c, content=ab造假的事,不提了?, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210127/50a003c4097845e182c08afd64d8a509/bd766dfebe9c40e0bca2dae964601bdc.jpg, createdBy=22de5454917, createdName=carrotlyl, createdTime=Sat Aug 13 15:39:16 CST 2022, time=2022-08-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470598, encodeId=fdd514e05984a, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Thu Aug 11 00:45:57 CST 2022, time=2022-08-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577916, encodeId=db3d15e7916fd, content=<a href='/topic/show?id=cda91148004' target=_blank style='color:#2F92EE;'>#Medicine#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11480, encryptionId=cda91148004, topicName=Medicine)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=54cd16396700, createdName=ms1692212821629096, createdTime=Thu Aug 11 00:45:57 CST 2022, time=2022-08-11, status=1, ipAttribution=)]
    2023-04-22 ms5000000159272953 来自广东省

    已经认认真真学习了,

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1885935, encodeId=2707188593512, 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=Sat Mar 18 16:45:57 CST 2023, time=2023-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1818254, encodeId=430c181825434, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Sun Aug 28 06:45:57 CST 2022, time=2022-08-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2127752, encodeId=fd42212e752bf, content=已经认认真真学习了,, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=55488636654, createdName=ms5000000159272953, createdTime=Sat Apr 22 23:27:45 CST 2023, time=2023-04-22, status=1, ipAttribution=广东省), GetPortalCommentsPageByObjectIdResponse(id=2127152, encodeId=d3eb212e1520f, content=我已经认真学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=55488636654, createdName=ms5000000159272953, createdTime=Wed Apr 19 23:42:35 CST 2023, time=2023-04-19, status=1, ipAttribution=广东省), 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createdName=jeanqiuqiu, createdTime=Mon Sep 12 07:45:57 CST 2022, time=2022-09-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817231, encodeId=c018181e23120, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Sat Oct 22 04:45:57 CST 2022, time=2022-10-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1238477, encodeId=241412384e77c, content=ab造假的事,不提了?, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210127/50a003c4097845e182c08afd64d8a509/bd766dfebe9c40e0bca2dae964601bdc.jpg, createdBy=22de5454917, createdName=carrotlyl, createdTime=Sat Aug 13 15:39:16 CST 2022, time=2022-08-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470598, encodeId=fdd514e05984a, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Thu Aug 11 00:45:57 CST 2022, time=2022-08-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577916, encodeId=db3d15e7916fd, content=<a href='/topic/show?id=cda91148004' target=_blank style='color:#2F92EE;'>#Medicine#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11480, encryptionId=cda91148004, topicName=Medicine)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=54cd16396700, createdName=ms1692212821629096, createdTime=Thu Aug 11 00:45:57 CST 2022, time=2022-08-11, status=1, ipAttribution=)]
    2023-04-19 ms5000000159272953 来自广东省

    我已经认真学习了

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=1885935, encodeId=2707188593512, 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=Sat Mar 18 16:45:57 CST 2023, time=2023-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1818254, encodeId=430c181825434, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, 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createdName=jeanqiuqiu, createdTime=Mon Sep 12 07:45:57 CST 2022, time=2022-09-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817231, encodeId=c018181e23120, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Sat Oct 22 04:45:57 CST 2022, time=2022-10-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1238477, encodeId=241412384e77c, content=ab造假的事,不提了?, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210127/50a003c4097845e182c08afd64d8a509/bd766dfebe9c40e0bca2dae964601bdc.jpg, createdBy=22de5454917, createdName=carrotlyl, createdTime=Sat Aug 13 15:39:16 CST 2022, time=2022-08-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470598, encodeId=fdd514e05984a, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Thu Aug 11 00:45:57 CST 2022, time=2022-08-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577916, encodeId=db3d15e7916fd, content=<a href='/topic/show?id=cda91148004' target=_blank style='color:#2F92EE;'>#Medicine#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11480, encryptionId=cda91148004, topicName=Medicine)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=54cd16396700, createdName=ms1692212821629096, createdTime=Thu Aug 11 00:45:57 CST 2022, time=2022-08-11, status=1, ipAttribution=)]
    2022-10-26 kalseyzl
  6. 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createdName=jeanqiuqiu, createdTime=Mon Sep 12 07:45:57 CST 2022, time=2022-09-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817231, encodeId=c018181e23120, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Sat Oct 22 04:45:57 CST 2022, time=2022-10-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1238477, encodeId=241412384e77c, content=ab造假的事,不提了?, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210127/50a003c4097845e182c08afd64d8a509/bd766dfebe9c40e0bca2dae964601bdc.jpg, createdBy=22de5454917, createdName=carrotlyl, createdTime=Sat Aug 13 15:39:16 CST 2022, time=2022-08-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470598, encodeId=fdd514e05984a, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Thu Aug 11 00:45:57 CST 2022, time=2022-08-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577916, encodeId=db3d15e7916fd, content=<a href='/topic/show?id=cda91148004' target=_blank style='color:#2F92EE;'>#Medicine#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11480, encryptionId=cda91148004, topicName=Medicine)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=54cd16396700, createdName=ms1692212821629096, createdTime=Thu Aug 11 00:45:57 CST 2022, time=2022-08-11, status=1, ipAttribution=)]
    2022-09-12 jeanqiuqiu
  7. 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  8. 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topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210127/50a003c4097845e182c08afd64d8a509/bd766dfebe9c40e0bca2dae964601bdc.jpg, createdBy=22de5454917, createdName=carrotlyl, createdTime=Sat Aug 13 15:39:16 CST 2022, time=2022-08-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470598, encodeId=fdd514e05984a, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Thu Aug 11 00:45:57 CST 2022, time=2022-08-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1577916, encodeId=db3d15e7916fd, content=<a href='/topic/show?id=cda91148004' target=_blank style='color:#2F92EE;'>#Medicine#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11480, encryptionId=cda91148004, topicName=Medicine)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=54cd16396700, createdName=ms1692212821629096, createdTime=Thu Aug 11 00:45:57 CST 2022, time=2022-08-11, status=1, ipAttribution=)]
    2022-08-13 carrotlyl

    ab造假的事,不提了?

    0

  9. 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