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唐獎生醫獎得主剖析細胞激素研究
為等待突破的疾病治療帶來希望與曙光

三位唐獎得主分別以「介白素-1:系統型及局部型發炎中主要的媒介物質」、「洞悉自體免疫的分子機制轉譯成有效的治療」、「介白素-6:從關節炎到T細胞療法(CAR-T)與新型冠狀肺炎之應用」主題,闡述細胞激素在發炎及COVID-19所扮演的角色及治療。

繼諾貝爾獎暨唐獎得主本庶佑(Tasuku Honjo)博士昨(11/26)日以「癌症免疫療法的前瞻發展」主題在亞太國際藥理學會議(14th Asia Pacific Federation of Pharmacologist)進行開場演講,給予醫藥界許多啟發,今(11/27)日下午接續由唐獎教育基金會攜手台灣藥理學會舉辦「唐獎第四屆得獎人演講-生醫場」(Tang Prize Lecture),非常難得同時邀請到2020年唐獎生技醫藥獎三位得主查爾斯‧迪納雷羅(Charles Dinarello)、馬克‧費爾德曼(Marc Feldmann)及岸本忠三(Tadamitsu Kishimoto)發表演講,並由台北醫學大學張文昌董事長及台北醫學大學閻雲講座教授共同主持。三位唐獎得主分別以「介白素-1:系統型及局部型發炎中主要的媒介物質」、「洞悉自體免疫的分子機制轉譯成有效的治療」、「介白素-6:從關節炎到T細胞療法(CAR-T)與新型冠狀肺炎之應用」主題,闡述細胞激素在發炎及COVID-19所扮演的角色及治療。

首先由查爾斯‧迪納雷羅(Charles Dinarello)發表演講主題「介白素-1:系統型及局部型發炎中主要的媒介物質」,Dr. Dinarello從1971年著手純化人類白血球中的白血球致熱原談起,述說他歷經6年研究發現兩種會引起發燒的分子,被稱為IL-1α以及IL-1β,並在1977年發表在美國國家科學院院刊,就此為細胞激素研究樹立突破性里程碑,激發更多生命科學領域研究者投入免疫系統對人類生理影響的相關研究,促進細胞激素研究蓬勃發展。Dr. Dinarello並補充表示經歷早期人體實驗過後,細胞激素療法發展方向就從「給予細胞激素」轉為著重在「抑制細胞激素」,例如抑制IL-1、TNF、及IL-6。為讓聽眾充分了解IL-1家族如何組成促發炎細胞因子的複雜網絡,Dr. Dinarello亦詳細介紹IL-1家族成員信號傳導方式、促發炎與抗發炎特性、在不同發炎性疾病中展現的臨床症狀,讓聽眾更能理解。下半段演講以「探討阻斷IL-1臨床應用」為重點。Dr. Dinarello提到IL-1的過量產生會引發疾病,而IL-1Ra會抑制IL-1α和β並阻斷IL-1R的訊息傳遞。如今重組的IL-1Ra已發展為生物製劑藥品 anakinra,專門用來治療類風濕性關節炎,也可防止第二型糖尿病引發的血糖異常;另外諾華藥廠也成功研發抗IL-1β單株抗體藥物canakinumab,適用範圍從罕見的遺傳性疾病、風溼性疾病、自體發炎性疾病、心血管疾病等,最令人期待的是目前一項臨床試驗CANTOS,意外發現canakinumab對於癌症患者有效,因此Dr. Dinarello相信阻斷癌症中的IL-1亦可為癌症疾病帶來治療曙光。

馬克‧費爾德曼(Marc Feldmann)分享「洞悉自體免疫的分子機制轉譯成有效的治療」,Dr. Feldmann演講上半段主要分享如何發現抗TNF抗體藥物可有效治療類風濕性關節炎,而且不管高劑量或低劑量皆可阻斷TNF,能迅速減少其他發炎調節分子的產生,另外他與研究團隊早期也嘗試將抗TNF抗體藥物結合抗癌藥物胺甲喋呤,合併使用治療類風濕性關節炎病患,研究結果顯示大約50%患者有反應,因此Dr. Feldmann深信在每一位病患痊癒之前,他與團隊仍有很大的努力空間。演講後半則提到因TNF是個不尋常的調節分子,它有兩個不同的受體:引起發炎的TNFR1、作用完全相反的TNFR2,所以阻斷所有的TNF,等同於阻斷兩個受體,他解釋阻止了發炎產生,但也同時阻止身體抑制發炎反應。因此Dr. Feldmann和團隊正朝向開發更專一性的抗TNFR1藥物,阻斷TNFR1時,並不會改變調節T細胞的功能。此外,他也分享抗TNF在治療其他有迫切醫療需求中的的潛力,例如注射抗TNF到手掌,用來治療手部肌肉纖維化的臨床試驗案例,但是他亦補充說明抗TNF藥物目前明顯有兩個缺點:治療成本高、注射型藥物,因此抗TNF藥物朝口服劑型、減低藥價,勢必對疾病治療會帶來更大效益。Dr. Feldmann於演講中不斷地提到他在不同研究或試驗計畫的合作夥伴們,他強調從這些計畫中他學習到透過效率合作有助促使研究發展工作持續突破,他不斷地尋找人才合作,且深信團結合作比單打獨鬥更有成就。

岸本忠三(Tadamitsu Kishimoto)演講主題為「介白素-6:從關節炎到T細胞療法(CAR-T)與新型冠狀肺炎之應用」,重點包括:如何發現IL-6歷程、解釋IL-6為何具備多重性功能,促進抗體產生及誘發發炎反應,探討IL-6對自體免疫疾病產生的影響,以及IL-6如何引發細胞激素風暴等。岸本教授在演講一開始便點出IL-6過量產生與許多疾病相關,例如:心臟黏液瘤、卡斯爾曼病、類風濕性關節炎、兒童特發性關節炎,因此團隊為了治療IL-6過量產生所導致的發炎反應,便採取「阻斷IL-6訊號傳遞」方式來治療病人,因此成功開發人源化重組抗IL-6抗體之單株抗體藥物tocilizumab,目前此藥物已廣泛使用於全球100多國,可用於治療類風濕性關節炎及幼兒型原發性關節炎。至於如何調控IL-6的產生及為何慢性發炎疾病會大量產生IL-6,岸本教授解釋只要能穩定IL-6的mRNA,就能穩定IL-6訊號。為挽救CAR-T療法引起的細胞激素風暴,目前醫界也採用tocilizumab搭配治療副作用。有鑑於此,岸本教授及團隊在COVID-19疫情爆發時,推測tocilizumab對於陷入細胞激素風暴的COVID-19重症病人可產生療效,幾項重大臨床試驗也證實使用tocilizumab對於COVID-19重症病患可降低使用侵入式呼吸器治療或死亡風險,美國FDA和WHO皆通過緊急授權使用tocilizumab來治療COVID-19病人。岸本教授於演講中完整闡述過去50年帶領團隊投入IL-6基礎研究至臨床治療開發。

會後,唐獎教育基金會亦安排三位生醫獎得獎人演講於當日下午16時-19時在唐獎官方Youtube進行線上分享,邀請大家收看完整「唐獎第四屆得獎人演講-生醫場」直播影片。                                             

2014年選出免疫療法,2016年選出基因編輯,2018年選出標靶治療的唐獎,已經受世界矚目。2020年得主馬克·費爾德曼、查爾斯·迪納雷羅及岸本忠三這三位科學家的貢獻改變了世界,因他們而誕生的生物製劑造福了成千上萬因自體免疫或發炎性疾病而受苦的病患。而COVID-19 及癌症也都是發炎性疾病。邀請您一起見證2020年唐獎得主傑出成就與貢獻及分享這份榮譽與喜悅。YouTube中文字幕:

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