Beyond the Breakthrough: Can Protein-Destroying Drugs Deliver Better Treatment?
突破之外：蛋白降解藥物能否帶來更優治療？
by Tan Weiyun 作者：譚偉雲
[Biopharma] [生物製藥]
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After two decades of promise, a new way of destroying disease-causing proteins has finally reached the market. Now targeted protein degradation faces a tougher test: whether it can produce medicines that are not just novel, but better.經過二十年的發展前景鋪墊，一種全新的致病蛋白降解技術終於推向市場。如今，靶向蛋白降解技術正面臨更嚴峻的考驗：它能否研發出不僅新穎，而且更優質的藥物。
The US Food and Drug Administration in May approved vepdegestrant, or Veppanu, for certain patients with advanced breast cancer carrying ESR1 mutations, marking the first FDA approval of a PROTAC, or proteolysis-targeting chimera. The oral drug recruits the cell’s own protein-disposal machinery to break down the cancer-driving estrogen receptor.美國食品藥品監督管理局於5月批准了維普司他（Veppanu）用於攜帶ESR1突變的部分晚期乳腺癌患者，這是美國食品藥品監督管理局首次批准蛋白降解靶向嵌合體（PROTAC）類藥物。這款口服藥物會調動細胞自身的蛋白降解機制，分解驅動癌症發生的雌激素受體。
The approval gave the field something it had long lacked: proof that the technology could make it all the way from the laboratory to the market.這一批准爲該領域帶來了它長期以來所缺乏的東西：證明該技術能夠完全從實驗室走向市場。
But it also raised the bar. 但這也提高了門檻。
“Different targets need different technology approaches,” Dr. Yang Xiaobao told China Biz Buzz at the World Laureates Forum in Shanghai.“不同的目標需要不同的技術路徑，”楊曉波博士在上海世界頂尖科學家論壇上接受《中國商業新聞》採訪時表示。
The scientist-turned-entrepreneur is the founder and chairman of Gluetacs Therapeutics and has worked on protein degradation since 2013.這位由科學家轉型的企業家是 Gluetacs Therapeutics 的創始人兼董事長，自2013年起一直從事蛋白質降解相關研究。
Credit: Ti Gong圖片來源：Ti Gong
Caption: A laboratory at Gluetacs Therapeutics in Shanghai, where the biotech company develops targeted protein degradation drugs, including molecular glues and bifunctional degraders.說明：上海 Gluetacs Therapeutics 製藥公司的一間實驗室，這家生物技術公司在此研發靶向蛋白降解藥物，包括分子膠和雙功能降解劑。
Protein degraders, he said, will not simply replace inhibitors, or even chemotherapy.他表示，蛋白降解劑並不會簡單地取代抑制劑，甚至也不會取代化療。
Traditional targeted drugs generally work by blocking a particular function of a disease-causing protein. Degraders take a different route: they recruit the cell’s natural waste-disposal system to remove the protein itself.傳統靶向藥物通常通過阻斷致病蛋白的特定功能來發揮作用。降解劑則採取不同的途徑：它們招募細胞天然的廢物處理系統來清除蛋白本身。
That distinction can matter when a protein does more than one job. Some cancer-driving proteins, for example, also have non-enzymatic functions that conventional inhibitors may leave untouched. Removing the entire protein may block those additional functions and, in some cases, help overcome pathways that allow tumors to escape treatment, Yang said.當一種蛋白質承擔不止一種功能時，這種區別就顯得至關重要。楊表示，例如，一些致癌蛋白質還具有非酶促功能，而傳統抑制劑可能對這些功能毫無作用。去除整個蛋白質或許能阻斷這些額外功能，在某些情況下，還有助於克服腫瘤逃避治療的途徑。
Yet making a protein disappear in a laboratory is one thing. Turning that effect into a useful medicine is another.然而，在實驗室裏讓一種蛋白質消失是一回事，而將這種效果轉化爲有效的藥物則是另一回事。
A degrader still has to reach the right tissue, remove enough of the target without causing unacceptable toxicity and, most importantly, improve outcomes for patients.降解劑仍需抵達正確的組織，在不造成不可接受毒性的前提下去除足夠的靶標，而最重要的是改善患者的治療效果。
That challenge is now moving into the clinic.這一挑戰如今正進入臨牀試驗階段。
Yang’s research, which grew out of work at ShanghaiTech University, has produced candidates spanning blood cancers, solid tumors and autoimmune diseases. GT919, a molecular glue being developed for multiple myeloma, has reported Phase I data, while Yang said the program is moving into Phase II development. GT818, a bifunctional degrader targeting solid tumors, has entered Phase I and had reached its second dose cohort.楊的研究源於上海科技大學的相關工作，已研發出涵蓋血液癌症、實體瘤和自身免疫性疾病的候選藥物。用於治療多發性骨髓瘤的分子膠GT919已公佈一期臨牀試驗數據，楊表示該項目正進入二期研發階段。針對實體瘤的雙功能降解劑GT818已進入一期臨牀試驗，並已推進至第二個劑量隊列。
The commercial potential is already clear in multiple myeloma. Revlimid, or lenalidomide, long a backbone treatment for the blood cancer, generated US$12.82 billion in worldwide sales for Bristol Myers Squibb in 2021, before generic competition began eroding revenue.其商業潛力在多發性骨髓瘤領域已十分明確。來那度胺（Revlimid）長期以來一直是這種血液癌症的核心治療藥物，在仿製藥競爭開始侵蝕其收入之前，2021 年它爲百時美施貴寶公司創造了 128.2 億美元的全球銷售額。
Treatment is now moving into a new generation. In August, the FDA granted accelerated approval to BMS’s iberdomide, a cereblon E3 ligase modulator, or CELMoD, for previously treated multiple myeloma. China’s drug regulator followed with a conditional approval in September, bringing the same drug class into the Chinese market.治療現已邁入新一代。8月，美國食品藥品監督管理局（FDA）加速批准了百時美施貴寶公司（BMS）的伊比沙米德上市，這是一種腦蛋白E3連接酶調節劑（CELMoD），用於治療既往接受過治療的多發性骨髓瘤。中國藥品監管部門隨後於9月附條件批准該藥上市，使同類藥物進入中國市場。
The opportunity in China is also expanding as patients live longer with the disease. Yang described the country’s multiple myeloma population as sizable, while advances in treatment are increasingly turning the cancer into a condition that can be managed over many years for some patients, extending demand well beyond newly diagnosed cases.隨着患者帶病生存期的延長，中國市場的機遇也在不斷擴大。楊將中國多發性骨髓瘤患者羣體描述爲規模龐大，而治療技術的進步正逐漸使部分患者的癌症轉變爲一種可長期管理的疾病，這使得相關需求遠超新確診病例的範疇。
That is the market GT919 is targeting. Yang said the candidate is designed to improve selectivity and tolerability in multiple myeloma, particularly for patients who relapse or become resistant to existing therapies.這就是GT919瞄準的市場。楊表示，該候選藥物旨在提高多發性骨髓瘤的選擇性和耐受性，尤其針對對現有療法復發或產生耐藥性的患者。
The opportunity is also expanding beyond cancer. Developers are testing protein degradation in autoimmune and inflammatory diseases, while Yang said later programs from his team are also moving into autoimmune conditions.這一應用場景也正突破癌症領域。研發人員正在自身免疫性和炎症性疾病中測試蛋白質降解技術，而楊隨後表示，其團隊的相關項目也正向自身免疫性疾病領域拓展。
For Chinese biotechs, the next inflection point may be as much commercial as scientific.對於中國生物科技公司而言，下一個轉折點可能在商業化和科研領域同樣重要。
Yang said early human data can sharply change how overseas drugmakers value an asset.楊表示，早期人體試驗數據可能會極大地改變海外製藥商對一項資產的估值。
“If safety can hold up and we can also see some efficacy,” he said,adding that foreign drugmakers are generally more willing to pay for the risk attached to an early-stage program.“如果安全性能夠得到保障，同時我們也能看到一定的療效，”他表示，並補充說，外國製藥公司通常更願意爲早期項目相關的風險買單。
His team is already in discussions with multinational pharmaceutical companies and has received interest in licensing one of its assets overseas.他的團隊已在與跨國製藥公司展開洽談，並且其一項資產已收到海外授權許可的意向。
That reflects a broader change in drug development: owning an interesting platform is no longer enough. As more degraders enter human trials, clinical data are becoming the dividing line between technological promise and commercially valuable assets.這反映了藥物研發領域更廣泛的變革：擁有一個有趣的平臺已不再足夠。隨着越來越多的降解劑進入人體試驗，臨牀數據正成爲區分技術前景與商業價值資產的分界線。
The first approved PROTAC answered one question: this approach to targeted protein degradation can produce a medicine.首個獲批的PROTAC解答了一個問題：這種靶向蛋白降解方法能夠研發出藥物。
The next generation now has to answer a harder one: when is degradation actually the better way to treat disease?下一代現在必須回答一個更棘手的問題：在什麼情況下，降解療法實際上是治療疾病的更佳選擇？
For Yang, the answer depends on the target.對楊來說，答案取決於靶點。
Inhibitors will not disappear, he said. Neither will chemotherapy. The task is to choose the right tool for the right biological problem.他表示，抑制劑不會消失，化療也是如此。我們的任務是爲恰當的生物學問題選擇合適的工具。
That may ultimately be the clearest sign that protein degradation is maturing: success will depend less on whether a drug is called a PROTAC or a molecular glue than on whether it is simply a better medicine.這或許最終是蛋白質降解技術走向成熟的最明確信號：成功與否將不再取決於一種藥物被稱爲PROTAC還是分子膠，而在於它是否真的是更優質的藥物。
Editor: Yao Minji 編輯：姚敏吉
