The Children's Hospital of Philadelphia

编者按：近10年前，在蛋白降解技术尚处于早期探索阶段时，药明康德便前瞻性地布局相关能力，搭建起涵盖分子发现、合成、分析纯化与测试的一体化赋能平台，迄今已成功支持超过100款PROTAC分子的开发，其中20余款进入临床阶段，持续推动该领域从科学构想到临床现实的转化。近日，《自然》期刊发表专题文章，聚焦PROTAC技术在儿童实体瘤等高致死性癌症中的应用前景，系统回顾其从实验概念到临床突破的演进路径，并讲述国际科研团队瞄准MYCN等“不可成药”靶点，为儿童癌症患者带来治疗新希望的真实案例。蛋白降解疗法正加速突破技术边界，迈向更广泛的临床应用。“那些蛋白质暴力地夺走了我儿子的生命，我要把它们从其他孩子的世界里彻底清除。”——加文·林德伯格，一位因痛失爱子而投身儿童癌症研究资助之路的父亲，至今仍持续坚持这项誓言十余年…图片来源：123RF林德伯格的儿子埃文（Evan）在三岁时被发现具有神经母细胞瘤，这是一种发生在脑外神经组织、具有高度恶性的儿童实体瘤。埃文确诊时，癌症已广泛转移，他的治疗之路异常艰辛。长达四年的治疗包括反复化疗、放疗、免疫疗法和多次手术，几乎填满了他短暂的童年。最终，埃文于2010年离世，年仅七岁。这段经历不仅深深改变了埃文的家庭，也深刻影响了他的主治医生——费城儿童医院的儿科肿瘤专家Yael Mossé博士。在埃文离世后，她愈加坚定地投入到对神经母细胞瘤及其他儿童实体瘤的研究中，试图打破这一治疗瓶颈。“我已经在这个领域工作了二十多年，”她说，“虽然我们取得了一些进展，但在开发更具靶向性的治疗方案方面，仍有很长的路要走。”儿童实体瘤面临的挑战远比人们想象中更为复杂。虽然其发病率低于白血病等血液系统肿瘤，但在0至14岁儿童癌症相关死亡中，占比却超过一半。由于与成人癌症在生物学机制上存在显著差异，许多成人使用的抗癌药物在儿童身上往往难以奏效。令人关注的是，自2000年以来，美国FDA虽已批准逾180种抗癌新药，但真正专为儿童患者设计和开发的仍不足12种。图片来源：123RF这些数据一方面揭示了儿童癌症治疗领域长期以来的投入不足，另一方面也清晰地指出了一个明确的发展方向——为儿童患者量身打造的精准疗法正在成为迫切而现实的需求。正因如此，Mossé博士与林德伯格家庭在不同身份下汇聚目标，共同致力于推动这一关键使命：为每一位患病儿童争取更有效、更安全、也更可及的治疗选择。靶向蛋白质：从“不可成药”到“有药可医”在多年研究传统疗法收效有限之后，Mossé博士将希望寄托于一种全新的药物机制——蛋白降解靶向嵌合体（PROTAC）。与传统小分子药物通过阻断蛋白活性位点来“抑制”靶点不同，PROTAC采取的是更为激进的方式：它直接引导细胞自身的“垃圾清除系统”——泛素-蛋白酶体通路，将致病蛋白从源头上彻底降解，堪称“杀死蛋白”的新型武器。PROTAC的工作原理依赖于其独特的双功能结构：一端结合目标蛋白，另一端则招募泛素连接酶。后者会在目标蛋白上“挂上”泛素标签，标记其为应被清除的“废弃物”，随后被蛋白酶体识别并降解。英国邓迪大学生物化学家Alessio Ciulli教授将这一过程形象地称为“蛋白质的死亡之吻”。这一机制带来的最根本变革，是对成药空间的极大拓展。目前，FDA已批准的靶向药物主要集中在不到700种蛋白上，而在已知与癌症、神经退行性疾病等相关的致病蛋白中，有近3000种长期被视为“不可成药”——其中不少因蛋白表面平滑、缺乏有效结合口袋而难以设计传统抑制剂。例如转录因子MYCN、STAT6等，正是这类“药物开发禁区”的代表。而PROTAC的出现，为这些曾被视为“无法触及”的靶点带来了前所未有的希望。从实验室“花招”走向临床前沿PROTAC并非近几年才提出的假说。早在2001年，耶鲁大学化学生物学家Craig Crews博士与加州理工学院的Raymond Deshaies博士及其团队，便首次在实验条件下成功演示了PROTAC可实现蛋白质降解的潜力。然而，这项成果在当时并未获得主流科学界的重视。彼时，大多数人将其视作一项“有趣但不切实际”的实验室技术。2009年，当Alessio Ciulli教授开始涉足这一领域时，甚至被同行讥讽：“他们翻白眼，说，‘PROTAC？那玩意儿永远成不了药。’”直到2015年，情况才发生根本性转变。来自多个独立研究团队的三篇关键论文几乎同期发表，首次在细胞和动物模型中实现了靶蛋白的高效降解，彻底打破了外界对PROTAC“无法成药”的偏见。这些成果不仅标志着蛋白降解技术的可行性，也为产业界注入了信心，推动一系列专注于蛋白质降解的新兴企业迅速涌现，包括Arvinas、Amphista Therapeutics、C4 Therapeutics与Nurix Therapeutics等。与传统小分子药物相比，PROTAC具备多项独特优势。其最显著的特点是PROTAC分子不需持续占据靶点，仅需与目标蛋白短暂结合并完成标记，便可脱离并继续“寻找下一个猎物”。这一“走马灯式”的降解过程，意味着即使在低剂量条件下也可能实现长期、高效的治疗效果。更重要的是，许多疾病相关蛋白在体内往往具备多重功能，仅靠传统药物阻断其某一活性位点，难以全面遏制病理过程。而PROTAC通过彻底“消除”致病蛋白本体，有望从源头阻断所有致病通路，甚至可能避免耐药性的发展。这些特性使其被视为继靶向疗法、免疫疗法之后，又一具有变革潜力的药物模式。直面“不可成药”靶点：挑战MYCN埃文在生前曾参与Mossé博士主持的一项临床试验，尝试使用当时已有的靶向药物来治疗神经母细胞瘤。然而，治疗效果并不理想，肿瘤并未明显缩小。进一步的分子分析显示，埃文体内的肿瘤细胞存在MYCN基因扩增——这是一种与多种高度侵袭性儿童癌症密切相关的分子异常，也是儿童实体瘤中最令人头痛的“致命驱动因子”之一。MYCN是一种转录因子，在正常发育过程中调控细胞增殖，尤其在胎儿期扮演重要角色。但一旦过度表达，就会促使细胞失控分裂，从而驱动癌症的发生和快速进展。由于其缺乏可结合的活性口袋，MYCN长期被视为“不可成药”的代表性靶点，成为肿瘤生物学中的一道技术壁垒。2019年，在一次关于MYCN的学术会议上，Mossé博士受到蛋白降解公司Nurix Therapeutics一位创始人的启发，开始思考是否可以借助PROTAC这一新机制，来“绕过”传统药物的结构限制，直接诱导MYCN降解。她形容这次对话如同点燃了一个方向明确的火种。在私人基金的初步支持下，双方开启了合作，研究也随之迅速推进。2024年，Mossé博士牵头的研究团队获得了国际项目癌症大挑战（Cancer Grand Challenges）的资助，并与德国、英国、法国和奥地利的科学家组成跨国联合团队，正式组建了名为KOODAC的项目组。KOODAC是“Knocking Out Oncogenic Drivers And Curing Childhood Cancers”（清除致癌驱动因子，治愈儿童癌症）的缩写，目标是通过蛋白降解技术，靶向并消灭多种“不可成药”的癌症驱动蛋白。该团队当前的研发聚焦于包括MYCN在内的五个关键靶点，涵盖神经母细胞瘤、尤文肉瘤、横纹肌肉瘤和一种罕见儿童肝癌。与许多基础研究团队不同，KOODAC还特别纳入了患者家属的声音作为项目核心支持力量——埃文的父母加文与温蒂·林德伯格，正是其中的重要成员。过去十年来，他们持续为Mossé博士的研究提供资金支持，将个人悲剧转化为推动科学前进的动力。KOODAC的愿景不仅限于开发疗效显著的新药，更强调实用性与可及性。他们致力于开发出可口服、无需住院输注的PROTAC疗法，并确保其价格在中低收入国家也具备可负担性。因为在全球许多地区，高昂的治疗费用仍是儿童癌症患者失去治疗机会的主要障碍。PROTAC进入3期：距离首款上市仅一步之遥自2019年起，已有至少30款候选PROTAC分子进入临床试验阶段。尽管主要聚焦于癌症治疗，但其所应用的适应症也逐步拓展至帕金森病、炎症性疾病和慢性疼痛等非肿瘤领域。虽然目前尚无PROTAC药物正式获批上市，但部分管线已进入临床研发的后期阶段。图片来源：123RF其中最受瞩目的药物之一，是由Arvinas公司与辉瑞（Pfizer）联合开发的vepdegestrant。这是一款靶向雌激素受体（ER）的PROTAC分子，主要用于治疗激素受体阳性、HER2阴性的乳腺癌患者。今年3月公布的关键3期临床试验结果显示，在携带ESR1突变且已接受CDK4/6抑制剂和内分泌治疗后出现疾病进展的患者中，vepdegestrant相较活性对照，显著延长了无进展生存期（PFS），疾病进展或死亡的风险降低超过40%（HR<0.60），具有统计学显著性及临床意义。Arvinas公司已于近期向美国FDA递交新药申请，有望成为首款获批上市的PROTAC药物。尽管前景光明，PROTAC药物的开发仍面临不容忽视的挑战。一方面，这类分子目前难以有效作用于细胞膜蛋白或细胞外靶点，限制了其在部分疾病中的适用范围；另一方面，彻底清除整条蛋白路径可能带来不可预测的生理效应，包括潜在的毒性风险。因此，如何提升选择性、优化分子结构，并最大限度控制脱靶风险，将是PROTAC技术能否真正广泛应用、实现临床转化的关键所在。这一领域的发展，仍有赖于持续的基础研究和产业合作，在平衡疗效与安全性的基础上，探索更大范围的适应症可能性。分子胶：PROTAC之外的另一条路径在PROTAC迅速发展的同时，另一种蛋白降解策略——分子胶也正在悄然崛起，为攻克“不可成药”靶点提供了另一种可能。与PROTAC需要同时结合靶蛋白和泛素连接酶不同，分子胶的机制更为简洁：它通过改变泛素连接酶的表面构象，使其能够主动识别并招募特定靶蛋白进行降解。由于不依赖于与靶蛋白的直接结合，这类分子通常结构更小、合成难度更低，有望成为更具成本优势的新一代蛋白降解工具。值得注意的是，来那度胺（Revlimid）——这款广泛用于治疗多发性骨髓瘤的知名药物，虽最初并非以分子胶为设计目标，但后续研究表明，其实际作用机制正是通过分子胶路径实现。这一“意外发现”不仅验证了分子胶策略的可行性，也激发了产业界对该技术路径的系统性开发热情。目前，分子胶正成为多个研究团队探索新靶点的重要方向。在KOODAC团队中，来自维也纳CeMM分子医学研究中心的化学生物学家Georg Winter博士正带领其实验室，专注于筛选和优化适用于儿童实体瘤关键蛋白靶点的分子胶候选分子。同时，他也通过其共同创办的生物技术公司Proxygen，致力于推动这一领域的产业化进程，加速分子胶药物从实验室走向临床应用。为下一代的治愈希望而战曾任安进（Amgen）高级副总裁的Deshaies博士认为，无论是PROTAC还是分子胶，这类药物都有望在更广泛的疾病领域取得突破。“即使首款药物成功上市，任何一项新药技术的成熟都不是一蹴而就的过程，”他说，“整个行业通常需要约十年的集体努力，才能真正将技术推向成熟。如今的PROTAC，仍处于这一进程的初期阶段。”对Mossé博士而言，这条道路的艰难，她再清楚不过。多年来，她亲眼目睹过太多有希望的新疗法在儿童患者身上最终失效，甚至被迫中止开发。但这一次，她的态度格外坚定。“我真的相信，现在正是时候。我们能够把这些药物带到孩子们身边。”而对于林德伯格一家来说，这场战斗不仅仅关乎科研，更是一场无法回避的私人使命。尽管埃文已经离世多年，他们依然将失去孩子的伤痛转化为推动科学前进的持久动力，用行动延续埃文的生命意义。“那些蛋白质曾夺走我儿子的生命，”加文·林德伯格说，“我想让它们不再威胁任何一个孩子。”参考资料：[1] How protein-slayer drugs could beat some of the cruellest cancers. Retrieved May 10, 2025 from https://www.nature.com/articles/d41586-025-01350-2[2] Arvinas Reports First Quarter 2025 Financial Results and Provides Corporate Update. Retrieved from https://ir.arvinas.com/news-releases/news-release-details/arvinas-reports-first-quarter-2025-financial-results-and免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，传递医学新知

Dive Brief:Two senior officials at the Food and Drug Administration office that regulates gene therapies have reportedly been placed on administrative leave, resurfacing questions about the way the complex medicines will be regulated under new agency leadership.Nicole Verdun, a director of the Office of Therapeutic Products at the Center for Biologics Evaluation and Research, and her deputy director Rachael Anatol were both put on leave, according to a report from Stat News. Its unclear what drove the FDAs decision, but in an email to BioPharma Dive, Andrew Nixon, director of communications for the Department of Health and Human Services, wrote that center directors deserve to be supported by managers that are aligned with aggressive goals to expeditiously advance therapeutics for rare diseases using the gold standard of science.Verdun and Anatol have been top officials at the OTP for almost two years, and in that role have modernized the FDAs regulatory approach to cell and gene therapy, the Alliance for Regenerative Medicine said in a statement. Their dismissal follows the March resignation of longtime CBER director Peter Marks.Dive Insight:Prior to this year, cell and gene therapy research was already reeling, as murky commercial prospects led to a sustained pullback in funding for private as well as publicly traded companies.Since then, large staffing cuts at the FDA and turnover in the senior leadership that reviews gene therapies have amplified the fields angst. Marks departure was acutely felt by developers, as hed overseen dozens of approvals and strongly advocated for the FDA to be more flexible in reviewing cell and gene-based treatments, earning both praise and criticism. Successor Vinay Prasad has long criticized Marks decisionmaking, raising questions about whether the agency would adopt stricter standards.At a roundtable meeting hosted by the FDA earlier this month, many of the fields experts warned of a crisis. I have serious concerns about the future of cell and gene therapy in the United States, said Carl June, an immunologist and pioneering cell therapy researcher at the University of Pennsylvania. If we do not modernize our regulatory approach, we risk losing our leadership, undermining the long term viability of our biopharma industry.Prasad was receptive at the meeting, showing support for the kind of flexible trial designs and endpoints for rare conditions that hed criticized in the past. That session seemed to appease industry watchers, taking investors worst-case scenario off the table, wrote Leerink Partners analyst Mani Foroohar, in a note to clients Thursday.Verdun and Anatols surprise dismissal, though, renews uncertainty and will be taken as a clear negative, he added.Verdun was one of the reviewers Marks controversially overruled last year in broadly approving Elevidys,Sarepta Therapeutics gene therapy for Duchenne muscular dystrophy.Still, like Marks, Verdun and Anatol have advocated for accelerated approvals, in the process earning the trust and respect of the [cell and gene therapy] community and helping ensure the FDA was the global leader in the field, the Alliance for Regenerative Medicine said in a statement.I have always been struck by her commitment to patients and her brilliance as a physician, wrote Katherine High, a prominent gene therapy researcher and former head of a Childrens Hospital of Philadelphia lab Verdun trained at more than a decade ago, in an email. She has done a great deal of good for the advancement of medicine over the course of her career.Verduns firing is another sentiment hit and source of volatility for cell and gene therapy, Sami Corwin, an analyst with William Blair, wrote in a client note on Friday.Still, both Corwin and Foroohar acknowledged how Makary and Prasad have both been outspoken in supporting for cell and gene therapy, particularly for rare diseases. Industry watchers, then, are left to read the tea leaves following more agency turnover, Foroohar wrote.Its unclear what this signals, he wrote. Is Prasad simply cleaning house, or was there a deeper philosophical rift between him and Verdun over the agencys future direction? '

With the eight new members of the Centers for Disease Control and Prevention's (CDC's) vaccine advisory committee set to meet next week, a draft agenda released Wednesday shows some significant departures from — and notable additions to — the list of vaccines the panelists were expected to review and vote on. The new appointees were named by Health and Human Services Secretary Robert F. Kennedy Jr. last week, just two days after he fired all 17 sitting members of the Advisory Committee on Immunization Practices (ACIP). FirstWord is conducting a poll to gauge how US physicians feel about the overhaul (see – Physician Views Preview: Vaccine trust on trial after ACIP upended).The ACIP meeting, originally scheduled for three days, has been shortened to just two: June 25 and 26. Several vaccines that had been slated for discussion have been removed from the agenda, including meningococcal, pneumococcal, cytomegalovirus and lyme disease jabs. A presentation and subsequent vote on childhood and adult HPV vaccines are also absent, which may have Merck & Co. breathing a sigh of relief. Martin Kulldorff, one of the new ACIP appointees, was reportedly an expert witness in multiple lawsuits alleging that the pharma intentionally hid safety risks for its HPV shot Gardasil (see – Vital Signs: Ahead of key deadlines, biopharma shrugs off latest policy portents).ACIP will still review anthrax, chikungunya and COVID-19 vaccines; a vote on the latter's use had been expected, but is not listed on the agenda. Maternal and paediatric respiratory syncytial virus (RSV) vaccines are still scheduled for a discussion and vote, including Merck's newly approved RSV preventative antibody Enflonsia (clesrovimab-cfor). The product, along with Sanofi and AstraZeneca's Beyfortus (nirsevimab-alip), are cleared to protect neonates and infants, but ACIP's recommendation will dictate their usage. For more on the two preventative products, see Spotlight On: Five factors shaping the RSV antibody showdown.New to the agendaThe agenda also featured two new additions. A yet-to-be-determined person will give a presentation on the measles, mumps, rubella and varicella (MMRV) vaccine in children under the age of five years old, and propose recommendations for the jab's use in that age group.  And while flu jabs, part of the original slate of topics, remain on the agenda, the discussion now includes an additional presentation and vote specifically on thimerosal-containing flu vaccines. Similarly, the person giving this new presentation is listed as "TBD."In the absence of a CDC director, Kennedy, who has made non-factual and critical statements in the past about the measles vaccine and thimerosal, is responsible for adopting — or rejecting — any recommendations made by ACIP. Measles historyDuring a recent Senate hearing, Kennedy claimed that the measles vaccine was not tested in a placebo-controlled trial. Sen. Bill Cassidy (R-La) later pointed out that this assertion was not true, and corrected Kennedy. At the same hearing, Sen. Chris Murphy (D-Conn.) questioned Kennedy's support of the measles vaccine, accusing him of "repeatedly undermining the vaccine with information that is contested by public health experts."When pressed by Murphy to say he supports the measles vaccine, Kennedy refused to answer.Kennedy's stance against the measles vaccine dates back at least several years. In 2019, he traveled to Samoa a few months before a measles outbreak that caused 1867 hospitalisations and 83 deaths, mostly in children. Alec Ekeroma, Samoa’s director general of health, told the Guardian in an interview last year that on that visit, Kennedy led a "significant disinformation campaign" stoking distrust in vaccines. Autism link debunkedThimerosal, a preservative added to multi-dose vaccine vials to prevent growth of bacteria and fungi, has also been a long-time target of Kennedy's. Thimerosal contains ethylmercury, a type of mercury that is rapidly cleared from the body and is distinct from the potentially toxic variant of methylmercury. The MMR vaccine, which used to contain thimerosal, was linked to autism in a widely debunked Lancet paper published by Andrew Wakefield in 1998. According to the Children's Hospital of Philadelphia, "the studies were deemed fraudulent and data misrepresented."While the CDC recommended removing thimerosal from vaccines routinely given to infants as a precautionary measure in 1999, multiple studies conducted by the agency have since concluded that there is no association between thimerosal-containing vaccines and an increased risk for autism spectrum disorder. However, Kennedy wrote in a 2005 article — printed by the Rolling Stone and published online by Salon — that thimerosal "appeared to be responsible for a dramatic increase in autism and a host of other neurological disorders among children." He also claimed "government health agencies colluded with Big Pharma to hide the risks of thimerosal from the public."The story was later removed from Salon's website after "evidence continued to emerge debunking the vaccines and autism link," said Joan Walsh, who was editor-in-chief when the article was published. "But continued revelations of the flaws and even fraud tainting the science behind the connection make taking down the story the right thing to do."It's unclear what will be discussed during the presentation on thimerosal at the ACIP meeting on June 26. According to the FDA, only three approved multi-dose vaccine vials still contain thimerosal: Seqirus' Afluria and Flucelvax, and Sanofi's Fluzone.