ATR

中国上海，北京时间2025年4月30日 - 英派药业在2025年4月25日至30日于芝加哥举行的2025年美国癌症研究协会（AACR）年会上，以壁报形式公布ATR抑制剂IMP9064的发现和早期开发结果。壁报展示标题：一种高活性和高选择性的ATR抑制剂IMP9064的发现和开发日期及时间：星期二，2025年4月29日，美国中部时间上午9:00 至上午12:00 地点：Section 15，PO.ET06.07壁报编号：#4203结果总结IMP9064是由英派药业自主研发的一款高活性、高选择性的ATR抑制剂，临床前研究显示其对ATR有强效抑制活性，并在激酶中具有高度选择性，同时对多种ATM缺陷型肿瘤细胞展现出很强的细胞毒性。该药物在临床前研究中也展现出长半衰期和高暴露量的药代动力学特征。IMP9064在结直肠癌CDX模型中显示出剂量相关的抗肿瘤作用，且动物耐受良好。此外，体外和体内研究结果表明，IMP9064与其他药物（PARP抑制剂、WEE1抑制剂、PKMYT1抑制剂或HER2抗体偶联药物）联合使用时，具有良好的抗肿瘤活性和协同作用。目前，IMP9064已进入临床1/2期研究，以评估单独治疗或与PARP抑制剂Senaparib联合治疗晚期实体瘤患者的安全性和有效性（NCT05269316），其2期推荐剂量（RP2D）已经确定，并正在针对特定肿瘤患者进行扩展研究。关于英派药业英派药业致力于研发具有自主知识产权的靶向抗癌创新药，专注于合成致死作用机制。公司以DNA损伤修复通路（DDR）自主研发产品为基础，构建了全球生物医药公司中覆盖面最广的DDR产品管线之一，并且正在逐步拓展到更多的全新的合成致死靶点。公司管线包括PARP抑制剂塞纳帕利（Senaparib/IMP4297）、Wee1抑制剂（IMP7068）、ATR抑制剂（IMP9064）、PARP1选择性抑制剂 (IMP1734，与美国Eikon Therapeutics合作开发)以及多个其他DDR靶点抑制剂。其中最成熟的研发项目PARP抑制剂塞纳帕利在全球范围包含中国已开展卵巢癌、小细胞肺癌等适应症的临床II/III期研究。塞纳帕利用于晚期卵巢癌全人群一线维持治疗的III期临床研究（FLAMES）已达到主要研究终点，显示了同类最佳的药效和安全性。基于FLAMES研究成果，中国国家药监局（NMPA）已批准了塞纳帕利的新药上市申请。Wee1抑制剂IMP7068和ATR抑制剂IMP9064已在包括美国、中国在内的全球多个国家及地区开展I期临床研究，确定了临床二期推荐剂量（RP2D）。PARP1选择性抑制剂IMP1734 已经获得 FDA和NMPA的临床试验许可，在2024年初完成第一例患者入组。 更多信息请浏览www.impacttherapeutics.com投资者关系及媒体英派药业+86 21 6841 1121IR@impacttherapeutics.com

Artios Pharma, a startup developing drugs that weaken a tumor’s ability to maintain its DNA, announced positive results in a subset of patients with advanced cancer. It’s the first big data reveal for the Cambridge, UK-based startup, which has been relatively quiet since 2021, when it struck a drug discovery partnership with Novartis and raised $153 million in Series C financing. The company’s drug, called ART0380, inhibits a DNA repair enzyme called ATR. When administered with a low dose of the chemotherapy irinotecan, the drug shrank tumors in 37% of patients whose cancer was considered “deficient” in another DNA damage response protein dubbed ATM, according to data from a Phase 1/2 study. In patients whose tumors lacked the ATM protein entirely, the response rate was 50%, with a median duration of response of 5.7 months so far. The response rate was 22% in patients with low levels of ATM. Patients with the ATM protein, however, did not respond to the therapy. “All those patients unfortunately progress quickly and unfortunately die very quickly,” Artios Chief Medical Officer Ian Smith told Endpoints News in an interview. The new data, presented Tuesday at the American Association for Cancer Research meeting, comes from 58 patients with advanced-stage and metastatic solid tumors who were treated at the dose the company plans to use in a Phase 2 study. Artios CEO Niall Martin told Endpoints that the company has funds “through 2026.” He said the startup is looking to raise another round of private funding to test its ATR inhibitor in pancreatic and colorectal cancers before pursuing bigger and broader tissue-agnostic studies. Martin said the company’s partnership with Novartis, which wasn’t focused on its ATR inhibitor, identified several targets that could potentially be paired with Novartis’ radioligand therapies, including its prostate cancer drug Pluvicto, and discussions are underway on next steps. Artios had struck a partnership with Merck KGaA in 2020 to search for drugs that target other DNA repair proteins, but Martin told Endpoints that partnership has ended. Artios was founded in 2016 to discover a new wave of drugs that target complex networks of proteins dedicated to the faithful replication and preservation of our genomes. While cancer can survive, and even thrive, with some DNA repair enzymes missing, too many missing pieces can cause the cancer to self-destruct. A class of drugs called PARP inhibitors exploit this vulnerability by blocking the eponymous DNA repair protein in tumors that have mutations in genes called BRCA1 and BRCA2, which are also important for DNA repair. Several companies have been searching for the next combination of targets that can deliver a similar double whammy to tumors, but progress has been slow. “The field hasn’t really evolved much since PARP inhibitors,” Martin said. “So we’ve been really thinking about what are the layers of DNA damage that are created in tumors that could be used as their sort of Achilles heel.” One of those layers, according to Artios, is a phenomenon called replication stress, which can occur when DNA replication, a key step for dividing cells, is blocked. ATR and ATM are two proteins that detect and clear up these blockages. Many forms of chemotherapy obstruct DNA replication. By first inducing a bit more of that stress with a low dose of chemo — but not enough to kill the cancer itself — and then blocking ATR in tumors with little to no ATM, Artios hoped to deliver a triple whammy to tumors. “There’s always been a push to get rid of chemotherapy and have targeted drugs,” Smith said.“But if you can’t get rid of chemotherapy, what you can do is really minimize it. And that’s what we’ve done here.” Smith said the company saw two complete responses, including one in a 62-year-old female who had pancreatic cancer but has been off treatment and cancer-free since August 2023. Neutropenia, a decline in white blood cells, was the most common side effect seen in 53% of patients, with grade 3 neutropenia in 45% of patients. Anemia occurred in 41% of patients. Fatigue, diarrhea, nausea and vomiting were also common side effects. Several other drugmakers have developed their own ATR inhibitors, but lackluster results have caused some pharma companies, including Bayer and Roche, to discontinue or pare back these efforts. “ATR inhibitors have been languishing,” Smith said. “The response rates are low relative to the toxicity that you tend to get.” Roche cut its partnership with Repare Therapeutics in 2024, which paused its ATR inhibitor program earlier this year after modest responses in only 19% and 17% of endometrial and ovarian cancer patients, respectively. Merck KGaA dropped its first ATR inhibitor, berzosertib, but is still testing a second one, called tuvusertib. And AstraZeneca is testing its ATR inhibitor ceralasertib in a Phase 3 study in lung cancer with its immunotherapy Imfinzi, which is expected to complete in August. Artios executives told Endpoints that other ATR inhibitors have faltered for three reasons: the drug’s half-life was too long, leading to intolerable toxicity; the drug was tested as a monotherapy, leading to low efficacy; or the drug was paired with the wrong therapies or tested in the wrong genetic subtypes of cancer. Martin said the company plans to develop a companion diagnostic to identify patients that are most likely to respond to its drug, with an initial focus on ATM. But Artios is looking for other biomarkers that may make tumors vulnerable to ATM inhibitors too. “This whole process of replication stress can be in up to 30% to 40% of tumors,” Martin said. “So there’s a huge area of biology which no one really has tapped into.”

在美国芝加哥举办的2025年美国癌症研究协会（AACR）年会上，双载荷ADC成了新焦点。根据大会发布的摘要，至少14款双载荷ADC将亮相，国内药企相关产品占据了半壁江山，其中大多数项目此前从未披露过。而就在一年前的AACR大会，还仅仅只有4个双载荷ADC的身影。在ADC成为药物研发顶流的时代，双载荷前景极具想象力，或将成为ADC领域的下一个大爆点。1双载荷的魅力尽管ADC目前在多种肿瘤疾病中均展现出潜力，但肿瘤异质性和耐药仍是该领域目前最大的挑战，前者可导致肿瘤的持续复发与转移，而后者则会导致肿瘤的侵袭性生长和低生存率，所以如今绝大多数ADC研究目的均是为了克服这些障碍，而双载荷ADC或将成为潜在的解决方案。双载荷ADC通过在一种抗体上偶联两种或多种不同载荷或同一载荷的两种不同Linker，灵活调整药抗比（DAR）值，提高ADC活性，产生添加或协同效应，提高治疗效果，扩展适应症范围，并克服耐药性。然而，两种生物活性分子因作用机制不同、生物活性各异、药代性质差别，其起效剂量、毒性剂量均有不同，采用简单的1：1的比例与抗体偶联形成的ADC，难以保证分子有效且安全，成药的可能性较低。选择合适的荷载药物及其和抗体连接方式是成功的关键。双载荷ADC药物采取不同机制设计。毒素的组合方式决定了作用机制和疗效。在构建双载荷ADC方面，研究者们已经探索出多种方法：一种是利用两个反应位点分步进行构建，在抗体的不同位点引入单链Linker和有效载荷；另一种就是利用单一反应位点引入分支Linker，再通过点击化学反应引入有效载荷。尽管双载荷ADC构建方法目前已经较为成熟，但仍需进一步研究和改进。目前来看，双载荷ADC具备三大核心优势：1、协同增效：针对不同生物学通路（如微管破坏+DNA损伤）或同一通路的不同节点（如EGFR抑制+HER3阻断）进行联合打击，显著提升杀伤效率。例如，同时搭载拓扑异构酶抑制剂和PARP抑制剂的ADC，可针对HRR缺陷和同源重组正常肿瘤均产生强效杀伤。2、耐药预防：通过多机制联合作用降低耐药压力。例如，微管抑制剂与免疫调节剂（如STING激动剂）的组合，既能直接杀伤肿瘤细胞，又能激活抗肿瘤免疫，形成“杀伤－免疫”正反馈循环。3、旁观者效应：部分载荷（如RNA干扰分子）可靶向肿瘤相关成纤维细胞或免疫抑制细胞，重塑微环境以增强整体疗效。2热度拉满尽管就现阶段而言，全球双载荷ADC的研发仍处于早期探索阶段，但这一赛道如今却拥有前所未有的研发热度，以至于全球药企短时间内就掀起了一场“抢位赛”，其中国内康弘药业率先出线，其研发的KH815成为全球首个进入临床试验的新型双载荷（dual-payload）抗体偶联药物（ADC），并在此次AACR亮相备受业内关注。KH815是一种具有抗耐药潜力的靶向滋养层细胞表面抗原2（TROP2）的新型双载荷ADC，其双载荷能实现同时在RNA水平和DNA水平对肿瘤细胞的抑制，具有双效协同机制。此外，还能降低P-gp和HSP70蛋白的表达，克服耐药，增加细胞对化疗药物的敏感性。在双抗原+双载荷领域，杭州多禧的DXC018、上海亲和力生物的IMD2113、康宁杰瑞的JSKN021以及拓济的TJ102成为讨论焦点。前三者均围绕HER2/EGFR靶点展开，各有千秋；TJ102则另辟蹊径，剑走偏锋，选择靶向CDH6和叶酸受体α。作为连续两年参展AACR的全球双荷领域领先的瑞士公司Araris Biotech今年带来了一个靶向Nectin-4的三payload ADC，采用了两种不同的Topo1i加MMAE的组合，DAR值分别为Topo1i(2)+Topo1i(2)+MMAE(2)。在去年AACR上，Araris则公布了HER2 ADC（抗体为曲妥珠单抗，有效载荷是两种不同的TOP1i）和NaPi2b ADC（有效载荷是两种不同的TOP1i）的临床前数据，结果表明双TOP1i ADC可以最大限度地提高ADC的疗效并改善治疗指数，并且Araris的Linker非常稳定。Araris致力于开发一流的ADC，其专有连接子偶联平台AraLinQ无需对抗体进行改造，就可以在抗体的特定氨基酸上连接载荷，这一技术可通过高效的一步反应将多个协同抗癌载荷偶联到单一抗体上。这一独特的技术平台，让ADC领域老玩家罗氏心动不已，今年年初其子公司ChugaiPharmaceutical以总金额7.8亿美元达成与其共同开发下一代ADC的合作，两个月之后日本大鹏制药更是以4亿美元首付款,总金额11.4亿美元将Araris收入囊中。两项重磅交易也说明了双载荷ADC的未来前景巨大。据ApexOnco等公开数据显示，目前全球已有超20家制药企业已公布其双载荷ADC领域的布局情况，除Araris、Adcoris、GeneQuantum、Alphamab、Hummingbird、Sutro、BrickBio等海外Biotech外，国内也有多家药企涉足其中，如爱科瑞思、康宁杰瑞、百奥赛图、宜联生物、信达生物等。从靶点来看，主流的选择仍然是单靶，以较为成熟的HER2、TROP2为主，双靶点和双payload的选择或许难度更高但也是差异化的方向，而在payload的选择上则是在探索更多元化的组合，以求最大限度的发挥双payload的潜力。信达生物的双载荷ADC近日也传来好消息，其申报的1类新药靶向CEACAM5的双载荷抗体偶联药物（ADC）IBI3020在国内获批临床，拟开发治疗不可切除、局部晚期或转移性实体瘤。虽载荷暂未公开，预计不久将开启1期临床试验。虽然承诺会发布相关试验海报，但遗憾的是，并未出现在此次AACR摘要之中，大概率会在后续的ASCO等重要学术会议上展示。同样缺席本次AACR的还有美国生物技术公司CrossBridge Bio。这家公司去年11月刚刚完成1000万美元的私募融资，其主攻方向便是双荷载ADC。其管线中研发进度最快的为CB-120，为TROP-2双载荷ADC，载荷为exatecan和ATR抑制剂。3结语从当下局势来看，康弘的KH815和信达的IBI3020已率先叩响临床大门，但这场竞赛才刚刚拉开帷幕，未来充满诸多不确定性。首当其冲的就是疗效与安全的平衡问题。双载荷ADC的设计绝非简单的“1+1”模式，双载荷ADC需要同时携带两种不同机制的细胞毒性药物，导致体内代谢路径复杂化，两种载荷的释放动力学、协同效应及毒性叠加风险难以预测。双载荷ADC大热的背后，有着清晰且现实的临床需求。在实际治疗过程中，接受ADC治疗的患者出现复发的原因复杂多样，靶抗原丢失、对载荷产生耐药性等问题屡见不鲜。双载荷ADC能否成功突破这些困境，为肿瘤患者带来新的生机与希望，最终还得依靠严谨的临床来给出答案。参考来源1.各公司官网2.Fu,Z.,et al.,Antibody drug conjugate:the"biological missile"for targeted cancer therapy.Signal Transduct Target Ther,2022.7(1):p.93.声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 史蒂文合作、投稿、转载开白 | 马老师 18323856316（同微信） 阅读原文，是受欢迎的文章哦