Berzosertib

SEATTLE and SINGAPORE, May 27, 2026 (GLOBE NEWSWIRE) -- Callio Therapeutics, a biotherapeutics company advancing dual-payload antibody-drug conjugates (ADCs) with a targeted, multi-mechanism approach to cancer treatment, today announced that it will present a trial-in-progress poster highlighting the Phase 1 trial design of CLIO-8221 at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting (May 29-June 2) in Chicago. CLIO-8221 is a first-in-class dual-payload ADC currently in Phase 1 clinical development ( NCT07300943 ) for HER2-expressing solid tumors. “CLIO-8221 is the first program from Callio Therapeutics’ dual-payload ADC pipeline to enter the clinic, advancing our strategy to develop rationally designed payload combinations for hard-to-treat tumors,” said Naomi Hunder, MD, Chief Medical Officer of Callio Therapeutics. “Developed with our proprietary linker technology and payload combination platform, CLIO-8221 is a first-in-class dual-payload ADC designed to deliver a topoisomerase 1 inhibitor and an ATR inhibitor directly to HER2-expressing tumors to address key mechanisms of resistance to existing HER2-targeted ADCs, including trastuzumab deruxtecan. With our Phase 1 trial now enrolling patients with advanced HER2-expressing solid tumors, we look forward to generating clinical data that will inform its potential as a differentiated treatment option.” “Patients with HER2-expressing solid tumors who progress on currently available HER2-targeted therapies continue to have limited treatment options,” said Timothy A. Yap, MBBS, PhD, lead investigator at The University of Texas MD Anderson Cancer Center for the CLIO-8221 Phase 1 trial, and presenting author of the poster. “CLIO-8221 represents an innovative dual-payload approach to overcome resistance associated with existing HER2-targeted ADCs. This trial marks an important step in evaluating whether combining topoisomerase 1 and ATR inhibition within a single HER2-targeted ADC can expand treatment possibilities for patients with HER2-expressing solid tumors.” The Phase 1 clinical trial recruitment is ongoing in Australia and the United States, and the company plans to activate sites in China. At ASCO, Callio Therapeutics will present previously disclosed preclinical data (AACR 2026) that support the therapeutic potential of CLIO-8221 and the Phase 1 trial design: By simultaneously delivering a topoisomerase 1 inhibitor (exatecan) and an ATR inhibitor (berzosertib), CLIO-8221 drives direct tumor cell killing at doses that also support a robust bystander effect, achieving superior in vivo efficacy compared to single-payload ADCs CLIO-8221 demonstrated potent anti-tumor activity across varying HER2 expression levels and drove tumor regression after a single dose in both trastuzumab deruxtecan-sensitive and -insensitive models CLIO-8221 exhibited a highly favorable safety profile; it was well-tolerated in non-human primates with no significant adverse effects observed at doses of 70 mg/kg (highest dose tested), establishing a No-Observed-Adverse-Effect Level (NOAEL) significantly higher than that of trastuzumab deruxtecan Phase 1 of the study is a dose escalation with optional dose level expansions, and dose escalation may enroll across HER2-expressing cancers, including cancers that did not respond to or relapsed after trastuzumab deruxtecan treatment Presentation details: Poster/Abstract Title: Phase 1/2 Study of CLIO-8221, a HER2-targeted, dual-payload exatecan and ATR inhibitor antibody-drug conjugate (ADC) in patients with advanced HER2-expressing solid tumors Poster Session : Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology Date & Time : May 30, 2026, 1:30 PM - 4:30 PM CDT Location: McCormick Place, Hall A – Posters and Exhibits Presenter : Timothy A. Yap, MBBS, PhD, The University of Texas MD Anderson Cancer Center Abstract Number: TPS3162 Poster Board: 295b The full abstract is available on the ASCO Annual Meeting website. The poster will be available on the ASCO website on May 30, 2026. About CLIO-8221 HER2 is a clinically validated target for antibody-drug conjugates (ADCs), with multiple approved therapies demonstrating meaningful benefit across tumor types, however, most patients eventually progress on treatment despite retaining HER2 expression. Mechanistic resistance to cytotoxic payloads has emerged as a key reason for treatment failure. CLIO-8221 is a novel, first-in-class dual-payload ADC targeting HER2, designed to address this challenge. CLIO-8221 delivers two mechanistically complementary payloads, a topoisomerase 1 (Topo1) inhibitor and an ATR inhibitor, directly to HER2-expressing tumors. While Topo1 inhibitors have shown strong clinical activity, activation of the DNA damage response following Topo1 inhibitor-induced replication stress represents a potential major driver of resistance. By simultaneously inhibiting Topo1 and blocking the DNA damage response through ATR inhibition, CLIO-8221 is engineered to overcome payload insensitivity and sensitize tumors to Topo1 inhibition. Developed using proprietary linker and ADC platform technologies, CLIO-8221 aims to maximize anti-tumor activity while reducing systemic toxicity, offering the potential for deeper and more durable responses in patients who have progressed on existing HER2-targeted therapies. About Callio Therapeutics Callio Therapeutics is a clinical‑stage company engineering oncology-focused dual-payload ADCs for the next frontier of targeted cancer therapy. Powered by a proprietary platform featuring adaptable, modular linker technology, Callio Therapeutics is developing a focused pipeline of dual-payload ADCs engineered with rational, synergistic payload combinations matched to specific tumor biology and to counter multiple mechanisms of resistance. CLIO-8221, the company’s lead candidate, is a HER2-targeted dual-payload ADC currently being evaluated in a Phase 1 clinical trial. Callio Therapeutics is built on technology and programs licensed from Hummingbird Bioscience, an AI-enabled biotherapeutics company and R&D collaborator. Headquartered in Seattle and Singapore, and backed by top life science investors, Callio Therapeutics is built to discover and deliver, with an experienced team with a track record of success. For more information, visit and follow Callio Therapeutics on LinkedIn. Contacts Media: Crystal Ho media@calliotx.com Ally Stubin – ICR Healthcare Ally.Stubin@ICRHealthcare.com (646) 667-1861 Investors: ir@calliotx.com Stephanie Carrington – ICR Healthcare stephanie.carrington@ICRHealthcare.com (646) 277-1282

美国国立卫生研究院的科学家在分析乳腺癌样本的R-loop全基因组图谱时，意外发现一个位于BRCA1启动子区域的稳定R-loop结构。其存在与患者对PARP抑制剂的敏感性呈显著负相关。这个曾被视作转录副产物的三链核酸结构，此刻正以沉默的方式改写肿瘤治疗的逻辑。它不再是实验室里被忽视的“噪音”，而是癌症基因组中一枚隐藏的开关。 R-loop由一条RNA链与一条DNA链杂交，同时置换出另一条DNA单链，形成独特的RNA:DNA杂合体。在健康细胞中，它参与转录调控、端粒维护和免疫球蛋白类别转换。但一旦失控，便会成为基因组不稳定的源头。一篇发表于《Molecular Therapy Oncology》的综述系统梳理了R-loop在癌症中的三重病理轴：其一，它直接阻碍复制叉前进，诱发DNA双链断裂；其二，它暴露的单链DNA区域易被胞嘧啶脱氨酶攻击，导致突变累积；其三，它通过招募染色质重塑因子，异常沉默或激活关键肿瘤抑制基因。这三条路径并非孤立运作，而是相互交织，在癌细胞内部形成一张精密的破坏网络。 检测技术的局限曾是R-loop研究的最大瓶颈。传统的S9.6抗体免疫荧光法虽然直观，却因抗体对双链RNA的交叉反应而饱受争议。DNA-RNA免疫沉淀测序（DRIP-seq）能够提供全基因组图谱，但分辨率受限于片段化长度，难以定位精确的碱基对。近年来，基于核酸酶切割的R-loop测序技术（如R-ChIP和R-loop CUT&Tag）将分辨率提升至单核苷酸水平，代价是实验流程复杂且对样本质量要求极高。综述作者直言，没有一种方法能同时满足通量、分辨率和特异性。研究者必须根据问题选择工具，否则数据解读可能南辕北辙。 治疗策略的探索正在加速。直接调控R-loop的尝试包括使用核糖核酸酶H1（RNase H1）降解杂合体，或通过小分子稳定RNA:DNA结构来抑制特定致癌基因的转录。但全身性清除R-loop会破坏正常细胞的功能，因为生理性R-loop同样不可或缺。另一条路径更显精妙：合成致死。癌细胞因R-loop积累已处于复制应激的临界状态，若进一步抑制同源重组修复或DNA损伤检查点，便可能触发选择性死亡。PARP抑制剂在BRCA突变乳腺癌中的成功已暗示这一逻辑，而最新临床前数据显示，ATR抑制剂在R-loop高表达的卵巢癌模型中表现出单药活性。然而，生物标志物的缺失让患者分层举步维艰。没有可靠的R-loop定量指标，临床试验无异于盲人摸象。 一把双刃剑，我们究竟能不能用好它？答案或许就藏在多组学数据与AI算法的交叉路口。当转录组、表观基因组和蛋白质组数据被整合进深度学习模型，R-loop的动态变化可能不再是黑箱。已经有团队尝试用图神经网络预测R-loop形成位点与染色质三维结构的共变关系。初步结果显示，某些在正常组织中不稳定的R-loop，在肿瘤中却因染色质环的异常而获得持久性。对于生物医药行业而言，现在不是要不要关注R-loop的问题，而是如何避开技术陷阱、找到真正可转化的切入点。毕竟，一个连检测都还没搞明白的靶点，谈何成药？但反过来，一旦突破，它可能就是下一个浪潮的起点。当AI算法开始解析R-loop与染色质三维结构的共变关系时，或许我们离答案只差一次实验验证的距离。而这次验证，可能就藏在某位研究者今天下午刚跑完的电泳胶上。 结论 R-loop这把双刃剑的锋利程度，取决于我们手中握着什么样的工具。研究团队在综述中反复强调一个核心矛盾：R-loop既是基因组维持正常转录所必需的调控元件，又是驱动肿瘤基因组不稳定的主要源头。这种双重身份的切换，往往只取决于一个碱基的位置、一个染色质环的构象、或者一个复制叉停留的时间差。正因为如此，单纯地将R-loop视为“好”或“坏”的二分法，在生物学意义上毫无价值。 真正的问题在于：当R-loop从生理性调控滑向病理性积累时，那条临界线画在哪里，以及我们能否在它越线之前将其识别出来。 从检测技术的演进来看，这个识别过程远比想象中困难。S9.6抗体作为R-loop研究中最广泛使用的工具，其双链RNA交叉反应问题已困扰领域超过十年。研究团队在综述中毫不避讳地指出，依赖单一抗体得出的结论可能需要重新审视。DRIP-seq虽然提供了全基因组视角，但片段化步骤丢失了R-loop的空间位置信息，让研究者无法判断一个杂合体究竟位于基因启动子、内含子还是远端的增强子区域。 R-ChIP和R-loop CUT&Tag将分辨率推进到单核苷酸级别，代价是实验通量急剧下降，且对细胞起始量的要求让许多临床样本望而却步。这形成了一个尴尬的局面：技术越精确，越不适合真实世界的肿瘤样本；技术越通用，数据噪音越大。研究团队给出的建议不是等待一个完美方法的出现，而是根据具体生物学问题选择最不坏的方案。如果目标是定位某个致癌基因启动子上的R-loop，R-ChIP可能是首选；如果目标是描绘全基因组分布图谱，DRIP-seq仍然是不可替代的起点。 多组学整合的提出，正是为了弥补单一检测技术的先天缺陷。研究团队认为，R-loop的动态调控不能仅靠DNA-RNA杂交体的直接检测来理解，还需要转录组、表观基因组、蛋白质组数据的协同解析。一个R-loop是否具有病理意义，取决于它周围的染色质状态、转录活性、以及DNA修复蛋白的招募情况。例如，同一个R-loop在活跃转录的基因座上可能只是转录过程中的正常中间体，但当它出现在异染色质区域时，就可能引发转录-复制冲突，进而导致DNA双链断裂。 这种上下文依赖的特性，决定了单纯的R-loop丰度测量无法提供临床决策所需的信息。研究团队在综述中列举了肺癌、膀胱癌和前列腺癌中的具体案例，展示了如何通过多组学数据交叉验证来识别具有驱动潜力的R-loop事件。但这些案例也暴露了当前整合方法的短板。不同组学数据之间的维度不匹配，让因果推断变得极其困难。一个R-loop的出现，究竟是导致基因沉默的原因，还是基因沉默后的结果？这个问题在静态数据中几乎无法回答。 治疗策略的探索同样面临这一困境。直接调控R-loop的路径看似直接，实则布满陷阱。RNase H1的过表达可以清除细胞内绝大部分R-loop，但在小鼠模型中导致广泛的转录紊乱和细胞凋亡。因为生理性R-loop在正常细胞中承担着维持转录延伸、保护CpG岛免受甲基化等重要功能。小分子稳定RNA:DNA结构的策略则更危险。一旦选错靶点，可能将原本无害的R-loop变成基因组不稳定的引爆点。研究团队在综述中谨慎地指出，直接调控策略只有在实现空间特异性靶向的前提下才有临床价值，而目前没有任何技术能够做到这一点。 相比之下，合成致死策略展现出更清晰的理论基础：癌细胞因R-loop积累已处于复制应激的高压状态，进一步抑制其DNA损伤修复通路，可以触发选择性死亡。PARP抑制剂在BRCA突变乳腺癌中的成功，从逻辑上验证了这一思路。但研究团队也提醒，PARP抑制剂的疗效与R-loop水平之间的直接关联尚未在临床试验中得到证实。ATR抑制剂在R-loop高表达卵巢癌模型中的单药活性仍停留在临床前阶段。缺乏可靠的生物标志物，让这些策略的临床转化如同在暗夜中航行。方向或许正确，但无法判断是否偏离了航线。 临床转化的障碍不止于技术层面。肿瘤异质性意味着同一个患者的不同病灶，甚至同一个病灶的不同区域，R-loop的丰度和分布可能截然不同。一篇基于循环肿瘤细胞的分析显示，同一患者外周血中不同细胞间的R-loop水平差异可达两个数量级，这让基于单次活检的检测结果失去了代表性。正常组织毒性则是另一道难以绕过的门槛。R-loop在快速增殖的正常组织（如骨髓和肠道上皮）中同样高度活跃，系统性清除或稳定R-loop的干预手段，很可能在杀死肿瘤细胞之前先击垮患者的造血功能。 适应性耐药的问题同样不容忽视。癌细胞在R-loop靶向药物的压力下，可能通过上调RNase H1表达、激活替代修复通路、或者改变转录程序来逃逸治疗压力。研究团队在综述中引用了一项临床前研究的数据：经过连续三轮ATR抑制剂处理后的卵巢癌细胞系，其R-loop水平反而下降至基线以下，表明癌细胞已经找到了绕过药物靶点的生存路径。药代动力学的限制则让问题更加复杂。目前进入临床试验的几款R-loop靶向药物，包括camptothecin衍生物、DHX9抑制剂ATX-559和G4稳定剂CX-5461，均存在半衰期短、组织分布不均、以及血脑屏障穿透力不足等问题。CX-5461在BRCA突变癌症患者中取得14%的部分缓解率，这一数字虽然令人鼓舞，但距离成为标准治疗方案仍有相当距离。 研究团队在综述的展望部分，将希望寄托于两个技术方向：单分子荧光探针和人工智能算法。单分子荧光探针的设计目标，是解决当前检测方法无法实时追踪R-loop动态变化的根本缺陷。如果能够开发出对RNA:DNA杂合体具有高特异性、且能在活细胞中实时成像的荧光探针，研究者将首次获得观察R-loop形成和解离全过程的能力。这将直接回答一个悬而未决的核心问题：R-loop在细胞周期中的寿命究竟有多长？它在复制叉到来之前能否被及时清除？研究团队认为，这一技术突破将从根本上改变R-loop研究的范式，从静态快照转向动态追踪。 人工智能算法则被寄望于解决多组学数据整合中的维度不匹配和因果推断难题。scDART和DeepER等模型已经开始被用于预测R-loop形成位点与染色质三维结构的共变关系。初步结果显示，某些在正常组织中不稳定的R-loop，在肿瘤中因染色质环的异常而获得持久性。这些算法能否从海量多组学数据中提取出具有临床预测价值的特征，将决定R-loop研究能否从基础实验室进入临床决策室。 Figure 1 Molecular mechanisms connecting R-loops with replication stress and DSB, transcription dysregulation, and aberrant RNA processingR-loops are triple-helical nucleic acid structures comprising an RNA:DNA hybrid duplex and a displaced single-stranded DNA molecule. These structures pose dual threats to genomic stability: they stall replication forks by physically obstructing helicase progression and immobilize RNA polymerase II, triggering DNA damage responses and transcriptional arrest. To prevent genomic catastrophe, cellular safeguard mechanisms actively resolve pathological R-loops. Failure of these controls propagates DNA damage, fueling tumor evolution. Key resolution enzymes (including BRCA1/FANCD2, TOP1/ARID1A, RNaseH1, and SETX/DDX1/DHX9) protect genomic integrity;notably, exposed ssDNA can activate and be cleaved by AID. Furthermore, R-loops triggered by TRCs can directly mediate double-strand breaks and single-strand breaks (SSBs). Mutations impairing BRCA1 function weaken homologous recombination (HR), favoring error-prone non-homologous end joining (NHEJ). Persistent R-loops also cause transcriptional dysregulation and promote transcription-associated DSBs. Additionally, mutations in splicing factors like SRSF2 induce RNAPII stalling and increase R-loop formation, leading to aberrant splicing of genes such as PTPMT1, BCL2L1, MDM2, TRA2B, and MKNK2, which alters transcriptional function. Finally, R-loop accumulation driven by DICER1 mutations manifests as gene amplification and chromosomal rearrangements. Figure 3 Multi-omics integration strategy for detecting R-loopsTumor heterogeneity necessitates spatially resolved multi-omics to dissect R-loop dynamics. First, integrating DRIP-seq with GFP-dRH live-cell imaging pinpoints R-loop genomic locations. Second, combined ATAC-seq/H3K27ac-seq profiling reveals R-loop co-occupancy with open chromatin and active enhancers, linking them to epigenetic regulation. Third, spatial transcriptome and Ribo-seq integration builds a multi-layered model from transcription initiation through mRNA distribution to translational output, comprehensively defining R-loop roles within gene networks. This uncovers novel biology obscured in single-dimensional analyses and establishes R-loop-mediated transcription-translation coupling. Finally, S9.6 CoIP/RDProx combined with IP-MS identifies R-loop-associated proteins and interaction networks, yielding actionable therapeutic targets. Figure 4 R-Loops as emerging therapeutic targets in cancerR-loop-targeted anticancer strategies operate through two core mechanisms: left: directly inhibiting key regulators to drive harmful R-loop buildup and replication failure. This includes TOP1/2 inhibitors (CPT, topotecan, belotecan, irinotecan, and its active metabolite SN38);DHX9 inhibitor (ATX-968);and G4 ligands (CX-5461, PDS, Braco-19). Right: taking advantage of synthetic lethality to worsen existing R-loop defects in cancer cells. Examples include combining PARP inhibitors (rucaparib, olaparib, CEP-8983, ABT-888), or ATR inhibitors (ceralasertib, VE-821, VX-970) with TOP1 inhibitors (LMP-400, CBX-12). 爱谱蒂康深耕蛋白质组学多年，现推出第二代阵列扫描全景解析空间蛋白质组技术，以四大核心突破直击临床研究痛点： 1、极简样本需求——单样本仅需3张切片即可完成全维度检测，大幅降低珍贵临床样本消耗，尤其适配组织稀缺型研究场景； 2、广域阵列扫描——单次扫描覆盖3000+像素点（最高达6000+），实现组织切片全覆盖，精准捕捉免疫细胞亚群的空间分布特征和组织微环境的分子表征； 3、深度全景解析力——单像素点蛋白鉴定数高至7000+，配合100μm级分辨率（可升级至细胞级），可完整绘制免疫微环境的分子互作网络； 4、多维数据云平台——可与单细胞转录组、转录因子组、免疫肽组、神经肽组等多维度数据深度整合，精准刻画上述维度数据的空间分布特征； 作为多组学检测分析服务引领者，爱谱蒂康不仅提供蛋白质组学、代谢组学、转录组学等单组学服务，更擅长多组学联合分析。凭借领先的质谱平台、专业的生信团队及全程项目跟进机制，我们已积累丰富的临床高维度多组学研究经验，助力科研团队在肿瘤免疫微环境、代谢性疾病等领域实现突破。 选择爱谱蒂康，即选择从技术局限到创新突破的跨越——我们以单细胞级空间蛋白组技术为基石，以多组学数据云平台为支撑，为您开启精准医学的新时代，让每一份样本都成为通向答案的关键钥匙。 *实际像素数量与样本形状、检测规模和成本有关，以实际评估为准 **实际鉴定数与样本类型、组织形态以及分辨率有关，以实际评估为准 ***实际分辨率与样本大小与像素数量有关，以实际评估为准 在生命科学领域，空间蛋白质组学是理解组织功能和疾病机制的关键。传统的空间蛋白质组学技术，如免疫组化（IHC）和成像质谱（IMC），虽然能够提供单细胞分辨率的蛋白质表达信息，但通常仅限于检测几十种蛋白质。而LCM点阵切割检测方法虽然能够鉴定切片不同区域空间点，但难以实现高分辨率的全组织映射。上海爱谱蒂康生物科技有限公司推出的第二代全景扫描空间蛋白质组学技术，标志着空间多组学领域迈入了新的纪元。该技术以其卓越的全景覆盖能力和μm级分辨率，为解析组织微环境的空间异质性提供了强大的工具。 🌟学术影响力 目前，空间蛋白质组学技术入选Nature Methods发布的"年度十大顶级学术影响力技术"，标志着空间组学技术进入发展的新纪元。 🔍 技术特点 检测能力 支持FFPE样本的全景式空间蛋白检测 检测精度达到微米级水平 已成功绘制肠道和脑组织的空间蛋白定位图谱 应用领域 在组织研究中，该技术可用于： 1、组织空间蛋白质组分析 2、组织免疫肽/新抗原的空间定位研究 3、组织中心到边缘的空间梯度特征分析 4、组织微环境和细胞活性评估 📋 送样要求 样品类型：动物组织FFPE切片 推荐送样量：5片连续切片 具体要求： 切片厚度：5μm或10μm 1张进行HE染色封片 4张连续切片（白片）不封片 载玻片选择防脱材质 建议选择包埋年限较短的切片 运输方式：常温或冰袋运输，建议用切片盒避免变形