A Phase 1b/2 Open-Label Clinical Study to Evaluate the Safety and Efficacy of MK-6070 and Ifinatamab Deruxtecan (I-DXd) in Participants With Relapsed/Refractory Extensive-Stage Small Cell Lung Cancer - MK-6070-002

开始日期2025-03-25

申办/合作机构

Merck Sharp & Dohme LLC

NCT06780137

/ Recruiting临床1/2期

A Phase 1b/2 Open-Label Clinical Study to Evaluate the Safety and Efficacy of MK-6070 and Ifinatamab Deruxtecan (I-DXd) in Participants With Relapsed/Refractory Extensive-Stage Small Cell Lung Cancer

Researchers are looking for new ways to treat people with extensive-stage small cell lung cancer (SCLC) that has relapsed or is refractory. Gocatamig is a new type of immunotherapy that uses a person's immune system to find and destroy cancer cells. Ifinatamab deruxtecan (also known as I-DXd) is a drug which binds to a specific target on cancer cells and delivers treatment to destroy those cells. Durvalumab is a different type of immunotherapy that also destroys cancer cells. Researchers want to know if giving gocatamig, I-DXd, and gocatamig with I-DXd or durvalumab can treat SCLC that did not respond or stopped responding to a prior treatment.
The goals of this study are to learn:
* If gocatamig alone, I-DXd alone, and gocatamig with I-DXd or durvalumab are safe and well tolerated
* If people who receive gocatamig alone, I-DXd alone, and gocatamig with I-DXd or durvalumab have their SCLC get smaller or go away

开始日期2025-02-27

申办/合作机构

Merck Sharp & Dohme LLC

[+1]

NCT04471727

/ Recruiting临床1/2期

A Phase 1/2 Open-label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and Pharmacokinetics of HPN328 Monotherapy and HPN328 With Atezolizumab or Ifinatamab Deruxtecan (I-DXd) in Patients With Advanced Cancers Associated With Expression of Delta-like Canonical Notch Ligand 3 (DLL3).

This study will investigate the maximum tolerated dose, the recommended dose for expansion (RDE), safety, efficacy, and pharmacokinetics of gocatamig alone, gocatamig with Atezolizumab and gocatamig with I-DXd in participants with advanced cancers associated with expression of Delta-like Canonical Notch Ligand 3 (DLL3).

开始日期2020-12-14

申办/合作机构

Harpoon Therapeutics, Inc.

[+1]

100 项与 Gocatamig 相关的临床结果

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100 项与 Gocatamig 相关的转化医学

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100 项与 Gocatamig 相关的专利（医药）

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项与 Gocatamig 相关的文献（医药）

2024-09-04·Molecular cancer therapeutics

HPN328, a Trispecific T Cell–Activating Protein Construct Targeting DLL3-Expressing Solid Tumors

Article

作者: O’Rear, Jessica ; Barath, Manasi ; Yu, Timothy Z. ; Carlin, Kevin ; Aaron, Wade H. ; Hundal, Avneel S. ; Bush, Mabel C. ; Law, Che-Leung ; Wesche, Holger ; Hemmati, Golzar ; Lemon, Bryan D. ; Anand, Banmeet S. ; Santiago, Linda ; Cremin, Michael ; Molloy, Mary E. ; Lin, S.J. ; Valenzuela, Laura B. ; Yu, Stephen ; Patnaik, Purbasa ; Wu, Chi-Heng ; Strobel, Kathryn L. ; Callihan, Evan C. ; Sotelo Rocha, Sony ; Evans, Thomas ; Guerrero, Maria G. ; Lao, Llewelyn ; Sun, Liping L. ; Laurie, Payton ; Austin, Richard J.

Abstract:

Delta-like ligand 3 (DLL3) is expressed in more than 70% of small cell lung cancers (SCLCs) and other neuroendocrine-derived tumor types. SCLC is highly aggressive, and limited therapeutic options lead to poor prognosis for patients. HPN328 is a trispecific T cell–activating construct (TriTAC) consisting of three binding domains: a CD3 binder for T-cell engagement, an albumin binder for half-life extension, and a DLL3 binder for tumor cell engagement. In vitro assays, rodent models, and non-human primates were used to assess the activity of HPN328. HPN328 induces potent dose-dependent killing of DLL3-expressing SCLC cell lines in vitro, concomitant with T-cell activation and cytokine release. In an NCI-H82 xenograft model with established tumors, HPN328 treatment led to T-cell recruitment and anti-tumor activity. In an immunocompetent mouse model expressing a human CD3ε epitope, mice previously treated with HPN328 withstood tumor rechallenge, demonstrating long-term anti-tumor immunity. When repeat doses were administered to cynomolgus monkeys, HPN328 was well tolerated up to 10 mg/kg. Pharmacodynamic changes, such as transient cytokine elevation, were observed, consistent with the expected mechanism of action of T-cell engagers. HPN328 exhibited linear pharmacokinetics in the given dose range with a serum half-life of 78 to 187 hours, supporting weekly or less frequent administration of HPN328 in humans. Preclinical and nonclinical characterization suggests that HPN328 is a highly efficacious, safe, and novel therapeutic candidate. A phase 1/2 clinical trial is currently underway testing safety and efficacy in patients with DLL3-expressing malignancies.

Journal of hematology & oncology

Review

Abstract:

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are, unfortunately, followed by rapid disease recurrence in most patients. Current treatment options are limited, with no therapies specifically approved as third-line or beyond. Delta-like ligand 3 (DLL3), a Notch inhibitory ligand, is an attractive therapeutic target because it is overexpressed on the surface of SCLC cells with minimal to no expression on normal cells. Several DLL3-targeted therapies are being developed for the treatment of SCLC and other neuroendocrine carcinomas, including antibody-drug conjugates (ADCs), T-cell engager (TCE) molecules, and chimeric antigen receptor (CAR) therapies. First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules—tarlatamab (formerly known as AMG 757), BI 764532, and HPN328—and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.

Frontiers in Immunology

Harnessing delta-like ligand 3: bridging biomarker discovery to next-generation immunotherapies in refractory small cell lung cancer

Review

作者: Chen, Xin ; Zhao, Zhenggang ; Guo, Lin ; Feng, Mingqian ; Zuo, Dianbao ; Tang, Jing ; Chen, Guoping ; Ji, Kangkang

Small cell lung cancer (SCLC), accounting for 10–20% of lung cancers, remains one of the most aggressive neuroendocrine malignancies, with fewer than 7% of patients surviving beyond five years. While the addition of immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy has modestly improved outcomes, long-term benefits are limited to a subset of patients, highlighting the critical need for reliable biomarkers and innovative therapies. Delta-like ligand 3 (DLL3), a Notch signaling regulator overexpressed in 70–80% of SCLC tumors, has emerged as a simultaneous biomarker and therapeutic target. This review aims to synthesize recent advances in DLL3-targeted strategies, bridging biomarker-driven diagnostics to next-generation immunotherapies, while addressing clinical challenges and future directions. The 2024 FDA approval of tarlatamab—a bispecific T-cell engager (BiTE) targeting DLL3 and CD3—marks a pivotal advancement, demonstrating improvement in survival in refractory disease. This review examines three key advances reshaping SCLC management: (1) mechanistic links between DLL3-driven tumorigenesis and PD-L1-mediated immunosuppression, (2) clinical progress in antibody-drug conjugates (ADCs) with next-generation payloads (e.g., FZ-AD005), multispecific BiTEs (e.g., HPN328), and engineered CAR-T/NK cells with enhanced metabolic resilience, and (3) precision strategies combining liquid biopsy for dynamic DLL3 profiling with immuno-PET imaging using [89Zr]Zr-DFO-SC16. Emerging synergies, such as combining DLL3-targeted BiTEs with ICIs to amplify T-cell infiltration or reprogramming CAR-T mitochondrial metabolism, further underscore the potential of multimodal approaches. Together, these developments signal a transformative era in SCLC treatment, where molecular diagnostics and engineered immunotherapies converge to address unmet clinical needs.

144

项与 Gocatamig 相关的新闻（医药）

2025-07-07

·ioncology

中肿张力教授团队重磅综述：肺癌新一代免疫治疗

点击上方蓝字关注我们编者按：肺癌仍然是全球癌症相关死亡的主要原因。在过去几十年里，免疫治疗为肺癌治疗领域带来了革命性突破，其中以靶向PD-1/PD-L1和CTLA-4抑制剂为代表的免疫检查点抑制剂显著改善了患者的生存预后。然而，临床实践中仍面临两大关键挑战：部分患者存在原发性耐药（对免疫检查点抑制剂无应答），以及大多数初始应答者最终出现获得性耐药导致疾病复发。针对免疫耐药问题，目前多种具有不同靶点和作用方式的免疫疗法正在肺癌的临床试验中开展。近日，中山大学肿瘤防治中心张力教授团队在顶级期刊Nature Reviews Clinical Oncology发表题为 “The next-generation of immunotherapies for lung cancers”（《肺癌新一代免疫治疗》）的重磅综述。该综述系统总结了肺癌免疫治疗的耐药机制，并全面梳理了新一代免疫治疗策略的最新进展，包括新型免疫检查点调节剂、新型免疫细胞衔接器、过继细胞疗法和治疗性肺癌疫苗等，为肺癌新一代免疫治疗指明了研究方向。通讯作者张力 ▶ 中山大学肿瘤防治中心内科主任导师、肺癌首席专家，博士生导师，二级教授▶ 中国抗癌协会癌症康复与姑息治疗专业委员会主任委员▶ 中国抗癌协会肿瘤药物临床研究专业委员会候任主任委员▶ 中国临床肿瘤学会免疫治疗专家委员会主任委员▶ 中国临床肿瘤学会非小细胞肺癌专家委员会副主任委员▶ 中国临床肿瘤学会肿瘤支持与康复治疗专家委员会副主任委员▶ 广东省医学会临床研究学分会主任委员▶ 广东省临床医学会精准医学分会主任委员第一作者赵珅▶ 副主任医师、副研究员、硕士生导师▶ 中山大学临床医学八年制▶ 广东省临床医学会肺癌精准治疗与临床研究专业委员会秘书▶ 广东省抗癌协会化疗专业委员会青委会委员▶ 2023年CSCO“35位最具潜力青年肿瘤医生”▶ 研究方向：肺癌靶向治疗、免疫治疗的临床及转化研究▶ 主持课题：国家自然科学基金、中国博士后基金、中山大学肿瘤防治中心优秀青年人才项目、中国科协科技智库青年人才计划。赵洪云▶ 教授、主任医师、博士生导师▶ 中山大学肿瘤防治中心I期病房主任、临床研究部副主任▶ 广东省杰出青年医学人才、岭南名医▶ 中山大学肿瘤防治中心高层次人才特殊支持计划“临床医学科学家”▶ 广东省临床医学学会肺癌精准治疗及临床研究专委会主任委员▶ 中国抗癌协会肿瘤药物临床研究专业委员会青年委员会副主任委员▶ 《健康中国2030》肿瘤健康之“肺癌规范化诊疗”项目组专家顾问肿瘤微环境（TME）是由多种细胞、细胞外基质及可溶性成分构成的复杂生态系统，而TME的动态变化是目前抗肿瘤免疫治疗面临的一项重大挑战。根据免疫细胞浸润和功能状态，肺癌的免疫微环境可分为三类:1、免疫炎症型（“热肿瘤”）：以高表达TMB和PD-L1为特征，对免疫检查点抑制剂反应率高，如KRAS突变或驱动基因阴性的非小细胞肺癌。2、免疫荒漠型（“冷肿瘤”）：低表达TMB和PD-L1，对免疫检查点抑制剂应答率较低，如EGFR/ALK突变的非小细胞肺癌。3、免疫排斥型：尽管高表达TMB和PD-L1，但对免疫检查点抑制剂疗效仍较差，如KRAS和STK11/KEAP1/SMARCA4共突变非小细胞肺癌。图1.不同类型的肿瘤微环境这种免疫分型为精准治疗策略的选择提供了重要依据。目前，大量创新性免疫治疗药物已进入临床前和临床研究阶段。新型免疫检查点调节剂抗PD-(L)1抑制剂的临床应用成功极大地推动了免疫检查点调节剂的研发进程。目前，通过免疫检查点调节来增强T细胞抗肿瘤活性的策略主要可分为两大类：一类是联合其他免疫调节靶点以增强治疗效果；另一类是靶向其他免疫检查点分子来补充PD-(L)1阻断的不足。1、PD-(L)1联合靶向治疗策略在增强PD-(L)1阻断效果的策略中，联合抗血管生成治疗以及转化生长因子-β（TGF-β）展现出显著的效果。例如，同时靶向PD-(L)1和VEGF通路的双特异性抗体ivonescimab和同时靶向PD-(L)1 x TGF-β的双特异性抗体SHR-1701。HARMONi-A 3期研究数据显示，ivonescimab联合化疗方案显著延长TKI治疗失败的EGFR突变型NSCLC患者的中位无进展生存时间，推动其在中国获批上市。随后的HARMONi-2研究进一步证实，在PD-L1阳性的初治患者中，ivonescimab单药治疗的客观缓解率显著高于pembrolizumab。目前，同类机制的PM8002（抗PD-L1×VEGF）双特异性抗体也已在NSCLC中显示出初步疗效。在一项针对不可切除III期NSCLC患者的概念验证性2期试验中，SHR-1701显示出良好的疗效和安全性，手术转化率较高。SHR-1701单药治疗在PD-L1阳性、EGFR突变或PD-(L)1获得性耐药的晚期NSCLC患者中也表现出抗肿瘤活性。其他同类药物如JS201和Y101D目前仍处于临床开发早期阶段。2、其他免疫检查点联合策略在补充PD-(L)1阻断的策略中，CTLA-4靶向治疗最具代表性。CTLA-4在效应T细胞和Tregs表面高表达，其阻断可同时增强T细胞活化和减轻免疫抑制。CheckMate 227、CheckMate 9LA和POSEIDON等研究证实，PD-(L)1/CTLA-4联合方案在晚期NSCLC中具有确切的临床获益。为优化治疗策略，多种靶向PD-(L)1×CTLA-4的双特异性抗体，包括volrustomig、cadonilimab、QL1706和erfonrilimab等正在研发。其中，QL1706联合bevacizumab和化疗方案在EGFR-TKI耐药患者中取得了54.8%的客观缓解率和8.5个月的中位无进展生存时间，展现出良好的应用前景。除此之外，新一代CTLA-4靶向药物在克服PD-(L)1耐药方面展现出独特优势。例如，新型靶点保留型抗CTLA4抗体gotistobart，其通过优化pH敏感性来避免溶酶体降解，从而促进CTLA4循环利用。临床前模型显示，该药物能选择性耗竭Treg细胞并降低毒性。在首次人体1/2期试验中，gotistobart单药治疗在抗PD-(L)1抑制剂经治的NSCLC患者，客观缓解率达27%，疾病控制率为82%。目前3期试验正在开展中。除CTLA-4外，LAG-3、CD73和NKG2A等靶点也展现出临床潜力。LAG-3抑制剂relatlimab联合nivolumab在PD-L1阳性非鳞NSCLC一线治疗中显示出优于nivolumab单药的疗效，3期临床试验正在进行。CD73靶向治疗方面，oleclumab联合durvalumab在3期NSCLC维持治疗中显示出优于单药的无进展生存时间获益，3期临床研究正在进行。NKG2A抑制剂monalizumab联合durvalumab在3期NSCLC中显示出协同效应，同样被纳入PACIFIC-9研究评估。在肺癌中发现的其他免疫检查点还包括OX40、4-1BB、TIM3和TIGIT。目前，靶向TIM3和TIGIT抑制剂的多项临床研究正在进行。图2.代表性新型免疫检查点抑制剂及作用机制新型免疫细胞衔接器免疫细胞衔接器是一类通过工程化抗体技术重新定向免疫细胞（特别是T细胞）以特异性识别和清除肿瘤细胞的治疗药物。该领域的开创性药物是靶向CD3和CD19的双特异性T细胞衔接器blinatumomab。典型的T细胞衔接器由两部分组成：一个靶向T细胞表面CD3复合物的结合域和一个靶向肿瘤特异性抗原（TSA）的结合域，通过同时结合这两种分子激活T细胞介导的细胞毒性。然而，大多数实体瘤主要表达肿瘤相关抗原（TAA），这些抗原在正常组织中也有不同程度表达。因此，如何平衡抗肿瘤活性和靶向/非靶向毒性是开发针对实体瘤的免疫细胞衔接器面临的主要挑战。目前主要通过以下三种策略解决这一难题：1、提高肿瘤选择性：具体方法包括：①选择更具肿瘤特异性的靶抗原，如DLL3、Claudin18.2、前列腺特异性膜抗原（PSMA）和EGFRv3等；②同时靶向多个肿瘤抗原；③采用XmAb等技术增加抗原结合价数；④靶向肽-MHC复合物；⑤开发需要肿瘤微环境特异性激活的前药。例如，同时靶向CD3和DLL3的双特异性抗体tarlatamab。DLL3在神经内分泌肿瘤中高表达而在正常组织中表达受限，是理想的治疗靶点。DeLLphi-301研究显示，tarlatamab在经治SCLC患者中的客观缓解率达32%-40%，中位无进展生存时间为3.9-4.9个月。目前正在开展多项3期临床试验（DeLLphi-304、DeLLphi-305和DeLLphi-306）。其他针对肺癌开发的T细胞衔接器包括靶向CEA的RO6958688、靶向SSTR2的tidutamab、靶向PSMA的CC-1和靶向PSCA的GEM3PSCA等。靶向肽-MHC复合物的免疫动员单克隆T细胞受体（ImmTAC）技术则代表了新一代T细胞衔接器设计。与常规双特异性抗体不同，ImmTAC通过工程化TCR识别由MHC分子呈递的肿瘤抗原肽，可靶向细胞内抗原。brenetafusp是靶向PRAME的ImmTAC，目前正在进行用于治疗PRAME阳性晚期实体瘤的1/2期研究和黑色素瘤的3期试验。此外，最新研究策略聚焦于靶向由突变癌基因产生的新抗原，将进一步提升T细胞衔接器的肿瘤特异性与抗肿瘤活性。2、调节T细胞活化水平：具体方法包括：①调整结合亲和力；②优化分子结构；③开发条件性激活系统等。三特异性T细胞激活构建体（TriTAC）是该领域的代表性分子，其特点是包含CD3结合域、人血清白蛋白结合域和肿瘤抗原结合。HPN328（MK-6070）是一种靶向CD3/HSA/DLL3的TriTAC，正在SCLC和其他DLL3过表达肿瘤患者中进行1/2期临床试验。3、靶向其他免疫效应细胞：除T细胞外，靶向NK细胞和髓系细胞的衔接器也逐渐展现出临床潜力。AFM24是一种靶向CD16A和EGFR的双特异性NK细胞衔接器，其联合atezolizumab在经治EGFR野生型NSCLC患者中显示出26.7%的客观缓解率。免疫刺激抗体偶联物（ISAC）则是髓系细胞衔接器的代表，它将靶向抗体与免疫刺激剂（如TLR或STING激动剂）偶联，通过重编程肿瘤相关巨噬细胞发挥抗肿瘤作用。已在临床试验中的代表性ISACs包括TAC-001(抗CD22抗体与TLR9激动剂)和TAK-500(抗CCR2抗体与STING激动剂)等。过继细胞疗法肺癌领域的过继细胞疗法发展较为缓慢。目前，研究最多的有嵌合抗原受体（CAR）T细胞疗法、T细胞受体(TCR)T细胞疗法和肿瘤浸润淋巴细胞(TIL)疗法。1、CAR-T细胞疗法在肺癌治疗领域，研究者已开发出靶向EGFR、MUC1、间皮素、PSCA、CEA、HER2、GPC3、ROR1和PD-L1等多种CAR-T细胞产品。临床研究显示，EGFR CAR-T和间皮素CAR-T在EGFR阳性肿瘤患者以及恶性胸膜间皮瘤中显示出一定的临床活性。然而，ROR1 CAR-T和PD-L1 CAR-T由于治疗窗较窄和毒性问题，其临床开发已被终止。CAR-T疗法在肺癌治疗中也面临诸多挑战。首先，肺癌相关抗原多为肿瘤相关抗原而非肿瘤特异性抗原，在正常组织中也有表达，导致"on-target, off-tumor"毒性风险。其次，肿瘤异质性使得同一肿瘤内可能存在不同抗原表达亚群，增加了治疗难度。此外，TME的免疫抑制特性、物理屏障阻碍CAR-T细胞浸润、制备工艺复杂且成本高昂等因素都限制了CAR-T疗法的临床应用。为应对这些挑战，下一代CAR-T疗法正在发展中。2、TCR-T细胞疗法与CAR-T细胞相比，TCR-T细胞具有可靶向细胞内抗原、抗原识别灵敏度更高、信号传导更接近生理水平等优势。靶向黑色素瘤相关抗原4（MAGE-A4）的TCR-T疗法ADP-A2M4是首个获得FDA批准用于治疗不可切除或转移性滑膜肉瘤的TCR-T产品。其改良版ADP-A2M4CD8在HLA-A02阳性实体瘤（包括NSCLC）患者中显示出35.6%的客观缓解率。其他在研的TCR-T疗法还包括靶向KRAS G12V和TP53 R175H等驱动基因突变的产品。TCR-T疗法的主要限制包括HLA限制性、靶抗原局限性和安全性风险。为解决这些问题，研究者开发了多种创新方法，如TCR融合构建体通过改造信号传导域实现HLA非依赖识别；基于患者肿瘤突变谱设计新抗原特异性TCR-T细胞的个性化治疗方案；以及使用CRISPR/Cas9基因编辑技术精确调控TCR表达等。3、TIL治疗TIL疗法利用从肿瘤组织分离的天然肿瘤反应性T细胞，经体外扩增后回输患者体内。lifileucel在NSCLC中的2期临床研究显示，单药治疗PD-1耐药患者的客观缓解率为21.4%，与pembrolizumab联合治疗初治患者的客观缓解率达64.3%。然而，TIL疗法面临制备工艺复杂、最佳细胞亚群不确定和支持性治疗毒性等挑战。新一代TIL技术通过表达膜结合IL-15（如OBX-115）、基因修饰（如PD-1敲除的IOV-4001）以及优化快速扩增工艺等方法，显著提升了治疗效果和安全性。治疗性癌症疫苗根据靶向抗原的特性，肺癌治疗性疫苗可分为三类：靶向共享抗原的疫苗、个性化抗原疫苗和匿名抗原疫苗。1、靶向共享抗原的疫苗早期开发的疫苗多采用TAA如MUC1、MAGE-A3和NY-ESO-1等作为靶点。由于这些抗原在肺癌发生发展中的生物学功能不明确，其在3期随机对照试验中均未能显著改善患者生存。相比之下，靶向功能明确的抗原疫苗展现出更好的临床前景。CIMAvax-EGF作为靶向EGF的肽疫苗，在3期试验中作为NSCLC一线化疗后的维持治疗，显著延长了患者总生存期。PD-(L)1-Vaxx则通过模拟PD-1的B细胞表位诱导多克隆抗PD-1抗体产生，在PD-(L)1抑制剂耐药的NSCLC患者中观察到客观缓解。近年来，共享抗原疫苗的研发策略主要聚焦于两个方向：多靶点疫苗设计和新型树突状细胞激活策略。OSE2101作为靶向CEA、p53、HER-2、MAGE-A2和MAGE-A3五种抗原的多价疫苗，在3期研究中显著改善了经治HLA-A2阳性NSCLC患者的总生存。目前正在开展OSE2101联合多西他赛治疗免疫耐药NSCLC的3期研究。基于mRNA技术的多靶点疫苗如BI1361849（编码6种NSCLC相关抗原）、mRNA-4359（靶向PD-L1和IDO1）和BNT116（靶向6种TAA）也显示出良好的安全性和初步疗效。值得注意的是，新一代疫苗更倾向于靶向TSA而非TAA，如靶向KRAS G12D/G12R突变的ELI-002 2P疫苗和靶向EGFR突变的ABOR2013 mRNA疫苗，这些疫苗在早期临床试验中已展现出令人鼓舞的抗肿瘤活性。2、个性化抗原疫苗个性化抗原疫苗代表了精准医疗在肿瘤疫苗领域的实践。这类疫苗基于患者个体肿瘤突变谱，通过生物信息学预测免疫原性新抗原进行定制化设计。V940（mRNA-4157）可编码多达34种个体化新抗原，在1期研究中成功诱导了新抗原特异性T细胞应答，目前正在开展治疗NSCLC的3期临床试验。然而，这类疫苗面临诸多挑战：新抗原预测算法的准确性受限于肿瘤异质性和微环境复杂性；疫苗制备周期长（通常需要4-8周）；监管审批流程复杂等。这些因素都限制了其临床转化效率。3、匿名抗原疫苗匿名抗原疫苗采用同种异体肿瘤细胞或基因修饰的树突状细胞作为抗原来源，理论上能够涵盖更全面的肿瘤抗原谱。Belagenpumatucel-L、Tergenpumatucel-L、Viagenpumatucel-L等同种异体肿瘤细胞的疫苗在早期研究中显示出一定疗效，但在3期试验中未能证实生存获益。树突状细胞疫苗如Ad-CCL21-DC和DCVAC/LuCa通过不同机制增强抗肿瘤免疫，在1/2期研究中显示出延长无进展生存时间的效果。此外，Fms样酪氨酸激酶3配体（Flt3L）等树突状细胞激动剂联合局部放疗，在部分NSCLC患者中诱发了远隔效应，为联合治疗策略提供了新思路。本综述主要梳理了肺癌免疫治疗领域的最新进展，概括上述新型治疗策略的作用机制和临床转化前景。通过对现有研究成果的整合分析，首次基于分子机制和临床应用提供新型免疫治疗发展的全面视角，将有助于推动肺癌精准免疫治疗的研发及临床转化。中山大学肿瘤防治中心赵珅副主任医师、赵洪云教授为该文章的共同第一作者，中山大学肿瘤防治中心张力教授为该文章的通讯作者。（来源：中山大学肿瘤防治中心）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

免疫疗法CSCO会议疫苗

2025-06-19

·氨基观察

DLL3卷到了三抗

氨基观察-创新药组原创出品作者 | 沙晓微围绕DLL3（Delta样配体3）靶点的竞争，日趋激烈，已经从双抗进入到三抗时代。罗氏的RO7616789、默沙东的MK-6070，都是已进入临床阶段的靶向DLL3的三抗。如今，国内企业也在加入这场竞争。在今年的ASCO大会上，泽璟制药的DLL3三特异性抗体药物ZG006引发了市场关注。ZG006能否成功尚不得而知，但它仍然预示着，随着市场对DLL3靶点兴趣度的增加，对技术和理念的要求也将变得更高。/ 01 /三抗的野心DLL3靶点的热度，是由双抗带动起来的，其中的主角是安进的Tarlatamab。2024年5月16日，FDA加速批准了Tarlatamab用于治疗广泛期小细胞肺癌（ES-SCLC）患者。相比TCE，三抗则通过“共刺激”或“多价结合”的设计，试图在稳定安全性的前提下提高抗肿瘤疗效。从分子结构上看，ZG006是一种靶向CD3与两个不同DLL3表位的三特异性抗体。其设计理念在于，通过不同DLL3表位的识别实现双位点识别。在此基础上，抗CD3结合T细胞，将T细胞拉近肿瘤细胞，并利用T细胞特异性杀伤肿瘤细胞。这样的药物设计使得在低表达肿瘤背景下也能形成稳定的整合。ZG006的“双重靶向+单点激活”设计在稳定安全性的前提下提高疗效，同时降低非特异性T细胞活化风险。除了泽璟制药的ZG006，罗氏的RO7616789以及默沙东的MK-6070都是已进入临床阶段的靶向DLL3的三特异性抗体。其中，MK-6070是默沙东斥资6.8亿美金收购Harpoon Therapeutics，所获得的一款靶向DLL3/CD3/Ablumin的三抗。与ZG006不同的是，其靶向DLL3的抗体为纳米抗体，结合CD3的抗体为scFv形式，而Ablumin的加入目的是为了延长半衰期。/ 02 /未来谁能脱颖而出三抗能否脱颖而出还不得而知，但充分说明了市场对于DLL3的期待。DLL3作为一种Notch抑制配体，其过表达可促进小细胞肺癌细胞的生长及迁移侵袭能力，还参与影响肿瘤对铂类化疗的耐药性。超过80%的SCLC和其他高级神经内分泌癌（NEC）细胞表面过表达DLL3蛋白，这种与正常细胞差异表达及定位特征使其成为SCLC的重要治疗靶点。考虑到SCLC当前有效疗法稀缺，自然也会吸引药企不断入局。在DLL3靶点上，不仅有TCE的竞争， ADC的表现同样不可忽视。提到DLL3的ADC药物，都会想到艾伯维的Rova-T。早期临床研究结果出色，使其直接跳过二期临床开展大规模的三期实验，但最终未能成功闯关。艾伯维58亿美元的教训，并没有阻挡DLL3在ADC领域的前进。就在今年5月16日，恒瑞医药登记了一项DLL3 ADC药物SHR-4849，并宣布启动一项联合其他抗肿瘤药物在恶性实体瘤患者的多中心、开放标签的二期临床研究。在早期临床试验中，11位可评估的SCLC患者中，SHR-4849取得73%的客观缓解率（ORR），且安全性较好。再鼎医药的DLL3 ADC药物ZL-1310同样表现喜人。刚刚落幕的ASCO 2025大会上，再鼎医药公布了ZL-1310治疗ES-SCLC全球1a/1b期临床数据。在74例可评估患者中，ORR达67%，并在22例存在脑转移患者中观察到68%的ORR。可以说，在DLL3这个“老”靶点上，技术迭代带来的惊喜会一直存在。当然，对于部分入局者来说，如果实力不够，也可能意味着被淘汰。PS：欢迎扫描下方二维码，添加氨基君微信号交流。

抗体药物偶联物ASCO会议临床2期免疫疗法加速审批

2025-06-19

·PipelineReview

IDeate-Prostate01 Phase 3 Trial of Ifinatamab Deruxtecan Initiated in Patients with Pretreated Metastatic Castration-Resistant Prostate Cancer

BASKING RIDGE, NJ & RAHWAY, NJ, USA I June 18, 2025 I The first patient has been dosed in the IDeate-Prostate01 phase 3 trial evaluating the efficacy and safety of investigational ifinatamab deruxtecan (I-DXd) versus docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC) with disease progression during or after treatment with an androgen receptor pathway inhibitor. Ifinatamab deruxtecan is a specifically engineered, potential first-in-class B7-H3 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed by Daiichi Sankyo and Merck (NYSE: MRK), known as MSD outside of the United States and Canada. While localized prostate cancer has a five-year survival rate of more than 90%, survival decreases to 31% in the advanced or metastatic stage. 1 Current standard of care for patients with mCRPC includes treatment with androgen receptor pathway inhibitors followed by taxane-based chemotherapy. 2-5 However, due to poor prognosis associated with previously treated mCRPC, many patients do not receive subsequent therapy, reinforcing the need for new approaches to improve outcomes. 6 “Despite the emergence of new therapies, the current treatment landscape for patients with metastatic castration-resistant prostate cancer is challenging, and there is a need for new treatments,” said Mark Rutstein, MD, Head, Therapeutic Area Oncology Development, Daiichi Sankyo. “Following the promising results seen in our earlier phase trial, IDeate-Prostate01 has been initiated to evaluate whether ifinatamab deruxtecan may replace standard taxane-based chemotherapy as a potential treatment strategy in patients with metastatic castration-resistant prostate cancer with disease progression during or after treatment with androgen receptor pathway inhibitors.” “IDeate-Prostate01 marks the initiation of the third pivotal trial in the ifinatamab deruxtecan development program and reinforces our commitment to addressing critical unmet needs for patients,” said Marjorie Green, MD, Senior Vice President and Head of Oncology, Global Clinical Development, Merck Research Laboratories. “Our continued progress in the exploration of this potential first-in-class B7-H3 antibody drug conjugate in collaboration with Daiichi Sankyo, speaks to our pursuit of novel science in the hopes of making a difference for patients in need of new options.” The initiation of IDeate-Prostate01 is based on results from the IDeate-PanTumor01 phase 1/2 trial previously presented at the 2022 and 2023 European Society of Medical Oncology (ESMO) Congresses where ifinatamab deruxtecan showed promising responses in heavily pretreated patients with mCRPC. About the IDeate-Prostate01 Trial IDeate-Prostate01 is a multicenter, open-label, randomized phase 3 trial evaluating the safety and efficacy of ifinatamab deruxtecan (12 mg/kg) versus docetaxel (75 mg/m 2 ) plus corticosteroid in patients with mCRPC. Eligible patients must have received prior treatment with one or two androgen receptor pathway inhibitors and experienced disease progression during or after at least eight weeks of treatment. The dual primary endpoints of IDeate-Prostate01 are overall survival and radiographic progression-free survival. Secondary endpoints include objective response rate, time to first subsequent therapy, duration of response, time to pain progression, time to prostate-specific antigen (PSA) progression, PSA response, time to first symptomatic skeletal-related event and safety. IDeate-Prostate01 will enroll approximately 1,440 patients across Asia, Europe, North America and Oceania. For more information, please visit ClinicalTrials.gov . About Metastatic Castration-Resistant Prostate Cancer Prostate cancer is the second most common cancer in men, and the fifth leading cause of cancer death in men worldwide. 7 Nearly 1.5 million prostate cancer cases were diagnosed in 2022, with approximately 400,000 deaths globally. 7 While localized prostate cancer has a five-year survival rate of more than 90%, survival decreases to 31% in advanced or metastatic stage. 1 Approximately 10% to 20% of early-stage prostate cancer cases progress to metastatic disease within five years of treatment on hormonal therapies such as androgen deprivation therapy. 8,9 Current standard of care for patients with mCRPC includes treatment with androgen receptor pathway inhibitors followed by taxane-based chemotherapy. However, due to poor prognosis associated with previously treated mCRPC, many patients do not receive subsequent therapy, reinforcing the need for new approaches to improve outcomes. 6 About B7-H3 B7-H3 is a transmembrane protein that belongs to the B7 family of proteins, which bind to the CD28 family of receptors that includes PD-1. 10,11 B7-H3 is overexpressed in a wide range of cancer types, including mCRPC and its overexpression has been shown to correlate with poor prognosis, making B7-H3 a promising therapeutic target. 12-15 There are currently no B7-H3 directed medicines approved for the treatment of any cancer. About Ifinatamab Deruxtecan Ifinatamab deruxtecan (I-DXd) is an investigational potential first-in-class B7-H3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ifinatamab deruxtecan is comprised of a humanized anti-B7-H3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. Ifinatamab deruxtecan has been granted orphan drug designation by the U.S. Food and Drug Administration, European Commission, Japan Ministry of Health, Labour and Welfare and Taiwan Food and Drug Administration for the treatment of small cell lung cancer. About the Ifinatamab Deruxtecan Clinical Development Program A comprehensive global clinical development program is underway evaluating the efficacy and safety of ifinatamab deruxtecan across multiple B7-H3 targetable cancers. Trials in combination with other anticancer treatments also are underway. About the Daiichi Sankyo and Merck Collaboration Daiichi Sankyo and Merck entered into a global collaboration in October 2023 to jointly develop and commercialize patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug deruxtecan (R-DXd), except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply. In August 2024 , the global co-development and co-commercialization agreement was expanded to include gocatamig (MK-6070/DS3280), which the companies will jointly develop and commercialize worldwide, except in Japan where Merck will maintain exclusive rights. Merck will be solely responsible for manufacturing and supply for gocatamig. About the ADC Portfolio of Daiichi Sankyo The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo. The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU ® , a HER2 directed ADC, and DATROWAY ® , a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc, Rahway, NJ, USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo. The second consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform. Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established. About Daiichi Sankyo Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical needs. For more information, please visit www.daiichisankyo.com . Merck’s Focus on Cancer Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www-merck-com.libproxy1.nus.edu.sg/research/oncology . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter) , Facebook , Instagram , YouTube and LinkedIn . References: SOURCE: Merck

临床3期孤儿药引进/卖出临床结果抗体药物偶联物

100 项与 Gocatamig 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
广泛期小细胞肺癌	临床2期	美国	Merck Sharp & Dohme LLC	2025-02-27
广泛期小细胞肺癌	临床2期	日本	Merck Sharp & Dohme LLC	2025-02-27
广泛期小细胞肺癌	临床2期	澳大利亚	Merck Sharp & Dohme LLC	2025-02-27
广泛期小细胞肺癌	临床2期	智利	Merck Sharp & Dohme LLC	2025-02-27
广泛期小细胞肺癌	临床2期	以色列	Merck Sharp & Dohme LLC	2025-02-27
广泛期小细胞肺癌	临床2期	韩国	Merck Sharp & Dohme LLC	2025-02-27
广泛期小细胞肺癌	临床2期	西班牙	Merck Sharp & Dohme LLC	2025-02-27
广泛期小细胞肺癌	临床2期	土耳其	Merck Sharp & Dohme LLC	2025-02-27
晚期癌症	临床2期	美国	Harpoon Therapeutics, Inc.	2020-12-14
神经内分泌癌	临床2期	美国	Harpoon Therapeutics, Inc.	2020-12-14

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04471727 (WCLC2024) 人工标引	临床1/2期	小细胞肺癌 DLL3 expression	49	MK-6070 IV weekly	襯艱網鏇憲繭襯齋衊獵(鑰糧蓋夢窪築築觸淵構) = 觸製衊願淵廠觸蓋襯築壓鹹鏇鏇衊繭鏇壓廠淵 (簾積構淵壓願窪顧蓋選, 19 ~ 58) 更多	积极	2024-09-09
NCT04471727 (WCLC2024) 人工标引	临床1/2期	小细胞肺癌 DLL3 expression	49	MK-6070 Q2W	襯艱網鏇憲繭襯齋衊獵(鑰糧蓋夢窪築築觸淵構) = 壓範衊壓艱蓋顧壓願襯壓鹹鏇鏇衊繭鏇壓廠淵 (簾積構淵壓願窪顧蓋選, 5 ~ 42) 更多	积极	2024-09-09
NCT04471727 (ASCO2024) 人工标引	临床1/2期	小细胞肺癌 \| 神经内分泌肿瘤 DLL3 Expression	86	HPN328 1 mg priming dose with 12 or 24 mg target doses QW or Q2W	鏇蓋餘積積醖醖廠鏇鹽(衊選鑰顧網構選築鏇顧) = Treatment-related AEs in ≥ 10% of pts included CRS (59% [30% G1, 26% G2, 3% G3+]), dysgeusia (36%), fatigue (34%), diarrhea (19%), nausea (17%), vomiting (14%), decreased appetite and decreased neutrophil count (13% each), and weight decreased (11%). 衊鹽繭鹹簾顧壓淵顧鏇 (鬱夢繭願鹹鬱構構衊選 ) 更多	积极	2024-05-24
NCT04471727 (ESMO 12023 \| ESMO 22023) 人工标引	临床1/2期	小细胞肺癌 \| 神经内分泌肿瘤	44	HPN328	餘夢鑰艱襯艱構繭觸憲(築襯鏇壓範鏇獵淵齋齋) = in >10% of pts included CRS (46%), fatigue (23%), dysgeusia (21%), nausea (18%), pyrexia and vomiting (16% each), and anemia (11%). 製簾積鏇衊築觸壓衊鏇 (積夢鬱糧遞範觸願範積 ) 更多	积极	2023-10-23
NCT04471727 (ASCO2022) 人工标引	临床1/2期	小细胞肺癌 \| 神经内分泌肿瘤	16	HPN 328	夢襯願餘鹽衊鹹築襯夢(憲選夢衊憲鑰觸壓糧觸) = 製鹽願壓簾觸廠衊製夢鬱廠餘製觸積願願觸顧 (積壓醖願襯窪蓋簾憲顧 ) 更多	积极	2022-06-02