HER3 x HER2 Biclonics、Immunoglobulin g1, bispecific, anti-(human epidermal growth factor receptors, her2 and her3) (humanized clone mcla-128 .gamma.1-chain), disulfide with humanized clone mcla-128 light chain, dimer、Mcla-128 (igg1 bispecific antibody with enhanced antibody-dependent cell-mediated cytotoxicity (adcc) activity targeting her2 and her3 receptors.)

+ [8]

靶点

HER2 x HER3

作用方式

拮抗剂

作用机制

HER2拮抗剂(受体蛋白酪氨酸激酶 erbB-2拮抗剂)、HER3拮抗剂(受体酪氨酸蛋白激酶erbB-3拮抗剂)

治疗领域

肿瘤消化系统疾病内分泌与代谢疾病+ [2]

在研适应症

NRG1 融合的胰腺腺癌NRG1融合阳性非小细胞肺癌不能切除的胆管癌+ [2]

非在研适应症

ER阳性HER2低表达乳腺癌转移性去势抵抗性前列腺癌HER2阳性转移性乳腺癌

原研机构

Merus NV

在研机构

Partner Therapeutics, Inc.

Merus NV

非在研机构-

权益机构

Partner Therapeutics, Inc.

Merus NV

最高研发阶段批准上市

首次获批日期

美国 (2024-12-04),

NRG1 融合的胰腺腺癌NRG1融合阳性非小细胞肺癌

最高研发阶段(中国)无进展

特殊审评优先审评 (美国)、突破性疗法 (美国)、加速批准 (美国)、孤儿药 (美国)

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结构/序列

Sequence Code 43197L

来源: *****

Sequence Code 26101535H

来源: *****

Sequence Code 315583329H

来源: *****

关联

项与泽诺库珠单抗相关的临床试验

NCT05588609

/ Terminated临床2期

A Phase 2 Study Evaluating Activity of Zenocutuzumab (MCLA-128) in Patients With or Without Molecularly Defined Cancers

This is a Phase II, open-label, 2-arm, multicenter, international study designed to evaluate the efficacy of zenocutuzumab alone or in combination in patients with the following diagnoses:
Group A: NRG1+ NSCLC Group B: mCRPC

开始日期2022-11-17

申办/合作机构

Merus NV

NCT03321981

/ Completed临床2期

Phase 2 Study of MCLA-128-based Combinations in Metastatic Breast Cancer (MBC): MCLA-128/Trastuzumab/Chemotherapy in HER2-positive MBC and MCLA-128/Endocrine Therapy in Estrogen Receptor Positive and Low HER2 Expression MBC

A Phase 2, open-label, multicenter international study will be performed to evaluate the efficacy of MCLA-128-based combinations. Three combination treatments will be evaluated, two in Cohort 1 and one in Cohort 2.
MCLA-128 (zenocutuzumab) is given in combinations in two metastatic breast cancer (MBC) populations, Human Epidermal Growth Factor Receptor (HER) 2-positive/amplified (Cohort 1) and Estrogen Receptor-positive/low HER2 expression (Cohort2).
Two combinations treatments will be evaluated in Cohort 1, the doublet and triplet. Initially zenocutuzumab is given in combination with trastuzumab in the doublet. After the safety of the doublet has been assessed in 4-6 patients, MCLA-128 is given in combination with trastuzumab and vinorelbine in the triplet, in parallel to the efficacy expansion of the doublet.
The doublet and triplet combinations are both evaluated in two steps with an initial safety run-in followed by a cohort efficacy expansion. In total up to 40 patients evaluable for efficacy are included in both the doublet and triplet.
In Cohort 2 zenocutuzumab is administered in combination with the same previous endocrine therapy on which progressive disease is radiologically documented. A total of up to 40 patients evaluable for efficacy are included in the Cohort 2.

开始日期2018-01-15

申办/合作机构

Merus NV

NCT02912949

/ Active, not recruiting临床2期

A Phase I/II Study of MCLA-128, a Full Length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients With Solid Tumors (eNRGy)

This is a Phase I/II, open-label, multi-center, multi-national, dose escalation, single agent study to assess the safety, tolerability, PK, PD, immunogenicity and anti-tumor activity of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion (eNRGy)

开始日期2015-01-01

申办/合作机构

Partner Therapeutics, Inc.

100 项与泽诺库珠单抗相关的临床结果

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100 项与泽诺库珠单抗相关的转化医学

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100 项与泽诺库珠单抗相关的专利（医药）

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项与泽诺库珠单抗相关的文献（医药）

2026-04-02·MOLECULAR CANCER THERAPEUTICS

Targeting Tumor Microenvironment–Derived NRG1-HER2/3 Signaling with Zenocutuzumab Restores Sensitivity to AR Inhibition in PTEN Wild-type Prostate Cancer

Article

作者: Mao, Ninghui ; Chang, Qing ; Salsabeel, Nazifa ; Carver, Brett S. ; de Stanchina, Elisa ; Lee, Young Sun ; Shinder, Brian M. ; Chen, Xiaoping ; Gopalan, Anuradha ; Sawyers, Charles L. ; Kaur, Harmanpreet ; Zhang, Zeda

Abstract:

Investigating the mechanisms of acquired resistance to antiandrogens remains a critical clinical need as patients with prostate cancer inevitably develop resistance to androgen receptor (AR)–targeted therapies. Previously, we demonstrated that neuregulin 1 (NRG1) derived from cancer-associated fibroblasts (CAF) promotes antiandrogen resistance through human epidermal growth factor receptor 3 (HER3)–AKT signaling. In this study, we sought to further dissect the molecular context in which NRG1-induced PI3K signaling activation plays a dominant role in driving resistance and evaluate whether targeting HER2/3 dimerization can influence sensitivity to AR inhibition. IHC analysis of radical prostatectomy specimens from patients with prostate cancer treated with or without neoadjuvant hormonal therapy shows that NRG1 was significantly upregulated following AR inhibition, independent of PTEN status. However, we found that stimulation with recombinant NRG1 or CAF-conditioned media induced resistance to AR inhibition only in PTEN wild-type prostate cancer cells and not in PTEN-deficient cells. Selective inhibition of NRG1 using the clinical-grade bispecific humanized immunoglobulin G1, zenocutuzumab (Zeno, MCLA-128), restored sensitivity to AR-targeted therapies in PTEN wild-type tumors, demonstrating its efficacy as a potential therapeutic agent to block the effects of NRG1. In the context of PTEN loss and AR inhibitor resistance, Zeno did not restore sensitivity. These findings highlight the critical molecular context in which tumor microenvironment–derived NRG1 affects responsiveness to AR inhibition and suggest that targeting NRG1 is a promising strategy for overcoming resistance to androgen blockade in PTEN wild-type prostate cancers.

2026-02-01·IEEE Transactions on Cybernetics

ε-Dependent/Independent Dynamic Event-Triggered Control of Switched Two-Time-Scale Systems

Article

作者: Wang, Yan-Wu ; Zeng, Ze-Hong ; Xiao, Jiang-Wen ; Liu, Xiao-Kang

This article investigates the event-triggered composite control problem for switched two-time-scale systems (TTSSs). First, the stabilization problem of switched TTSSs under switching composite control is addressed. Unlike existing results that require the singular perturbation parameter (SPP) to be sufficiently small or to satisfy specific linear matrix inequality conditions, an explicit upper bound of the SPP is derived. Then, both SPP-dependent and SPP-independent dynamic event-triggered mechanisms are developed to reduce the computational burden associated with control signal updates in switched TTSSs. These mechanisms are novel in that they incorporate the boundary layer system and explicitly balance the fast and slow time-scale dynamics. Furthermore, two sufficient stability conditions are established: one concerning the upper bound of the SPP and the other concerning the mode-dependent average dwell time, ensuring the stability of switched TTSSs under the respective mechanisms. In addition, Zeno's behavior is excluded in both cases. Finally, three numerical examples, including a comparative study, are provided to demonstrate the effectiveness and advantages of the proposed results.

2025-12-31·mAbs

Antibodies to watch in 2025

Review

作者: Kapoor, Vaishali ; Crescioli, Silvia ; Kaplon, Hélène ; Reichert, Janice M. ; Visweswaraiah, Jyothsna ; Wang, Lin

The commercial development of antibody therapeutics is a global enterprise involving thousands of biopharmaceutical firms and supporting service organizations. To date, their combined efforts have resulted in over 200 marketed antibody therapeutics and a pipeline of nearly 1,400 investigational product candidates that are undergoing evaluation in clinical studies as treatments for a wide variety of diseases. Here, we discuss key events in antibody therapeutics development that occurred during 2024 and forecast key events related to the late-stage clinical pipeline that may occur in 2025. In particular, we report on 21 antibody therapeutics granted a first approval in at least one country or region during 2024, including bispecific antibodies tarlatamab (IMDELLTRA®), zanidatamab (Ziihera®), zenocutuzumab (BIZENGRI®), odronextamab (Ordspono®), ivonescimab (®), and antibody-drug conjugate (ADC) sacituzumab tirumotecan (®). We also discuss 30 investigational antibody therapeutics for which marketing applications were undergoing review by at least one regulatory agency, as of our last update on December 9, 2024, including ADCs datopotamab deruxtecan, telisotuzumab vedotin, patritumab deruxtecan, trastuzumab botidotin, becotatug vedotin, and trastuzumab rezetecan. Of 178 antibody therapeutics we include in the late-stage pipeline, we summarize key data for 18 for which marketing applications may be submitted by the end of 2025, such as bi- or multispecific antibodies denecimig, sonelokimab, erfonrilimab, and anbenitamab. Key trends in the development and approval of antibody formats such as bispecifics and ADCs, as well as clinical-phase transition and global approval success rates for these antibody formats, are reported.

190

项与泽诺库珠单抗相关的新闻（医药）

2026-04-20

·ioncology

一线曲帕双靶方案进展后如何“排兵布阵”？浅析相关耐药机制与HER2阳性晚期乳腺癌后线治疗新进展

编者按曲妥珠单抗+帕妥珠单抗组成的“曲帕双靶”方案，长期以来是人表皮生长因子受体2（HER2）阳性晚期乳腺癌一线治疗的标准方案，但疾病进展和治疗耐药仍不可避免。为进一步改善患者整体生存预后，需深入探索明确“曲帕双靶”方案多维交织的耐药机制，并依据现有循证医学证据，优化精准治疗药物的治疗顺序，尽量使以德曲妥珠单抗（T-DXd）为代表的抗体偶联药物（ADC）、小分子酪氨酸激酶抑制剂（TKI）类靶向药等现有治疗选择的疗效最大化。本文将盘点HER2阳性晚期乳腺癌一线治疗曲帕双靶方案已知耐药机制、“曲帕双靶”治疗后现有二线及以上治疗选择和诊疗指南推荐现状、有望用于后线治疗的在研新药，以期为广大读者提供参考。 Part.1 曲帕双靶方案已知耐药机制浅析导致对曲帕双靶方案耐药的机制，可分为曲妥珠单抗相关耐药机制和双靶联合耐药机制两类，主要与曲妥珠单抗耐药相关的机制如下： 01 HER2受体结构改变约30%患者表达缺失胞外域亚段IV的p95HER2截短片段，导致曲妥珠单抗失去结合位点，但其保留的胞内激酶域仍能介导持续信号传导，与治疗耐药及不良预后相关。d16-HER2剪接变体可通过形成同源二聚体激活SRC激酶，在增强肿瘤致瘤性的同时降低癌细胞对曲妥珠单抗的敏感性。L755S, V777L及S310F等HER2错义突变发生率较低（约3.5%），但能通过增强下游通路活性或促进异源二聚化介导耐药。源自肿瘤内异质性的克隆选择或曲妥珠单抗诱导的受体内吞或降解（作用较次要），可能导致HER2表达下调或缺失，进而影响疗效。 02 粘蛋白4（Mucin 4/MUC4）介导的位阻与表位屏蔽 MUC4能与HER2结合形成复合物，通过物理位阻效应屏蔽结合表位，阻碍曲妥珠单抗与受体亚段IV的接触；TNF-α即可通过上调MUC4表达，驱动曲妥珠单抗的获得性耐药。 03 PI3K-AKT-mTOR通路持续激活 PIK3CA突变在HER2阳性乳腺癌中检出率约20%-30%，其可持续激活下游AKT-mTOR通路，并使信号激活绕过HER2受体的被阻断；协同发生的PTEN缺失（发生率约59%）则同样可导致AKT持续激活，二者可共同解释多达71%的PI3K-AKT-mTOR通路激活病例。在细胞周期层面，AKT过度活化会加速p27kip1的磷酸化降解，从而解除曲妥珠单抗诱导的G1期停滞，并联同Cyclin E过表达与CDK4/6活化，使癌细胞在HER2受体被阻断的情况下仍能维持增殖。 04 经替代生长因子受体的旁路信号激活当HER2通路受抑制时，癌细胞会利用补偿性Crosstalk维持生长信号，可分为HER家族内部代偿（如NRG1诱导的HER3活化，EGFR过表达）与非HER家族旁路的激活，后者包括IGF-1R信号增强、MET通路（其拷贝数增加与治疗失败相关）、EphA2表达上调、AXL与HER2形成异源二聚体，Notch受体促进癌症干细胞存活与自我更新（与复发性疾病相关）等。 05 宿主免疫反应受损与肿瘤微环境改变 FcγRIIIα介导的抗体依赖的细胞介导的细胞毒作用（ADCC）为曲妥珠单抗的主要杀伤机制，因此携带FcγRIIIα-158V高亲和力等位基因的患者通常预后更佳；而宿主相关因素导致的NK细胞功能下降、T细胞活性受抑制，以及肿瘤自身分泌TGF-β, NmU或上调PD-L1等免疫逃逸机制，均会削弱曲妥珠单抗疗效。肿瘤微环境也会通过免疫相关机制，如成纤维细胞通泌FGF5、间质释放外泌体信号等，诱导癌细胞对曲妥珠单抗耐药。 06 代谢适应与糖酵解增强曲妥珠单抗耐药细胞表现出与Warburg effect一致的糖酵解增强和代谢可塑性，在治疗压力下具有在糖酵解和氧化磷酸化（OXPHOS）之间切换，以满足能量需求的能力，上述代谢重编程也会参与治疗耐药，具体机制包括HER2–HSF1介导的乳酸脱氢酶A（LDH-A）过表达、线粒体ATP合酶上调、ANKRD44表达沉默、胞质磷脂酶A2α（cPLA2α）上调等。 07 凋亡逃逸增强与DNA损伤应答异常曲妥珠单抗获得性耐药通常伴随凋亡逃逸能力的增强和DNA损伤反应（DDR）的失调，前者往往由于STAT3激活导致抗凋亡蛋白，如survivin, XIAP, Bcl-2家族表达上调，后者则由于ATM和RB1等调节因子基因表达改变。 08 双靶联合治疗时的耐药机制曲妥珠单抗+帕妥珠单抗的联合增效，源于二者可结合HER2受体不同表位实现互补：曲妥珠单抗结合亚段IV以抑制配体非依赖性同源二聚化和受体水解脱落，而帕妥珠单抗结合亚段II（二聚化臂）产生空间位阻，有效阻断曲妥珠单抗无法独立抑制的配体依赖性HER2-HER3异源二聚化，从而增加癌细胞表面Fc区密度，促进NK细胞和巨噬细胞上Fcγ受体（如CD16）多价结合，诱导比单药更强效的ADCC效应。然而，p95HER2表达等受体结构改变、HER2激酶域突变（L755S、V777L、S310F）及HER2表达下调/丢失，均仍可导致曲帕双靶治疗耐药；下游PI3K-AKT-mOTR通路持续激活及非HER家族的旁路补偿信号，亦可支撑癌细胞持续存活。宿主FcγRIIIa多态性、免疫功能受损、肿瘤分泌因子（TGF-β、神经调节蛋白U、PD-L1）及基质成分（CAF衍生的FGF5、外泌体信号）仍可在双靶治疗时介导免疫逃逸。近期还有研究显示，长期暴露于曲帕双靶治疗可诱导HER4激活与MAPK信号上调，导致超过600种蛋白表达改变及潜在的更复杂耐药机制[1]。 △曲妥珠单抗/曲帕双靶常见耐药机制一览[1] Part.2 曲帕双靶耐药后治疗的指南推荐现状与相应证据欧洲内科肿瘤学会（ESMO）转移性乳腺癌在线指南，已指定T-DXd为曲帕双靶一线治疗进展后的首选二线方案；对于不适合局部治疗的活动性脑转移患者，曲妥珠单抗+图卡替尼+卡培他滨联合方案（即图卡替尼三联方案）与T-DXd均被推荐。中国临床肿瘤学会（CSCO）乳腺癌诊疗指南未单独列出曲帕双靶一线治疗失败后推荐方案，但T-DXd及吡咯替尼+卡培他滨联合方案被I级推荐，用于含曲帕双靶方案的曲妥珠单抗治疗失败患者。在三线治疗阶段，指南通常推荐选择此前未使用方案，如T-DXd单药治疗或图卡替尼三联方案，也可考虑选用恩美曲妥珠单抗（T-DM1）；ESMO及美国NCCN和ASCO等指南，还建议在后线治疗中持续序贯使用可及的HER2靶向药物，通过不同靶向药物（单克隆抗体、TKI及ADC）的不同作用机制，尽可能针对异质且不断演化的耐药机制，最大程度实现病情控制。作为新一代HER2 ADC，T-DXd药物结构独特，其药物抗体比（DAR）达到8，并通过可裂解四肽连接子搭载高活性的拓扑异构酶I抑制剂（exatecan衍生物），还具有显著的“旁观者效应”。即使对曲帕双靶耐药患者，只要癌细胞仍维持足够的HER2表达，以介导药物结合与内吞，T-DXd即可对肿瘤发挥杀伤效力。综合临床研究数据、病例报告及耐药患者分析，PIK3CA突变[2]、HER2激酶域突变（L755S、V777L）等部分已知曲妥珠单抗耐药机制，或不会影响T-DXd疗效，但HER2表达下调[3]等耐药机制可能将限制T-DXd疗效。 DESTINY-Breast03（DB-03）研究确立了T-DXd在二线及以上治疗中的标准地位，研究结果显示：T-DXd组患者的中位无进展生存期（PFS）为28.8个月，而T-DM1组为6.8个月（HR 0.33；p < 0.000001），两组中位总生存期（OS）分别为56.4个月与42.7个月（HR 0.73）；T-DXd组的客观缓解率（ORR）为79.7%，T-DM1组为34.2%[4]。由于DB-03研究约60%入组患者既往接受过帕妥珠单抗治疗，实际即提供了T-DXd用于曲帕双靶一线治疗耐药患者后续治疗的重要证据。此外，早先开展的DB-02研究也已支持T-DXd用于三线及以上治疗。对曲帕双靶一线治疗后进展的患者，还可考虑使用图卡替尼三联方案（基于HER2CLIMB研究）、吡咯替尼+卡培他滨联合方案（基于PHENIX研究）及其它HER2 ADC（如瑞康曲妥珠单抗）；三线治疗阶段除使用以上两种方案中此前未使用的方案外，也可考虑T-DM1单药治疗、奈拉替尼+卡培他滨、马吉妥昔单抗+化疗、拉帕替尼+卡培他滨方案，乃至曲帕双靶再挑战等。 △DESTINY-Breast03研究PFS数据 △DESTINY-Breast03研究最终OS数据 Part.3 未来有望用于曲帕双靶经治患者的在研新药为克服包括曲帕双靶方案在内的现有HER2靶向治疗耐药性，众多在研新药正全速推进临床研究，例如同时靶向HER2/HER2、HER2/HER3、HER2/CD3及HER2/CD16抗原组合的双特异性抗体（BsAbs），代表性药物包括zanidatamab、KN026、zenocutuzumab，以及p95HER2×CD3和HER2×CD16双特异性抗体等；TKI药物方面，不可逆HER抑制剂poziotinib、可逆泛HER抑制剂epertinib均值得关注；新型ADC药物中，trastuzumab duocarmazine (T-Duo/SYD985)、ARX788及多种国产HER2 ADC也已获批或即将获批，有望用于曲帕双靶耐药患者的后线治疗。参考文献： [1] Yamamoto Y. Overcoming Trastuzumab-Pertuzumab Resistance and Optimizing Sequential Anti-HER2 Therapy in HER2-Positive Metastatic Breast Cancer. Cancers (Basel). 2026;18(6):932. Published 2026 Mar 13. doi:10.3390/cancers18060932 [2] Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2026;394(6):551-562. doi:10.1056/NEJMoa2508668 [3] Chen W, Gupta A, Mai N, et al. Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and Binding. Cancer Discov. 2026;16(2):235-249. doi:10.1158/2159-8290.CD-25-0647 [4] Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401(10371):105-117. doi:10.1016/S0140-6736(22)02420-5 本资料仅供医疗卫生专业人士参考，请勿向非医疗卫生专业人士发放材料编码：CN-20260416-00002 （来源：《肿瘤瞭望》编辑部）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。

抗体药物偶联物放射疗法临床结果

2026-04-17

·Biotech前瞻

NRG1融合阳性胆管癌，终于有药了—Zenocutuzumab向FDA发起冲刺

点击蓝字关注我们本期看点胆管癌素以进展迅猛、预后极差著称，即便在精准医疗蓬勃发展的今天，大多数患者仍面临有限的治疗选择与令人沮丧的生存数据。而在这一已然严峻的疾病背景下，携带NRG1基因融合的患者群体更是长期处于治疗的"盲区"——这一罕见的致癌驱动变异，因检测手段受限与认知不足，往往在临床实践中被忽视和遗漏。如今，随着zenocutuzumab补充生物制品许可申请（sBLA）的正式递交，以及美国国家综合癌症网络（NCCN）的指南纳入，这一沉默已久的患者群体，正在迎来精准治疗时代真正属于自己的曙光。 HER3与NRG1 的黄金搭配，解决不可成药难题，双抗提前获批本期内容 01 sBLA正式递交：监管层面的重要里程碑 02 NCCN指南纳入：临床实践层面的权威背书 03 eNRGy研究：支撑申请的核心临床数据 04 总结与展望【01 sBLA正式递交：监管层面的重要里程碑】 Partner Therapeutics已就zenocutuzumab-zbco（商品名：Bizengri）向美国FDA递交补充生物制品许可申请，适应症为携带NRG1基因融合的成人晚期不可切除或转移性胆管癌。这一申请的递交，标志着zenocutuzumab在胆管癌领域的开发进程迈入关键监管阶段。 Partner Therapeutics首席开发官Pritesh J. Gandhi博士在声明中指出："此次申请是推动zenocutuzumab惠及NRG1融合阳性胆管癌患者的重要一步。这一患者群体治疗选择极为有限，历史预后数据同样不容乐观。胆管癌本身是一种极具挑战性的高度侵袭性疾病，我们相信现有数据充分支持zenocutuzumab填补这一由NRG1基因融合驱动肿瘤患者的关键临床需求。"他同时强调，基于组织的RNA检测对于识别NRG1等罕见致癌融合变异至关重要，是确保携带此类可干预变异的患者不被遗漏的核心手段。 02 NCCN指南纳入：临床实践层面的权威背书与sBLA递交同步，NCCN已将zenocutuzumab正式纳入胆道肿瘤临床实践指南，作为NRG1融合阳性胆管癌的推荐治疗选项。具体而言，zenocutuzumab获得了后线治疗的2A类推荐，以及一线治疗的2B类推荐。 NCCN指南推荐级别的差异，反映了现有循证证据的成熟程度与临床共识的形成阶段。2A类推荐意味着基于较低级别证据、但专家组高度一致的推荐意见，而2B类推荐则代表基于较低级别证据、专家组意见存在一定分歧的推荐。尽管如此，在NRG1融合阳性胆管癌这一极度罕见的分子亚型中，能够同时获得两线治疗的指南纳入，本身已是对该药物临床价值的有力肯定，也将直接影响临床医生的用药决策与患者的治疗可及性。【03 eNRGy研究：支撑申请的核心临床数据】上述监管进展与指南纳入，均以I/II期eNRGy研究（NCT02912949）的临床数据为核心依据。eNRGy是一项开放标签、多中心、国际性、剂量递增研究，入组对象为携带NRG1基因融合的成人实体瘤患者，入组标准涵盖ECOG体能状态评分0至2分、预计生存期不低于12周，以及相应的血液学基线指标要求。在胆管癌队列中，zenocutuzumab展现出具有临床意义的疗效数据：经盲态独立中心评审（BICR）评估，客观缓解率（ORR）达36.8%（95% CI，16.3%~61.6%），中位缓解持续时间（DOR）为12.9个月。在安全性方面，zenocutuzumab整体耐受性良好，未见因不良事件导致的治疗中止病例，展现出相对可控的安全性特征。在NRG1融合阳性胆管癌这一预后历来极差的罕见分子亚型中，上述数据具有重要的临床参考价值。 04 总结与展望 zenocutuzumab的临床开发历程，也再次将分子检测的重要性推至聚光灯下。NRG1基因融合属于罕见的致癌驱动变异，在胆管癌患者中的发生率相对低，若缺乏系统性、高灵敏度的检测手段，极易在常规临床实践中被漏检。基于组织的RNA检测，是识别NRG1等罕见融合变异的必要手段，也是确保患者不因检测缺失而错失精准治疗机会的核心保障。随着zenocutuzumab的监管进程推进，如何在临床实践中系统推广NRG1融合的规范化检测，将成为这一治疗方案真正落地、惠及患者的关键前提。对于胆管癌诊疗团队而言，将NRG1融合检测纳入分子病理常规评估流程，或许已是当下不可回避的临床命题。新增科普账号，用更通俗的语言讲透临床知识，欢迎关注。 ★

2026-04-16

·allsci.com

Partner Therapeutics seeking third indication for Bizengri in NRG1 fusion-positive cholangiocarcinoma

Partner Therapeutics submitted a supplemental Biologics License Application (sBLA) to the US FDA on April 14, 2026 for Bizengri (zenocutuzumab-zbco), seeking approval for adults with advanced unresectable or metastatic cholangiocarcinoma harboring an NRG1 gene fusion. The filing marks the first regulatory submission for Bizengri in this bile duct malignancy with the aim of adding a third indication to the molecule’s existing accelerated approvals in NRG1 fusion-positive non-small cell lung cancer and pancreatic adenocarcinoma. The sBLA seeks approval without restriction to a specific line of therapy, the company said. The filing is supported by data from the eNRGy study, a basket trial evaluating zenocutuzumab-zbco across NRG1 fusion-positive solid tumors. No priority review or accelerated pathway designation was disclosed in the announcement, and the company did not provide a projected PDUFA date. Bizengri’s cholangiocarcinoma data The cholangiocarcinoma cohort of the eNRGy study generated an overall response rate of 36.8% (95% CI: 16.3, 61.6%) and a median duration of response of 12.9 months, as assessed by blinded independent central review. No patients in that cohort discontinued therapy due to adverse events, the company said. The mechanism underlying the filing differs from all currently approved CCA therapies: zenocutuzumab-zbco is a bispecific antibody that simultaneously blocks HER2/HER3 heterodimerization and NRG1 fusion interactions with HER3, disrupting downstream signaling driven by NRG1 chimeric ligands rather than the chimeric receptors targeted by FGFR inhibitors such as pemigatinib and futibatinib. NRG1 fusions are estimated to occur in fewer than 2% of cholangiocarcinoma cases, and the source material states that no approved therapies currently target this molecular subgroup in the disease. The rarity of the alteration creates a diagnostic challenge: unlike NTRK, RET, or FGFR fusions, NRG1 fusions produce chimeric ligands that are frequently missed by DNA-only next-generation sequencing panels and require tissue-based RNA testing for reliable detection. Partner Therapeutics noted this in its announcement, with Chief Development Officer Pritesh Gandhi stating that RNA testing is essential to ensure patients with NRG1-driven tumors are identified. NCCN guidelines The filing arrives alongside a notable guideline development. The National Comprehensive Cancer Network added zenocutuzumab-zbco to its oncology clinical practice guidelines for biliary tract cancers as a Category 2A subsequent-line therapy and as a Category 2B recommendation for front-line treatment of NRG1 fusion-positive cholangiocarcinoma — the latter positioning preceding any formal regulatory approval for the indication. Dr. James Cleary of Dana-Farber Cancer Institute, commenting in the release, described NRG1 gene fusions as an actionable biomarker in this disease and said the eNRGy data suggest targeted inhibition with zenocutuzumab may represent a meaningful treatment approach. The cholangiocarcinoma treatment landscape has undergone substantial change since 2020, when pemigatinib became the first targeted therapy approved in the disease. Ivosidenib followed in 2021 for IDH1-mutant CCA, futibatinib in 2022 for FGFR2 fusion-positive intrahepatic disease, and durvalumab in combination with gemcitabine and cisplatin was approved the same year for first-line biliary tract cancer regardless of biomarker status. Pembrolizumab combined with gemcitabine and cisplatin received approval in 2023 for the same unselected population. Despite this expansion, the molecular subgroup defined by NRG1 fusions has remained without a specifically labeled therapy, and the eNRGy data represent the primary clinical evidence base for this population in CCA. The sBLA adds to a field where accelerated approval pathways have played a central role, and where the durability of those approvals has varied. Infigratinib, an FGFR1–3 inhibitor that received accelerated approval in 2021 for FGFR2 fusion-positive CCA, was voluntarily withdrawn in 2024 after a confirmatory trial failed to verify clinical benefit — a precedent that underscores the regulatory risk associated with response-rate-based submissions in this disease. The eNRGy cholangiocarcinoma cohort was small, as is typical for trials enrolling rare fusion-defined populations, and the 95% confidence interval for the reported ORR is correspondingly wide. Bizengri’s existing accelerated approvals in NSCLC and pancreatic adenocarcinoma were also granted based on overall response rate and duration of response, with continued approval in those indications contingent on confirmatory trial data. The cholangiocarcinoma sBLA follows the same evidentiary model. Partner Therapeutics holds exclusive US rights to develop and commercialize zenocutuzumab-zbco under an agreement with Merus B.V., a wholly owned subsidiary of Genmab. Leave a Reply Cancel reply Your email address will not be published. Required fields are marked * Comment * Name * Email * Website

100 项与泽诺库珠单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11991	-	-	DB15559

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
NRG1 融合的胰腺腺癌	美国	Merus NV	2024-12-04
NRG1融合阳性非小细胞肺癌	美国	Merus NV	2024-12-04

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
不能切除的胆管癌	申请上市	美国	Partner Therapeutics, Inc.	2026-04-14
转移性胆管癌	申请上市	美国	Partner Therapeutics, Inc.	2026-04-14
转移性去势抵抗性前列腺癌	临床2期	美国	Merus NV	2022-11-17
ER阳性HER2低表达乳腺癌	临床2期	美国	Merus NV	2018-01-15
ER阳性HER2低表达乳腺癌	临床2期	比利时	Merus NV	2018-01-15
ER阳性HER2低表达乳腺癌	临床2期	法国	Merus NV	2018-01-15
ER阳性HER2低表达乳腺癌	临床2期	荷兰	Merus NV	2018-01-15
ER阳性HER2低表达乳腺癌	临床2期	葡萄牙	Merus NV	2018-01-15
ER阳性HER2低表达乳腺癌	临床2期	西班牙	Merus NV	2018-01-15
ER阳性HER2低表达乳腺癌	临床2期	英国	Merus NV	2018-01-15

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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


NCT02912949 (eNRGy, ASCO_GI2026)	临床2期	NRG1融合阳性胰腺癌 \| 胆管癌 NRG1+	17	Zenocutuzumab (NRG1+ gastrointestinal tumors)	憲蓋糧繭淵願鏇夢糧顧(願蓋網餘糧鹽顧衊選積) = 築蓋艱積蓋觸鹹鹽淵獵選夢醖餘蓋壓鏇餘築醖 (蓋蓋襯廠襯憲鹽淵醖鹽 ) 更多	积极	2026-01-08
NCT02912949 (Pubmed \| N Engl J Med) 人工标引	临床2期	NRG1融合阳性实体瘤	204	Zenocutuzumab 750 mg	鏇鏇蓋齋衊餘鹽築餘築(顧艱觸觸遞醖憲艱廠膚) = 衊構鹽餘鬱淵鹹窪憲鏇壓構窪鑰廠艱淵積製齋 (鹹網顧衊糧衊餘醖製憲, 23 ~ 37) 更多	积极	2025-02-06
				Zenocutuzumab 750 mg (NSCLC)	鏇鏇蓋齋衊餘鹽築餘築(顧艱觸觸遞醖憲艱廠膚) = 壓襯構餘觸鑰鏇壓膚鹽壓構窪鑰廠艱淵積製齋 (鹹網顧衊糧衊餘醖製憲, 20 ~ 39)
NCT02912949 (eNRGy, FDA_CDER) 人工标引	临床2期	NRG1融合阳性胰腺癌 NRG1 Fusion	30	BIZENGRI	網餘獵鬱鑰夢醖鹽衊鏇(夢餘醖簾衊壓鏇製鑰選) = 齋選鹽願遞積淵遞構蓋窪餘簾餘繭鹹築艱範顧 (顧鑰觸夢壓窪繭顧醖鑰, 23 ~ 59) 更多	积极	2024-12-04
				BIZENGRI (NRG1 Partner ATP1B1)	網餘獵鬱鑰夢醖鹽衊鏇(夢餘醖簾衊壓鏇製鑰選) = 積廠簾醖願膚觸積蓋蓋窪餘簾餘繭鹹築艱範顧 (顧鑰觸夢壓窪繭顧醖鑰, 23 ~ 77) 更多
NCT02912949 (eNRGy, FDA_CDER) 人工标引	临床2期	NRG1融合阳性非小细胞肺癌 NRG1 Fusion	64	BIZENGRI (Previously Treated with Systemic Therapy)	廠糧繭範憲夢鑰醖齋膚(艱繭願夢築憲糧糧鬱齋) = 鏇壓獵製襯壓夢獵衊繭齋糧積鬱觸繭廠願觸鏇 (鏇繭觸鑰願齋遞鬱鹹遞, 22 ~ 46) 更多	积极	2024-12-04
				BIZENGRI (NRG1 Partner CD74)	廠糧繭範憲夢鑰醖齋膚(艱繭願夢築憲糧糧鬱齋) = 願衊選簾廠選簾遞蓋簾齋糧積鬱觸繭廠願觸鏇 (鏇繭觸鑰願齋遞鬱鹹遞, 18 ~ 50) 更多
NCT03321981 (CTgov)	临床2期	HER2阳性转移性乳腺癌 \| 转移性乳腺癌 \| ER阳性HER2低表达乳腺癌	105	Trastuzumab+Zenocutuzumab (Cohort 1 Doublet)	繭衊鏇顧製鑰繭鏇餘遞 = 齋簾構餘糧製蓋製廠衊壓齋鑰糧衊蓋窪廠醖觸 (積積膚鑰憲積艱淵繭鹹, 鏇鏇餘簾積構糧蓋齋壓 ~ 獵選範鬱積衊鏇糧壓築) 更多	-	2024-03-07
				Trastuzumab+Zenocutuzumab+Vinorelbine (Cohort 1 Triplet)	繭衊鏇顧製鑰繭鏇餘遞 = 齋襯網醖膚衊顧觸夢構壓齋鑰糧衊蓋窪廠醖觸 (積積膚鑰憲積艱淵繭鹹, 壓製糧憲鹹壓夢憲遞鬱 ~ 觸簾糧築願衊鹽網醖糧) 更多
NCT02912949 (ESMO_ASIA2023) 人工标引	临床2期	NRG1融合阳性非小细胞肺癌 NRG1 Fusion	85	Zenocutuzumab	選積糧淵願憲遞選廠網(襯鹹鏇築壓憲壓製夢顧) = 壓襯鏇構鏇積餘顧積膚觸選醖觸壓餘顧積網簾 (遞積遞襯窪膚鹽簾淵壓, 23 ~ 47) 更多	积极	2023-12-02
NCT02912949 (eNRGy, ESMO 12023 \| ESMO 22023) 人工标引	临床2期	NRG1融合阳性胰腺癌 NRG1 fusion positive	38	Zenocutuzumab	餘繭艱鹽憲襯糧顧顧鑰(鬱網鏇鏇繭鏇糧鑰餘鬱) = 選網艱壓蓋遞襯窪鏇壓獵繭襯餘鏇蓋範鹹鬱窪 (簾醖鏇遞願顧廠壓衊廠, 26 ~ 65) 更多	积极	2023-10-23
NCT02912949 (eNRGy, ASCO2022)	临床2期	NRG1融合阳性实体瘤	99	Zenocutuzumab (MCLA-128)	鑰鏇鬱獵積觸製齋衊觸(選餘醖廠醖鹹願鏇遞鑰) = 製獵網淵餘獵築願繭鑰夢艱壓願鏇壓鬱繭糧鑰 (廠範範壓艱選廠觸醖鏇, 25 ~ 44) 更多	积极	2022-06-02
MCLA-128 (SABCS2022)	临床2期	HER2阳性转移性乳腺癌二线 HER2 positive \| HER3	39	Zenocutuzumab 750 mg	積糧夢襯鏇製窪顧憲遞(糧鹹積構製簾醖遞鑰觸) = 淵艱廠簾衊簾窪鹽壓淵願選蓋醖憲廠觸衊齋築 (築選鬱壓構願醖鹽願糧, 34 ~ 63) 更多	积极	2022-02-15
				Trastuzumab 8 mg/kg loading, then 6 mg/kg	積糧夢襯鏇製窪顧憲遞(糧鹹積構製簾醖遞鑰觸) = 艱積範網淵願餘壓築艱願選蓋醖憲廠觸衊齋築 (築選鬱壓構願醖鹽願糧, 38 ~ 71) 更多
NCT03321981 (Corporate Publications) 人工标引	临床2期	HER2阳性转移性乳腺癌 HER2 Positive \| HER2 Amplification	39	trastuzumab+vinorelbine+MCLA-128	淵窪繭鬱壓衊夢夢積簾(艱糧簾襯憲壓繭鬱襯鹽) = 鑰醖襯鏇範築積蓋壓遞淵遞醖鏇製鏇鏇鹽鏇鏇 (夢憲鑰襯願選齋鑰獵鬱, 34 ~ 63) 更多	积极	2021-12-10