This trial will study ladiratuzumab vedotin (LV) alone and with pembrolizumab to find out if it works to treat different types of solid tumors. It will also find out what side effects may occur. A side effect is anything the drug does besides treating cancer.

开始日期2019-10-09

申办/合作机构

Seagen, Inc.

[+1]

NCT03424005

/ Recruiting临床1/2期

A Phase Ib/II, Open-label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic Breast Cancer (Morpheus-panBC)

This is an umbrella study evaluating the efficacy and safety of multiple treatment combinations in participants with metastatic or inoperable locally advanced breast cancer.
The study will be performed in two stages. During Stage 1, seven cohorts will be enrolled in parallel in this study:
Cohort 1 will consist of programmed death-ligand 1 (PD-L1)-positive participants who have received no prior systemic therapy for metastatic or inoperable locally advanced triple-negative breast cancer (TNBC) (first-line [1L] PD-L1+ cohort).
Cohort 2 will consist of participants who had disease progression during or following 1L treatment with chemotherapy for metastatic or inoperable locally-advanced TNBC and have not received cancer immunotherapy (CIT) (second-line [2L] CIT-naïve cohort).
Cohort 3, 5, 6 and 7 will consist of participants with locally advanced or metastatic hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative disease with one or more PIK3CA mutations.
Cohort 4 will consist of participants with locally advanced or metastatic HER2+ /HER2-low disease with one or more PIK3CA mutations who had disease progression on standard-of-care therapies (HER2+ /HER2-low cohort).
In each cohort, eligible participants will initially be assigned to one of several treatment arms (Stage 1). During Stage 2, participants in the 2L CIT-naïve cohort who experience disease progression, loss of clinical benefit, or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different treatment combination, provided Stage 2 is open for enrollment and all eligibility criteria are met.

开始日期2018-03-30

申办/合作机构

Hoffmann-La Roche, Inc.

[+2]

NCT03310957

/ Completed临床1/2期

Single Arm, Open Label Phase 1b/2 Study of SGN-LIV1A in Combination With Pembrolizumab for First-Line Treatment of Patients With Unresectable Locally-Advanced or Metastatic Triple-Negative Breast Cancer

This trial studies ladiratuzumab vedotin (LV) with pembrolizumab in patients with triple-negative breast cancer. It will find out what side effects happen when participants get these two drugs. A side effect is anything the drugs do besides treating cancer. Pembrolizumab is a drug that can be used to treat triple-negative breast cancer. The trial will also find out if these drugs work to treat this type of cancer. Participants in this study have metastatic breast cancer. This means the cancer has spread to other parts of the body.

开始日期2018-02-27

申办/合作机构

Seagen, Inc.

[+1]

100 项与 Ladiratuzumab vedotin 相关的临床结果

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100 项与 Ladiratuzumab vedotin 相关的转化医学

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100 项与 Ladiratuzumab vedotin 相关的专利（医药）

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项与 Ladiratuzumab vedotin 相关的文献（医药）

2025-12-31·mAbs

A bispecific antibody-drug conjugate targeting pCAD and CDH17 has antitumor activity and improved tumor-specificity

Article

作者: Gesner, Thomas ; Logel, Claude ; Xie, Kathleen T. ; Cebe, Regis ; Wu, Nila C. ; Li, Xun ; Shi, Xingyi ; Velazquez, Roberto ; Simmons, Quincey ; Tschantz, William R. ; Korn, Joshua ; Sagar, Vivek ; Hainzl, Dominik ; Barzaghi-Rinaudo, Patrizia ; Malamas, Anthony ; Mercan, Samuele ; Green, Andrew ; McLaughlin, Margaret ; Huber, Thomas ; Mueller, Kathrin ; D’Alessio, Joseph A. ; Synan, Alyssa

P-cadherin (pCAD) and LI-cadherin (CDH17) are cell-surface proteins belonging to the cadherin superfamily that are both highly expressed in colorectal cancer. This co-expression profile presents a novel and attractive opportunity for a dual targeting approach using an antibody-drug conjugate (ADC). In this study, we used a unique avidity-driven in vitro screening approach to generate pCAD x CDH17 bispecific antibodies that selectively target cells expressing both antigens over cells expressing only pCAD or only CDH17. Based on in vitro binding and inhibition of cell proliferation results, we selected a lead bispecific antibody to link to the cytotoxic payload monomethyl auristatin E (MMAE) to generate a pCAD x CDH17 bispecific MMAE ADC. In in vivo dual flank mouse models, we demonstrated antitumor activity of the bispecific ADC in tumors expressing both antigens but not in tumors expressing only pCAD or only CDH17. Overall, the preclinical data presented here support the proof-of-concept bispecific antibody discovery approach, demonstrating a rational design for screening antibodies by prioritizing cross-arm avid IgGs to target dual-positive cells.

2025-06-12·ACS Medicinal Chemistry Letters

Site-Selective Anti-PD-L1 Antibody–MMAE Conjugate for Enhanced NSCLC Therapy

Article

作者: Kwon, Se Jeong ; Son, Jinyoung ; Chung, Sang J.

Nonsmall cell lung cancer (NSCLC) presents significant therapeutic challenges, causing advancements in targeted therapies. We have developed a site-selective antibody-drug conjugate (ADC), durvalumab-monomethyl auristatin E (MMAE), with a drug-antibody ratio (DAR) of 4, specifically targeting programmed death-ligand 1 (PD-L1), aimed at enhancing NSCLC therapy. Utilizing the innovative AbClick Pro linker, this ADC ensures stable, site-specific conjugation of MMAE to durvalumab, preserving antibody functionality and integrity. In vivo studies demonstrate that durvalumab-MMAE achieves substantial tumor growth inhibition in NSCLC xenograft models, with an impressive tumor growth inhibition rate of over 60% at lower dosages without significant toxicity. These results, combined with a favorable pharmacokinetic profile featuring extended half-life and low clearance, highlight the potential of durvalumab-MMAE (DAR4) as a potent next-generation ADC for treating PD-L1-expressing cancers, offering a promising avenue for improved NSCLC patient outcomes.

2025-06-02·MOLECULAR PHARMACEUTICS

Cleavable PEGylation Enhances the Antitumor Efficacy of Small-Sized Antibody–Drug Conjugates

Article

作者: Ding, Yu ; Zhang, Hongru ; Yang, Liu ; Yin, Dongming ; Hong, Zhangyong ; Han, Jiani ; Wang, Jian ; Wang, Xi ; Xu, Keyuan

Antibody-drug conjugates (ADCs) have emerged as a promising class of cancer therapeutics. However, traditional ADCs are often limited by poor tumor penetration due to their large molecular size. While the use of small-sized antibody fragments or analogues can improve tumor permeability, this approach typically results in an extremely shortened blood circulation half-life, which diminishes the therapeutic benefits and brings other metabolic challenges. In addition, the expression of target antigens on normal tissues often leads to unnecessary on-target/off-tumor toxicity. To address these issues, we developed a novel tumor site-specific cleavable PEGylation strategy for small-sized ADC design. The small ADC molecule Z_HER2-MMAE was site-specifically PEGylated at its N-terminus with a 20 kDa polyethylene glycol (PEG) chain and a uPA (LSGRSDNH) cleavage sequence was inserted between them (PEG_20k-U-Z_HER2-MMAE). Our results showed that PEG_20k-U-Z_HER2-MMAE achieves a similar half-life extension (6.4 and 6.0 h) compared to the conventional PEG_20k-Z_HER2-MMAE, both representing about a 26-fold improvement compared to Z_HER2-MMAE. Importantly, PEG_20k-U-Z_HER2-MMAE exhibited significantly higher drug accumulation at the tumor site, leading to the complete eradication of NCI-N87 and SK-OV-3 tumors at a dose of 5.5 mg/kg. Additionally, it demonstrated a maximum tolerated dose (MTD) exceeding 35 mg/kg, while the noncleavable PEG_20k-Z_HER2-MMAE could only slow tumor growth. In addition, compared to Z_HER2-MMAE, the in vitro cytotoxic activity of PEG_20k-Z_HER2-MMAE or PEG_20k-U-Z_HER2-MMAE was reduced by about 50 times, with the latter expected to reduce the on-target/off-tumor side effects due to the specific activation by uPA at tumor sites. These data fully demonstrate the effectiveness and high safety of our tumor-specific cleavable PEGylation strategy, supporting the potential in the development of next-generation ADCs for cancer therapy.

项与 Ladiratuzumab vedotin 相关的新闻（医药）

2026-04-23

·创胜医药TranscentaTherapeutics

创胜医药公布新型LIV1 ADC TST013最新数据，展示其在前列腺癌及ER阳性/HER2阴性乳腺癌PDX模型中显著的抗肿瘤活性

// 美国新泽西州普林斯顿和中国苏州，2026年4月23日， —— 创胜医药(06628.HK)，一家具备生物药品发现、研发、工艺开发和生产全流程整合能力的临床阶段的国际生物制药公司，今日宣布在2026年美国癌症研究协会（AACR）年会上公布其靶向LIV1的专有抗体偶联药物（ADC）临床前研究数据。数据表明该药物具有显著的抗肿瘤活性、基于载荷差异化的疗效，以及良好的耐受性特征，支持其在LIV1阳性实体瘤中的进一步开发。 LIV1属于锌转运蛋白家族成员，在正常组织中表达有限，但在多种肿瘤中高频过表达，包括乳腺癌（93%）、前列腺癌（72%）及肺癌（10%），因此成为ADC药物开发中极具吸引力的细胞表面靶点。创胜医药开发了48D6，一种新型专有人源化抗LIV1单克隆抗体，具有高亲和力、高特异性及良好的内吞能力。通过Retrogenix细胞微阵列技术评估，48D6被证实与其他人类蛋白无非特异性相互作用，确认了其高度的靶点特异性。基于48D6，创胜医药采用糖基转移酶介导的特定位点偶联平台开发了两款ADC候选药物：ADC-2（偶联拓扑异构酶I抑制剂载荷）和ADC-3（偶联MMAE载荷）。在Balb/c小鼠中开展的药代动力学研究显示，ADC-2的半衰期约为10.4–11.6天，显著长于基准对照SGN-LIV1A类似物（3.7–3.9天），并与裸抗48D6（13.8–15.6天）相当，表明其具有良好的体内稳定性。体内药效研究表明，在LIV1表达的ER阳性/HER2阴性乳腺癌及非小细胞肺癌（NSCLC）患者来源异种移植（PDX）模型中，ADC-2在每周一次、连续四周、剂量为6 mg/kg的给药方案下展现出显著的抗肿瘤活性。在LIV1表达的前列腺癌PDX模型中，ADC-2在前两次给药后显示有限的肿瘤抑制作用。在第3次给药起替换为基于MMAE的ADC-3后，ADC-3对前列腺肿瘤生长产生了显著抑制作用。在LIV1高表达的前列腺癌PDX模型中，停止给药后，ADC-3对肿瘤生长的抑制作用持续超过70天。在评估安全性与耐受性的探索性毒理学研究中，ADC-2在小鼠内经多次给药后，在所有测试剂量下均表现出良好耐受性。60 mg/kg组在给药期间观察到轻微损伤，但在恢复期结束时完全恢复。基于上述结果，ADC-2在小鼠中的最大耐受剂量（MTD）确定为60 mg/kg。ADC-3的安全性与耐受性尚未开展相关研究。上述数据表明，创胜医药靶向LIV1的ADC-2及ADC-3在ER阳性/HER2阴性乳腺癌（占乳腺癌的60%）及前列腺癌PDX模型中作为单药治疗均展现出显著的抗肿瘤活性，且两者在小鼠中均表现出良好的耐受性。创胜开发的靶向LIV1的ADC在三阴性乳腺癌（TNBC）肿瘤模型中同样展现出显著的抗肿瘤活性，相关数据已于2024 SABCS公布。这些结果支持创胜医药进一步推进该产品在LIV1阳性实体瘤中的研究与开发。创胜医药是一家临床阶段的在生物药发现、研发、工艺开发和生产方面具有全面综合能力的生物制药公司。创胜医药总部位于苏州，已成功搭建了全球的业务布局：在苏州设有药物发现、临床和转化研究中心，在杭州拥有工艺与产品开发中心以及药物生产基地，在中国，美国和欧洲分别设有临床开发中心。创胜医药正在开发多元化的产品管线，包含数十种新型生物药，涵盖了肿瘤及非肿瘤适应症，包括骨科，自身免疫性疾病和肾脏疾病等。如需了解关于创胜医药的更多信息，请访问公司网站：www.transcenta.com 或领英账号：Transcenta Therapeutics。如您有意了解我司资本合作事宜，敬请通过ir@transcenta.com 与我们建立联系，共探合作机遇。

2026-04-23

·BioSpace

Transcenta Therapeutics Presents New Data for its Novel LIV1-Targeting ADC TST013 Demonstrating Potent Anti-Tumor Activity in PDX Models of Prostate Cancer and ER Positive /HER2 Negative Breast Cancer

PRINCETON, N.J. and SUZHOU, China, April 23, 2026 (GLOBE NEWSWIRE) -- Transcenta Therapeutics (HKEX: 06628), a global clinical stage biopharmaceutical company with fully-integrated capabilities in discovery, research, development and manufacturing of antibody-based therapeutics, today announced the presentation of preclinical data highlighting its proprietary LIV1-targeting antibody-drug conjugates (ADC) at the 2026 AACR Annual Meeting. The data demonstrate strong anti-tumor activity, differentiated payload-dependent efficacy, and favorable tolerability pro supporting further development in LIV1-positive solid tumors. LIV1 is a member of the zinc transporter family, with limited normal tissue expression, and is found to be overexpressed with high prevalence in breast (93%), prostate (72%) and lung (10%) cancers, making it an attractive cell surface target for developing ADC therapeutics. Transcenta Therapeutics has developed 48D6, a novel proprietary humanized anti-LIV1 monoclonal antibody with high affinity, specificity, and internalization capability. Using Retrogenix cell microarray technology, 48D6 demonstrated no non-specific interactions with other human proteins, confirming its high target specificity. Leveraging 48D6, Transcenta Therapeutics then generated two ADC candidates using a glycotransferase-mediated site-specific conjugation platform: ADC-2, conjugated with a Topoisomerase I inhibitor payload, and ADC-3, conjugated with MMAE. Pharmacokinetic studies in Balb/c mice showed that ADC-2 exhibited a half-life of approximately 10.4–11.6 days, significantly longer than that of a benchmark SGN-LIV1A analog (3.7–3.9 days), and comparable to the naked antibody 48D6 (13.8–15.6 days), indicating favorable in vivo stability. In vivo efficacy studies demonstrated that ADC-2 elicited potent anti-tumor activity in LIV1-expressing ER+/HER2- breast cancer and non-small cell lung cancer (NSCLC) patient-derived xenograft (PDX) models at a dose of 6 mg/kg administered once weekly for four weeks. For LIV1 expressing prostate PDX models, ADC-2 demonstrated limited tumor growth inhibition after two doses. After MMAE-based ADC-3 replaced ADC-2 from the 3rd dose, ADC-3 inhibited the growth of the prostate tumor significantly. In a LIV1 high expressing prostate PDX, the tumor growth was suppressed by ADC-3 for more than 70 days after the dosing was stopped. In exploratory toxicity studies to assess safety and tolerability, ADC-2 was well tolerated following repeated administrations in mice at all doses tested. Slight lesions were observed in 60 mg/kg group during the treatment period and fully recovered at the end of the recovery period. Based on these results, the maximum tolerated dose (MTD) of ADC-2 in mice was determined at 60 mg/kg. The safety and tolerability of ADC-3 has not yet been explored. Collectively, these data demonstrate that Transcenta’s LIV1-targeting ADC-2 and ADC-3 programs exhibited strong anti-tumor activities as monotherapy in PDX models of ER+/HER2- breast cancer (representing ~60% of all breast cancers) and also prostate cancer. ADC-2 also displayed excellent tolerability pro mice. Notably, Transcenta’s LIV1-targeting ADCs also demonstrated potent anti-tumor activity in triple-negative breast cancer (TNBC) tumor models, with data previously presented at the 2024 SABCS. These results support further investigation of Transcenta’s LIV1 ADCs in LIV1-positive solid tumors. About Transcenta Therapeutics Transcenta Therapeutics (HKEX: 06628) is a global clinical stage biopharmaceutical company with fully integrated capabilities in antibody-based biotherapeutics discovery, research, development and manufacturing. Transcenta Therapeutics has established a global footprint, with its Headquarters and Discovery, Clinical and Translational Research Capabilities located in Suzhou, China, its Process and Product Development Center and Manufacturing Facility located in Hangzhou, China, and additional Clinical and Business Development Centers across China, the U.S. and Europe. Transcenta Therapeutics is developing a diverse pipeline of more than a dozen novel biologic therapies for oncology and selected non-oncology indications such as bone and kidney disorders. Media Contact: pr@transcenta.com

临床结果AACR会议抗体药物偶联物

2026-04-16

·药事纵横

从基础机制到临床转化——LIV-1靶向药物在乳腺癌治疗中的机制解析与临床进展

在全球女性恶性肿瘤流行病学调查中，乳腺癌发病率长期居高不下，不仅是威胁女性生命健康的“头号杀手”，更消耗着大量的公共卫生资源与家庭照护成本。随着肿瘤分子生物学的发展，靶向治疗与抗体偶联物（ADC）技术的革新为乳腺癌患者带来了长生存的曙光。然而，对于存在内分泌治疗耐药的雌激素受体（ER）阳性乳腺癌以及侵袭性极强的三阴性乳腺癌（TNBC），临床仍面临巨大的治疗瓶颈。近年来，一种定位于细胞膜上的锌铁调控转运蛋白——SLC39A6/ZIP6（简称LIV-1），逐渐走入肿瘤学研究的聚光灯下。自利物浦大学研究者首次在雌激素信号通路中发现该基因以来，其在乳腺癌淋巴结转移中的病理意义被逐步明确。LIV-1不仅是一种特征性的雌激素应答基因，更是调控肿瘤上皮-间质转化（EMT）、重塑肿瘤微环境的关键“锌离子开关”。伴随第三代抗体偶联药物（ADC）在实体瘤治疗中取得突破性进展，针对LIV-1靶点的转化医学研究已成为当前乳腺癌精准治疗的新热点。本文将从LIV-1的构效关系、病理机制、多维信号调控网络以及最新临床转化成果等方面，进行科学、客观、深度的剖析。一、LIV-1的分子结构与生物学功能细胞膜脂质双分子层是物质运输与细胞通讯的关键功能界面。LIV-1属于ZIP锌转运蛋白家族中的LZT亚家族，是人类九个同源蛋白之一。理解其作用机制，首先需要厘清其精密的分子拓扑结构。1.1精密的跨膜架构与锌离子配位机制 LIV-1具有典型的多跨膜螺旋结构，包含6至8个跨膜结构域。其中，第5个跨膜结构域含有一段高度保守的金属蛋白酶样基序——H-E-X-X-P-H-E-X-G-D序列（X为可变氨基酸）。这一特殊的三维构象能够精准适配锌离子的空间结合需求，直接驱动锌离子的跨膜配位与转运。在转运通道的调控上，分布于N-端和跨膜连接环区的多个组氨酸簇，为锌离子的捕获与转移提供了理想的分子架构。同时，跨膜通道调控元件C-P-A-L-L-Y模序通过构象变化调节通道的开闭，决定着锌离子的流动方向。此外，LIV-1序列中包含强PEST位点及其他潜在降解基序，这从分子层面解释了为何在非诱导状态下LIV-1在细胞内的基础表达水平相对较低，但其一旦被激活，便能高效发挥作用。图1. LIV-1亚家族预测结构示意图1.2锌稳态调控与肿瘤代谢重编程锌是维持细胞正常机能的关键金属元素，深度参与核酸合成、酶活性调控及细胞命运决定的级联反应。在正常的乳腺组织中，ZIP家族和ZnT反向转运系统构成锌稳态的双向调节网络。然而，在乳腺肿瘤微环境中，这一精密的离子调控体系遭到破坏。同位素示踪实验证实，LIV-1在细胞中的表达显著增加了细胞对锌的摄取能力。在乳腺病灶中，锌元素的异常富集与LIV-1的活跃表达呈空间共定位，导致细胞内锌超载。这种离子的异常重编程不仅直接调控了锌依赖性的信号级联反应，更与肿瘤血管生成、基质重塑及肿瘤异质性的演变密切相关。在系统性锌缺乏的病理条件下，LIV-1还会通过调节EMT信号轴发挥异常的“稳态修复”功能，从而在不知不觉中赋予了肿瘤细胞更强的生存适应力。二、LIV-1介导的信号通路与EMT调控上皮-间质转化（EMT）本是胚胎发育与组织再生的关键生理机制，但在恶性肿瘤中，它被劫持为触发肿瘤侵袭和转移的核心开关。LIV-1在EMT进程中扮演着极为独特的“桥梁分子”角色，其调控网络远超传统的认知范畴。2.1核心转录因子Snail与GSK-3β失活 LIV-1对EMT的调控最经典的路径依赖于锌指转录因子Snail。日本安诺团队在胰腺癌模型中首次揭示，LIV-1不仅是STAT3信号通路下游的效应分子，更能通过锌离子的内流直接或经Akt间接作用，使糖原合成酶激酶-3β（GSK-3β）发生磷酸化而失活。GSK-3β原本负责促进Snail蛋白的泛素化降解，其失活导致Snail在细胞核内大量积累。核内的Snail进而与E-钙黏蛋白（E-cadherin）基因启动子结合，引发E-cadherin基因沉默，最终导致细胞间黏附丧失，完成向间质形态的恶性转化。2.2多维度的信号级联网络除了Snail通路，LIV-1还广泛交织于多种促癌信号网络中： EGFR与MMP通路：在前列腺癌等模型中发现，LIV-1通过上调基质金属蛋白酶MMP2/9的表达，促进表皮生长因子受体（EGF）的激活，从而加速EMT级联反应。 ERK信号轴：中国科研团队在宫颈癌研究中证实，LIV-1可借助胞外信号调节激酶ERK1/2-Snail/Slug信号轴，直接调控肿瘤细胞的侵袭行为。内质网应激与细胞命运抉择：乌克兰敏琴科团队首次建立了内质网应激关键酶IRE1与LIV-1的分子联系。更为前沿的研究指出，LIV-1与线粒体葡萄糖调节蛋白E样蛋白1（GRPEL1）构成的调控轴，能够与蛋白磷酸酶2A-B55α全酶（PP2A-B55α）及凋亡诱导因子交互作用。这一发现在全基因组应激反应中，将LIV-1的功能从单纯的离子转运提升到了同时控制“有丝分裂退出”和“细胞死亡程序”的高度，为阐明癌细胞的命运抉择开拓了新方向。三、LIV-1在乳腺癌中的病理意义与预后价值将视角从分子维度拉回临床病理，LIV-1在乳腺癌中的表达图谱呈现出高度的亚型特异性与复杂的预后关联。3.1雌激素调控下的表达特征 1988年，曼宁团队在解析MCF-7乳腺癌细胞分子特征时首次克隆出受雌激素调控的LIV-1膜蛋白。后续研究运用基因表达谱技术验证了雌激素应答元件（ERE）对LIV-1启动子的直接调控。同时，胰岛素生长因子（IGF-1）通路也能独立诱导其高表达。临床病理学数据显示，LIV-1在ER阳性乳腺癌原发灶中的表达水平较良性组织提高3至5倍，在淋巴结转移灶中呈梯度升高。大样本队列研究证实，LIV-1转录水平与ER表达呈高度正相关（r=0.78，P<0.001），这使其成为Luminal A亚型鉴别及淋巴结转移诊断的重要参考标志物。3.2预后价值的“双面性”与微环境异质性在预后评估方面，LIV-1的表现曾一度令学界困惑。卡斯珀团队对111例乳腺癌组织的双维度检测显示，在浸润性导管癌亚组中，LIV-1高表达患者的5年无复发生存期和总生存期反而显著延长。机制研究在T47D细胞系中发现，LIV-1在此亚型中通过负向调控EMT发挥抑癌作用，且与上皮标志物E-cadherin呈共表达趋势。然而，这种“保护作用”并非绝对。在TNBC样本中，免疫组化检测显示LIV-1蛋白阳性率高达68.3%，高表达患者的无病生存期较对照组缩短41%（HR=1.56）。此外，肝细胞癌等研究也观察到LIV-1与E-cadherin呈负向关联。这种在不同肿瘤微环境中的“调控异质性”提示了LIV-1并非简单的促癌或抑癌基因，其最终走向取决于上下游分子网络（如STAT3的裂解修饰）以及细胞所处的基质环境。值得关注的是，研究证实LIV-1转染细胞在脱离基质黏附后仍保持增殖活性，这种被赋予的“抗失巢凋亡”能力，是解析乳腺癌远端转移扩散极为关键的分子学视角。四、LIV-1靶向药物在乳腺癌治疗中的临床转化基于LIV-1在乳腺癌尤其是TNBC中展现出的潜在治疗价值，针对该靶点的新型抗体偶联物（ADC）研发迎来了爆发期。ADC药物通过“靶向识别-内吞-溶酶体释放毒素”的三步走战略，有效克服了传统化疗特异性差、全身毒性大的缺陷。目前，全球进展最快的两款LIV-1靶向ADC药物为Ladiratuzumab vedotin（SGN-LIV1A）和国产创新药BRY812。图2. BRY812药物临床试验登记与信息公示平台披露相关信息4.1 SGN-LIV1A：领跑全球的LIV-1 ADC SGN-LIV1A由靶向LIV-1的人源化单克隆抗体、蛋白酶可切割连接子以及强效微管抑制剂单甲基澳瑞他汀E（MMAE）共价连接而成。其在临床开发中展现了连贯且深入的研究脉络。单药治疗探索（SGNLVA-001研究）：该I期剂量递增试验重点关注了转移性乳腺癌单药治疗的毒副反应与疗效。入组标准严苛，要求基线ECOG体能评分≤1且排除中重度周围神经病变患者。在二线治疗耐药的TNBC患者中，1.25 mg/kg剂量组的客观缓解率（ORR）达到了28%，整体TNBC人群的ORR为32%，疾病控制率（DCR）达64%，中位无进展生存期（PFS）为11.3周。值得注意的是，该研究并未强制要求患者具备高水平的LIV-1表达，提示该药物可能具有更广泛的适用人群。安全性方面，主要不良事件为1-2级的疲劳（59%）、恶心（51%）和脱发（36%），周围神经病变发生率为44%，同时需高度警惕中性粒细胞减少及个别的发热性中性粒细胞减少症。联合免疫治疗突破（SGNLVA-002研究）：免疫检查点抑制剂在TNBC中的单药响应率有限，联合策略成为破局关键。全球多中心Ib/II期SGNLVA-002试验评估了SGN-LIV1A联合帕博利珠单抗（PD-1抑制剂）在未经治疗的不可切除或转移性TNBC中的疗效。初步结果显示，联合治疗组的ORR提升至约35%，超过60%的受试者病情得到稳定控制。除了疗效的叠加，该研究重点监测了联合方案的安全性特征，证实了腹泻、恶心和疲劳等反应处于临床可管理范围内，为后续更大规模的随机对照试验（RCT）提供了坚实的数据支撑。 Morpheus-TNBC试验：在这一包含六种治疗组合的伞形试验中，SGN-LIV1A联合PD-L1抑制剂阿替利珠单抗的方案也在评估之列，这进一步拓宽了LIV-1 ADC与不同免疫微环境调控疗法协同作战的想象空间。4.2 BRY812：打破垄断的国产新锐在SGN-LIV1A之外，中国科研团队也在加速追赶。BRY812是一款通过不可逆化学偶联平台构建的新型LIV-1 ADC，同样以MMAE为毒性载荷。其核心优势在于采用了高度稳定的连接子技术。临床前研究显示，相较于同类药物，BRY812在血液循环中展现出更高的稳定性。这种结构的优化能够显著减少毒素在血液中的提前脱落和非特异性交换，从而在肿瘤靶区有效释放载荷的同时，大幅拓宽了药物的治疗窗，预示着其可能具有更优的安全性边界。 2023年，BRY812的临床试验申请正式获得中国国家药品监督管理局（NMPA）受理。这是一项在中国开展的单臂、非随机I期临床研究，旨在评估其在晚期恶性肿瘤患者中的安全性、耐受性并确定II期推荐剂量（RP2D）。BRY812不仅是国内首款进入临床阶段的LIV-1 ADC药物，也是全球继SGN-LIV1A之后第二个迈入临床研究的同靶点药物，标志着中国在乳腺癌前沿靶向研发领域已跻身国际先进行列。4.3跨癌种拓展：LIV-1的多维治疗潜力除乳腺癌外，LIV-1在结直肠癌、肝细胞癌、食管鳞癌及胃癌等上皮源性恶性肿瘤中均呈现异常高表达。在胰腺癌中，LIV-1通过调控miR-7网络维持肿瘤干性，抑制LIV-1可使肿瘤微球体形成能力锐减；在肝细胞癌中，其与转录因子CREB1相互作用劫持线粒体代谢；在食管鳞癌中，则通过上调HB-EGF激活MMP2/9促进侵袭。这些发现证明，当前正在进行中的LIV-1靶向药物临床试验（如BRY812针对晚期实体瘤的I期研究），未来极有望在多癌种领域实现治疗价值的横向拓展。此外，基础研究还揭示了LIV-1在T细胞激活过程中的上调表达现象。其功能缺失会导致免疫应答异常，这一发现为未来基于金属离子调控的免疫干预、甚至LIV-1靶向药物与新型免疫疗法的交叉联合，提供了极具前瞻性的创新思路。表1.SGN-LIV1A和BRY812相关临床研究五、结语总的来说，LIV-1作为调控肿瘤微环境与离子稳态的关键“锌离子开关”，其在乳腺癌发生、演进、转移及免疫调节中的核心作用已得到多维度的科学验证。尽管LIV-1在不同亚型乳腺癌中的调控异质性（如ER阳性中的抑癌倾向与TNBC中的促癌作用）仍需更深入的多维组学整合分析来破译，但以SGN-LIV1A和BRY812为代表的ADC药物，已经在难治性转移性乳腺癌（尤其是TNBC）中交出了令人鼓舞的初步答卷。未来，随着I/II期临床数据的不断成熟，精准筛选LIV-1表达优势人群、优化ADC联合免疫检查点抑制剂的排兵布阵、以及进一步降低脱靶神经毒性，将是决定这一靶点能否最终走向一线治疗的核心课题。目前全球尚无LIV-1靶向药物获批上市，这意味着该赛道仍是一片充满机遇的蓝海。从基础的亚细胞构象解析，到临床床旁的靶向干预，LIV-1转化研究的每一次突破，都在为构建器官特异性、个体化的精准靶向治疗方案提供坚实的分子生物学支撑。未来，靶向LIV-1的创新药物有望完成从实验室研究到临床应用的转化，为全球乳腺癌及实体瘤患者带来更为显著的生存获益。参考文献： 1. Alzahrani AM, Taylor KM. Zinc Transporters of the LIV-1 Subfamily in Various Cancers: Molecular Insights and Research Priorities for Saudi Arabia. Int J Mol Sci. 2025 Aug 21;26(16):8080. doi: 10.3390/ijms26168080. 2. Chen P, Wang B, Mo Q, et al. The LIV-1-GRPEL1 axis adjusts cell fate during anti-mitotic agent-damaged mitosis. EBioMedicine. 2019 Nov;49:26-39. doi: 10.1016/j.ebiom.2019.09.054. 3. Dressman MA, Walz TM, Lavedan C, et al. Genes that co-cluster with estrogen receptor alpha in microarray analysis of breast biopsies. Pharmacogenomics J. 2001;1(2):135-41. doi: 10.1038/sj.tpj.6500022. 4. Taylor KM, Morgan HE, Smart K, et al. The emerging role of the LIV-1 subfamily of zinc transporters in breast cancer. Mol Med. 2007 Jul-Aug;13(7-8):396-406. doi: 10.2119/2007-00040.Taylor. 5. Shen H, Qin H, Guo J. Concordant correlation of LIV-1 and E-cadherin expression in human breast cancer cell MCF-7. Mol Biol Rep. 2009 Apr;36(4):653-9. doi: 10.1007/s11033-008-9225-4. 6. Taylor KM. The LIV-1 Subfamily of Zinc Transporters: From Origins to Present Day Discoveries. Int J Mol Sci. 2023 Jan 9;24(2):1255. doi: 10.3390/ijms24021255. 7. https://www.chinadrugtrials.org.cn/index.html 8. Rizzo A, Cusmai A, Acquafredda S, et al. Ladiratuzumab vedotin for metastatic triple negative cancer: preliminary results, key challenges, and clinical potential. Expert Opin Investig Drugs. 2022 Jun;31(6):495-498. doi: 10.1080/13543784.2022.2042252. 作者：栗雅，主要从事药物质量控制与分析检测等方面工作立即扫码加入药事纵横交流群

抗体药物偶联物

100 项与 Ladiratuzumab vedotin 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
晚期恶性实体瘤	临床2期	美国	Seagen, Inc.	2019-10-09
晚期恶性实体瘤	临床2期	美国	Merck Sharp & Dohme Corp.	2019-10-09
晚期恶性实体瘤	临床2期	澳大利亚	Merck Sharp & Dohme Corp.	2019-10-09
晚期恶性实体瘤	临床2期	澳大利亚	Seagen, Inc.	2019-10-09
晚期恶性实体瘤	临床2期	意大利	Merck Sharp & Dohme Corp.	2019-10-09
晚期恶性实体瘤	临床2期	意大利	Seagen, Inc.	2019-10-09
晚期恶性实体瘤	临床2期	韩国	Seagen, Inc.	2019-10-09
晚期恶性实体瘤	临床2期	韩国	Merck Sharp & Dohme Corp.	2019-10-09
晚期恶性实体瘤	临床2期	中国台湾	Seagen, Inc.	2019-10-09
晚期恶性实体瘤	临床2期	中国台湾	Merck Sharp & Dohme Corp.	2019-10-09

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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


NCT03310957 (Unassigned, CTgov)	临床1/2期	三阴性乳腺癌	185	Pembrolizumab (Part A, B: SGN-LIV 2.0 mg/kg (Q3WK) + Pembrolizumab)	遞網蓋鏇簾鏇鹽網壓鏇 = 積鑰構選網壓蓋廠願顧遞淵製顧糧壓範憲範齋 (衊膚積壓積壓觸繭衊蓋, 齋顧壓製餘範鑰築遞鏇 ~ 憲鬱鏇鏇選製願壓廠衊) 更多	-	2025-12-12
NCT03310957 (Unassigned, CTgov)	临床1/2期	三阴性乳腺癌	185	SGN-LIV+Pembrolizumab (Part A, B: SGN-LIV 2.5 mg/kg (Q3WK) + Pembrolizumab)	遞網蓋鏇簾鏇鹽網壓鏇 = 壓醖衊製繭淵憲壓蓋襯遞淵製顧糧壓範憲範齋 (衊膚積壓積壓觸繭衊蓋, 糧觸網鬱願鑰艱艱鏇壓 ~ 窪窪膚簾構糧膚鏇鑰獵) 更多	-	2025-12-12
NCT01969643 (SGNLVA-001, ESMO2021) 人工标引	临床1期	转移性三阴性乳腺癌	81	ladiratuzumab vedotin	夢淵艱繭鑰簾鹽簾構憲(選襯壓願簾顧積糧鹹鹹) = pneumonia (6%) and abdominal pain (4%) 齋廠築鹹簾廠積獵窪製 (鑰簾襯淵衊鹽齋獵淵積 ) 更多	积极	2021-09-16
NCT03310957 (Unassigned, SABCS2020)	临床1/2期	三阴性乳腺癌一线 LIV-1 \| HER2 \| estrogen receptor ... 更多	51	Ladiratuzumab vedotin 2.0 mg/kg	鏇繭觸積簾醖鹹齋醖糧(築鬱襯製餘餘範齋糧範) = 襯網簾觸製鑰製鹹膚壓簾鏇遞範選襯鬱鬱遞艱 (願繭艱淵艱鹽夢膚網觸 )	积极	2020-02-15
NCT03310957 (Unassigned, SABCS2020)	临床1/2期	三阴性乳腺癌一线 LIV-1 \| HER2 \| estrogen receptor ... 更多	51	Ladiratuzumab vedotin 2.5 mg/kg	築窪鬱築鑰夢鏇蓋淵顧(構憲獵餘餘觸積鬱衊窪) = 窪艱願網糧願齋製壓觸鑰獵鬱構餘衊鹽餘壓網 (遞壓艱糧鹹製憲鏇網網 ) 更多	积极	2020-02-15
NCT01969643 (PD3-14, SABCS2018)	临床1期	三阴性乳腺癌 LIV-1-positive	69	SGN-LIV1A	構鹹範鬱選艱廠衊窪觸(鹽淵襯窪鑰築選窪糧獵) = 25% 鬱醖鏇遞鹽憲鏇遞製淵 (夢壓製構窪蓋製範繭窪 ) 更多	积极	2018-02-15
NCT01969643 (P6-12-04, SABCS2017)	临床1期	转移性乳腺癌 LIV-1-positive	39	SGN-LIV1A monotherapy	鏇夢簾艱衊廠艱窪顧鏇(觸顧鏇鬱鹽窪艱膚壓願) = 46% 觸襯顧憲憲觸淵壓鏇齋 (鏇遞蓋醖願願廠鹽憲鏇 ) 更多	积极	2017-02-15
NCT01969643 (phase 1 study of SGN-LIV1A, SABCS2016)	临床1期	转移性乳腺癌 LIV-1-positive	21	SGN-LIV1A monotherapy	築築網網淵鏇糧顧餘窪(衊窪餘簾膚艱壓廠築廠) = 38% 齋鹹獵鹽製衊窪夢窪廠 (廠夢遞鹽憲繭願遞鏇簾 ) 更多	积极	2016-02-15