BT-7480(BT-7480) - 药物靶点：4-1BB x nectin-4_在研适应症：晚期恶性实体瘤，Nectin-4阳性晚期恶性实体瘤_专利_临床

概要

基本信息

药物类型

合成多肽

别名

BT 7480、BT-7480、BT7480

靶点

4-1BB x nectin-4

作用方式

激动剂、抑制剂、刺激剂

作用机制

4-1BB激动剂(肿瘤坏死因子受体超家族成员9激动剂)、nectin-4抑制剂(细胞黏附分子nectin-4抑制剂)、细胞毒性T淋巴细胞刺激剂

治疗领域

肿瘤

在研适应症

晚期恶性实体瘤Nectin-4阳性晚期恶性实体瘤

非在研适应症-

原研机构

Bicycle Therapeutics Plc

在研机构

Bicycle Therapeutics Plc

非在研机构-

权益机构-

最高研发阶段临床1/2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

1

项与 BT-7480 相关的临床试验

NCT05163041

/ Active, not recruiting临床1/2期

Phase 1/2 Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT7480 in Patients With Nectin-4 Associated Advanced Malignancies

This clinical study is evaluating a drug called BT7480 alone and in combination with nivolumab in participants with advanced solid tumors associated with Nectin-4 expression.
The main goals of the study are to:
* Find the recommended dose of BT7480 that can be given safely to participants alone and in combination with nivolumab
* Learn about the side effects and effectiveness of BT7480 alone and in combination with nivolumab
* Learn about the effect BT7480 has on the body and how BT7480 is cleared by the body
* Learn about the side effects and effectiveness of BT7480 in patients with reduced kidney function

开始日期2021-11-02

申办/合作机构

Bicycle Therapeutics Plc

100 项与 BT-7480 相关的临床结果

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100 项与 BT-7480 相关的转化医学

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100 项与 BT-7480 相关的专利（医药）

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2

项与 BT-7480 相关的文献（医药）

2022-07-28·Journal of medicinal chemistry1区 · 医学

Discovery and Optimization of a Synthetic Class of Nectin-4-Targeted CD137 Agonists for Immuno-oncology

1区 · 医学

Article

作者: Jeffrey, Phil ; Kristensson, Julia ; Upadhyaya, Punit ; Repash, Elizabeth ; Keen, Nicholas ; Ma, Jun ; Kublin, Jessica ; McDonnell, Kevin ; Luus, Lia ; Lahdenranta, Johanna ; Hurov, Kristen ; Mudd, Gemma E.

CD137 (4-1BB) is a co-stimulatory receptor on immune cells and Nectin-4 is a cell adhesion molecule that is overexpressed in multiple tumor types. Using a series of poly(ethylene glycol) (PEG)-based linkers, synthetic bicyclic peptides targeting CD137 were conjugated to Bicycles targeting Nectin-4. The resulting bispecific molecules were potent CD137 agonists that require the presence of both Nectin-4-expressing tumor cells and CD137-expressing immune cells for activity. A multipronged approach was taken to optimize these Bicycle tumor-targeted immune cell agonists by exploring the impact of chemical configuration, binding affinity, and pharmacokinetics on CD137 agonism and antitumor activity. This effort resulted in the discovery of BT7480, which elicited robust CD137 agonism and maximum antitumor activity in syngeneic mouse models. A tumor-targeted approach to CD137 agonism using low-molecular-weight, short-acting molecules with high tumor penetration is a yet unexplored path in the clinic, where emerging data suggest that persistent target engagement, characteristic of biologics, may lead to suboptimal immune response.

2021-11-01·Journal for immunotherapy of cancer2区 · 医学

BT7480, a novel fully synthetic Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™) induces tumor localized CD137 agonism

2区 · 医学

ArticleOA

作者: Witty, David ; Jeffrey, Phil ; Kristensson, Julia ; Repash, Elizabeth ; Hurov, Kristen ; Campbell, Carly ; Kelly, Mike ; Blakemore, Stephen ; Kanakia, Drasti ; McDonnell, Kevin ; Ma, Jun ; Upadhyaya, Punit ; Cohen, Heather ; Brandish, Philip ; Haines, Eric ; Lahdenranta, Johanna ; You, Fanglei ; Keen, Nicholas

Background:

CD137 (4-1BB) is an immune costimulatory receptor with high therapeutic potential in cancer. We are creating tumor target-dependent CD137 agonists using a novel chemical approach based on fully synthetic constrained bicyclic peptide (Bicycle®) technology. Nectin-4 is overexpressed in multiple human cancers that may benefit from CD137 agonism. To this end, we have developed BT7480, a novel, first-in-class, Nectin-4/CD137 Bicycle tumor-targeted immune cell agonist™ (Bicycle TICA™).

Methods:

Nectin-4 and CD137 co-expression analyses in primary human cancer samples was performed. Chemical conjugation of two CD137 Bicycles to a Nectin-4 Bicycle led to BT7480, which was then evaluated using a suite of in vitro and in vivo assays to characterize its pharmacology and mechanism of action.

Results:

Transcriptional profiling revealed that Nectin-4 and CD137 were co-expressed in a variety of human cancers with high unmet need and spatial proteomic imaging found CD137-expressing immune cells were deeply penetrant within the tumor near Nectin-4-expressing cancer cells. BT7480 binds potently, specifically, and simultaneously to Nectin-4 and CD137. In co-cultures of human peripheral blood mononuclear cells and tumor cells, this co-ligation causes robust Nectin-4-dependent CD137 agonism that is more potent than an anti-CD137 antibody agonist. Treatment of immunocompetent mice bearing Nectin-4-expressing tumors with BT7480 elicited a profound reprogramming of the tumor immune microenvironment including an early and rapid myeloid cell activation that precedes T cell infiltration and upregulation of cytotoxicity-related genes. BT7480 induces complete tumor regressions and resistance to tumor re-challenge. Importantly, antitumor activity is not dependent on continuous high drug levels in the plasma since a once weekly dosing cycle provides maximum antitumor activity despite minimal drug remaining in the plasma after day 2. BT7480 appears well tolerated in both rats and non-human primates at doses far greater than those expected to be clinically relevant, including absence of the hepatic toxicity observed with non-targeted CD137 agonists.

Conclusion:

BT7480 is a highly potent Nectin-4-dependent CD137 agonist that produces complete regressions and antitumor immunity with only intermittent drug exposure in syngeneic mouse tumor models and is well tolerated in preclinical safety species. This work supports the clinical investigation of BT7480 for the treatment of cancer in humans.

74

项与 BT-7480 相关的新闻（医药）

2025-10-23

·肿瘤药学杂志

抗体偶联药物在乳腺癌精准治疗中的创新靶点与多策略转化研究进展

本文刊登于《肿瘤药学》2025, 15(4): 444-454. DOI: 10.3969/j.issn.2095-1264.2025.04.02. 【引用本文】马艺文, 李晓睿, 姜翠, 等. 抗体偶联药物在乳腺癌精准治疗中的创新靶点与多策略转化研究进展[J]. 肿瘤药学, 2025, 15(4): 444-454. DOI: 10.3969/j.issn.2095-1264.2025.04.02. 作者：马艺文，李晓睿，姜翠，鄂颖，蒋雷，刘军，孙涛通信作者：孙涛，大连理工大学附属肿瘤医院/中国医科大学附属肿瘤医院/辽宁省肿瘤医院，博士，主任医师。乳腺癌是全球女性发病率最高的恶性肿瘤，在中国也呈现出显著的疾病负担。2022年，中国新发乳腺癌病例约42万例［1］。根据激素受体（hormone receptor，HR）和人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）的表达差异，乳腺癌可分为3种主要分子亚型：即HR阳性/HER2阴性型（HR+/HER2-，占60%～70%）、HER2阳性型（占15%～20%）和三阴性乳腺癌（triple-negative breast cancer， TNBC，占10%～15%）。这些亚型在治疗策略与预后方面存在显著差异。针对HR+/HER2-型患者，内分泌治疗联合CDK4/6抑制剂已成为标准治疗方案，但部分患者因耐药导致复发风险升高。HER2阳性型乳腺癌曾因侵袭性强、预后差的特点而备受关注，直至抗HER2靶向药物问世后，患者的生存结局才得以显著改善。然而，TNBC因缺乏有效的治疗靶点，长期依赖化疗且易发生转移和复发，成为临床治疗的难点。因此，尽管乳腺癌治疗已取得重大进展，但仍需探索高效低毒的创新疗法，以克服当前治疗策略的局限性［2］。抗体偶联药物（antibody-drug conjugate，ADC）的问世实现了靶向治疗与细胞毒性药物的创新融合，开启了肿瘤精准治疗的新时代。传统化疗因存在全身毒性且缺乏靶向性而备受诟病，单克隆抗体虽能实现特异性靶向递送，但其单药疗效往往有限，而ADC可通过化学连接子将靶向抗体与强效细胞毒性药物偶联，既能够实现对肿瘤细胞的特异性精准杀伤，又显著降低了对正常组织的损伤，因此被誉为“魔法子弹”。2013年，首款针对HER2阳性乳腺癌的ADC恩美曲妥珠单抗（trastuzumab emtansine， T-DM1）获批上市，显著改善了晚期HER2阳性乳腺癌患者的预后，成为抗HER2治疗的重要策略［3］。此后，以德曲妥珠单抗（trastuzumab deruxtecan， DS-8201a， T-DXd）为代表的第二代ADC进一步突破了传统靶向治疗的局限。其独特的旁观者效应可有效杀伤邻近的异质性肿瘤细胞，且在HER2低表达患者中展现出突破性疗效，显著拓宽了HER2靶向治疗的适用人群［4］。对于TNBC，靶向滋养层细胞表面抗原2（trophoblast cell surface antigen 2，TROP2）的ADC戈沙妥珠单抗（sacituzumab govitecan，SG）的获批，成功填补了该亚型靶向治疗的空白［5］。 ADC已彻底改变乳腺癌的治疗格局。当前，新型ADC的研发正蓬勃推进，包括新靶点抗体开发（如B7-H3、B7-H4、Nectin-4和HER3等）、双特异性靶向策略探索和双载荷ADC研发等方向。这些创新策略有望显著提升疗效、优化安全性并拓展适应证。随着更多新型ADC进入临床试验阶段，乳腺癌的治疗正朝着高效低毒、精准可及的方向持续迈进。本文将重点聚焦乳腺癌领域ADC的作用机制，并系统梳理新型ADC的研发进展。 1 ADC的作用机制 ADC通过结合靶抗原、内化转运、接头酶切或降解及胞内有效载荷释放的级联反应实现精准靶向治疗。 1.1　靶向肿瘤相关抗原的抗体靶向肿瘤相关抗原的抗体能够识别在肿瘤细胞中高表达而在非恶性细胞中低表达或不表达的抗原。在乳腺癌中，HER2和TROP2是经典的ADC靶点。HER2在约20%的乳腺癌患者中过表达，靶向HER2的ADC包括T-DM1、DS-8201a和维迪西妥单抗（disitamab vedotin， RC48）等。TROP2在TNBC中高表达，以TROP2为靶点的ADC包括SG、Dato-DXd（datopotamab deruxtecan）和芦康沙妥珠单抗（sacituzumab tirumotecan，SKB264）等。ADC中的抗体部分通过特异性结合肿瘤细胞表面受体实现靶向递送，通常还会经人源化改造，以降低免疫原性并延长半衰期［6］。 1.2　连接子 ADC的连接子直接影响细胞毒性有效载荷的释放效率与药物稳定性，在保障ADC的疗效和安全性中发挥关键作用。ADC的连接子主要分为不可裂解和可裂解两种类型。不可裂解连接子（如T-DM1中使用的硫醚连接子），其降解依赖于抗体部分在溶酶体内的完全降解，因此疗效与靶抗原（如HER2和TROP2）的表达水平和内吞效率密切相关。这类连接子通常具有更优的系统稳定性，脱靶毒性风险较低［7］。可裂解连接子（如DS-8201和Dato-DXd中的四肽连接子、SG中的CL2A连接子），可借助肿瘤微环境的特异性酶或低pH条件实现特异性裂解，并释放有效载荷，但也可能在循环系统中发生非特异性裂解，导致有效载荷过早释放，进而增加脱靶毒性的风险［8-10］。 1.3　细胞毒性有效载荷 ADC中的细胞毒性载荷大致可分为微管抑制剂与DNA损伤剂两类。微管抑制剂包括美登素衍生物（mertansine， DM1）、甲基澳瑞他汀E（monomethyl auristatin E，MMAE）等，该类抑制剂可通过阻断微管聚合来抑制细胞分裂，对处于分裂期的肿瘤细胞具有杀伤作用［11］。DNA损伤剂则包括德卢替康（deruxtecan，DXd）、伊立替康活性代谢物（7 - 乙基 - 10 - 羟基喜树碱，7-Ethyl-10-hydroxycamptothecin，SN-38）、拓扑异构酶Ⅰ抑制剂KL610023等，该类损伤剂通过破坏DNA结构实现细胞杀伤，且对静息期细胞同样具有杀伤效果［12］。 2 靶向HER2和TROP2的ADC 在乳腺癌中，靶向HER2和TROP2的ADC最为常见（表1）。 2.1　靶向HER2的ADC 目前已经上市的靶向HER2的ADC包括T-DM1、DS-8201a和RC48。 2.1.1　T-DM1　基于Ⅲ期临床试验EMILIA和KATHERINE的研究结果，T-DM1已获批用于 HER2阳性晚期乳腺癌的二线治疗，以及接受过以紫杉烷类联合曲妥珠单抗为基础的新辅助治疗后仍残存侵袭性病灶的HER2阳性早期乳腺癌患者的辅助治疗。EMILIA试验是一项对比T-DM1与卡培他滨联合拉帕替尼方案二线治疗HER2阳性转移性乳腺癌患者的Ⅲ期临床研究，结果显示，T-DM1组患者的中位无进展生存期（median progression-free survival，mPFS）显著优于联合化疗组（9.6个月 vs. 6.4个月），中位总生存期（median overall survival，mOS）也较联合化疗组显著延长（29.9个月 vs. 25.9个月）［3， 13］。KATHERINE试验的初步结果表明，在新辅助治疗后存在残留病灶的HER2阳性早期乳腺癌患者中，与曲妥珠单抗相比，T-DM1辅助治疗可显著提高患者的3年无侵袭性疾病生存率（88.3% vs. 77.0%）［14］。 2.1.2　DS-8201a　基于DESTINY-Breast03和DESTINY-Breast04两项关键研究结果，新一代ADC DS-8201a已获批用于治疗既往接受过一种或一种以上抗HER2药物治疗的不可切除或转移性HER2阳性乳腺癌成人患者，以及既往在转移性疾病阶段接受过至少一种系统治疗的，或在辅助化疗期间或完成辅助化疗之后6个月内复发的、不可切除或转移性HER2低表达乳腺癌成人患者。DESTINY-Breast03研究将DS-8201a与T-DM1进行头对头比较，结果显示，DS-8201a组患者的mPFS显著优于T-DM1组（29.0个月 vs. 7.2个月），mOS亦显著延长（52.6个月 vs. 42.7个月）［15］。随着随访时间延长，DS-8201a持续展现出优于T-DM1的疗效，且安全性可控。由于DS-8201a的细胞毒性载荷DXd具有较高的膜通透性，使其具备强大的旁观者效应，在HER2表达高度异质性的肿瘤中同样能够发挥抗肿瘤活性［16］。因此，DESTINY-Breast04研究纳入了既往接受过一线或二线化疗的HER2低表达乳腺癌患者，研究发现，与医生选择的化疗方案相比，DS-8201a可显著改善患者的mPFS（9.9个月vs. 5.1个月）和OS（23.4个月vs. 16.8个月）［4］。该研究直接推动NCCN临床实践指南将HER2低表达乳腺癌（IHC 1+/2+且FISH-）确立为独立治疗亚型，重塑了乳腺癌分子分型框架，开启了HER2低表达乳腺癌早期治疗的新格局。 2.1.3　RC48　靶向HER2的ADC RC48同样具有旁观者效应。该药目前已在中国获批HER2阳性胃癌的适应证，但尚未获批乳腺癌相关适应证。根据Ⅰ/Ⅰb期C001 CANCER（开放性、单臂设计）研究结果，RC48治疗HER2阳性晚期乳腺癌的客观缓解率（objective response rate，ORR）为42.9%，mPFS为5.7个月；在HER2低表达乳腺癌患者中，ORR为33.3%，mPFS为5.1个月［17］。安全性分析显示其不良事件谱与既往研究一致，未报告新的治疗相关不良事件。另一款靶向HER2的ADC——trastuzumab duocarmazine （SYD985）的Ⅲ期TULIP研究已完成。该研究结果显示，SYD985组HER2阳性晚期乳腺癌患者的mPFS为7.0个月，显著优于医生选择化疗组的4.9个月［18］。然而，SYD985组眼毒性的发生率高达78.1%，导致治疗中断率升高（SYD985组35.4% vs.医生选择化疗组 5.8%），其长期安全性仍需进一步评估。ARX788是无旁观者效应的新一代ADC。在Ⅲ期ACE-Breast-02研究中，ARX788治疗HER2阳性晚期乳腺癌的mPFS达到11.3个月，显著优于拉帕替尼+卡培他滨方案组的5.8个月［19-20］。我国自主研发的ADC BL-M07D1在Ⅰ期临床研究中展现出潜在抗肿瘤活性：15例HER2阳性晚期乳腺癌患者的ORR为60%，疾病控制率（disease control rate，DCR）达100%［21］。目前，BL-M07D1的Ⅲ期临床试验正在评估其在HER2阳性乳腺癌术后辅助治疗中的疗效，结果尚未公布。其他靶向HER2的新一代ADC，如A166（NCT05311397）和FS-1502（NCT03944499）等，仍在陆续开展临床试验，早期临床数据显示出可管理的安全性特征、良好的药代动力学特性和抗肿瘤活性，或可为HER2阳性乳腺癌患者提供新的治疗选择。 2.2　靶向TROP2的ADC SG是首个上市的靶向TROP2的ADC，已获批用于TNBC的二线及以上治疗，以及既往接受过内分泌治疗且在转移性疾病阶段接受过至少2种系统治疗的不可切除局部晚期或转移性的HR+/HER2-乳腺癌的治疗。SG经典的Ⅲ期临床试验ASCENT研究显示，在TNBC患者中，SG组的mPFS较化疗组显著延长（4.8个月vs. 1.7个月），mOS亦显著改善（11.8个月vs. 6.9个月），且SG安全性可控，治疗相关停药发生率≤5%，未出现治疗相关死亡［22］。此外，Ⅲ期TROPiCS-02研究聚焦HR+/HER2-乳腺癌，同样评估了SG与化疗的疗效差异，结果提示SG可显著改善经多线治疗的HR+/HER2-转移性乳腺癌患者的mPFS（5.5个月vs. 4.0个月）和mOS（14.4个月vs. 11.2个月）［23］。ASCENT系列的其他研究正在评估SG一线治疗及联合治疗方案的疗效，有望进一步拓展其适用人群。 2025年1月，由阿斯利康研发的新一代TROP2-ADC药物Dato-DXd被美国食品药品监督管理局（Food and Drug Administration，FDA）批准用于治疗既往接受过内分泌治疗和化疗的不可切除或转移性HR+/HER2-乳腺癌成人患者。支持此次获批的Ⅲ期TROPION-Breast01研究评估了Dato-DXd在HR+/HER2-晚期乳腺癌后线治疗中的疗效，结果显示Dato-DXd组的mPFS显著优于化疗组（6.9个月vs. 4.9个月），且≥3级TRAEs发生率显著降低（20.8% vs. 44.7%）［24］。目前，该研究的中期OS数据尚未成熟，但已呈现出获益趋势（HR=0.84，95% CI：0.62~1.14）。 2024年11月27日，我国首个靶向TROP2的ADC SKB264获国家药品监督管理局批准，用于治疗既往接受过至少2种系统治疗的不可切除的局部晚期或转移性TNBC成人患者。一项Ⅲ期OptiTROP-Breast01研究结果显示，SKB264较化疗可显著延长患者的mPFS（6.7个月vs. 2.5个月），并提高ORR（45.4% vs. 12.0%），但mOS尚未达到。SKB264的安全性可控，最常见的3级或更高级别的不良反应是中性粒细胞计数减少，SKB264组的发生率为34.6%，化疗组为47.0%［25］。该研究结果支持SKB264作为转移性TNBC经治患者的新治疗选择。 3 新型ADC 目前，全球制药企业正在陆续开发新型ADC，其创新机制多聚焦于靶点多元化和载荷多功能化（表1）。 3.1　创新靶点多项临床试验正探索B7-H3、B7-H4、Nectin-4、HER3及LIV-1等其他肿瘤相关表面抗原作为ADC治疗靶点的潜力，这些创新靶点ADC的开发旨在突破现有治疗格局，扩大适应证覆盖范围，尤其为对标准治疗耐药或难治性实体瘤患者提供新的治疗选择。 3.1.1　B7-H3　B7-H3（CD276）属于B7免疫检查点分子家族，在非小细胞肺癌、乳腺癌等多种实体瘤中呈特异性高表达，且与肿瘤免疫逃逸、侵袭性及不良预后相关［26-27］。目前靶向B7-H3的ADC多处于早期研发阶段，尚无药物获批上市。DS-7300 是首个进入Ⅲ期临床研究阶段的B7-H3-ADC，该临床试验方案主要针对晚期食管鳞状细胞癌患者，尚未纳入乳腺癌患者。但DS-7300针对转移性实体瘤（含HER2低表达乳腺癌患者）的Ⅰb/Ⅱ期临床研究（NCT06330064）正在招募中，目前尚未公布研究结果。临床前研究显示，DS-7300在体外、患者来源的异种移植（patient-derived xenograft，PDX）小鼠及食蟹猴等模型中，对表达B7-H3的肿瘤具有有效的抗肿瘤活性，且具备可接受的药代动力学特征与耐受性［28］。2023年，ESMO大会公布的DS-7300Ⅰ/Ⅱ期研究（NCT04145622）更新数据显示，在121例晚期实体瘤（无乳腺癌）患者中，约30%的患者达到客观缓解［29］。其他靶向B7-H3的ADC（如MGC018）的临床前研究及实体瘤中Ⅰ期剂量递增临床试验（NCT05293496）结果提示其具有良好的抗肿瘤活性与安全性［30］。Ⅰ/Ⅱ期临床试验（NCT03729596）正探索MGC018在晚期实体瘤患者中的安全性、药代动力学、药效学及抗肿瘤活性。2021年，ASCO大会公布的Ⅰ期剂量递增临床试验结果显示，MGC018在实体瘤治疗中初步展现出对黑色素瘤的抗肿瘤活性特征，其安全性处于临床可控范围内，但相关扩展性研究数据仍需后续报道［31］。 3.1.2　B7-H4　B7-H4（VTCN1）与B7-H3同属B7免疫检查点分子家族，在乳腺癌、卵巢癌、肺癌等多种实体瘤中高表达，可通过抑制T细胞功能促进肿瘤免疫逃逸［26， 32］。B7-H4因其高表达与不良预后相关，成为ADC研发的热门靶点之一。目前尚无靶向B7-H4的ADC获批上市。HS-20089是一款靶向B7-H4的ADC，已进入Ⅰ期临床研究（NCT06336707）。2023年，ESMO大会公布了该药物治疗实体瘤的初期数据：在16例TNBC患者中，PR率为37.5%（NCT05263479）［33］。2025年3月，HS-20089的Ⅲ期临床试验已在卵巢癌、输卵管癌或原发性腹膜癌等其他实体瘤中展开，乳腺癌适应证仍需进一步探索。阿斯利康研发的AZD8205在临床前研究中显示出治疗B7-H4高表达肿瘤的潜力［34］。其Ⅰ/Ⅱa期临床试验（NCT05123482）初步结果显示，在以≥1.6 mg·kg-1剂量治疗的43例患者中，9例患有卵巢癌、乳腺癌或子宫内膜癌的患者确认部分缓解（20.9%），且安全性可控，最常见的不良反应是恶心（58.7%）、中性粒细胞减少症（56.5%）和贫血（50.0%），目前尚未公布进一步的研究数据［35］。此外，SGN-B7H4V（NCT05194072）等其他靶向B7-H4的ADC在临床前模型中显示出抗肿瘤活性［36］，其Ⅰ期研究初步结果显示，在25例接受SGN-B7H4V治疗的可评估乳腺癌患者中，7例获得客观缓解，且安全性良好［37］。 3.1.3　Nectin-4　Nectin-4是一种细胞黏附分子，在人胚胎和胎盘组织中特异性富集，而在成人正常组织中表达水平显著下降［38］。靶向Nectin-4的ADC enfortumab vedotin（EV）已获批用于治疗转移性尿路上皮癌［39］。临床前研究显示，EV在表达Nectin-4的乳腺癌、膀胱癌、胰腺癌和肺癌异种移植模型中均可抑制肿瘤的生长，尤其在乳腺癌模型中可诱导肿瘤消退［40］。2024年，ASCO大会公布了Ⅱ期EV-202研究（NCT04225117）的初步结果：在TNBC队列中，EV的ORR为8%，mPFS为3.5个月；在HR+/HER2-乳腺癌队列中，ORR为7%，mPFS为5.4个月［41］。该结果表明，EV在乳腺癌中具有一定的抗肿瘤活性，且安全性总体可控，但仍需更大样本量的研究进一步验证其临床价值。 3.1.4　HER3　HER3与HER2同属于表皮生长因子受体家族。HER3虽缺乏激酶活性，但常与HER2等其他受体形成异二聚体，激活下游信号通路（如PI3K/AKT），进而促进肿瘤细胞增殖、转移及耐药。HER3过表达通常被认为与HER2阳性或HR+/HER2-亚型的耐药性相关，因此，HER3成为ADC开发的潜在靶点之一［42］。靶向HER3的ADC HER3-DXd已进入Ⅰ/Ⅱ期临床试验，结果显示，其在转移性HR+/HER2-乳腺癌患者中的ORR为30.1%，mPFS为7.4个月；在TNBC患者中的ORR为22.6%，mPFS为5.5个月；在HER2阳性乳腺癌患者中的ORR为42.9%，mPFS为11.0个月；任何级别不良反应中最常见的为恶心（79.7%）、血小板计数减少（62.1%）、中性粒细胞计数减少（61.0%）［43］。这些结果提示，HER3-DXd在既往接受过大量治疗的不同临床亚型乳腺癌患者中显示出可控的安全性和持久的疗效，但仍需进一步的循证依据评估其在表达HER3的转移性乳腺癌患者中的疗效。 3.1.5　LIV-1　LIV-1（SLC39A6）是一种锌转运蛋白，其表达水平与肿瘤的进展和转移相关。在HR+/HER2-乳腺癌中，LIV-1呈高表达状态，且与肿瘤转移风险和不良预后显著相关［44］。由于LIV-1在肿瘤组织中特异性高表达，而在正常组织中低表达，这一特性使其成为ADC开发的潜在靶点。目前，全球尚无靶向LIV-1的ADC获批上市。临床前研究表明，靶向LIV-1的ADC SGN-LIV1A对表达LIV-1的肿瘤模型具有特异性抗肿瘤活性［45］。针对TNBC的Ⅱ期临床试验（NCT03310957）正在评估SGN-LIV1A的疗效，尚未公布研究结果。其他靶向LIV-1的ADC，如国产新药BRY812，目前已完成临床前研究，正在招募患者进入Ⅰ期临床试验阶段（NCT06038058）。 3.2　双特异性ADC 双特异性ADC的设计策略主要包含两类：靶向同一抗原的不同表位，或同时靶向两个不同抗原。通过组合两种单克隆抗体或构建双特异性抗体，这类ADC可形成具有空间协同效应的靶向结构。其双特异性结合特性不仅增强了抗原结合亲和力，还能通过交叉连接促进受体聚集，从而显著提升对肿瘤细胞的特异性识别率，尤其适用于靶抗原低表达的肿瘤微环境，可突破单一抗体的靶向局限性［46］。在乳腺癌治疗领域，双靶向策略常聚焦于HER2与其他靶点（如HER3、TROP2）的联合，或免疫检查点分子（如PD-L1、B7-H3）的共靶向。如靶向HER2的ECD4和ECD2结构域双表位的ADC ZW49，其双特异性双表位抗体较曲妥珠单抗具有更强的内化能力和抗肿瘤活性［47］。2022年，ESMO大会公布了ZW49的Ⅰ期临床试验（NCT03821233）数据：在29例接受ZW49治疗的患者中，ORR为28%，DCR为72%，其安全性可控，最常见的不良反应包括角膜炎（42%）、脱发（25%）和腹泻（21%）［48］。而另一种靶向HER2双表位的ADC JSKN003在Ⅰ期临床试验（NCT05494918）中展示出较好的疗效：总体ORR为50.0%，DCR为90.6%；其中HER2低表达乳腺癌队列的ORR为40.0%，HER2高表达乳腺癌队列的ORR为80.0%，且耐受性良好［49］。目前，JSKN003正在开展Ⅲ期临床试验，以评估其对HER2低表达乳腺癌患者的疗效和安全性。此外，靶向EGFR/HER3的双抗ADC BL-B01D1已完成Ⅰ期临床试验，初步结果显示：在174例可评价的EGFR/HER3表达阳性实体瘤患者中，ORR约为34%，mPFS约为6.9个月，且安全性良好，最常见的不良反应是中性粒细胞减少症（47%）、贫血（39%）［50］。目前，其Ⅲ期临床试验正在入组患者，旨在评估该药在晚期HR+/HER2-乳腺癌和TNBC患者中的疗效和安全性。其他在研的双特异性ADC如AZD9592（靶向EGFR/c-MET）正在进行Ⅰ期临床试验（NCT05647122）。 3.3　双载荷ADC 双载荷ADC通过连接两种不同作用机制的有效载荷，实现细胞毒性药物的协同增效，并能通过交叉抑制肿瘤信号通路，在体外研究中有效延缓肿瘤获得性耐药细胞克隆的形成，从而有效克服肿瘤耐药性［51］。目前，乳腺癌领域尚无双载荷ADC进入临床试验阶段。全球首个靶向EGFR/HER3的双抗-双载荷ADC JSKN021，由双特异性抗体与拓扑异构酶Ⅰ（topoisomerase Ⅰ，TOPO1）抑制剂及MMAE共同偶联而成。2025年，美国癌症研究协会（American Association for Cancer Research，AACR）年会公布的临床前研究显示，JSKN021能够在应对肿瘤异质性的同时最大限度地降低“靶向脱瘤”毒性，具有增强的稳定性和更优的均一性，可能是一种极具转化价值的新型抗肿瘤治疗药物［52］。另一款靶向TROP2的双载荷ADC KH815，同时荷载了TOPO1抑制剂与RNA聚合酶Ⅱ（Pol Ⅱ）抑制剂。临床前研究显示：该药物对不同TROP2表达水平的肿瘤细胞均具有纳摩尔级杀伤效力；在多个瘤种的细胞源性异种移植（cell-derived xenograft， CDX）和PDX模型中，表现出剂量依赖性肿瘤生长抑制；并且有可能克服对荷载TOPO1抑制剂的ADC的耐药性［53］。其他双载荷ADC（如KHN922与DXC018）正逐步进入研发阶段。其中，KHN922同时携带TOPO1抑制剂与Pol Ⅱ抑制剂，DXC018则联合抗代谢物与TOPO1抑制剂［54-55］。虽然双载荷ADC在克服肿瘤的异质性和抗耐药性方面显示出潜在优势，但也必须警惕其可能出现的加和或协同毒性。如双表位双抗ADC MEDI4276因安全性问题已被终止开发：尽管其临床前数据显示良好的抗肿瘤活性，但Ⅰ期临床试验数据显示，最常见的3/4级药物相关不良事件为转氨酶升高（21.3%），且有5例患者因药物相关不良事件导致治疗中断［56］。为优化治疗窗，研究者正开发多种正交偶联策略，以构建高均一性、明确药物抗体比的双载荷ADC［57］。这些策略可确保两种有效载荷的有效整合，优化协同作用，从而增强治疗效果并降低不良反应。 3.4　免疫刺激抗体偶联物（immunostimulatory antibody conjugate，ISAC） ISAC与传统ADC不同，其有效载荷多为免疫刺激分子，如Toll样受体7（Toll-like receptor 7， TLR7）、TLR8、TLR9激动剂或干扰素基因刺激蛋白（stimulator of interferon genes，STING）激动剂等。ISAC能够在直接杀伤肿瘤细胞的同时激活肿瘤微环境中的免疫应答，将“冷肿瘤”转化为“热肿瘤”，且具备与其他免疫检查点药物联合使用的潜在可能性［58］。目前，此类药物研发尚处于早期阶段，尚无针对乳腺癌的ISAC药物获批上市。SBT6050是一种荷载TLR8激动剂的ISAC药物，其Ⅰ/Ⅱb期临床试验（NCT05091528）中期数据显示，尽管SBT6050可成功诱导患者体内髓系细胞、NK细胞和T细胞活化，但在14例可评估患者中，总ORR仅7%，安全性尚可管理［59］。在接受SBT6050剂量为0.6 mg·kg-1的患者中，最常见（>25%）的治疗相关不良事件为寒战、腹泻、疲劳、低血压、注射部位反应、恶心、发热和呕吐。该研究结果表明，SBT6050在耐受剂量下治疗效果欠佳，研发难度较大。 BT7480是一种荷载CD137激动剂的ISAC药物。临床前研究数据证实，其可调控肿瘤免疫微环境的重编程，诱导T细胞浸润增加，且在体内模型中耐受性良好，但其临床缓解数据尚未公布［60］。荷载TLR7激动剂的ISAC药物NJH395，其临床前和Ⅰ期临床研究结果显示，以HER2为靶点的NJH395在HER2阳性非乳腺晚期恶性肿瘤患者中表现出了显著的抗肿瘤活性，且可通过触发局部免疫应答，导致肿瘤消退和免疫记忆，在临床前研究中显示出调控细胞因子释放和增强免疫原性的潜力［61］。XMT-2056是另一款在研的靶向HER2的ISAC（含STING激动剂载荷），临床前研究结果显示，其可诱导肿瘤消退［62］，目前正处于多中心、开放设计的Ⅰ期临床试验（NCT05514717）阶段。值得注意的是，该Ⅰ期临床试验因出现1例治疗相关的死亡事件被FDA暂停研究，经方案修订后，现已恢复剂量爬坡研究，目前尚未公布有效性数据。从药物研发进程角度分析，ISAC目前尚处于开发初始阶段。尽管该药物在理论层面具有明确的科学依据和良好的临床前数据，但其临床试验（尤其在剂量递增阶段）显示毒性显著增强。这一毒性问题可能成为其临床转化的关键制约因素。 4 总结与展望 ADC的问世是乳腺癌精准治疗领域的重大突破，其凭借独特的靶向递送机制与高效细胞毒效应的协同作用，重塑了不同分子亚型乳腺癌的临床治疗格局。然而，ADC在全面临床应用中仍面临多重亟待解决的问题：一方面，ADC的耐药机制复杂多样，如靶抗原表达下调或呈高异质性分布、溶酶体降解通路异常及载荷药物外排泵功能亢进等，均可能限制患者的长期获益；另一方面，ADC的安全性仍需进一步优化，新型ADC的研发需审慎权衡增强旁观者效应与诱发脱靶毒性之间的利弊。当前，针对新型靶点的ADC研发、双表位特异性ADC构建、双效细胞毒载荷ADC开发及免疫刺激型ADC设计等创新策略已进入临床前及临床研发阶段，这些策略通过多靶点协同作用机制及载荷药物功能优化，有望突破现有治疗的局限性，为乳腺癌患者提供更多新的治疗选择。［1］ BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA Cancer J Clin, 2024, 74(3): 229-263. DOI:10.3322/caac.21834. ［2］ XIONG X, ZHENG L W, DING Y, et al. Breast cancer: pathogenesis and treatments [J]. Signal Transduct Target Ther, 2025, 10(1): 49. DOI:10.1038/s41392-024-02108-4. ［3］ VERMA S, MILES D, GIANNI L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer [J]. N Engl J Med, 2012, 367(19): 1783-1791. DOI:10.1056/nejmoa1209124. ［4］ MODI S, JACOT W, YAMASHITA T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer [J]. N Engl J Med, 2022, 387(1): 9-20. DOI:10.1056/nejmoa2203690. ［5］ BARDIA A, HURVITZ S A, TOLANEY S M, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer [J]. N Engl J Med, 2021, 384(16): 1529-1541. DOI:10.1056/nejmoa2028485. ［6］ KANG S, KIM S B. Toxicities and management strategies of emerging antibody-drug conjugates in breast cancer [J]. Ther Adv Med Oncol, 2025, 17: 17588359251324889. DOI: 10.1177/17588359251324889. ［7］ LEWIS PHILLIPS G D, LI G, DUGGER D L, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate [J]. Cancer Res, 2008, 68(22): 9280-9290. DOI:10.1158/0008-5472.can-08-1776. ［8］ OGITANI Y, AIDA T, HAGIHARA K, et al. DS-8201a, A novel HER2-targeting ADC with a novel DNA topoisomerase Ⅰ inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1 [J]. Clin Cancer Res, 2016, 22(20): 5097-5108. DOI:10.1158/1078-0432.ccr-15-2822. ［9］ OKAJIMA D, YASUDA S, MAEJIMA T, et al. Datopotamab deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells [J]. Mol Cancer Ther, 2021, 20(12): 2329-2340. DOI:10.1158/1535-7163.mct-21-0206. ［10］ TOLANEY S M, CARDILLO T M, CHOU C C, et al. The mode of action and clinical outcomes of sacituzumab govitecan in solid tumors [J]. Clin Cancer Res, 2025, 31(8): 1390-1399. DOI:10.1158/1078-0432.ccr-24-1525. ［11］ YIN W, XU T Q, DING H Z, et al. Comparison of HER2-targeted affibody conjugates loaded with auristatin- and maytansine-derived drugs [J]. J Control Release, 2023, 355: 515-527. DOI:10.1016/j.jconrel.2023.02.005. ［12］ BOCCI M, ZANA A, PRINCIPI L, et al. In vivo activation of FAP-cleavable small molecule-drug conjugates for the targeted delivery of camptothecins and tubulin poisons to the tumor microenvironment [J]. J Control Release, 2024, 367: 779-790. DOI:10.1016/j.jconrel.2024.02.014. ［13］ DIÉRAS V, MILES D, VERMA S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial [J]. Lancet Oncol, 2017, 18(6): 732-742. DOI:10.1016/S1470-2045(17)30312-1. ［14］ VON MINCKWITZ G, HUANG C S, MANO M S, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer [J]. N Engl J Med, 2019, 380(7): 617-628. DOI:10.1056/nejmoa1814017. ［15］ CORTÉS J, HURVITZ S A, IM S A, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial [J]. Nat Med, 2024, 30(8): 2208-2215. DOI:10.1038/s41591-024-03021-7. ［16］ OGITANI Y, HAGIHARA K, OITATE M, et al. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity [J]. Cancer Sci, 2016, 107(7): 1039-1046. DOI:10.1111/cas.12966. ［17］ WANG J, LIU Y, ZHANG Q, et al. Disitamab vedotin, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpression and HER2-low advanced breast cancer: a phase Ⅰ/Ⅰb study [J]. Cancer Commun (Lond), 2024, 44(7): 833-851. DOI:10.1002/cac2.12577. ［18］ TURNER N, SAURA C, AFTIMOS P, et al. Trastuzumab duocarmazine in pretreated human epidermal growth factor receptor 2-positive advanced or metastatic breast cancer: an open-label, randomized, phase Ⅲ trial (TULIP) [J]. J Clin Oncol, 2025, 43(5): 513-523. DOI:10.1200/jco.24.00529. ［19］ SKIDMORE L, SAKAMURI S, KNUDSEN N A, et al. ARX788, a site-specific anti-HER2 antibody-drug conjugate, demonstrates potent and selective activity in HER2-low and T-DM1-resistant breast and gastric cancers [J]. Mol Cancer Ther, 2020, 19(9): 1833-1843. DOI:10.1158/1535-7163.mct-19-1004. ［20］ HU X, ZHANG Q, WANG L, et al. ACE-breast-02: a randomized phase Ⅲ trial of ARX788 versus lapatinib plus capecitabine for HER2-positive advanced breast cancer [J]. Signal Transduct Target Ther, 2025, 10(1): 56. DOI:10.1038/s41392-025-02149-3. ［21］ SONG E, YAO H, WANG Y, et al. 685P BL-M07D1, a HER2 antibody-drug conjugate in subjects with locally advanced or metastatic HER2 expressing breast cancer and other solid tumors [J]. Ann Oncol, 2023, 34: S478-S479. DOI:10.1016/j.annonc.2023.09.1871. ［22］ BARDIA A, RUGO H S, TOLANEY S M, et al. Final results from the randomized phase Ⅲ ASCENT clinical trial in metastatic triple-negative breast cancer and association of outcomes by human epidermal growth factor receptor 2 and trophoblast cell surface antigen 2 expression [J]. J Clin Oncol, 2024, 42(15): 1738-1744. DOI:10.1200/jco.23.01409. ［23］ RUGO H S, BARDIA A, MARMÉ F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial [J]. Lancet, 2023, 402(10411): 1423-1433. DOI:10.1016/S0140-6736(23)01245-X. ［24］ BARDIA A, JHAVERI K, IM S A, et al. Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer: primary results from TROPION-Breast01 [J]. J Clin Oncol, 2025, 43(3): 285-296. DOI:10.1200/jco.24.00920. ［25］ YIN Y, FAN Y, OUYANG Q, et al. Sacituzumab tirumotecan in previously treated metastatic triple-negative breast cancer: a randomized phase 3 trial [J]. Nat Med, 2025, 31(6): 1969-1975. DOI:10.1038/s41591-025-03630-w. ［26］ LUO Y M, YUAN Y, LIU D, et al. Targeting novel immune checkpoints in the B7-H family: advancing cancer immunotherapy from bench to bedside [J]. Trends Cancer, 2025, 11(6): 540-559. DOI:10.1016/j.trecan.2025.02.007. ［27］ KOUMPRENTZIOTIS I A, THEOCHAROPOULOS C, FOTEINOU D, et al. New emerging targets in cancer immunotherapy: the role of B7-H3 [J]. Vaccines (Basel), 2024, 12(1): 54. DOI:10.3390/vaccines12010054. ［28］ YAMATO M, HASEGAWA J, MAEJIMA T, et al. DS-7300a, a DNA topoisomerase I inhibitor, DXd-based antibody-drug conjugate targeting B7-H3, exerts potent antitumor activities in preclinical models [J]. Mol Cancer Ther, 2022, 21(4): 635-646. DOI:10.1158/1535-7163.mct-21-0554. ［29］ PATEL M R, DOI T, KOYAMA T, et al. 690P Ifinatamab deruxtecan (I-DXd; DS-7300) in patients with advanced solid tumors: Updated clinical and biomarker results from a phase Ⅰ/Ⅱ study [J]. Ann Oncol, 2023, 34: S481-S482. DOI:10.1016/j.annonc.2023.09.1876. ［30］ SCRIBNER J A, BROWN J G, SON T, et al. Preclinical development of MGC018, a duocarmycin-based antibody-drug conjugate targeting B7-H3 for solid cancer [J]. Mol Cancer Ther, 2020, 19(11): 2235-2244. DOI:10.1158/1535-7163.mct-20-0116. ［31］ JANG S, POWDERLY J D, SPIRA A I, et al. Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors [J]. J Clin Oncol, 2021, 39(15_suppl): 2631. DOI:10.1200/jco.2021.39.15_suppl.2631. ［32］ QI Y, HU L, JI C X, et al. B7-H4 reduces the infiltration of CD8+ T cells and induces their anti-tumor dysfunction in gliomas [J]. Neoplasia, 2024, 54: 101007. DOI:10.1016/j.neo.2024.101007. ［33］ WU J, ZHANG J, LI H, et al. First-in-human/phase Ⅰ trial of HS-20089, a B7-H4 ADC, in patients with advanced solid tumors [J]. Ann Oncol, 2023, 34: S336. DOI:10.1016/j.annonc.2023.09.558. ［34］ KINNEER K, WORTMANN P, COOPER Z A, et al. Design and preclinical evaluation of a novel B7-H4-directed antibody-drug conjugate, AZD8205, alone and in combination with the PARP1-selective inhibitor AZD5305 [J]. Clin Cancer Res, 2023, 29(6): 1086-1101. DOI:10.1158/1078-0432.ccr-22-2630. ［35］ MERIC-BERNSTAM F, NAITO Y, GAILLARD S, et al. Initial results from a first-in-human study of the B7-H4-directed antibody-drug conjugate (ADC) AZD8205 (puxitatug samrotecan) in patients with advanced/metastatic solid tumors [J]. Ann Oncol, 2024, 35: S485-S486. DOI:10.1016/j.annonc.2024.08.673. ［36］ GRAY E, ULRICH M, EPP A, et al. SGN-B7H4V, an investigational vedotin ADC directed to the immune checkpoint ligand B7-H4, shows promising activity in preclinical models [J]. J Immunother Cancer, 2023, 11(10): e007572. DOI:10.1136/jitc-2023-007572. ［37］ PEREZ C A, HENRY J T, LAKHANI N, et al. 660MO First-in-human study of SGN-B7H4V, a B7-H4-directed vedotin ADC, in patients with advanced solid tumors: Preliminary results of a phase Ⅰ study (SGNB7H4V-001) [J]. Ann Oncol, 2023, 34: S464-S465. DOI:10.1016/j.annonc.2023.09.1846. ［38］ KHOSRAVANIAN M J, MIRZAEI Y, MER A H, et al. Nectin-4-directed antibody-drug conjugates (ADCs): spotlight on preclinical and clinical evidence [J]. Life Sci, 2024, 352: 122910. DOI:10.1016/j.lfs.2024.122910. ［39］ POWLES T, VALDERRAMA B P, GUPTA S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer [J]. N Engl J Med, 2024, 390(10): 875-888. DOI:10.1056/nejmoa2312117. ［40］ CHALLITA-EID P M, SATPAYEV D, YANG P, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models [J]. Cancer Res, 2016, 76(10): 3003-3013. DOI:10.1158/0008-5472.can-15-1313. ［41］ GIORDANO A, AWAN AALI ALI, YANG BRUCE J, et al. Enfortumab vedotin (EV) in triple-negative breast cancer (TNBC) and HR+/HER2- breast cancer (BC) cohorts of EV-202 [J]. J Clin Oncol, 2024, 42(16_suppl): 1005. DOI:10.1200/jco.2024.42.16_suppl.1005. ［42］ PAPA F, GRINDA T, RASSY E, et al. Long road towards effective HER3 targeting in breast cancer [J]. Cancer Treat Rev, 2024, 129: 102786. DOI:10.1016/j.ctrv.2024.102786. ［43］ KROP I E, MASUDA N, MUKOHARA T, et al. Patritumab deruxtecan (HER3-DXd), a human epidermal growth factor receptor 3-directed antibody-drug conjugate, in patients with previously treated human epidermal growth factor receptor 3-expressing metastatic breast cancer: a multicenter, phase Ⅰ/Ⅱ trial [J]. J Clin Oncol, 2023, 41(36): 5550-5560. DOI:10.1200/jco.23.00882. ［44］ TAYLOR K M. The LIV-1 subfamily of zinc transporters: from origins to present day discoveries [J]. Int J Mol Sci, 2023, 24(2): 1255. DOI:10.3390/ijms24021255. ［45］ SUSSMAN D, SMITH L M, ANDERSON M E, et al. SGN-LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer [J]. Mol Cancer Ther, 2014, 13(12): 2991-3000. DOI:10.1158/1535-7163.mct-13-0896. ［46］ GU Y, WANG Z, WANG Y. Bispecific antibody drug conjugates: making 1+1>2 [J]. Acta Pharm Sin B, 2024, 14(5): 1965-1986. DOI:10.1016/j.apsb.2024.01.009. ［47］ WEISSER N E, SANCHES M, ESCOBAR-CABRERA E, et al. An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity [J]. Nat Commun, 2023, 14(1): 1394. DOI:10.1038/s41467-023-37029-3. ［48］ JHAVERI K, HAN H, DOTAN E, et al. Preliminary results from a phase Ⅰ study using the bispecific, human epidermal growth factor 2 (HER2)-targeting antibody-drug conjugate (ADC) zanidatamab zovodotin (ZW49) in solid cancers [J]. Ann Oncol, 2022, 33: S749-S750. DOI:10.1016/j.annonc.2022.07.589. ［49］ BEECROFT C, GAO B, PARK J, et al. Abstract CT179: safety and efficacy of JSKN003 in patients with advanced/metastatic solid tumors: a first-in-human, dose-escalation, multicenter, open-label, phase Ⅰ study [J]. Cancer Res, 2024, 84(7_Supplement): CT179. DOI:10.1158/1538-7445.am2024-ct179. ［50］ MA Y X, HUANG Y, ZHAO Y Y, et al. BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study [J]. Lancet Oncol, 2024, 25(7): 901-911. DOI:10.1016/S1470-2045(24)00159-1. ［51］ TAO J J, GU Y L, ZHOU W, et al. Dual-payload antibody-drug conjugates: Taking a dual shot [J]. Eur J Med Chem, 2025, 281: 116995. DOI:10.1016/j.ejmech.2024.116995. ［52］ XU T, LI F, LAI Z L, et al. JSKN021, an innovative site-specific dual-payload bispecific antibody drug conjugate targeting EGFR and HER3 exhibits potent preclinical activities [J]. Cancer Res, 2025, 85(8_Supplement_1): 5451. DOI:10.1158/1538-7445.am2025-5451. ［53］ ZHAO Y H, REN P F, GUAN M L, et al. KH815, a novel dual-payload TROP2-directed antibody-drug conjugate, shows potent antitumor efficacy in pre-clinical tumor model [J]. Cancer Res, 2025, 85(8_Supplement_1): 1585. DOI:10.1158/1538-7445.am2025-1585. ［54］ ZHAO Y H, REN P F, GUAN M L, et al. A novel dual-payload HER3-directed antibody-drug conjugate, shows potent antitumor efficacy in HER3-low in vivo tumor models [J]. Cancer Res, 2025, 85(8_Supplement_1): 1587. DOI:10.1158/1538-7445.am2025-1587. ［55］ GUO H H, DU Y, HUANG Y Y, et al. DXC018: a novel HER2 dual-payload bispecific ADC with promising potential for gastrointestinal cancers and other solid tumors [J]. Cancer Res, 2025, 85(8_Supplement_1): 2872. DOI:10.1158/1538-7445.am2025-2872. ［56］ PEGRAM M D, HAMILTON E P, TAN A R, et al. First-in-human, phase 1 dose-escalation study of biparatopic anti-HER2 antibody-drug conjugate MEDI4276 in patients with HER2-positive advanced breast or gastric cancer [J]. Mol Cancer Ther, 2021, 20(8): 1442-1453. DOI:10.1158/1535-7163.mct-20-0014. ［57］ LEVENGOOD M R, ZHANG X, HUNTER J H, et al. Orthogonal cysteine protection enables homogeneous multi-drug antibody-drug conjugates [J]. Angew Chem Int Ed Engl, 2017, 56(3): 733-737. DOI:10.1002/anie.201608292. ［58］ FU C, TONG W W, YU L F, et al. When will the immune-stimulating antibody conjugates (ISACs) be transferred from bench to bedside? [J]. Pharmacol Res, 2024, 203: 107160. DOI:10.1016/j.phrs.2024.107160. ［59］ KLEMPNER S J, BEERAM M, CHAN A, et al. Interim results of a phase Ⅰ/Ⅰb study of SBT6050 monotherapy and pembrolizumab combination in patients with advanced HER2-expressing or amplified solid tumors [J]. Annals of Oncology, 2021, 32: S450. ［60］ HUROV K, LAHDENRANTA J, UPADHYAYA P, et al. BT7480, a novel fully synthetic Bicycle tumor-targeted immune cell agonistTM (Bicycle TICATM) induces tumor localized CD137 agonism [J]. J Immunother Cancer, 2021, 9(11): e002883. DOI:10.1136/jitc-2021-002883. ［61］ JANKU F, HAN S W, DOI T, et al. Preclinical characterization and phase Ⅰ study of an anti-HER2-TLR7 immune-stimulator antibody conjugate in patients with HER2+ malignancies [J]. Cancer Immunol Res, 2022, 10(12): 1441-1461. DOI:10.1158/2326-6066.cir-21-0722. ［62］ BUKHALID R A, DUVALL J R, LANCASTER K, et al. XMT-2056, a HER2-directed STING agonist antibody-drug conjugate, induces innate antitumor immune responses by acting on cancer cells and tumor-resident immune cells [J]. Clin Cancer Res, 2025, 31(9): 1766-1782. DOI:10.1158/1078-0432.ccr-24-2449. ［63］ ZHANG J, LIU R, GAO S, et al. Phase Ⅰ study of A166, an antibody‒drug conjugate in advanced HER2-expressing solid tumours [J]. NPJ Breast Cancer, 2023, 9(1): 28. DOI:10.1038/s41523-023-00522-5. ［64］ LI Q, CHENG Y, TONG Z, et al. HER2-targeting antibody drug conjugate FS-1502 in HER2-expressing metastatic breast cancer: a phase 1a/1b trial [J]. Nat Commun, 2024, 15(1): 5158. DOI:10.1038/s41467-024-48798-w. 《肿瘤药学》是由湖南省卫生健康委员会主管，湖南省肿瘤医院（中南大学湘雅医学院附属肿瘤医院）主办的我国唯一一本肿瘤领域对接药学领域的核心期刊，是中国抗癌协会系列期刊。自2016年已连续9年入选《中国科技核心期刊》目录。目前已被美国《化学文摘》、荷兰《医学文摘》、波兰《哥白尼索引》、美国《乌利希期刊指南》、中国生物医学文摘数据库、知网、万方、维普等数据库收录。经携手合作与共同努力，本刊正式入选“中国科技期刊卓越行动计划(二期)”集群(集团)化试点项目。并于2024年成功立项“湖南省培育世界一流湘版科技期刊建设工程项目”。网站链接：www.zgzlyx.com 工作邮箱：zgzlyx2011@163.com 电话号码：0731-89762609

抗体药物偶联物

2025-05-01

·Business Wire

Bicycle Therapeutics Reports Recent Business Progress and First Quarter 2025 Financial Results

CAMBRIDGE, England & BOSTON--(BUSINESS WIRE)--Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle®) technology, today reported recent business progress and financial results for the first quarter ended March 31, 2025. “In the first quarter, we continued to advance our business priorities and our pipeline of oncology therapeutics. We were pleased to share additional human imaging data that continue to validate the potential of MT1-MMP as a novel cancer target and demonstrate the positive properties of our Bicycle Radioconjugate molecules for radiopharmaceutical use,” said Bicycle Therapeutics CEO Kevin Lee, Ph.D. “Our work to develop zelenectide pevedotin for various Nectin-4 associated cancers continues to progress, as we recently initiated our Phase 1/2 Duravelo-3 trial for NECTIN4 gene-amplified breast cancer and remain on track for dose selection in our Phase 2/3 Duravelo-2 trial for metastatic urothelial cancer in the second half of this year. Additionally, with new members on our leadership team, Board of Directors and Clinical Advisory Board, and expected financial runaway extending to the second half of 2027, we remain focused on continuing to execute our strategy and make meaningful advances for patients.” First Quarter 2025 and Recent Events Additional human imaging data for an early Bicycle ® Radioconjugate (BRC ® ) molecule targeting MT1-MMP presented at the American Association for Cancer Research (AACR) Annual Meeting 2025. A poster presentation included new data from a second patient who underwent MT1-MMP-PET/CT imaging that build on previously announced data. Altogether, the data continue to validate the potential of MT1-MMP as a novel cancer target and demonstrate the positive properties of BRC molecules for radiopharmaceutical use. Importantly, the imaging data from these two patients are representative of the data generated to date in 12 out of 14 patients with various solid tumors. Bicycle Therapeutics continues to advance its emerging BRC pipeline, with initial EphA2 human imaging data expected in 2H 2025 and company-sponsored clinical trials planned for 2026. Two abstracts accepted for poster presentation at the 2025 American Society for Clinical Oncology (ASCO) Annual Meeting. Bicycle Therapeutics will present two abstracts highlighting the development of zelenectide pevedotin for metastatic urothelial cancer (mUC). The first abstract outlines previously disclosed topline combination data for zelenectide pevedotin plus pembrolizumab in first-line mUC from the Phase 1 Duravelo-1 trial, while the second abstract provides an overview of the ongoing Phase 2/3 Duravelo-2 registrational trial for zelenectide pevedotin in mUC. Dose selection in Duravelo-2 remains on track for the second half of the year. Phase 1/2 Duravelo-3 trial for zelenectide pevedotin in NECTIN4-amplified breast cancer open and actively recruiting patients. Bicycle Therapeutics previously announced a development strategy leveraging NECTIN4 amplification for zelenectide pevedotin in breast cancer, lung cancer and multiple tumor types. The strategy is based on the company’s discovery that the NECTIN4 gene sits on a commonly amplified chromosomal site in cancer, creating more copies of the gene and often translating to more protein expression. Data from post-hoc analyses of late-line breast cancer and lung cancer patients enrolled in Duravelo-1 showed enhanced anti-tumor activity of zelenectide pevedotin in patients with NECTIN4 amplification and/or polysomy. Based on these data, the U.S. Food and Drug Administration granted Fast Track designation to zelenectide pevedotin for the treatment of adult patients with previously treated, NECTIN4-amplified, advanced or metastatic triple-negative breast cancer and non-small cell lung cancer. The Duravelo-3 breast cancer trial is the first of several planned trials to expand the development of zelenectide pevedotin for additional solid tumors. Announced new Board of Directors and key clinical leadership appointments. Felix J. Baker, Ph.D., will succeed Pierre Legault, MBA, CPA, as chairman of the Bicycle Therapeutics Board of Directors as Mr. Legault and Richard Kender, MBA, will retire from the Board following the company’s Annual General Meeting on June 17, 2025. In addition, world-renowned oncology experts Alessandro Riva, M.D., and Fabrice André, M.D., Ph.D., have joined the company’s Board of Directors and Clinical Advisory Board, respectively. Furthermore, Eric Westin, M.D., has been promoted to chief medical officer and Jim MacDonald-Clink has been promoted to senior vice president, head of business development, following the transitions of Santiago Arroyo, M.D., Ph.D., chief development officer, and Nigel Crockett, Ph.D., chief business officer, to advisor roles as distinguished fellows. Participation in Upcoming Investor Conferences Bicycle Therapeutics management will participate in a fireside chat at the 2025 RBC Capital Markets Global Healthcare Conference on Tuesday, May 20, at 2:05 p.m. ET. A live webcast of the fireside chat will be accessible from the Investor section of the company’s website at www.bicycletherapeutics.com. A replay of the webcast will be archived and available following the event. First Quarter 2025 Financial Results Cash and cash equivalents were $793.0 million as of March 31, 2025, compared to $879.5 million as of December 31, 2024. The decrease in cash and cash equivalents is primarily due to cash used in operations, including increased cash payments for clinical program activities. Research and development (R&D) expenses were $59.1 million for the three months ended March 31, 2025, compared to $34.9 million for the three months ended March 31, 2024. The increase in expense of $24.2 million was primarily due to increased clinical program expenses for zelenectide pevedotin development, increased personnel-related expenses and lower U.K. R&D tax credits period over period. General and administrative expenses were $21.1 million for the three months ended March 31, 2025, compared to $16.4 million for the three months ended March 31, 2024. The increase in expense of $4.7 million was primarily due to increased professional and consulting fees as well as increased personnel-related costs, including incremental share-based compensation expense of $0.5 million for the three months ended March 31, 2025. Net loss was $60.8 million, or $(0.88) basic and diluted net loss per share, for the three months ended March 31, 2025, compared to net loss of $26.6 million or $(0.62) basic and diluted net loss per share, for three months ended March 31, 2024. About Bicycle Therapeutics Bicycle Therapeutics is a clinical-stage pharmaceutical company developing a novel class of medicines, referred to as Bicycle® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained with small molecule scaffolds to form two loops that stabilize their structural geometry. This constraint facilitates target binding with high affinity and selectivity, making Bicycle molecules attractive candidates for drug development. The company is evaluating zelenectide pevedotin (formerly BT8009), a Bicycle® Drug Conjugate (BDC™) targeting Nectin-4, a well-validated tumor antigen; BT5528, a BDC molecule targeting EphA2, a historically undruggable target; and BT7480, a Bicycle Tumor-Targeted Immune Cell Agonist® (Bicycle TICA®) targeting Nectin-4 and agonizing CD137, in company-sponsored clinical trials. Additionally, the company is developing Bicycle® Radioconjugates (BRC®) for radiopharmaceutical use and, through various partnerships, is exploring the use of Bicycle® technology to develop therapies for diseases beyond oncology. Bicycle Therapeutics is headquartered in Cambridge, UK, with many key functions and members of its leadership team located in Cambridge, Mass. For more information, visit bicycletherapeutics.com. Forward Looking Statements This press release may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding the validation of MT1-MMP as a cancer target and BRCs having positive properties for radiopharmaceutical use; the initiation of new clinical trials, the progress of Bicycle’s ongoing clinical trials and the timing of dose selection in the Duravelo-2 clinical trial; Bicycle’s expected financial runway; and the use of Bicycle Therapeutics’ technology through various partnerships to develop therapies for diseases beyond oncology. Bicycle Therapeutics may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in research and development and in the initiation, progress and completion of clinical trials and clinical development of Bicycle Therapeutics’ product candidates; the risk that Bicycle Therapeutics may not realize the intended benefits of its partnerships; the risk that Bicycle Therapeutics may the risk that Bicycle’s projections regarding its expected cash runway are inaccurate or that its conduct of its business requires more cash than anticipated; and other important factors, any of which could cause Bicycle Therapeutics’ actual results to differ from those contained in the forward-looking statements, are described in greater detail in the section entitled “Risk Factors” in Bicycle Therapeutics’ Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) on February 25, 2025, as well as in other filings Bicycle Therapeutics may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Bicycle Therapeutics expressly disclaims any obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. Bicycle Therapeutics plc Condensed Consolidated Statements of Operations and Comprehensive Loss (In thousands, except share and per share data) (Unaudited) Three Months Ended March 31, 2025 2024 Collaboration revenue $ 9,977 $ 19,530 Operating expenses: Research and development 59,058 34,864 General and administrative 21,123 16,382 Total operating expenses 80,181 51,246 Loss from operations (70,204 ) (31,716 ) Other income (expense): Interest and other income 8,414 5,624 Interest expense (51 ) (821 ) Total other income, net 8,363 4,803 Net loss before income tax provision (61,841 ) (26,913 ) Benefit from income taxes (1,087 ) (350 ) Net loss $ (60,754 ) $ (26,563 ) Net loss per share, basic and diluted $ (0.88 ) $ (0.62 ) Weighted average ordinary shares outstanding, basic and diluted 69,196,945 42,560,091 Balance Sheets Data (In thousands) (Unaudited) March 31, 2025 December 31, 2024 792,973 879,520 798,463 861,375 883,894 956,868 740,333 793,060

临床1期财报高管变更

2025-02-25

·Business Wire

Bicycle Therapeutics Reports Recent Business Progress and Fourth Quarter and Full Year 2024 Financial Results

CAMBRIDGE, England & BOSTON--(BUSINESS WIRE)--Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle®) technology, today reported financial results for the fourth quarter and full year ended December 31, 2024, and provided recent corporate updates. “In 2024, the significant progress across our pipeline and business continued to validate our approach to developing next-generation precision-guided therapeutics. We believe that zelenectide pevedotin’s promising anti-tumor activity and differentiated safety profile could transform the treatment landscape not only for patients with metastatic urothelial cancer but also NECTIN4 gene-amplified solid tumors. Additionally, our encouraging first human imaging data for MT1-MMP demonstrates the potential of our technology platform to produce radiopharmaceutical medicines to novel targets,” said Bicycle Therapeutics CEO Kevin Lee, Ph.D. “With a clear strategy to build on this foundation and financial runway into the second half of 2027, we are strongly positioned for another year of execution across our research and development pipeline of oncology, radiopharmaceuticals and partnered programs as we work to bring innovative therapies to cancer patients.” Fourth Quarter 2024 and Recent Events Announced updated topline combination data for zelenectide pevedotin plus pembrolizumab in first-line metastatic urothelial cancer (mUC). As of Jan. 3, 2025, updated topline results from the ongoing Phase 1 Duravelo-1 trial evaluating zelenectide pevedotin 5 mg/m 2 weekly plus pembrolizumab 200 mg once every 3 weeks in 22 first-line cisplatin-ineligible patients with mUC continued to show promising anti-tumor activity and a differentiated safety profile. Among 20 efficacy evaluable patients, a 65% overall response rate (ORR) (13/20) was achieved, and a 50% ORR (10/20) was reached among patients with confirmed responses. Of the 3 unconfirmed responses, 1 patient remained on treatment at the time of the reported clinical results. Median duration of response (mDOR) is not yet mature, with 12 patients still on treatment at the time of the reported clinical results. The safety and tolerability profile continues to be broadly consistent with other Phase 1 zelenectide pevedotin monotherapy and combination cohorts. Adverse events of clinical interest such as peripheral neuropathy, skin reactions and eye disorders were primarily low grade. All cases of Grade 3 treatment-related adverse events (TRAEs) of clinical interest were reversible, and there were no Grade 4 or Grade 5 TRAEs of clinical interest. Among 20 efficacy evaluable patients, a 65% overall response rate (ORR) (13/20) was achieved, and a 50% ORR (10/20) was reached among patients with confirmed responses. Of the 3 unconfirmed responses, 1 patient remained on treatment at the time of the reported clinical results. Median duration of response (mDOR) is not yet mature, with 12 patients still on treatment at the time of the reported clinical results. The safety and tolerability profile continues to be broadly consistent with other Phase 1 zelenectide pevedotin monotherapy and combination cohorts. Adverse events of clinical interest such as peripheral neuropathy, skin reactions and eye disorders were primarily low grade. All cases of Grade 3 treatment-related adverse events (TRAEs) of clinical interest were reversible, and there were no Grade 4 or Grade 5 TRAEs of clinical interest. Bicycle Therapeutics is currently conducting the Phase 2/3 Duravelo-2 registrational trial evaluating zelenectide pevedotin plus pembrolizumab versus chemotherapy in first-line mUC (Cohort 1), and zelenectide pevedotin monotherapy and in combination with pembrolizumab in late-line mUC (Cohort 2). In each cohort, two doses of zelenectide pevedotin – 5 mg/m2 weekly and 6 mg/m2 two weeks on, one week off – are being assessed before a planned final dose selection in 2H 2025. Announced development strategy leveraging NECTIN4 gene amplification for zelenectide pevedotin in breast cancer, lung cancer and multiple tumor types. During the 2024 San Antonio Breast Conference Symposium, Bicycle Therapeutics presented data from post-hoc analyses of late-line breast cancer and lung cancer patients enrolled in the Phase 1/2 Duravelo-1 trial evaluating zelenectide pevedotin 5 mg/m 2 weekly. Results showed enhanced anti-tumor activity of zelenectide pevedotin monotherapy in patients with NECTIN4 gene amplification and/or polysomy. Among 38 breast cancer patients enrolled, 35 patients were efficacy evaluable. Additionally, 23 breast cancer patient samples were available for NECTIN4 testing, of which 8 demonstrated NECTIN4 gene amplification or harbored NECTIN4 polysomy. Results showed a 62.5% ORR (5/8) in patients with NECTIN4 gene amplification and/or polysomy versus 14.3% ORR (5/35) in efficacy-evaluable patients. All responses were seen in patients with NECTIN4 gene amplification and/or polysomy. Among 32 triple-negative breast cancer (TNBC) patients enrolled, 30 patients were efficacy evaluable. Additionally, 19 TNBC patient samples were available for NECTIN4 testing, of which 7 demonstrated NECTIN4 gene amplification or harbored a NECTIN4 polysomy. Results showed a 57.1% ORR (4/7) in patients with NECTIN4 gene amplification and/or polysomy versus 13.3% ORR (4/30) in efficacy-evaluable patients. All responses were seen in patients with NECTIN4 gene amplification and/or polysomy. Notably, all 3 patients with NECTIN4 gene amplification who responded to zelenectide pevedotin had prior treatment with sacituzumab govitecan. Among 40 non-small cell lung cancer (NSCLC) patients enrolled, 34 patients were efficacy evaluable. Additionally, 19 NSCLC patient samples were available for NECTIN4 testing, of which 6 demonstrated NECTIN4 gene amplification. Five out of 6 patients with NECTIN4 gene amplification were efficacy evaluable. Results showed a 40.0% ORR (2/5) in patients with NECTIN4 gene amplification versus 8.8% ORR (3/34) among efficacy-evaluable patients. Of the 3 partial responses, 2 were confirmed and 1 was unconfirmed. Two out of 3 responses were seen in patients with NECTIN4 gene amplification. Among 38 breast cancer patients enrolled, 35 patients were efficacy evaluable. Additionally, 23 breast cancer patient samples were available for NECTIN4 testing, of which 8 demonstrated NECTIN4 gene amplification or harbored NECTIN4 polysomy. Results showed a 62.5% ORR (5/8) in patients with NECTIN4 gene amplification and/or polysomy versus 14.3% ORR (5/35) in efficacy-evaluable patients. All responses were seen in patients with NECTIN4 gene amplification and/or polysomy. Among 32 triple-negative breast cancer (TNBC) patients enrolled, 30 patients were efficacy evaluable. Additionally, 19 TNBC patient samples were available for NECTIN4 testing, of which 7 demonstrated NECTIN4 gene amplification or harbored a NECTIN4 polysomy. Results showed a 57.1% ORR (4/7) in patients with NECTIN4 gene amplification and/or polysomy versus 13.3% ORR (4/30) in efficacy-evaluable patients. All responses were seen in patients with NECTIN4 gene amplification and/or polysomy. Notably, all 3 patients with NECTIN4 gene amplification who responded to zelenectide pevedotin had prior treatment with sacituzumab govitecan. Among 40 non-small cell lung cancer (NSCLC) patients enrolled, 34 patients were efficacy evaluable. Additionally, 19 NSCLC patient samples were available for NECTIN4 testing, of which 6 demonstrated NECTIN4 gene amplification. Five out of 6 patients with NECTIN4 gene amplification were efficacy evaluable. Results showed a 40.0% ORR (2/5) in patients with NECTIN4 gene amplification versus 8.8% ORR (3/34) among efficacy-evaluable patients. Of the 3 partial responses, 2 were confirmed and 1 was unconfirmed. Two out of 3 responses were seen in patients with NECTIN4 gene amplification. Zelenectide pevedotin was generally well tolerated, demonstrating a safety and tolerability profile consistent with data from other Duravelo-1 cohorts, and TRAEs were primarily low grade, further supporting the potential for NECTIN4 gene amplification to serve as a biomarker for therapy stratification. Based on these data, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to zelenectide pevedotin for the treatment of adult patients with previously treated, NECTIN4 gene-amplified, advanced or metastatic TNBC and NSCLC. Bicycle Therapeutics has continued to build a robust patent estate related to the use of NECTIN4 gene amplification as a biomarker for patient selection. The company plans to initiate several additional Phase 1/2 trials evaluating zelenectide pevedotin in NECTIN4 gene-amplified cancer, including breast cancer (Duravelo-3) in 1H 2025 and lung cancer (Duravelo-4) and multi-tumor (Duravelo-5) in 2H 2025. Announced first human imaging data for a Bicycle ® Radionuclide Conjugate (BRC ® ) targeting MT1-MMP and outlined strategy for leadership in next-generation radiopharmaceuticals. Data presented at the European Association of Nuclear Medicine 2024 Congress validate the potential of MT1-MMP as a novel target in the treatment of cancer, demonstrate the translatability of BRC preclinical data and highlight the potential of Bicycle ® molecules for targeted radionuclide therapy. In an oral presentation, the German Cancer Consortium (DKTK) shared results of fluorine-18-labelled FDG-PET/CT imaging and gallium-68-labelled BRC MT1-MMP PET/CT imaging in a 65-year-old male diagnosed with advanced pulmonary adenocarcinoma, the most common type of NSCLC, in the lung and lymph nodes. MT1-MMP imaging demonstrated tracer uptake in the primary tumor in the lung and lymph node and bone metastases, consistent with FDG imaging. Additionally, the MT1-MMP BRC tracer showed renal excretion, with all other organs showing only a negligible tracer uptake. Preclinical data presented by Bicycle Therapeutics demonstrated the suitability of Bicycle molecules to deliver indium to tumors in vivo due to their favorable properties, including specific tumor uptake, rapid tumor penetration and rapid renal elimination. Additionally, imaging showed how the biodistribution profile of BRCs can be optimized to maintain high tumor uptake and retention while significantly reducing kidney levels. In an oral presentation, the German Cancer Consortium (DKTK) shared results of fluorine-18-labelled FDG-PET/CT imaging and gallium-68-labelled BRC MT1-MMP PET/CT imaging in a 65-year-old male diagnosed with advanced pulmonary adenocarcinoma, the most common type of NSCLC, in the lung and lymph nodes. MT1-MMP imaging demonstrated tracer uptake in the primary tumor in the lung and lymph node and bone metastases, consistent with FDG imaging. Additionally, the MT1-MMP BRC tracer showed renal excretion, with all other organs showing only a negligible tracer uptake. Preclinical data presented by Bicycle Therapeutics demonstrated the suitability of Bicycle molecules to deliver indium to tumors in vivo due to their favorable properties, including specific tumor uptake, rapid tumor penetration and rapid renal elimination. Additionally, imaging showed how the biodistribution profile of BRCs can be optimized to maintain high tumor uptake and retention while significantly reducing kidney levels. Bicycle Therapeutics continues to advance its emerging BRC pipeline, with additional MT1-MMP human imaging data anticipated in mid-2025 and initial EphA2 human imaging data expected in 2H 2025. The company is targeting clinical trials for its first radiotherapeutic program to begin in 2026. Expanded Clinical Advisory Board with the appointment of three distinguished oncology experts to further support the advancement of the company’s clinical programs. Bicycle Therapeutics welcomed Howard A. “Skip” Burris, III, M.D., president and chief medical officer of Sarah Cannon Research Institute; Markus Eckstein, M.D., a board-certified senior consultant pathologist at the University Hospital Erlangen (FAU Erlangen-Nürnberg); and Niklas Klümper, M.D., senior consultant for Urology & Genitourinary Oncology at the University Hospital Bonn. Participation in Upcoming Investor Conferences Bicycle Therapeutics management will participate in a fireside chat at the TD Cowen 45th Annual Health Care Conference on Tuesday, March 4, at 9:50 a.m. ET. A live webcast of the fireside chat will be accessible from the Investor section of the company’s website at www.bicycletherapeutics.com. A replay of the webcast will be archived and available following the event. Fourth Quarter and Year End 2024 Financial Results Cash and cash equivalents were $879.5 million as of December 31, 2024, compared to $526.4 million as of December 31, 2023. The increase in cash and cash equivalents is primarily due to net proceeds from the company’s private investment in public equity (PIPE) financing in May 2024 and share option exercises, offset by the repayment of the company’s debt facility with Hercules Capital, Inc. in July 2024 and cash used in operating activities. Research and development (R&D) expenses were $49.8 million for the three months ended December 31, 2024, and $173.0 million for the year ended December 31, 2024, compared to $44.7 million for the three months ended December 31, 2023, and $156.5 million for the year ended December 31, 2023. The increases in expense of $5.1 million and $16.5 million for the three months and year ended December 31, 2024, respectively, were primarily due to increased clinical program expenses for zelenectide pevedotin development and increased personnel-related expenses, including incremental share-based compensation expense of $2.2 million and $3.8 million for the three months and year ended December 31, 2024, respectively, offset by decreased clinical program expenses for Bicycle Tumor-Targeted Immune Cell Agonist ® molecule development, lower discovery, platform and other expenses, and higher U.K. R&D tax credits period over period. General and administrative expenses were $21.6 million for the three months ended December 31, 2024, and $72.2 million for the year ended December 31, 2024, compared to $14.9 million for the three months ended December 31, 2023, and $60.4 million for the year ended December 31, 2023. The increases of $6.7 million and $11.8 million for the three months and year ended December 31, 2024, respectively, were primarily due to increased personnel-related expenses, including incremental share-based compensation expense $0.3 million and $1.8 million for the three months and year ended December 31, 2024, respectively, as well as increased professional and consulting fees. Net loss was $51.9 million, or $(0.75) basic and diluted net loss per share, for the three months ended December 31, 2024, and net loss was $169.0 million, or $(2.90) basic and diluted net loss per share, for the year ended December 31, 2024, compared to net loss of $49.1 million or $(1.16) basic and diluted net loss per share, for three months ended December 31, 2023, and net loss of $180.7 million or $(5.08) basic and diluted net loss per share, for the year ended December 31, 2023. About Bicycle Therapeutics Bicycle Therapeutics is a clinical-stage pharmaceutical company developing a novel class of medicines, referred to as Bicycle® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained with small molecule scaffolds to form two loops that stabilize their structural geometry. This constraint facilitates target binding with high affinity and selectivity, making Bicycle molecules attractive candidates for drug development. The company is evaluating zelenectide pevedotin (formerly BT8009), a Bicycle® Toxin Conjugate (BTC®) targeting Nectin-4, a well-validated tumor antigen; BT5528, a BTC molecule targeting EphA2, a historically undruggable target; and BT7480, a Bicycle Tumor-Targeted Immune Cell Agonist® (Bicycle TICA®) targeting Nectin-4 and agonizing CD137, in company-sponsored clinical trials. Additionally, the company is developing Bicycle® Radionuclide Conjugates (BRC®) for radiopharmaceutical use and, through various partnerships, is exploring the use of Bicycle® technology to develop therapies for diseases beyond oncology. Bicycle Therapeutics is headquartered in Cambridge, UK, with many key functions and members of its leadership team located in Cambridge, Mass. For more information, visit www.bicycletherapeutics.com. Forward Looking Statements This press release may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding the potential for zelenectide pevedotin to transform the treatment landscape for patients with mUC and NECTIN4 gene-amplified solid tumors; the potential for Bicycle Therapeutics’ technology to produce radiopharmaceutical medicines; the company’s ability to build on its foundation, including with respect to execution across its pipeline; the planned dose selection for Duravelo-2; the anticipated initiation of clinical trials of zelenectide pevedotin in breast cancer, lung cancer and multi-tumor types and of the company’s first radiotherapeutic program; the timing of announcement of human imaging data for MT1-MMP and EphA2 targeting BRCs; expectations with respect to Bicycle Therapeutics’ financial runway; and the use of Bicycle Therapeutics’ technology through various partnerships to develop potential therapies in diseases beyond oncology. Bicycle Therapeutics may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in research and development and in the initiation, progress and completion of clinical trials and clinical development of Bicycle Therapeutics’ product candidates; the risk that Bicycle Therapeutics may not realize the intended benefits of its technology, partnerships or NECTIN4 gene-amplification strategy; the risk that Bicycle Therapeutics may not achieve any of its clinical development strategies; timing of results from clinical trials; whether the outcomes of preclinical studies and prior clinical trials will be predictive of future clinical trial results; the risk that trials may have unsatisfactory outcomes; potential adverse effects arising from the testing or use of Bicycle Therapeutics’ product candidates; the risk that Bicycle Therapeutics’ projections regarding its expected cash runway are inaccurate or that its conduct of its business requires more cash than anticipated; and other important factors, any of which could cause Bicycle Therapeutics’ actual results to differ from those contained in the forward-looking statements, are described in greater detail in the section entitled “Risk Factors” in Bicycle Therapeutics’ Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on October 31, 2024, as well as in other filings Bicycle Therapeutics may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Bicycle Therapeutics expressly disclaims any obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law. Bicycle Therapeutics plc Condensed Consolidated Statements of Operations and Comprehensive Loss (In thousands, except share and per share data) (Unaudited) Three Months Ended Year Ended December 31, December 31, 2024 2023 2024 2023 Collaboration revenue $ 3,708 $ 5,331 $ 35,275 $ 26,976 Operating expenses: Research and development 49,778 44,697 172,966 156,496 General and administrative 21,593 14,869 72,181 60,426 Total operating expenses 71,371 59,566 245,147 216,922 Loss from operations (67,663 ) (54,235 ) (209,872 ) (189,946 ) Other income (expense): Interest and other income 10,303 6,276 34,284 14,002 Interest expense (52 ) (820 ) (1,730 ) (3,263 ) Loss on extinguishment of debt — — (954 ) — Gain on extinguishment of research and development funding liability 4,476 — 4,476 — Total other income, net 14,727 5,456 36,076 10,739 Net loss before income tax provision (52,936 ) (48,779 ) (173,796 ) (179,207 ) (Benefit from) provision for income taxes (1,082 ) 320 (4,765 ) 1,457 Net loss $ (51,854 ) $ (49,099 ) $ (169,031 ) $ (180,664 ) Net loss per share, basic and diluted $ (0.75 ) $ (1.16 ) $ (2.90 ) $ (5.08 ) Weighted average ordinary shares outstanding, basic and diluted 69,051,745 42,419,326 58,207,593 35,592,362 Balance Sheets Data (In thousands) (Unaudited) December 31, December 31, 2024 2023 Cash and cash equivalents $ 879,520 $ 526,423 Working capital 861,375 492,331 Total assets 956,868 595,344 Total shareholders’ equity 793,060 370,932

临床结果临床1期财报

100 项与 BT-7480 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	Bicycle Therapeutics Plc	2021-11-02
晚期恶性实体瘤	临床2期	英国	Bicycle Therapeutics Plc	2021-11-02
Nectin-4阳性晚期恶性实体瘤	临床2期	美国	Bicycle Therapeutics Plc	2021-11-02
Nectin-4阳性晚期恶性实体瘤	临床2期	英国	Bicycle Therapeutics Plc	2021-11-02

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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


NCT05163041 (ESMO2024) 人工标引	临床1/2期	晚期恶性实体瘤	39	BT7480	蓋鹽願衊蓋鹽憲遞鹽餘(選繭糧選製衊鹽遞鑰齋) = 鬱選簾夢繭艱淵蓋壓襯淵鑰齋鏇淵餘鹽窪膚製 (醖憲獵鹹夢網壓鬱繭願 ) 更多	积极	2024-09-14