PO.ET06.06 · 实验与分子治疗

由 Zelenectide Pevedotin 靶向的 NECTIN4 扩增型乳腺癌：扩增与表达频繁、一致且稳定

NECTIN4-a mplified breast cancer targeted by Zelenectide Pevedotin: Amplification and expression are frequent, concordant, and stable

编号 7227 展板 19 时间 4/22 09:00–12:00 区域 Section 18 主讲 Alexander Azizi, BA;MA;MS

分会场 Tumor Diagnostics, Prognostics, and Therapeutic Outcomes

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作者与单位 Authors & Affiliations

Alexander Azizi¹, Niklas Klümper², Emma Colliver¹, Alexander Quaas³, Birgid Schoemig-Markiefka³, Arndt Hartmann⁴, Christoph Kuppe⁵, Manuel Ritter², Viktor Grünwald⁶, Michael Hölzel⁷, Chris Bailey¹, Gustavo Arruda Bezerra⁸, Nicholas Guthertz⁸, Sergey Nikolaev⁹, Fabrice Andre⁹, Charles Swanton¹, Johannes Braegelmann³, Markus Eckstein¹⁰

¹The Francis Crick Institute, London, United Kingdom,²University of Bonn, Bonn, Germany,³University of Cologne, Cologne, Germany,⁴Inst. of Pathology, University Hospital Erlangen, Erlangen, Germany,⁵RWTH Aachen, Aachen, Germany,⁶Essen University Hospital, Essen, Germany,⁷University Medical Centre Bonn, Bonn, Germany,⁸Bicycle Therapeutics, Cambridge, United Kingdom,⁹Gustave Roussy, Villejuif, France,¹⁰FAU Erlangen-Nürnberg, Nurnberg, Germany

摘要 Abstract

中文摘要

背景： NECTIN4 扩增 (amp) 可预测对 Nectin4 靶向治疗的反应。在 I/II 期 Duravelo-1 试验 (NCT04561362) 中，NECTIN4 扩增型乳腺癌 (BC) 对 Bicycle® 药物偶联物 (BDC™) zelenectide pevedotin (zele，原名 BT8009) 显示出高于非扩增型肿瘤的反应率 (57.1% 对比 6.3%) (Klümper 等，SABCS 2024)。这些发现促使 FDA 授予其快速通道认定，并开展了针对 NECTIN4 扩增型 BC 的 II 期 Duravelo-3 试验 (NCT06840483)。为进一步表征 NECTIN4 及其可靶向性，我们评估了其流行率、跨 BC 数据集的生物学特征，并描述了其基于结构-活性的靶向作用。方法：分析了来自 METABRIC (n=2173)、TCGA (n=1079) 和 TRANSNEO (n=166) 的公开多组学原发性 BC 数据。专有原发性组织数据 (Cologne 队列，n=252) 将高 NECTIN4 拷贝数 (CN；通过 FISH 检测的扩增/多体) 与表达和 BC 亚型联系起来。转移性分析在 META-PRISM (n=59) 上进行。高 NECTIN4 CN 定义为 >2× 倍体 (扩增) 或 ≥6 拷贝 (多体)。结构和生物物理学研究 (晶体学、SPR) 评估了 zele 的结合。结果：高 NECTIN4 CN 见于 21.1% (METABRIC)、30.8% (TCGA) 和 29.5% (TRANSNEO) 的病例，在扩增方面排名第 97.5 百分位 (TCGA，所有基因)。按亚型分，HR+、HER2+ 和 TNBC 肿瘤的高 CN 分别为 21%、19% 和 20% (METABRIC) 以及 30%、29% 和 36% (TCGA)。CN 与升高的 mRNA (p < 2 × 10⁻¹⁶) 和蛋白表达 (p = 2 × 10⁻⁶) 相关。未观察到按免疫浸润或胚系 BRCA 状态的差异。在 Cologne 队列中，高 NECTIN4 CN (19.1%) 与膜性 Nectin-4 表达强相关 (H 评分中位数 150 对比 0，p = 8.8 × 10⁻²⁸)。在 META-PRISM 转移灶中，高 CN 流行率相似 (29%) 且与 RNA 表达相关 (r² = 0.34，p < 0.00001)。Zelenectide pevedotin 以高亲和力结合 Nectin-4 结构域 1 (Kd 2.5 ± 1.5 nM)，构象变化极小 (RMSD 0.435 Å)。其紧凑的双环支架 (4.2 kDa，表面积 1900 Å²) 提供了比传统抗体更小的占位面积，同时保持强大的靶点结合，并具有快速肾清除 (t½ <1 h)，这应有助于快速的肿瘤渗透和 MMAE 有效载荷的高效递送。结论： NECTIN4 扩增频繁，与高 RNA 和蛋白表达一致，且在原发性和转移性 BC 之间频率稳定。BDC zelenectide pevedotin 能以高亲和力有效结合 Nectin-4。NECTIN4 扩增在各乳腺癌亚型中的频率和稳定性支持将其作为 Nectin-4 靶向试验中患者筛选生物标志物进行评估。

查看英文原文 English abstract

Background NECTIN4 amplification (amp) can predict response to Nectin4-targeted therapy. In the Phase I/II Duravelo-1 trial (NCT04561362), NECTIN4 -amp breast cancer (BC) showed higher response rates to the Bicycle® Drug Conjugate (BDC™) zelenectide pevedotin (zele, formerly BT8009) versus non-amp tumors (57.1% vs. 6.3%) (Klümper et al, SABCS 2024). These findings led to FDA Fast Track designation and the Phase II Duravelo-3 trial in NECTIN4 -amp BC (NCT06840483). To further characterize NECTIN4 and its targetability, we assessed its prevalence, biology across BC datasets, and describe its structure-activity based targeting. Methods Public, multi-omic primary BC data from METABRIC (n=2173), TCGA (n=1079), and TRANSNEO (n=166) were analyzed. Proprietary primary tissue data (Cologne cohort, n=252) linked high NECTIN4 copy number (CN; amp/polysomy via FISH) with expression and BC subtypes. Metastatic analyses were conducted on META-PRISM (n=59). High NECTIN4 CN was defined as >2× ploidy (amp) or ≥6 copies (polysomy). Structural and biophysical studies (crystallography, SPR) assessed zele's binding. Results High NECTIN4 CN was observed in 21.1% (METABRIC), 30.8% (TCGA), and 29.5% (TRANSNEO) of cases, ranking in the 97.5th percentile for amp (TCGA, all genes). By subtype, HR+, HER2+, and TNBC tumors exhibited high CN in 21%, 19%, and 20% (METABRIC) and 30%, 29%, and 36% (TCGA), respectively. CN correlated with elevated mRNA (p < 2 × 10⁻¹⁶) and protein expression (p = 2 × 10⁻⁶). No differences were observed by immune infiltrate or germline BRCA status. In the Cologne cohort, high NECTIN4 CN (19.1%) strongly correlated with membranous Nectin-4 expression (median H-score 150 vs 0, p = 8.8 × 10⁻²⁸). In META-PRISM metastases, high CN prevalence was similar (29%) and correlated with RNA expression (r² = 0.34, p < 0.00001). Zelenectide pevedotin binds Nectin-4 domain 1 with high affinity (Kd 2.5 ± 1.5 nM) and minimal conformational change (RMSD 0.435 Å). Its compact bicyclic scaffold (4.2 kDa, surface area 1900 Å²) provides a smaller footprint than conventional antibodies while maintaining strong target engagement, and rapid renal clearance (t½ <1 h), which should support rapid tumor penetration, and efficient delivery of the MMAE payload. Conclusions NECTIN4 amplification is frequent, concordant with high RNA and protein expression, and stable in frequency between primary and metastatic BC. Nectin-4 can be effectively engaged by the BDC zelenectide pevedotin with high affinity. The frequency and stability of NECTIN4 amplification across breast cancer subtypes supports its evaluation as a biomarker for patient selection in Nectin-4-targeted trials.

利益披露 Disclosure

A. Azizi, WHYZE Health Independent Contractor. Revena Independent Contractor. Nxera Pharma Independent Contractor. N. Klümper, Bicycle Therapeutics Independent Contractor, Stock, ). Astellas Independent Contractor. Novartis Independent Contractor, Travel. Eisai Independent Contractor. Merck Independent Contractor, Travel. MSD Independent Contractor. Ipsen Travel. Johnson & Johnson Travel. A. Quaas, None.. B. Schoemig-Markiefka, None. A. Hartmann, AbbVie Independent Contractor. AstraZeneca Independent Contractor, ). Biocartis Independent Contractor, ). BMS Independent Contractor. Boehringer Ingelheim Independent Contractor. Cepheid Independent Contractor, ). Diaceutis Independent Contractor. Gilead Independent Contractor, ). Illumina Independent Contractor, ). Ipsen Independent Contractor. Janssen Independent Contractor, ). Lilly Independent Contractor. Merck Independent Contractor. MSD Independent Contractor. Novartis Independent Contractor, ). Pfizer Independent Contractor. QUIP GmbH Independent Contractor, ). Owkin ). C. Kuppe, Bayer Independent Contractor. OMAPiX Independent Contractor. InsilicoMedicine Independent Contractor. M. Ritter, Medac Independent Contractor, ), Travel. Janssen Independent Contractor. Procept Biorobotics ). V. Grünwald, Novartis Independent Contractor. Amgen Independent Contractor. Apogepha Independent Contractor. Astellas Independent Contractor. AstraZeneca Independent Contractor, ), Travel. BMS Independent Contractor, ). Eisai Independent Contractor. Ipsen Independent Contractor, Travel. Janssen Independent Contractor. Merck Independent Contractor, Travel. MSD Independent Contractor, ). Novartis Independent Contractor. Oncorena Independent Contractor. PCI Biotech Independent Contractor. Pfizer Independent Contractor. Bicycle Therapeutics Independent Contractor. M. Hölzel, OncoMAGENTx Inc Independent Contractor, Travel. TME Pharma AG Independent Contractor, ), Travel. C. Bailey, None. G. Arruda Bezerra, Bicycle Therapeutics Employment, Stock. N. Guthertz, Bicycle Therapeutics Employment, Stock. S. Nikolaev, None. J. Braegelmann, Bayer ). Merck Travel. M. Eckstein, Bicycle Therapeutics Independent Contractor, Stock, ). Eisai Independent Contractor. MSD Independent Contractor. AstraZeneca Independent Contractor, ). Janssen Independent Contractor, ). Cepheid Independent Contractor, ). Roche Independent Contractor, ). Astellas Independent Contractor. Diaceutics Independent Contractor. Owkin Independent Contractor. BMS Independent Contractor. Merck Independent Contractor. Ferring Independent Contractor. GenomicHealth Independent Contractor. Gilead ). STRATIFYER ). QUIP GmbH ).

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