PO.CH01.02 · 化学
利用深度VHH抗体库(IBMET)进行TNBC和胰腺癌的超敏结构生物标志物发现：一个用于组织无关靶点鉴定的转化平台
Ultra-sensitive structural biomarker discovery for TNBC and pancreatic cancer using a deep VHH repertoire (IBMET): A translational platform for tissue-agnostic target identification
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摘要 Abstract
中文摘要
背景：在存在大量未满足医疗需求(UMN)的癌症中，可靠且肿瘤选择性的表面生物标志物的有限可及性持续阻碍着治疗药物的开发。这一挑战在三阴性乳腺癌(TNBC)和胰腺导管腺癌(PDAC)中尤为明显，目前可用的靶点往往表现出特异性不足或在患者亚组间适用性受限。
方法：我们建立了反向生物标志物探索技术(IBMET)，这是一个用于检测肿瘤细胞上病理性结构改变的系统性框架。IBMET利用来源于羊驼的大型VHH抗体库作为高灵敏度的结构探针。用多种肿瘤细胞系免疫羊驼，并使用噬菌体展示和二代测序对所得VHH文库进行分析。基于统计学富集选择候选抗体，并通过IHC/IF在广泛的肿瘤和正常组织谱系中进行评估。抗原鉴定通过交联免疫沉淀、SDS-PAGE和LC-MS/MS进行。使用乳腺癌活检队列(n = 106)检验临床相关性。
结果：IBMET鉴定出多个与TNBC和PDAC相关的结构生物标志物候选物。先导抗体VHH89选择性识别一种此前未被表征的ALCAM低分子量异构体(约70 kDa；命名为ALCAM70)。VHH89在肿瘤组织中显示出病灶选择性染色，而在正常器官中反应性极低，表明其具有高度的肿瘤特异性。在临床乳腺癌标本中，VHH89在超过20%的TNBC病例中呈阳性。此外，部分胰腺癌和胆管癌标本也显示VHH89阳性，提示该异构体可能代表一种存在于多种肿瘤类型中的结构性改变抗原。
结论：IBMET提供了一种可重复且可扩展的方法，用于鉴定仅凭基因组或转录组分析可能无法检测到的结构定义型生物标志物。通过系统性排除与正常组织反应的抗体并富集肿瘤相关构象表位，IBMET拓宽了侵袭性癌症可干预靶点的范围。这些发现支持将IBMET衍生抗体整合到新一代抗体偶联药物、放射性配体疗法和伴随诊断的开发中。为促进更广泛的验证，COGNANO将在AACR 2026上提供八种PDAC选择性VHH抗体供研究使用。
查看英文原文 English abstract
Background: In cancers with substantial unmet medical need (UMN), the limited availability of reliable and tumor-selective surface biomarkers continues to hinder therapeutic development. This challenge is particularly evident in triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC), where currently available targets often show insufficient specificity or restricted applicability across patient subgroups.
Methods: We established the Inverse Biomarker Exploration Technology (IBMET), a systematic framework designed to detect pathological structural alterations on tumor cells. IBMET utilizes a large alpaca-derived VHH antibody repertoire as highly sensitive structural probes. Alpacas were immunized with multiple tumor cell lines, and the resulting VHH library was analyzed using phage display and next-generation sequencing. Candidate antibodies were selected based on statistical enrichment and evaluated by IHC/IF across an extensive panel of tumor and normal tissues. Antigen identification was performed by cross-linking immunoprecipitation, SDS-PAGE, and LC-MS/MS. Clinical relevance was examined using a breast cancer biopsy cohort (n = 106).
Results: IBMET identified several structural biomarker candidates relevant to TNBC and PDAC. The lead antibody, VHH89, selectively recognized a previously uncharacterized low-molecular-weight isoform of ALCAM (approximately 70 kDa; designated ALCAM70). VHH89 showed lesion-selective staining in tumor tissues with minimal reactivity in normal organs, indicating a high degree of tumor specificity. In clinical breast cancer specimens, VHH89 demonstrated positivity in more than 20% of TNBC cases. In addition, subsets of pancreatic cancer and cholangiocarcinoma specimens also showed VHH89 positivity, suggesting that this isoform may represent a structurally altered antigen present across multiple tumor types.
Conclusion: IBMET offers a reproducible and scalable approach for identifying structurally defined biomarkers that may not be detectable using genomic or transcriptomic analyses alone. By systematically excluding antibodies that react with normal tissues and enriching for tumor-associated conformational epitopes, IBMET broadens the spectrum of actionable targets for aggressive cancers. These findings support the potential integration of IBMET-derived antibodies into the development of next-generation antibody-drug conjugates, radioligand therapies, and companion diagnostics. To facilitate broader validation, COGNANO will make eight PDAC-selective VHH antibodies available for research use at AACR 2026.
利益披露 Disclosure
A. Imura, None..
R. Maeda, None..
H. Yamazaki, None..
T. Inoue, None..
S. Aakashi-Tanaka, None..
H. Tsukada, None.