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核心技术专利：CN118964589B侵权必究
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基于抗体的白细胞介素-2递送可调节免疫抑制性肿瘤微环境，并在同基因小鼠的胰腺导管腺癌中实现治愈。

Antibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice.

作者信息

Carbone Carmine, De Luca Roberto, Puca Emanuele, Agostini Antonio, Caggiano Alessia, Priori Lorenzo, Esposito Annachiara, Ascrizzi Serena, Piro Geny, Salvatore Lisa, De Sanctis Francesco, Ugel Stefano, Corbo Vincenzo, Neri Dario, Tortora Giampaolo

机构信息

Department of Medical and Surgical Sciences, Medical Oncology , Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Rome, Italy.

Philochem AG, Libernstrasse 3, Otelfingen, 8112, Switzerland.

出版信息

J Exp Clin Cancer Res. 2025 Jan 7;44(1):7. doi: 10.1186/s13046-024-03238-x.

DOI:10.1186/s13046-024-03238-x
PMID:39773310
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11705946/
Abstract

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly type of cancer, with an extremely low five-year overall survival rate. To date, current treatment options primarily involve various chemotherapies, which often prove ineffective and are associated with substantial toxicity. Furthermore, immunotherapies utilizing checkpoint inhibitors have shown limited efficacy in this context, highlighting an urgent need for novel therapeutic strategies. This study investigates the preclinical efficacy of an innovative targeted therapy based on antibody-cytokine fusion proteins, specifically interleukin-2 (IL-2), a pivotal driver of cell-mediated immunity, fused to L19 antibody, which selectively binds to extra domain B of fibronectin (EDB-FN1) expressed in the tumor microenvironment. METHODS: We tested the effectiveness of different immunocytokines through in vivo characterization in syngeneic C57BL/6J orthotopic mouse models of PDAC. Based on these results, we decided to focus on L19-IL2. To assess the efficacy of this immunocytokine we developed an ex-vivo immune-spheroid interaction platform derived from murine 3D pancreatic cultures, and telomerase reverse transcriptase (TERT) specific T-lymphocytes. Moreover, we evaluated the anti-cancer effect of L19-IL2 in combination with standard therapy in vivo experiments in PDAC mouse models. Tumor samples collected after the treatments were characterized for tumor infiltrating immune cell components by bulk RNA sequencing (RNA-seq) and spatial transcriptomics (Stereo-seq) analysis. RESULTS: The tumor-targeted L19-IL2 fusion protein demonstrated potent, dose-dependent anti-tumor activity in mice with pancreatic tumors resistant to standard chemotherapy. Spatial Transcriptomics (ST) and RNA-seq analyses indicated that L19-IL2 treatment induced a significant influx of immune cells into the tumor microenvironment, with these cells expressing activation markers like granzymes, perforins, and the IL-2 receptors. CONCLUSIONS: Our results demonstrated that L19-IL2 enhances immune infiltration and cytotoxicity, remodeling the "cold" tumor microenvironment (TME) in PDAC. This innovative antibody-cytokine fusion protein improves therapeutic outcomes, paving the way for novel targeted treatment strategies in PDAC.

摘要

背景：胰腺导管腺癌（PDAC）是最具侵袭性和致命性的癌症类型之一，五年总生存率极低。迄今为止，目前的治疗选择主要包括各种化疗，但往往证明无效且伴有严重毒性。此外，在这种情况下，利用检查点抑制剂的免疫疗法显示出有限的疗效，凸显了对新型治疗策略的迫切需求。本研究调查了一种基于抗体-细胞因子融合蛋白的创新靶向疗法的临床前疗效，该融合蛋白是将细胞介导免疫的关键驱动因子白细胞介素-2（IL-2）与L19抗体融合而成，L19抗体可选择性结合肿瘤微环境中表达的纤连蛋白额外结构域B（EDB-FN1）。 方法：我们通过在同基因C57BL/6J原位小鼠PDAC模型中的体内表征来测试不同免疫细胞因子的有效性。基于这些结果，我们决定专注于L19-IL2。为了评估这种免疫细胞因子的疗效，我们开发了一种源自小鼠3D胰腺培养物和端粒酶逆转录酶（TERT）特异性T淋巴细胞的体外免疫球状体相互作用平台。此外，我们在PDAC小鼠模型的体内实验中评估了L19-IL2与标准疗法联合的抗癌效果。治疗后收集的肿瘤样本通过批量RNA测序（RNA-seq）和空间转录组学（Stereo-seq）分析来表征肿瘤浸润免疫细胞成分。 结果：肿瘤靶向性L19-IL2融合蛋白在对标准化疗耐药的胰腺肿瘤小鼠中表现出强效、剂量依赖性的抗肿瘤活性。空间转录组学（ST）和RNA-seq分析表明，L19-IL2治疗诱导免疫细胞大量流入肿瘤微环境，这些细胞表达颗粒酶、穿孔素和IL-2受体等激活标志物。 结论：我们的结果表明，L19-IL2增强免疫浸润和细胞毒性，重塑PDAC中的“冷”肿瘤微环境（TME）。这种创新的抗体-细胞因子融合蛋白改善了治疗效果，为PDAC的新型靶向治疗策略铺平了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/11df486bfebb/13046_2024_3238_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/51f8d449c90f/13046_2024_3238_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/c9a401fe3e8e/13046_2024_3238_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/ccdd34f63ee9/13046_2024_3238_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/d44accfbd167/13046_2024_3238_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/84ac4b157a3f/13046_2024_3238_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/0cebe8342b83/13046_2024_3238_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/11df486bfebb/13046_2024_3238_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/51f8d449c90f/13046_2024_3238_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/c9a401fe3e8e/13046_2024_3238_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/ccdd34f63ee9/13046_2024_3238_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/d44accfbd167/13046_2024_3238_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/84ac4b157a3f/13046_2024_3238_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/0cebe8342b83/13046_2024_3238_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6a7/11705946/11df486bfebb/13046_2024_3238_Fig7_HTML.jpg

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[4]
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[5]
NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis.

JAMA Netw Open. 2024-1-2

[6]
Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer.

J Transl Med. 2023-11-23

[7]
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