使用锆标记的治疗性抗体NC318对Siglec-15进行免疫PET成像

IF 2.8 4区 医学 Q2 Medicine
E. Jagoda, F. Basuli, C. Olkowski, Ido D. Weiss, Tim E. Phelps, Karen J. Wong, Anita T. Ton, Kelly C. Lane, S. Adler, D. Butcher, E. Edmondson, S. Langermann, P. Choyke
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Cancer cell lines expressing variable Siglec-15 levels were used for in vitro cell binding studies and tumor xenograft mouse models for biodistributions. [89Zr]Zr-DFO-NC318 biodistribution and PET imaging studies to determine tissue uptakes (tissue : muscle ratios, T : M) included pharmacokinetic evaluation in Siglec-15+tumor xenografts and immunocompetent mice, blocking with nonradioactive NC318 (20, 100, and 300 μg) and xenografts with low/negligible Siglec-15 expressing tumors. Results. [89Zr]Zr-DFO-NC318 exhibited high affinity (\n \n \n \n K\n \n \n d\n \n \n \n ~4 nM) for Siglec-15 and distinguished between moderate and negligible Siglec-15 expression levels in cancer cell lines. The highest [89Zr]Zr-DFO-NC318 uptakes occurred in the spleen and lymph nodes of the Siglec-15+tumor xenografts at all time points followed by Siglec-15+tumor uptake which was lower although highly retained. In immunocompetent mice, the spleen and lymph nodes exhibited lower uptakes indicating that the athymic xenografts had increased Siglec-15+ immune cells. Specific [89Zr]Zr-DFO-NC318 binding to Siglec-15 was proven with NC318 blocking studies in which dose-dependent decreases in Siglec-15+tumor T : Ms were observed. Higher than expected, tumor T : Ms were seen in lower expressing tumors likely due to the contribution of murine Siglec-15+ immune cells in the tumor microenvironment as confirmed by immunohistochemistry. Siglec-15+tumors were identified on PET images whereas low/negligible expressing tumors showed lower uptakes. Conclusions. In vitro and in vivo [89Zr]Zr-DFO-NC318 uptakes correlated with Siglec-15 expression levels in target tissues. 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引用次数: 1

摘要

客观的唾液酸结合免疫球蛋白样凝集素15(Siglec-15)在各种癌症中过表达,这导致了治疗性抗Siglec-15单克隆抗体(mAb)的开发。在这些临床前研究中,用锆-89标记治疗性mAb NC318(抗人/鼠Siglec-15mAb),并在表达Siglec-15的人癌症细胞和小鼠异种移植物中评估其作为临床诊断显像剂的潜在用途。方法。用锆-89放射性标记结合去铁胺的NC318,合成[89Zr]Zr-DFO-NC318。表达可变Siglec-15水平的癌症细胞系用于体外细胞结合研究和用于生物分布的肿瘤异种移植小鼠模型。[89Zr]Zr-DFO-NC318生物分布和PET成像研究,以确定组织吸收(组织 : 肌肉比例,T : M) 包括Siglec-15+肿瘤异种移植物和免疫活性小鼠的药代动力学评估,用非放射性NC318(20、100和300 μg)和具有低/可忽略的Siglec-15表达肿瘤的异种移植物。后果[89Zr]Zr-DFO-NC318表现出高亲和力(Kd~4 nM),并在癌症细胞系中的中等和可忽略的Siglec-15表达水平之间进行区分。在所有时间点,最高的[89Zr]Zr-DFO-NC318摄取发生在Siglec-15+肿瘤异种移植物的脾脏和淋巴结中,其次是Siglec-15-肿瘤摄取,尽管其高度保留,但较低。在免疫活性小鼠中,脾脏和淋巴结的摄取量较低,表明无胸腺异种移植物增加了Siglec-15+免疫细胞。NC318阻断研究证实了特异性[89Zr]Zr-DFO-NC318与Siglec-15的结合,其中Siglec-15+肿瘤T : 观察到Ms。高于预期,肿瘤T : Ms在低表达肿瘤中可见,这可能是由于小鼠Siglec-15+免疫细胞在肿瘤微环境中的贡献,如免疫组织化学所证实的。Siglec-15+肿瘤在PET图像上被识别,而低/可忽略表达的肿瘤显示出较低的摄取。结论。体外和体内[89Zr]Zr-DFO-NC318摄取与靶组织中Siglec-15的表达水平相关。尽管肿瘤微环境中的免疫细胞亚群被摄取,但这些结果表明,临床[89Zr]Zr-DFO-NC318 PET成像在选择Siglec-15靶向治疗的患者方面可能具有价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Immuno-PET Imaging of Siglec-15 Using the Zirconium-89-Labeled Therapeutic Antibody, NC318
Objective. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is overexpressed in various cancers which has led to the development of therapeutic anti-Siglec-15 monoconal antibodies (mAbs). In these preclinical studies, the therapeutic mAb, NC318 (antihuman/murine Siglec-15 mAb), was labeled with zirconium-89 and evaluated in human Siglec-15 expressing cancer cells and mouse xenografts for potential use as a clinical diagnostic imaging agent. Methods. Desferrioxamine-conjugated NC318 was radiolabeled with zirconium-89 to synthesize [89Zr]Zr-DFO-NC318. Cancer cell lines expressing variable Siglec-15 levels were used for in vitro cell binding studies and tumor xenograft mouse models for biodistributions. [89Zr]Zr-DFO-NC318 biodistribution and PET imaging studies to determine tissue uptakes (tissue : muscle ratios, T : M) included pharmacokinetic evaluation in Siglec-15+tumor xenografts and immunocompetent mice, blocking with nonradioactive NC318 (20, 100, and 300 μg) and xenografts with low/negligible Siglec-15 expressing tumors. Results. [89Zr]Zr-DFO-NC318 exhibited high affinity ( K d ~4 nM) for Siglec-15 and distinguished between moderate and negligible Siglec-15 expression levels in cancer cell lines. The highest [89Zr]Zr-DFO-NC318 uptakes occurred in the spleen and lymph nodes of the Siglec-15+tumor xenografts at all time points followed by Siglec-15+tumor uptake which was lower although highly retained. In immunocompetent mice, the spleen and lymph nodes exhibited lower uptakes indicating that the athymic xenografts had increased Siglec-15+ immune cells. Specific [89Zr]Zr-DFO-NC318 binding to Siglec-15 was proven with NC318 blocking studies in which dose-dependent decreases in Siglec-15+tumor T : Ms were observed. Higher than expected, tumor T : Ms were seen in lower expressing tumors likely due to the contribution of murine Siglec-15+ immune cells in the tumor microenvironment as confirmed by immunohistochemistry. Siglec-15+tumors were identified on PET images whereas low/negligible expressing tumors showed lower uptakes. Conclusions. In vitro and in vivo [89Zr]Zr-DFO-NC318 uptakes correlated with Siglec-15 expression levels in target tissues. Despite uptake in immune cell subsets in the tumor microenvironment, these results suggest that clinical [89Zr]Zr-DFO-NC318 PET imaging may have value in selecting patients for Siglec-15-targeted therapies.
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来源期刊
Molecular Imaging
Molecular Imaging 生物-核医学
CiteScore
4.50
自引率
3.60%
发文量
21
审稿时长
>12 weeks
期刊介绍: Molecular Imaging is a peer-reviewed, open access journal highlighting the breadth of molecular imaging research from basic science to preclinical studies to human applications. This serves both the scientific and clinical communities by disseminating novel results and concepts relevant to the biological study of normal and disease processes in both basic and translational studies ranging from mice to humans.
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