Initial insights into the interaction of antibodies radiolabeled with Lutetium-177 and Actinium-225 with tumor microenvironment in experimental human and canine osteosarcoma

IF 3.6 4区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Nuclear medicine and biology Pub Date : 2024-05-01 DOI:10.1016/j.nucmedbio.2024.108917

Sabeena Giri , Kevin J.H. Allen , Chandra Bose Prabaharan , Jonathan Bonet Ramirez , Luciano Fiore , Maruti Uppalapati , Ekaterina Dadachova

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Abstract

Background

Osteosarcoma (OS) is a prevalent primary bone cancer affecting both humans and canines. This study describes initial insights into the interaction of the human monoclonal antibody IF3 to an insulin-like growth factor 2 receptor (IGF2R) radiolabeled with either alpha-emitting Actinium-225 (²²⁵Ac) or beta-emitting Lutetium-177 (¹⁷⁷Lu) radionuclides with the OS cells and tumor microenvironment (TME) in experimental human and canine OS.

Basic procedures

SCID mice bearing canine Gracie or human OS-33 OS tumors were treated with ¹⁷⁷Lu- or ²²⁵Ac-labeled IF3 antibody, sacrificed at 24, 72 or 168 h post-treatment and their tumors were analyzed by immunohistochemistry (IHC) for the presence of OS cells, various elements of TME as well as for the double DNA strand breaks with γH2AX and caspase 3 assays.

Main findings

IHC revealed a reduction in IGF2R-positive OS cells and OS stem cell populations post therapy with ²²⁵Ac- and ¹⁷⁷Lu-labeled IF3 antibody. Notably, radiolabeled IF3 antibody effectively diminished pro-tumorigenic M2 macrophages, highlighting its therapeutic promise. The study also unveiled varied responses of natural killer (NK) cells and M1 macrophages, shedding light on the intricate TME interplay. Time-dependent increase in γ-H2AX staining in canine Gracie and human OS-33 tumors treated with [¹⁷⁷Lu]Lu-IF3 and [²²⁵Ac]Ac-IF3 was observed at 24 and 72 h post-RIT.

Principal conclusions

These findings suggest that radiolabeled antibodies offer a hopeful avenue for personalized OS treatment, emphasizing the importance of understanding their impact on the TME and potential synergies with immunotherapy.

Abstract Image

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用镥-177 和锕-225 放射性标记的抗体与肿瘤微环境在实验性人类和犬骨肉瘤中的相互作用的初步见解

背景骨肉瘤（OS）是一种常见的原发性骨癌，对人类和犬都有影响。本研究介绍了人类单克隆抗体 IF3 与胰岛素样生长因子 2 受体（IGF2R）放射性标记的α-发射型 Actinium-225 (225Ac) 或β-发射型 Lutetium-177 (177Lu) 放射性核素在实验性人类和犬骨肉瘤中与骨肉瘤细胞和肿瘤微环境（TME）相互作用的初步见解。基本程序用 177Lu 或 225Ac 标记的 IF3 抗体处理携带犬 Gracie 或人 OS-33 OS 肿瘤的 SID 小鼠，在处理后 24、72 或 168 小时处死，并用免疫组织化学（IHC）分析其肿瘤中 OS 细胞、TME 的各种元素以及用 γH2AX 和 caspase 3 检测 DNA 双断裂。主要发现IHC显示，使用225Ac和177Lu标记的IF3抗体治疗后，IGF2R阳性OS细胞和OS干细胞数量减少。值得注意的是，放射性标记的 IF3 抗体有效地减少了促肿瘤生成的 M2 巨噬细胞，突显了其治疗前景。研究还揭示了自然杀伤（NK）细胞和M1巨噬细胞的不同反应，揭示了TME之间错综复杂的相互作用。用[177Lu]Lu-IF3和[225Ac]Ac-IF3治疗犬Gracie和人OS-33肿瘤后，在RIT后24小时和72小时观察到γ-H2AX染色的时间依赖性增加。

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来源期刊

Nuclear medicine and biology 医学-核医学

CiteScore

6.00

自引率

9.70%

发文量

479

审稿时长

51 days

期刊介绍： Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.