A biorthogonal chemistry approach for high-contrast antibody imaging of lymphoma at early time points.

IF 3.1 3区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

EJNMMI Research Pub Date : 2025-03-24 DOI:10.1186/s13550-025-01213-x

Swarbhanu Sarkar, Jonathan M Pham, Kimberly J Edwards, Nitika Sharma, Kexiang Xu, A Paden King, Andres Fernandez Del Castillo, Michael D Farwell, Daniel A Pryma, Stephen J Schuster, Mark A Sellmyer

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引用次数: 0

Abstract

Background: Monoclonal antibodies are highly specific for their targets making them effective for cancer therapy. However, their large molecular weight causes slow blood clearance, often requiring weeks to be removed from circulation. This limitation affects companion nuclear imaging and antibody-based diagnostics, necessitating delayed imaging. We report the expansion of a methodology improving positron emission tomography (PET) contrast of the lymphoma biomarker CD20 at early time points after radiolabeled antibody administration. Intact radioimmunoconjugates are allowed to stay in circulation long enough to accumulate in tumors, and then, using a chemical trigger, we induced rapid clearance of the radioactivity from non-target tissues by cleaving the linker between the antibody and the radioactivity. For brevity, we refer to the this as the Tetrazine KnockOut (TKO) method which uses the transcyclooctene-tetrazine (TCO-Tz) reaction, wherein an antibody is conjugated with linker containing TCO and a radioisotope.

Results: We optimized the TCO linker with several different radioisotopes and evaluated the ability of tetrazines to knockout radioactivity from circulating antibodies. We explored several cell types and antibodies with varying internalization rates, to characterize the parameters of TKO and tested [⁸⁹Zr]Zr-DFO-TCO-rituximab in a lymphoma model with PET imaging after Tz or vehicle administration. Treatment with Tz induced > 70% cleavage of the TCO linker in vitro within 30 min. Internalizing radioimmunoconjugates exhibited similar cellular uptake with Tz compared to vehicle, whereas decreased uptake was seen with slowly internalizing antibodies. In rodents, Tz rapidly liberated the radioactivity from the antibody, cleared from the blood, and accumulated in the bladder. TKO resulted in > 50% decreased radioactivity in non-target organs following Tz injection. No decrease in tumor uptake was observed when rate of antibody internalization is higher in a lymphoma model, and the target-to-background ratio increased by > twofold in comparison with Tz nontreated groups at 24 h.

Conclusion: The TKO approach potentiates early imaging of rituximab radioimmunoconjugates and has translational potential for lymphoma imaging.

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早期淋巴瘤高对比抗体显像的双正交化学方法。

背景：单克隆抗体对其靶点具有高度特异性，使其在癌症治疗中有效。然而，它们的大分子量导致血液清除缓慢，通常需要数周才能从循环中清除。这一限制影响伴随核成像和基于抗体的诊断，需要延迟成像。我们报告了一种方法的扩展，该方法在放射标记抗体给药后的早期时间点改善了淋巴瘤生物标志物CD20的正电子发射断层扫描（PET）对比。完整的放射免疫偶联物被允许在循环中停留足够长的时间，以在肿瘤中积累，然后，使用化学触发器，我们通过切割抗体和放射性之间的连接，诱导非目标组织的放射性快速清除。为简洁起见，我们将其称为四嗪敲除（TKO）方法，该方法使用环烯四嗪（TCO- tz）反应，其中抗体与含有TCO和放射性同位素的连接物偶联。结果：我们用几种不同的放射性同位素优化了TCO连接体，并评估了四氮嘧啶敲除循环抗体放射性的能力。我们探索了几种具有不同内化率的细胞类型和抗体，以表征TKO的参数，并在Tz或载药后的淋巴瘤模型中检测了[89Zr] zr - dfo - tco -利妥昔单抗。Tz处理在体外30分钟内诱导bbb70 %的TCO连接体切割。与载体相比，内化的放射免疫偶联物与Tz表现出相似的细胞摄取，而缓慢内化的抗体则表现出摄取减少。在啮齿类动物中，Tz迅速从抗体中释放出放射性物质，从血液中清除，并积聚在膀胱中。TKO导致注射Tz后非靶器官放射性降低50%。在淋巴瘤模型中，当抗体内化率较高时，肿瘤摄取并未减少，24 h时与未治疗组相比，靶本比增加了2倍。结论：TKO方法增强了利妥昔单抗放射免疫偶联物的早期成像，并具有淋巴瘤成像的转化潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EJNMMI Research RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING&nb-

CiteScore

5.90

自引率

3.10%

发文量

审稿时长

13 weeks

期刊介绍： EJNMMI Research publishes new basic, translational and clinical research in the field of nuclear medicine and molecular imaging. Regular features include original research articles, rapid communication of preliminary data on innovative research, interesting case reports, editorials, and letters to the editor. Educational articles on basic sciences, fundamental aspects and controversy related to pre-clinical and clinical research or ethical aspects of research are also welcome. Timely reviews provide updates on current applications, issues in imaging research and translational aspects of nuclear medicine and molecular imaging technologies. The main emphasis is placed on the development of targeted imaging with radiopharmaceuticals within the broader context of molecular probes to enhance understanding and characterisation of the complex biological processes underlying disease and to develop, test and guide new treatment modalities, including radionuclide therapy.