Head-to-head evaluation of DFO and 3,4,3-LI(1,2-HOPO) chelators through site-specific conjugation of Anti-STEAP1 antibody V6-19-D11 for 89Zr-immuno-PET imaging

IF 1.8 3区工程技术 Q3 CHEMISTRY, INORGANIC & NUCLEAR

Applied Radiation and Isotopes Pub Date : 2025-09-09 DOI:10.1016/j.apradiso.2025.112168

Syed Qaiser Shah, Saba Shirin

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引用次数: 0

Abstract

Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) is continuously overexpressed in PCa and represents a promising target for immuno-PET imaging. This study aimed to evaluate the in vitro and in vivo performance of two ⁸⁹Zr-labeled anti-STEAP1 immunoconjugates, ⁸⁹Zr-DFO-V6-19-D11 and ⁸⁹Zr-HOPO-V6-19-D11, in terms of tumor targeting, stability, and biodistribution with Standardized Uptake Values (SUVs) in LNCaP xenograft models. Site-specifically conjugated humanized anti-STEAP1 monoclonal antibody V6-19-D11 with p-SCN-Bn-DFO or 3,4,3-LI(1,2-HOPO)-maleimide and ⁸⁹Zr radiolabeling was assessed for radiochemical purity, serum stability, and immunoreactivity. All of the tracers were administered intravenously to LNCaP tumor-bearing nude mice, and biodistribution was quantitated at 24, 48, 72, and 96 h post-injection by γ-counting and SUV. Both radioconjugates were >98 % radiochemically pure, exhibited strong STEAP1 binding (KD ≈ 2.2 nM), and retained good immunoreactivity (>87 %). The HOPO-conjugate also demonstrated improved in vitro stability in serum (88.6 % intact at 96 h vs. 82.0 % for DFO). Tumor accumulation of ⁸⁹Zr-HOPO-V6-19-D11 was comparable or superior at all-time points (15.3 ± 1.5 %ID/g at 24 h, maximum 17.1 ± 1.2 %ID/g at 48 h and 15.9 ± 1.2 %ID/g at 96 h) with significantly reduced off-target uptake, notably in bone (96 h femur: 1.8 ± 0.3 %ID/g vs. 4.5 ± 0.4 %ID/g for DFO; p < 0.01). Tumor-to-background ratios, notably tumor-to-bone (8.8 vs. 3.4), favored the HOPO-based tracer. The ⁸⁹Zr-HOPO-V6-19-D11 immunoconjugate has better in vivo stability, reduced nonspecific bone uptake, and excellent tumor targeting, making it an outstanding candidate for quantitative immuno-PET imaging of STEAP1-positive prostate cancer. This study is indicative of the translational value of HOPO chelation chemistry for enhancing performance of zirconium-89–based antibody tracers for non-invasive cancer characterization.

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通过抗steap1抗体V6-19-D11的位点特异性偶联对DFO和3,4,3- li （1,2- hopo）螯合剂进行头对头评价，用于89zr -免疫- pet成像

前列腺-1六跨膜上皮抗原（STEAP1）在前列腺癌中持续过表达，是免疫pet成像的一个有希望的靶标。本研究旨在评价两种89zr标记的抗steap1免疫偶联物89Zr-DFO-V6-19-D11和89Zr-HOPO-V6-19-D11在LNCaP异种移植模型中的肿瘤靶向性、稳定性和标准化摄取值（SUVs）生物分布。用p-SCN-Bn-DFO或3,4,3- li (1,2- hopo)-马来酰亚胺和89Zr标记的位点特异性偶联人源抗steap1单克隆抗体V6-19-D11进行放射化学纯度、血清稳定性和免疫反应性评估。所有示踪剂均静脉注射LNCaP荷瘤裸鼠，并于注射后24、48、72、96 h用γ-计数和SUV测定其生物分布。两种放射偶联物的放射化学纯度均为>； 98%，具有很强的STEAP1结合（KD≈2.2 nM），并保持良好的免疫反应性（> 87%）。hopo -偶联物在血清中的体外稳定性也有所提高（96 h时88.6%完好无损，而DFO为82.0%）。89Zr-HOPO-V6-19-D11在所有时间点的肿瘤积累相当或更好（24小时15.3±1.5% ID/g， 48小时17.1±1.2% ID/g， 96小时15.9±1.2% ID/g），显著减少脱靶摄取，特别是在骨（96小时股骨：1.8±0.3% ID/g， DFO为4.5±0.4% ID/g; p < 0.01）。肿瘤与背景的比值，尤其是肿瘤与骨的比值（8.8比3.4），更倾向于基于hopo的示踪剂。89Zr-HOPO-V6-19-D11免疫偶联物具有更好的体内稳定性，减少非特异性骨摄取，以及出色的肿瘤靶向性，使其成为steap1阳性前列腺癌定量免疫pet成像的优秀候选物。该研究表明HOPO螯合化学在提高基于锆-89的抗体示踪剂在非侵入性癌症表征中的性能方面具有翻译价值。

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来源期刊

Applied Radiation and Isotopes 工程技术-核科学技术

CiteScore

3.00

自引率

12.50%

发文量

406

审稿时长

13.5 months

期刊介绍： Applied Radiation and Isotopes provides a high quality medium for the publication of substantial, original and scientific and technological papers on the development and peaceful application of nuclear, radiation and radionuclide techniques in chemistry, physics, biochemistry, biology, medicine, security, engineering and in the earth, planetary and environmental sciences, all including dosimetry. Nuclear techniques are defined in the broadest sense and both experimental and theoretical papers are welcome. They include the development and use of α- and β-particles, X-rays and γ-rays, neutrons and other nuclear particles and radiations from all sources, including radionuclides, synchrotron sources, cyclotrons and reactors and from the natural environment. The journal aims to publish papers with significance to an international audience, containing substantial novelty and scientific impact. The Editors reserve the rights to reject, with or without external review, papers that do not meet these criteria. Papers dealing with radiation processing, i.e., where radiation is used to bring about a biological, chemical or physical change in a material, should be directed to our sister journal Radiation Physics and Chemistry.