89Zr-labeled ImmunoPET targeting the cancer stem cell antigen CD133 using fully-human antibody constructs.

IF 3.1 3区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING
Kevin Wyszatko, Nancy Janzen, Luis Rafael Silva, Luke Kwon, Teesha Komal, Manuela Ventura, Chitra Venugopal, Sheila K Singh, John F Valliant, Saman Sadeghi
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Abstract

Background: Cancer stem cells play an important role in driving tumor growth and treatment resistance, which makes them a promising therapeutic target to prevent cancer recurrence. Emerging cancer stem cell-targeted therapies would benefit from companion diagnostic imaging probes to aid in patient selection and monitoring response to therapy. To this end, zirconium-89-radiolabeled immunoPET probes that target the cancer stem cell-antigen CD133 were developed using fully human antibody and antibody scFv-Fc scaffolds.

Results: ImmunoPET probes [89Zr]-DFO-RW03IgG (CA = 0.7 ± 0.1), [89Zr]-DFO-RW03IgG (CA = 3.0 ± 0.3), and [89Zr]-DFO-RW03scFv - Fc (CA = 2.9 ± 0.3) were radiolabeled with zirconium-89 (radiochemical yield 42 ± 5%, 97 ± 2%, 86 ± 12%, respectively) and each was isolated in > 97% radiochemical purity with specific activities of 120 ± 30, 270 ± 90, and 200 ± 60 MBq/mg, respectively. In vitro binding assays showed a low-nanomolar binding affinity of 0.6 to 1.1 nM (95% CI) for DFO-RW03IgG (CA = 0.7 ± 0.1), 0.3 to 1.9 nM (95% CI) for DFO-RW03IgG (CA = 3.0 ± 0.3), and 1.5 to 3.3 nM (95% CI) for DFO-RW03scFv - Fc (C/A = 0.3). Biodistribution studies found that [89Zr]-DFO-RW03scFv - Fc (CA = 2.9 ± 0.3) exhibited the highest tumor uptake (23 ± 4, 21 ± 2, and 23 ± 4%ID/g at 24, 48, and 72 h, respectively) and showed low uptake (< 6%ID/g) in all off-target organs at each timepoint (24, 48, and 72 h). Comparatively, [89Zr]-DFO-RW03IgG (CA = 0.7 ± 0.1) and [89Zr]-DFO-RW03IgG (CA = 3.0 ± 0.3) both reached maximum tumor uptake (16 ± 3%ID/g and 16 ± 2%ID/g, respectively) at 96 h p.i. and showed higher liver uptake (10.2 ± 3%ID/g and 15 ± 3%ID/g, respectively) at that timepoint. Region of interest analysis to assess PET images of mice administered [89Zr]-DFO-RW03scFv - Fc (CA = 2.9 ± 0.3) showed that this probe reached a maximum tumor uptake of 22 ± 1%ID/cc at 96 h, providing a tumor-to-liver ratio that exceeded 1:1 at 48 h p.i. Antibody-antigen mediated tumor uptake was demonstrated through biodistribution and PET imaging studies, where for each probe, co-injection of excess unlabeled RW03IgG resulted in > 60% reduced tumor uptake.

Conclusions: Fully human CD133-targeted immunoPET probes [89Zr]-DFO-RW03IgG and [89Zr]-DFO-RW03scFv - Fc accumulate in CD133-expressing tumors to enable their delineation through PET imaging. Having identified [89Zr]-DFO-RW03scFv - Fc (CA = 2.9 ± 0.3) as the most attractive construct for CD133-expressing tumor delineation, the next step is to evaluate this probe using patient-derived tumor models to test its detection limit prior to clinical translation.

使用全人抗体构建体的 89Zr 标记免疫 PET 靶向癌症干细胞抗原 CD133。
背景:癌症干细胞在推动肿瘤生长和治疗耐药性方面发挥着重要作用,这使其成为预防癌症复发的一个有前景的治疗靶点。新兴的癌症干细胞靶向疗法将受益于辅助诊断成像探针,以帮助选择患者和监测治疗反应。为此,我们利用全人源抗体和抗体scFv-Fc支架开发了靶向癌症干细胞抗原CD133的锆-89放射性标记免疫PET探针:结果:免疫PET探针[89Zr]-DFO-RW03IgG(CA = 0.7 ± 0.1)、[89Zr]-DFO-RW03IgG(CA = 3.0 ± 0.3)和[89Zr]-DFO-RW03scFv - Fc(CA = 2.9 ± 0.3)进行了锆-89 放射标记(放射化学收率分别为 42 ± 5%、97 ± 2%、86 ± 12%),并分离出了放射化学纯度大于 97% 的锆-89,其比活度分别为 120 ± 30、270 ± 90 和 200 ± 60 MBq/mg。体外结合试验显示,DFO-RW03IgG(CA = 0.7 ± 0.1)的低纳摩尔结合亲和力为 0.6 至 1.1 nM(95% CI),DFO-RW03IgG(CA = 3.0 ± 0.3)的低纳摩尔结合亲和力为 0.3 至 1.9 nM(95% CI),DFO-RW03scFv - Fc(C/A = 0.3)的低纳摩尔结合亲和力为 1.5 至 3.3 nM(95% CI)。生物分布研究发现,[89Zr]-DFO-RW03scFv - Fc(CA = 2.9 ± 0.3)的肿瘤摄取率最高(24、48 和 72 h 时分别为 23 ± 4、21 ± 2 和 23 ± 4%ID/g),而[89Zr]-DFO-RW03IgG(CA = 0.7±0.1)和[89Zr]-DFO-RW03IgG(CA = 3.0±0.3)均在96 h p.i.达到最大肿瘤摄取量(分别为16±3%ID/g和16±2%ID/g),并在该时间点显示较高的肝脏摄取量(分别为10.2±3%ID/g和15±3%ID/g)。对注射[89Zr]-DFO-RW03scFv - Fc(CA = 2.9 ± 0.3)的小鼠 PET 图像进行评估的感兴趣区分析表明,该探针在 96 小时时的最大肿瘤摄取量为 22 ± 1%ID/cc,在 48 小时时肿瘤与肝脏之比超过 1:1。i.抗体抗原介导的肿瘤摄取通过生物分布和 PET 成像研究得到证实,对于每种探针,联合注射过量未标记的 RW03IgG 可使肿瘤摄取量降低 60%以上:结论:全人类CD133靶向免疫PET探针[89Zr]-DFO-RW03IgG和[89Zr]-DFO-RW03scFv - Fc可在CD133表达的肿瘤中聚集,从而通过PET成像对肿瘤进行定性。在确定[89Zr]-DFO-RW03scFv - Fc(CA = 2.9 ± 0.3)是用于CD133表达肿瘤分界的最有吸引力的构建物之后,下一步是使用患者衍生肿瘤模型对该探针进行评估,以便在临床应用之前测试其检测极限。
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来源期刊
EJNMMI Research
EJNMMI Research RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING&nb-
CiteScore
5.90
自引率
3.10%
发文量
72
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.
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