Lei Kang1,2, Cuicui Li3,4, Qi Yang3, Logan Sutherlin5, Lin Wang6, Zhao Chen3, Kaelyn V Becker5, Nan Huo7, Yongkang Qiu3, Jonathan W Engle5, Rongfu Wang3, Chengzhi He6, Dawei Jiang8,9, Xiaojie Xu10, Weibo Cai11. 1. Department of Nuclear Medicine, Peking University First Hospital, Xicheng Dist, No. 8 Xishiku Str, Beijing, 100034, China. kanglei@bjmu.edu.cn. 2. Departments of Radiology and Medical Physics, University of Wisconsin - Madison, K6/562 Clinical Science Center, 600 Highland Ave, Madison, WI, 53705-2275, USA. kanglei@bjmu.edu.cn. 3. Department of Nuclear Medicine, Peking University First Hospital, Xicheng Dist, No. 8 Xishiku Str, Beijing, 100034, China. 4. Department of Nuclear Medicine, Beijing Friendship Hospital, Beijing, 100050, China. 5. Departments of Radiology and Medical Physics, University of Wisconsin - Madison, K6/562 Clinical Science Center, 600 Highland Ave, Madison, WI, 53705-2275, USA. 6. Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China. 7. Department of Medical Molecular Biology, Beijing Institute of Biotechnology, 27 Tai-Ping Rd, Beijing, 100850, China. 8. Departments of Radiology and Medical Physics, University of Wisconsin - Madison, K6/562 Clinical Science Center, 600 Highland Ave, Madison, WI, 53705-2275, USA. daweijiang@hust.edu.cn. 9. Department of Medical Molecular Biology, Beijing Institute of Biotechnology, 27 Tai-Ping Rd, Beijing, 100850, China. daweijiang@hust.edu.cn. 10. Department of Nuclear Medicine, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China. miraclexxj@126.com. 11. Departments of Radiology and Medical Physics, University of Wisconsin - Madison, K6/562 Clinical Science Center, 600 Highland Ave, Madison, WI, 53705-2275, USA. wcai@uwhealth.org.
Abstract
PURPOSE: Abnormal CD38 expression in some hematologic malignancies, including lymphoma, has made it a biomarker for targeted therapies. Daratumumab (Dara) is the first FDA-approved CD38-specific monoclonal antibody, enabling successfully immunoPET imaging over the past years. Radiolabeled Dara however has a long blood circulation and delayed tumor uptake which can limit its applications. The focus of this study is to develop 64Cu-labeled Dara-F(ab')2 for the visualization of CD38 in lymphoma models. METHODS: F(ab')2 fragment was prepared from Dara using an IdeS enzyme and purified with Protein A beads. Western blotting, flow cytometry, and surface plasmon resonance (SPR) were performed for in vitro assay. Probes were labeled with 64Cu after the chelation of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Small animal PET imaging and quantitative analysis were performed after injection of 64Cu-labeled Dara-F(ab')2, IgG-F(ab')2, and Dara for evaluation in lymphoma models. RESULTS: Flow cytometry and SPR assay proved the specific binding ability of Dara-F(ab')2 and NOTA-Dara-F(ab')2 in vitro. Radiolabeling yield of [64Cu]Cu-NOTA-Dara-F(ab')2 was over 90% and with a specific activity of 4.0 ± 0.6 × 103 MBq/μmol (n = 5). PET imaging showed [64Cu]Cu-NOTA-Dara-F(ab')2 had a rapid and high tumor uptake as early as 2 h (6.9 ± 1.2%ID/g) and peaked (9.5 ± 0.7%ID/g) at 12 h, whereas [64Cu]Cu-NOTA-Dara reached its tumor uptake peaked at 48 h (8.3 ± 1.4%ID/g, n = 4). In comparison, IgG-F(ab')2 and HBL-1 control groups found no noticeable tumor uptake. [64Cu]Cu-NOTA-Dara-F(ab')2 had significantly lower uptake in blood pool, bone, and muscle than [64Cu]Cu-NOTA-Dara and its tumor-to-blood and tumor-to-muscle ratios were significantly higher than controls. CONCLUSIONS: [64Cu]Cu-NOTA-Dara-F(ab')2 showed a rapid and high tumor uptake in CD38-positive lymphoma models with favorable imaging contrast, showing its promise as a potential PET imaging agent for future clinical applications.
PURPOSE: Abnormal CD38 expression in some hematologic malignancies, including lymphoma, has made it a biomarker for targeted therapies. Daratumumab (Dara) is the first FDA-approved CD38-specific monoclonal antibody, enabling successfully immunoPET imaging over the past years. Radiolabeled Dara however has a long blood circulation and delayed tumor uptake which can limit its applications. The focus of this study is to develop 64Cu-labeled Dara-F(ab')2 for the visualization of CD38 in lymphoma models. METHODS: F(ab')2 fragment was prepared from Dara using an IdeS enzyme and purified with Protein A beads. Western blotting, flow cytometry, and surface plasmon resonance (SPR) were performed for in vitro assay. Probes were labeled with 64Cu after the chelation of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Small animal PET imaging and quantitative analysis were performed after injection of 64Cu-labeled Dara-F(ab')2, IgG-F(ab')2, and Dara for evaluation in lymphoma models. RESULTS: Flow cytometry and SPR assay proved the specific binding ability of Dara-F(ab')2 and NOTA-Dara-F(ab')2 in vitro. Radiolabeling yield of [64Cu]Cu-NOTA-Dara-F(ab')2 was over 90% and with a specific activity of 4.0 ± 0.6 × 103 MBq/μmol (n = 5). PET imaging showed [64Cu]Cu-NOTA-Dara-F(ab')2 had a rapid and high tumor uptake as early as 2 h (6.9 ± 1.2%ID/g) and peaked (9.5 ± 0.7%ID/g) at 12 h, whereas [64Cu]Cu-NOTA-Dara reached its tumor uptake peaked at 48 h (8.3 ± 1.4%ID/g, n = 4). In comparison, IgG-F(ab')2 and HBL-1 control groups found no noticeable tumor uptake. [64Cu]Cu-NOTA-Dara-F(ab')2 had significantly lower uptake in blood pool, bone, and muscle than [64Cu]Cu-NOTA-Dara and its tumor-to-blood and tumor-to-muscle ratios were significantly higher than controls. CONCLUSIONS: [64Cu]Cu-NOTA-Dara-F(ab')2 showed a rapid and high tumor uptake in CD38-positive lymphoma models with favorable imaging contrast, showing its promise as a potential PET imaging agent for future clinical applications.
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