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ImmunoPET imaging of CD38 in murine lymphoma models using 89Zr-labeled daratumumab

  • Lei Kang
  • Dawei Jiang
  • Christopher G. England
  • Todd E. Barnhart
  • Bo Yu
  • Zachary T. Rosenkrans
  • Rongfu Wang
  • Jonathan W. Engle
  • Xiaojie Xu
  • Peng Huang
  • Weibo Cai
Original Article
  • 564 Downloads

Abstract

Purpose

CD38 is considered a potential biomarker for multiple myeloma (MM) and has shown a strong link with chronic lymphocytic leukemia due to high and uniform expression on plasma cells. In vivo evaluation of CD38 expression may provide useful information about lesion detection and prognosis of treatment in MM. In this study, immunoPET imaging with 89Zr-labeled daratumumab was used for differentiation of CD38 expression in murine lymphoma models to provide a potential non-invasive method for monitoring CD38 in the clinic.

Methods

Daratumumab was radiolabeled with 89Zr (t1/2 = 78.4 h) via conjugation with desferrioxamine (Df). After Western blot (WB) was used to screen CD38 expression in five lymphoma cell lines, flow cytometry and cellular binding assays were performed to test the binding ability of labeled or conjugated daratumumab with CD38 in vitro. PET imaging and biodistribution studies were performed to evaluate CD38 expression after injection of 89Zr-Df-daratumumab. 89Zr-Df-IgG was also evaluated as a non-specific control group in the Ramos model. Finally, CD38 expression in tumor tissues was verified by histological analysis.

Results

Using WB screening, the Ramos cell line was found to express the highest level of CD38 while the HBL-1 cell line had the lowest expression. Df-conjugated and 89Zr-labeled daratumumab displayed similar high binding affinities with Ramos cells. PET imaging of 89Zr-Df-daratumumab showed a high tumor uptake of up to 26.6 ± 8.0 %ID/g for Ramos at 120 h post-injection, and only up to 6.6 ± 2.9 %ID/g for HBL-1 (n = 4). Additionally, 89Zr-Df-IgG demonstrated a low tumor uptake in the Ramos model (only 4.3 ± 0.8 %ID/g at 120 h post-injection). Ex vivo biodistribution studies showed similar trends with imaging results. Immunofluorescence staining of tumor tissues verified higher CD38 expression of Ramos than that of HBL-1.

Conclusions

The role of 89Zr-Df-daratumumab was investigated for evaluating CD38 expression in lymphoma models non-invasively and was found to be to a promising imaging agent of CD38-positive hematological diseases such as MM in future clinical applications.

Keywords

Daratumumab Positron emission tomography (PET) CD38 B-cell lymphoma ImmunoPET Cancer 89Zr 

Notes

Acknowledgments

This work was supported by the University of Wisconsin - Madison, the National Institutes of Health (NIBIB/NCI 1R01CA169365, 1R01EB021336, P30CA014520, T32CA009206), the American Cancer Society (125246-RSG-13-099-01-CCE), the National Natural Science Foundation of China (81672602, 81472589, 31771036, 51703132, 51573096), the Beijing Nova Program (Z141102001814055, Z171100001117024), the Beijing Capital Special Development Application Program (Z141107002514159), PKU medicine-engineer collaborative seed program (BMU20160574), Logistics Scientific Research Project (BWS16J010) and the Basic Research Program of Shenzhen (JCYJ20170412111100742, JCYJ20160422091238319)

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Nuclear MedicinePeking University First HospitalBeijingChina
  2. 2.Department of RadiologyUniversity of Wisconsin - MadisonMadisonUSA
  3. 3.Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics, School of Biomedical Engineering, Health Science CenterShenzhen UniversityShenzhenChina
  4. 4.Department of Medical PhysicsUniversity of Wisconsin – MadisonMadisonUSA
  5. 5.School of PharmacyUniversity of Wisconsin – MadisonMadisonUSA
  6. 6.Department of Medical Molecular BiologyBeijing Institute of BiotechnologyBeijingChina
  7. 7.University of Wisconsin Carbone Cancer CenterMadisonUSA

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