Leveraging PET to image folate receptor α therapy of an antibody-drug conjugate Journal Article

Authors: Brand, C.; Sadique, A.; Houghton, J. L.; Gangangari, K.; Ponte, J. F.; Lewis, J. S.; Pillarsetty, N. V. K.; Konner, J. A.; Reiner, T.
Article Title: Leveraging PET to image folate receptor α therapy of an antibody-drug conjugate
Abstract: Background: The folate receptor α (FRα)-targeting antibody-drug conjugate (ADC), IMGN853, shows great antitumor activity against FRα-expressing tumors in vivo, but patient selection and consequently therapy outcome are based on immunohistochemistry. The aim of this study is to develop an antibody-derived immuno-PET imaging agent strategy for targeting FRα in ovarian cancer as a predictor of treatment success. Methods: We developed [89Zr]Zr-DFO-M9346A, a humanized antibody-based radiotracer targeting tumor-associated FRα in the preclinical setting. [89Zr]Zr-DFO-M9346A’s binding ability was tested in an in vitro uptake assay using cell lines with varying FRα expression levels. The diagnostic potential of [89Zr]Zr-M9346A was evaluated in KB and OV90 subcutaneous xenografts. Following intravenous injection of [89Zr]Zr-DFO-M9346A (~90 μCi, 50 μg), PET imaging and biodistribution studies were performed. We determined the blood half-life of [89Zr]Zr-DFO-M9346A and compared it to the therapeutic, radioiodinated ADC [131I]-IMGN853. Finally, in vivo studies using IMG853 as a therapeutic, paired with [89Zr]Zr-DFO-M9346A as a companion diagnostic were performed using OV90 xenografts. Results: DFO-M9346A was labeled with Zr-89 at 37 °C within 60 min and isolated in labeling yields of 85.7 ± 5.7%, radiochemical purities of 98.0 ± 0.7%, and specific activities of 3.08 ± 0.43 mCi/mg. We observed high specificity for binding FRα positive cells in vitro. For PET and biodistribution studies, [89Zr]Zr-M9346A displayed remarkable in vivo performance in terms of excellent tumor uptake for KB and OV xenografts (45.8 ± 29.0 %IA/g and 26.1 ± 7.2 %IA/g), with low non-target tissue uptake in other organs such as kidneys (4.5 ± 1.2 %IA/g and 4.3 ± 0.7 %IA/g). A direct comparison of the blood half life of [89Zr]Zr-M9346A and [131I]-IMGN853 corroborated the equivalency of the radiopharmaceutical and the ADC, paving the way for a companion PET imaging study. Conclusions: We developed a new folate receptor-targeted 89Zr-labeled PET imaging agent with excellent pharmacokinetics in vivo. Good tumor uptake in subcutaneous KB and OV90 xenografts were obtained, and ADC therapy studies were performed with the precision predictor. © 2018, The Author(s).
Keywords: pet imaging; 89zr; antibody-drug-conjugate; companion diagnostic
Journal Title: EJNMMI Research
Volume: 8
ISSN: 2191-219X
Publisher: Springer  
Date Published: 2018-08-28
Start Page: 87
Language: English
DOI: 10.1186/s13550-018-0437-x
PROVIDER: scopus
PMCID: PMC6113196
PUBMED: 30155674
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
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MSK Authors
  1. Jason Konner
    79 Konner
  2. Jason S Lewis
    239 Lewis
  3. Thomas Reiner
    70 Reiner
  4. Christian Brand
    19 Brand