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01.12.2018 | Original research | Ausgabe 1/2018 Open Access

EJNMMI Research 1/2018

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

Zeitschrift:
EJNMMI Research > Ausgabe 1/2018
Autoren:
Christian Brand, Ahmad Sadique, Jacob L. Houghton, Kishore Gangangari, Jose F. Ponte, Jason S. Lewis, Naga Vara Kishore Pillarsetty, Jason A. Konner, Thomas Reiner
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13550-018-0437-x) contains supplementary material, which is available to authorized users.

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.
Zusatzmaterial
Additional file 1: Figure S1. Size exclusion chromatograms of (a) M9346A and (b) DFO-M9346A. (PDF 279 kb)
13550_2018_437_MOESM1_ESM.pdf
Additional file 2: Figure S2. Lindmo immunoreactivity assay for 89Zr-labeled DFO-M9346A. (PDF 280 kb)
13550_2018_437_MOESM2_ESM.pdf
Additional file 3: Figure S3. Stability study in human plasma of [89Zr]Zr-DFO-M9346A. (PDF 280 kb)
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Additional file 4: Figure S4. Serial PET imaging at 4 h, 24 h, 48 h, and 72 h post-administration of [89Zr]Zr-DFO-M9346A in KB tumor bearing mice. (PDF 335 kb)
13550_2018_437_MOESM4_ESM.pdf
Additional file 5: Figure S5. Ex vivo biodistribution study at 24 h and 72 h post-injection of [89Zr]Zr-DFO-M9346A in KB tumor bearing mice. (PDF 335 kb)
13550_2018_437_MOESM5_ESM.pdf
Additional file 6: Figure S6. Ex vivo biodistribution study at 24 h and 48 h post-injection of [89Zr]Zr-DFO-M9346A in OV90 tumor bearing mice. (PDF 335 kb)
13550_2018_437_MOESM6_ESM.pdf
Additional file 7: Figure S7. Side-by-side comparison of the ex vivo biodistribution at 48 h post-injection of [89Zr]Zr-DFO-M9346A and [131I]-IMGN853 in OV90 tumor bearing mice. (PDF 102 kb)
13550_2018_437_MOESM7_ESM.pdf
Additional file 8: Figure S8. Weights of individual mouse over time during treatment. (PDF 280 kb)
13550_2018_437_MOESM8_ESM.pdf
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