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.

Electronic supplementary material

The online version of this article (10.1186/s13550-018-0437-x) contains supplementary material, which is available to authorized users.