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

Abstract

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

Folate Receptor α-Targeted 89Zr-M9346A Immuno-PET for Image-Guided Intervention with Mirvetuximab Soravtansine in Triple-Negative Breast Cancer

“…Similar pharmacokinetics of IMGN853 and 89 Zr-M9346A have been demonstrated by comparing blood retention in female athymic nude mice and ex vivo biodistribution in OV-90 xenograft between 131 I-radiolabeled IMGN853 and 89 Zr-M9346A. 38 Although further studies are required to confirm comparable pharmacokinetics of IMGN853 with the biodistribution of 89 Zr-M9346A, an unquestionable benefit of immuno-PET is its ability to noninvasively display in vivo pharmacokinetics of the radiotracer. Thus, time-course imaging can also reveal the dynamic variation of FRα in various organs, which is useful to optimize the IMGN853 treatment for maximal efficacy and minimal offtarget effect.…”

“…Different physicochemical properties between the 89 Zr-DFO-and maytansinoid DM4-conjugated M9346A could lead to distinct in vivo behaviors. Even though a preliminary comparison study is already published, 38 similar studies in different animal models including nonhuman primates will provide a better understanding. In addition, it would be beneficial to conduct further treatment studies with a different study design that focuses more on the individual difference of FRα expression and treatment efficacy in each PDX or xenograft.…”

Folate Transport and One-Carbon Metabolism in Targeted Therapies of Epithelial Ovarian Cancer

“…A folate conjugate (etarfolatide) conjugated with 99 mTc was investigated as a predictive biomarker in clinical trials [ 124 , 130 ], including a phase II clinical trial with vintafolide in women with recurrent platinum-resistant ovarian cancer [ 124 ]. The antibody-based agent 89 Zr-DFO-M9346A was used to measure FRα in murine ovarian cancer xenografts treated with mirvetuximab soravtansine [ 131 ].…”

Ovarian Cancer Targeted Theranostics

“…studies developed a 89 Zr-radiolabeled version of M9346A as a radiotracer for FRα detection. M9346A is the parent antibody of IMGN853 (19,20). Evaluation of 89 Zr-M9346A uptake in patient derived xenograft models of triple negative breast cancer and ovarian cancer with graded expression levels of FRα showed target specificity, sensitivity and correlated with treatment response to antibody drug conjugate.…”