PET with the<sup>89</sup>Zr-Labeled Transforming Growth Factor-β Antibody Fresolimumab in Tumor Models

Munnink, Thijs H. Oude; Arjaans, Marlous; Timmer‐Bosscha, Hetty; Schröder, Carolina P.; Hesselink, Jan Willem; Vedelaar, Silke R.; Walenkamp, Annemiek; Reiß, Michael; Gregory, Richard C.; Hooge, Marjolijn N. Lub-de; Vries, Elisabeth G.E. de

doi:10.2967/jnumed.111.092809

Cited by 51 publications

(68 citation statements)

References 34 publications

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“…This increase in ratio supports the notion of tumor-specific uptake. This pattern of tumor accumulation and increasing tumor-to-blood ratios over time was also seen in our preclinical study with 89 Zr-fresolimumab and in brain metastases in a clinical study with 89 Zr-trastuzumab in patients with metastatic breast cancer (13,18). Taken together, these findings suggest that 89 Zr-fresolimumab uptake not only was a reflection of antibody leakage due to a damaged blood-brain barrier but was tumor-specific and TGF-b-driven.…”

Section: Discussionsupporting

confidence: 64%

“…Conjugation and radiolabeling of fresolimumab were performed under good manufacturing conditions as previously described (13). Before the start of treatment with fresolimumab, patients were injected with 37 MBq (5 mg) of 89 Zr-fresolimumab.…”

Section: Imagingmentioning

confidence: 99%

“…For therapeutic success in brain tumors, it is essential for a monoclonal antibody such as fresolimumab to reach the target site in the brain. In tumor xenograft models, tumor uptake could be visualized and quantified with 89 Zr-fresolimumab PET (13). Therefore, the aim of this study was to visualize and quantify fresolimumab uptake in recurrent high-grade glioma using 89 Zrfresolimumab PET.…”

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confidence: 99%

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TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with ⁸⁹Zr-Fresolimumab PET

et al. 2015

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Transforming growth factor-b (TGF-b) signaling is involved in glioma development. The monoclonal antibody fresolimumab (GC1008) can neutralize all mammalian isoforms of TGF-b, and tumor uptake can be visualized and quantified with 89 Zr-fresolimumab PET in mice. The aim of this study was to investigate the fresolimumab uptake in recurrent high-grade gliomas using 89 Zr-fresolimumab PET and to assess treatment outcome in patients with recurrent high-grade glioma treated with fresolimumab. Methods: Patients with recurrent glioma were eligible. After intravenous administration of 37 MBq (5 mg) of 89 Zr-fresolimumab, PET scans were acquired on day 2 or day 4 after tracer injection. Thereafter, patients were treated with 5 mg of fresolimumab per kilogram intravenously every 3 wk. 89 Zr-fresolimumab tumor uptake was quantified as maximum standardized uptake value (SUV max ). MR imaging for response evaluation was performed after 3 infusions or as clinically indicated. Results: Twelve patients with recurrent high-grade glioma were included: 10 glioblastomas, 1 anaplastic oligodendroglioma, and 1 anaplastic astrocytoma. All patients underwent 89 Zr-fresolimumab PET 4 d after injection. In 4 patients, an additional PET scan was obtained on day 2 after injection. SUV max on day 4 in tumor lesions was 4.6 (range, 1.5-13.9) versus a median SUV mean of 0.3 (range, 0.2-0.5) in normal brain tissue. All patients showed clinical or radiologic progression after 1-3 infusions of fresolimumab. Median progression-free survival was 61 d (range, 25-80 d), and median overall survival was 106 d (range, 37-417 d). Conclusion: 89 Zr-fresolimumab penetrated recurrent high-grade gliomas very well but did not result in clinical benefit.

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Section: Discussionsupporting

confidence: 64%

Section: Imagingmentioning

confidence: 99%

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confidence: 99%

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TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with ⁸⁹Zr-Fresolimumab PET

et al. 2015

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“…Unlike 124 I, 89 Zr appears to be a residualizing radiometal potentially circumventing these problems (7). However, increased radioactivity in bone, as reported in recent studies (8,9) using 89 Zr as a PET tracer, has not been analyzed adequately yet to assess whether or not in vivo metal release or other mechanisms are involved. Again, a consequence could be that the assumption of a constant RMPR is wrong.…”

mentioning

confidence: 93%

PET/CT-Derived Whole-Body and Bone Marrow Dosimetry of ⁸⁹Zr-Cetuximab

Makris¹,

Boellaard²,

Lingen³

et al. 2015

J Nucl Med

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PET/CT imaging allows for image-based estimates of organ and red marrow (RM) residence times. The aim of this study was to derive PET/CT-based radiation dosimetry for 89 Zr-cetuximab, with special emphasis on determining RM-absorbed dose. Methods: Seven patients with colorectal cancer received 36.9 ± 0.8 MBq of 89 Zrcetuximab within 2 h after administration of a therapeutic dose of 500 mgÁm −2 of cetuximab. Whole-body PET/CT scans and blood samples were obtained at 1, 24, 48, 94, and 144 h after injection. RM activity concentrations were calculated from manual delineation of the lumbar vertebrae and blood samples, assuming a fixed RMto-plasma activity concentration ratio (RMPR) of 0.19. The cumulated activity was calculated as the area under the curve of the organ time-activity data (liver, lungs, kidneys, spleen, and RM), assuming physical decay after the last scan. The residence time for each organ was derived by dividing the cumulated activity with the total injected activity. The residence time in the remainder of the body was calculated as the maximum possible residence time minus the sum of residence time of source organs, assuming no excretion during the time course of the scans. The (self and total) RM-and organ-absorbed doses and effective whole-body radiation dose were obtained using dose conversion factors from OLINDA/ EXM 1.1. Several simplified 3-time-point dosimetry approaches were also evaluated. Results: The first approach yielded self and total RM doses of 0.17 ± 0.04 and 0.51 ± 0.06 mGyÁMBq −1 , respectively. The second approach deviated by −21% in self-dose and −6% in total dose. RMPR increased over time in 5 of 7 patients. The highest 89 Zr-absorbed dose was observed in the liver with 2.60 ± 0.78 mGyÁMBq −1 , followed by the kidneys, spleen, and lungs, whereas the effective whole-body dose was 0.61 ± 0.09 mSvÁMBq −1 . The simplified 3-time-point (1, 48, and 144 h) dosimetry approach deviated by at most 4% in both organ-absorbed doses and effective dose. Conclusion: Although the total RM dose estimates obtained with the 2 approaches differed only by at most 6%, the image-based approach is preferred because it accounts for nonconstant RMPR. The number of successive scans can be reduced to 3 without affecting effective dose estimates. PETusi ng long-lived radionuclides has proven to be a valuable tool for predicting the biodistribution of labeled monoclonal antibodies (mAbs) (1,2) and organ dosimetry for radioimmunotherapy (2). In addition, the dose-limiting tissue can be determined, enabling dose escalation and optimization of therapeutic treatment planning. In particular, a recent study showed that the biodistributions of 89 ZrDf-cetuximab and 88 Y-DOTA-cetuximab ( 88 Y as a substitute for 90 Y) were comparable for all organs (1). Another study from the same group demonstrated nearly identical biodistributions of 89 Zribritumomab and 90 Y-ibritumomab (2). Recently, the effect of radioimmunotherapy using 90 Y-cetuximab (combined with external-beam irradiation) on local tumor control in vivo was...

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“…It is already proven with numerous antibodies (39,(70)(71)(72)(73)(74) and other proteins (75,76) through the efforts of groups in The Netherlands where it has been developed in both preclinical and, with good manufacturing practices (GMP) production for tracer production and validation, in clinical settings. Although Zr-89 does have an extraneous high-energy gamma ray (909 keV), the image quality is good and the overall radiation burden is well tolerated (77).…”

Section: The Advent Of Zirconium-89mentioning

confidence: 99%

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

Williams¹

2012

AAPS J

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Abstract. Molecular imaging techniques for protein therapeutics rely on reporter labels, especially radionuclides or sometimes near-infrared fluorescent moieties, which must be introduced with minimal perturbation of the protein's function in vivo and are detected non-invasively during whole-body imaging. PET is the most sensitive whole-body imaging technique available, making it possible to perform biodistribution studies in humans with as little as 1 mg of injected antibody carrying 1 mCi (37 MBq) of zirconium-89 radiolabel. Different labeling chemistries facilitate a variety of optical and radionuclide methods that offer complementary information from microscopy and autoradiography and offer some trade-offs in whole-body imaging between cost and logistic difficulty and image quality and sensitivity (how much protein needs to be injected). Interpretation of tissue uptake requires consideration of label that has been catabolized and possibly residualized. Image contrast depends as much on background signal as it does on tissue uptake, and so the choice of injected dose and scan timing guides the selection of a suitable label and helps to optimize image quality. Although only recently developed, zirconium-89 PET techniques allow for the most quantitative tomographic imaging at millimeter resolution in small animals and they translate very well into clinical use as exemplified by studies of radiolabeled antibodies, including trastuzumab in breast cancer patients, in The Netherlands.

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PET with the⁸⁹Zr-Labeled Transforming Growth Factor-β Antibody Fresolimumab in Tumor Models

Cited by 51 publications

References 34 publications

TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with ⁸⁹Zr-Fresolimumab PET

TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with ⁸⁹Zr-Fresolimumab PET

PET/CT-Derived Whole-Body and Bone Marrow Dosimetry of ⁸⁹Zr-Cetuximab

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

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PET with the89Zr-Labeled Transforming Growth Factor-β Antibody Fresolimumab in Tumor Models

Cited by 51 publications

References 34 publications

TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with 89Zr-Fresolimumab PET

TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with 89Zr-Fresolimumab PET

PET/CT-Derived Whole-Body and Bone Marrow Dosimetry of 89Zr-Cetuximab

Tissue Distribution Studies of Protein Therapeutics Using Molecular Probes: Molecular Imaging

Contact Info

Product

Resources

About

PET with the⁸⁹Zr-Labeled Transforming Growth Factor-β Antibody Fresolimumab in Tumor Models

TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with ⁸⁹Zr-Fresolimumab PET

TGF-β Antibody Uptake in Recurrent High-Grade Glioma Imaged with ⁸⁹Zr-Fresolimumab PET

PET/CT-Derived Whole-Body and Bone Marrow Dosimetry of ⁸⁹Zr-Cetuximab