Glypican-3–Targeted <sup>89</sup>Zr PET Imaging of Hepatocellular Carcinoma

Sham, Jonathan G.; Kievit, Forrest M.; Grierson, John R.; Miyaoka, Robert S.; Yeh, Matthew M.; Zhang, Miqin; Yeung, Raymond S.; Minoshima, Shinsei; Park, James O.

doi:10.2967/jnumed.113.132118

Cited by 60 publications

(69 citation statements)

References 38 publications

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“…Orthotopic xenografts were created as previously described (9). Briefly, 8-wk-old female athymic Nu/J mice (Jackson Laboratories) were anesthetized using 1.5% inhaled isoflurane, and the left lobe of the liver was exposed through an upper midline laparotomy.…”

Section: Methodsmentioning

confidence: 99%

“…However, standard multiphase CT and MR imaging have limited spatial resolution and lack tissue specificity (5–8). Our group recently reported the use of a 89 Zr-conjugated monoclonal antibody (mAb) targeting the HCC-specific marker glypican-3 (GPC3) to address these limitations of conventional imaging approaches (9). Although demonstrating excellent sensitivity and specificity, the use of intact mAbs for targeted molecular imaging presents its own shortcomings.…”

mentioning

confidence: 99%

“…This rapid clearance leads to higher tumor-to-background ratios at earlier time points, allowing for a more clinically practical PET contrast agent. Although most whole-mAb immuno-PET conjugates require 3–5 d to achieve acceptable signal-to-noise ratios (9,26–28), F(ab′)2 conjugates can demonstrate similar imaging performance just hours after administration, theoretically allowing for same-day administration and imaging (17,19). …”

mentioning

confidence: 99%

“…Our recent work with 89 Zr PET imaging of HCC using an anti-GPC3 mAb (αGPC3) has shown promise (9), although 89 Zr-αGPC3 suffers from the same shortcomings as other mAb-based imaging probes. Its long blood half-life and relatively high background liver uptake hinders tumor-to-background ratios at early time points, necessitating an imaging delay of approximately 72 h to act as an effective contrast agent.…”

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Glypican-3–Targeting F(ab′)2 for ⁸⁹Zr PET of Hepatocellular Carcinoma

et al. 2014

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Hepatocellular carcinoma (HCC) is an increasingly lethal malignancy for which management is critically dependent on accurate imaging. Glypican-3 (GPC3) is a cell surface receptor overexpressed in most HCCs and provides a unique target for molecular diagnostics. The use of monoclonal antibodies (mAbs) that target GPC3 (αGPC3) in PET imaging has shown promise but comes with inherent limitations associated with mAbs such as long circulation times. This study used 89Zr-conjugated F(ab′)2 fragments directed against GPC3 (89Zr-αGPC3-F(ab′)2) to evaluate the feasibility of the fragments as a diagnostic immuno-PET imaging probe. Methods Immobilized ficin was used to digest αGPC3, creating αGPC3-F(ab′)2 fragments subsequently conjugated to 89Zr. In vivo biodistribution and PET studies were performed on GPC3-expressing HepG2 and GPC3-nonexpressing RH7777 orthotopic xenografts. Results Reliable αGPC3-F(ab′)2 production via immobilized ficin digestion was verified by high-performance liquid chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis. 89Zr-αGPC3-F(ab′)2 demonstrated F(ab′)2-dependent, antigen-specific cell binding. HepG2 tumor uptake was higher than any other tissue, peaking at 100 ± 21 percentage injected dose per gram (%ID/g) 24 h after injection, a value 33- to 38-fold higher than GPC3-nonexpressing RH7777 tumors. The blood half-life of the 89Zr-αGPC3-F(ab′)2 conjugate was approximately 11 h, compared with approximately 115 h for historic mAb controls. This shorter half-life enabled clear tumor visualization on PET 4 h after administration, with a resultant peak tumor-to-liver contrast ratio of 23.3. Blocking antigen-expressing tumors with an excess of nonradiolabeled αGPC3 resulted in decreased tumor uptake similar to native liver. The kidneys exhibited high tissue uptake, peaking at 24 h with 83 ± 12 %ID/g. HepG2 tumors ranging from 1.5 to 7 mm were clearly visible on PET, whereas larger RH7777 tumors displayed signal lower than background liver tissue. Conclusion This study demonstrates the feasibility of using 89Zr-αGPC3-F(ab′) 2 for intrahepatic tumor localization with small-animal PET. Faster blood clearance and lower background liver uptake enable excellent signal-to-noise ratios at early time points. Increased renal uptake is similar to that as has been seen with clinical radioactive peptide imaging. 89Zr-αGPC3-F(ab′)2 addresses some of the shortcomings of whole-antibody immuno-PET probes. Further optimization is warranted to maximize probe sensitivity and specificity in the process of clinical translation.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Glypican-3–Targeting F(ab′)2 for ⁸⁹Zr PET of Hepatocellular Carcinoma

et al. 2014

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“…clinical and clinical use in PET imaging continues to mature into a widespread technique (1)(2)(3)(4), limitations still remain: namely space, in which the antigens to which our antibody is targeting are located (intracellularly or cell surface, bound or circulating), and time, the extended period after which the imaging must take place, to allow for blood clearance of the long-circulating antibody. Typically, circulating antigens can be overcome by a predose of cold antibody to saturate these off-target sites, whereas limitations in timing can be overcome by simply imaging at longer time points.…”

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confidence: 99%