Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney

Rolleman, Edgar J.; Kooij, P. P. M.; Herder, Wouter W. de; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de

doi:10.1007/s00259-007-0457-7

Cited by 46 publications

(43 citation statements)

References 37 publications

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“…Elevated renal uptake does not, however, preclude peptide-targeted radionuclides from clinical use. 111 In-octreotide scintigraphy is widely used clinically despite demonstrating high renal uptake (40). In the case of 89 Zr-αGPC3-F(ab′)2, clinical utility would likely be maintained because HCC rarely metastasizes to the kidneys (41).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…Rolleman et al retrospectively studied 111 In-octreotide scans of patients who were scanned before and during treatment with unlabeled octreotide. A mean 18% reduction in kidney uptake during octreotide treatment was found, suggesting some involvement of somatostatin receptors in the renal uptake of 111 Inoctreotide (19). However, an excess of unlabeled octreotide may also interfere with binding of 111 In-octreotide to other receptors such as megalin.…”

Section: Proximal Tubular Reabsorption and Processingmentioning

confidence: 91%

Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention

Vegt¹,

Jong²,

Wetzels³

et al. 2010

J Nucl Med

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257

251

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Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-limiting nephrotoxicity. An overview of renal handling of radiolabeled peptides and resulting nephrotoxicity is presented, and strategies to reduce nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of competitive inhibitors of reabsorption also interferes with the interaction of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clinical PRRT. Furthermore, nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT.

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“…Recent experimental observations have suggested that the multiligand megalin/cubilin receptor complex localized at the apical membrane of renal proximal tubules could be the transport mechanism responsible for resorption and retention of the radiolabeled somatostatin analogs [17,18]. In addition, subtype 2 of somatostatin receptors was recently found to be probably involved in the uptake of radiolabeled somatostatin analogs in the kidney [19]. Further studies are necessary to analyze exact mechanisms of the renal uptake and to determine the significance of the individual transport mechanisms for renal accumulation of receptor-specifi c peptides.…”

Section: Introductionmentioning

confidence: 99%

In vitro comparison of renal handling and uptake of two somatostatin receptor-specific peptides labeled with indium-111

et al. 2008

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Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney

Cited by 46 publications

References 37 publications

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

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

Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention

In vitro comparison of renal handling and uptake of two somatostatin receptor-specific peptides labeled with indium-111

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Somatostatin receptor subtype 2-mediated uptake of radiolabelled somatostatin analogues in the human kidney

Cited by 46 publications

References 37 publications

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

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

Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention

In vitro comparison of renal handling and uptake of two somatostatin receptor-specific peptides labeled with indium-111

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

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