<i>In vitro</i> and <i>In vivo</i> Characterization of 64Cu-Labeled AbegrinTM, a Humanized Monoclonal Antibody against Integrin αvβ3

Cai, Weibo; Wu, Yun; Chen, Kai; Cao, Qizhen; Tice, David A.; Chen, Xiaoyuan

doi:10.1158/0008-5472.can-06-1480

Cited by 180 publications

(164 citation statements)

References 37 publications

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“…Despite the high affinity of these endogenous proteins for copper, in our study, only 5-10% of the injected dose accumulated in the liver [8.3 (Ϯ1.0%) ID/g in neuroblastoma-bearing animals; 6.0 (Ϯ1.1%) ID/g in melanomabearing animals], which is consistent with normal hepatic clearance of an intact IgG. This is approximately one-half the value reported by others for liver uptake of 64 Cu-labeled DOTA immunoconjugates (9,27).…”

Section: Discussionsupporting

confidence: 89%

“…The bifunctional chelators most commonly used for labeling proteins with copper radionuclides are based on the tetraazamacrocyclic chelators DOTA and TETA (5). Copper is, however, lost from these ligands in vivo with concomitant accumulation in the liver (9,27), where it is incorporated into endogenous copper-binding proteins, such as ceruloplasmin and superoxide dismutase (10,28). Copper plays an important role in many normal physiological processes and, hence, is bound by a variety of circulating and intracellular proteins such as copper transporting ATPases, cytochrome oxidase, and superoxide dismutase.…”

Section: Discussionmentioning

confidence: 99%

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Positron emission tomography (PET) imaging of neuroblastoma and melanoma with ⁶⁴ Cu-SarAr immunoconjugates

Voss¹,

Smith

DiBartolo

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

132

123

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The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement 18 F-FDG. Copper-64 ( 64 Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr (1-N-(4-aminobenzyl)-3, 6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine) for use in developing a new class of tumorspecific 64 Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, ch14.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiolabeling with 64 Cu resulted in >95% of the 64 Cu being chelated by the immunoconjugate. Specific activities of at least 10 Ci/ g (1 Ci ‫؍‬ 37 GBq) were routinely achieved, and no additional purification was required after 64 Cu labeling. Solid-phase radioimmunoassays and intact cell-binding assays confirmed retention of bioactivity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15-20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5-10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xenograft was significantly lower (<5% injected dose per gram). MicroPET imaging confirmed significant uptake of the tracer in GD-2-positive tumors, with minimal uptake in GD-2-negative tumors and nontarget tissues such as liver. The 64 Cu-SarAr-mAb system described here is potentially applicable to 64 Cu-PET imaging with a broad range of antibody or peptide-based imaging agents.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Positron emission tomography (PET) imaging of neuroblastoma and melanoma with ⁶⁴ Cu-SarAr immunoconjugates

Voss¹,

Smith

DiBartolo

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

132

123

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“…The compound was evaluated in cells that are known to express no, moderate and very high levels of αvβ3 integrin. [32,33] The magnitude of [ 3 H]12 binding to each cell line was consistent with αvβ3 expression levels ( Figure 4A). Non-radiolabeled c(RGDfK) (10µM) was included to competitively block specific binding to αvβ3.…”

Section: Resultssupporting

confidence: 62%

High‐Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging α_vβ₃ Integrin

et al. 2017

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Non-peptidic RGD-mimic ligands were designed and synthesized by click chemistry between an arginine-azide mimic and an aspartic acid-alkyne mimic. Some of these molecules combine excellent in vitro properties (high αvβ3 affinity, selectivity, drug-like logD, high metabolic stability) with a variety of radiolabeling options (e.g. tritium and [ 18 F]fluorine, plus compatibility with radio-iodination), not requiring the use of chelators or prosthetic groups. The binding mode of the resulting triazole RGD-mimics to αvβ3 or αIIbβ3 receptors was investigated by molecular modeling simulations. Compound 12 was successfully radiofluorinated and used for in vivo PET/CT studies in U87-tumour models, which showed only modest tumour uptake and retention, owing to rapid excretion. These results demonstrate that the novel click-RGD mimics are excellent radiolabeled probes for in vitro and cell-based studies on αvβ3 integrin, whereas further optimization of their pharmaco-kinetic and dynamic profile would be necessary for a successful use in in vivo imaging.

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“…Static microPET scans were performed on a PC-3 xenograft model (n 5 3, both GRPR-and integrin a v b 3 -positive) (24)(25)(26)(27), and selected coronal images at different time points after injection of 18 F-FB-BBN-RGD, 18 F-FB-BBN, or 18 F-FB-RGD are shown in Figure 3. The tumor was clearly visible with high contrast to contralateral background for 18 F-FB-BBN-RGD.…”

Section: Micropet Of Tumor-bearing Micementioning

confidence: 99%

¹⁸F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging

Li¹,

Wu²,

Chen³

et al. 2008

J Nucl Med

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129

138

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In vitro and In vivo Characterization of 64Cu-Labeled AbegrinTM, a Humanized Monoclonal Antibody against Integrin αvβ3

Abstract: Abegrin TM (MEDI-522 or Vitaxin TM ), a humanized monoclonal antibody against human integrin A v B 3 , is in clinical trials for cancer therapy. In vivo imaging using Abegrin TM

Cited by 180 publications

References 37 publications

Positron emission tomography (PET) imaging of neuroblastoma and melanoma with ⁶⁴ Cu-SarAr immunoconjugates

Positron emission tomography (PET) imaging of neuroblastoma and melanoma with ⁶⁴ Cu-SarAr immunoconjugates

High‐Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging α_vβ₃ Integrin

¹⁸F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging

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In vitro and In vivo Characterization of 64Cu-Labeled AbegrinTM, a Humanized Monoclonal Antibody against Integrin αvβ3

Abstract: Abegrin TM (MEDI-522 or Vitaxin TM ), a humanized monoclonal antibody against human integrin A v B 3 , is in clinical trials for cancer therapy. In vivo imaging using Abegrin TM

Cited by 180 publications

References 37 publications

Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64 Cu-SarAr immunoconjugates

Positron emission tomography (PET) imaging of neuroblastoma and melanoma with 64 Cu-SarAr immunoconjugates

High‐Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging αvβ3 Integrin

18F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging

Contact Info

Product

Resources

About

Positron emission tomography (PET) imaging of neuroblastoma and melanoma with ⁶⁴ Cu-SarAr immunoconjugates

Positron emission tomography (PET) imaging of neuroblastoma and melanoma with ⁶⁴ Cu-SarAr immunoconjugates

High‐Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging α_vβ₃ Integrin

¹⁸F-Labeled BBN-RGD Heterodimer for Prostate Cancer Imaging