<i>In vivo</i> Evaluation of 177Lu- and 67/64Cu-Labeled Recombinant Fragments of Antibody chCE7 for Radioimmunotherapy and PET Imaging of L1-CAM-Positive Tumors

Grünberg, Jürgen; Novak‐Hofer, Ilse; Honer, Michael; Zimmermann, Kurt; Knogler, Karin; Bläuenstein, Peter; Ametamey, Simon M.; Maecke, Helmut R.; Schubiger, P. August

doi:10.1158/1078-0432.ccr-05-0227

Cited by 77 publications

(45 citation statements)

References 32 publications

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“…In particular, the endothelial deficiency of L1 in a mouse model of cancer led to enhanced vessel stability and decreased tumor angiogenesis, resulting in reduced tumor growth and metastasis and prolonged mouse survival. Consistently, antibody-mediated targeting of L1 reduced (53) and by the suitability of L1 antibodies for tumor-imaging purposes as shown in mouse models (54). Second, based on the positive role of L1 in tumor neovascularization, in EC proliferation and migration, and in EndMT, it is reasonable to speculate that neutralizing L1 could represent a novel antiangiogenic strategy.…”

Section: Discussionmentioning

confidence: 67%

Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

Magrini¹,

Villa²,

Angiolini³

et al. 2014

J. Clin. Invest.

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Besides the nervous system, L1 is expressed in many human cancers, including ovarian and endometrial carcinoma, pancreatic ductal adenocarcinoma (PDAC), melanoma and glioblastoma. L1 expression confers motile and invasive properties to tumor cells, supporting cancer growth, metastasis, and chemoresistance and often acting as a marker of poor prognosis (8). L1 has also been detected in the hematopoietic system, in particular in immune cells of myelomonocytic and lymphoid origin (9), and we have previously reported L1-dependent transmigration of dendritic cells across the endothelium (10).An intriguing aspect of L1 biology is its expression in the vascular system: while no or very little L1 is detectable in the vasculature of most normal tissues, its level is markedly increased in the vasing the mechanisms of pathological angiogenesis and to identifying novel cancer vessel-specific markers.L1 (also known as L1CAM or CD171) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily and is composed of an extracellular portion, containing 6 Ig-like domains and 5 fibronectin type III repeats, followed by a transmembrane region, and a highly conserved cytoplasmic tail (5). L1 was discovered and characterized as a cell-adhesion molecule in the nervous system (6), where it is involved in neurite outgrowth and fasciculation as well as cell adhesion and migration. In addition to homophilic binding, L1 can establish cis-or trans-interactions with different binding partners, such as integrins, CD24, neurocan, neuropilin-1, and other members of the neural cell adhesion family (7).

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Section: Discussionmentioning

confidence: 67%

Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

Magrini¹,

Villa²,

Angiolini³

et al. 2014

J. Clin. Invest.

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“…We have shown that SarAr conjugation to both murine and chimerized mAb can be accomplished under nearly physiological conditions with no adverse affect on immunoreactivity. Incubation of the immunoconjugate with 64 Cu 2ϩ for 10-30 min results in nearly quantitative uptake of 64 Cu 2ϩ without the need for additional HPLC purification, yielding specific activities of Ϸ10 Ci/ g (Ϸ37 MBq/100 g), 2-3 times greater than previously published results using other chelating agents (9,25,26). Furthermore, these high specific activities were achieved without the need for postlabeling purification, as is required with other chelators.…”

Section: Discussionmentioning

confidence: 76%

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.

135

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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“…Mice were imaged 20 h after iv gold injection since IgG immunoconjugates accumulate maximally in tumours after approximately 20-24 h [20,21]. This time period also allows the gold blood volume to dissipate, giving lower backgrounds.…”

Section: Discussionmentioning

confidence: 99%

Micro-CT enables microlocalisation and quantification of Her2-targeted gold nanoparticles within tumour regions

Hainfeld

O’Connor²,

Dilmanian³

et al. 2011

BJR

223

183

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Objectives: Gold nanoparticles are of interest as potential in vivo diagnostic and therapeutic agents, as X-ray contrast agents, drug delivery vehicles and radiation enhancers. The aim of this study was to quantitatively determine their targeting and microlocalisation in mouse tumour models after intravenous injection by using micro-CT. Methods: Gold nanoparticles (15 nm) were coated with polyethylene glycol and covalently coupled to anti-Her2 antibodies (Herceptin). In vitro, conjugates incubated with Her2+ (BT-474) and Her2-(MCF7) human breast cancer cells showed specific targeted binding with a Her2+ to Her2-gold ratio of 39.4¡2.7:1. Nude mice, simultaneously bearing subcutaneous Her2+ and Her2-human breast tumours in opposite thighs were prepared. Gold nanoparticles alone, conjugated to Herceptin or to a non-specific antibody were compared. After intravenous injection of the gold nanoparticles, gold concentrations were determined by atomic absorption spectroscopy. Microlocalisation of gold was carried out by calibrated micro-CT, giving both the radiodensities and gold concentrations in tumour and non-tumour tissue. Results: All gold nanoparticle constructs showed accumulation, predominantly at tumour peripheries. However, the Herceptin-gold nanoparticles showed the best specific uptake in their periphery (15.8¡1.7% injected dose per gram), 1.6-fold higher than Her2-tumours and 22-fold higher than surrounding muscle. Imaging readily enabled detection of small, 1.5 mm-thick tumours. Conclusion: In this pre-clinical study, antibody-targeted 15 nm gold nanoparticles showed preferential uptake in cognate tumours, but even untargeted gold nanoparticles enhanced the visibility of tumour peripheries and enabled detection of millimetre-sized tumours. Micro-CT enabled quantification within various regions of a tumour.

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In vivo Evaluation of 177Lu- and 67/64Cu-Labeled Recombinant Fragments of Antibody chCE7 for Radioimmunotherapy and PET Imaging of L1-CAM-Positive Tumors

Cited by 77 publications

References 32 publications

Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

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

Micro-CT enables microlocalisation and quantification of Her2-targeted gold nanoparticles within tumour regions

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In vivo Evaluation of 177Lu- and 67/64Cu-Labeled Recombinant Fragments of Antibody chCE7 for Radioimmunotherapy and PET Imaging of L1-CAM-Positive Tumors

Cited by 77 publications

References 32 publications

Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

Endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalization

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

Micro-CT enables microlocalisation and quantification of Her2-targeted gold nanoparticles within tumour regions

Contact Info

Product

Resources

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