Imaging of HER2-expressing tumours using a synthetic Affibody molecule containing the 99mTc-chelating mercaptoacetyl-glycyl-glycyl-glycyl (MAG3) sequence

Engfeldt, Torun; Orlova, Anna; Tran, Thuy; Bruskin, Alexander; Widström, Charles; Karlström, Amelie Eriksson; Tolmachev, Vladimir

doi:10.1007/s00259-006-0266-4

Cited by 83 publications

(105 citation statements)

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“…Apparently, incorporation of the triglutamyl spacer reduced the on-rate of the binding, which caused increase of the dissociation constant from 49 pM for FBO-PEP4313 to 180 pM for FBO-E 3 -PEP4313. This was not entirely unexpected, as N-terminal modification has earlier caused some modulation of affinity of Affibody molecules 34,38 . However, our recent study 39 Reduction of the renal uptake was an interesting effect of the spacer.…”

Section: Discussionmentioning

confidence: 98%

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Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with ¹⁸F-4-Fluorobenzaldehyde

et al. 2013

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Section: Discussionmentioning

confidence: 98%

“…Binding specificity and cellular processing of 18 F-FBO-E 3 -PEP4313 was studied using HER2-expressing ovarian carcinoma SKOV-3 cells (1.6x10 6 receptors/cells 38 ). 18 F-FBO-E 3 -PEP4313 at a protein concentrations of 270 pM was added to 6 dishes (10 6 cells/ dish).…”

Section: In Vitro Binding Specificity and Cellular Processingmentioning

confidence: 99%

Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with ¹⁸F-4-Fluorobenzaldehyde

et al. 2013

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“…For use in comparative biodistribution experiments, the synthetic Affibody molecule maGGG-Z HER2:342 was labeled with 99m Tc according to a previously published method (22). A recombinant Affibody molecule (Z HER2:342 ) was indirectly radioiodinated using a succinimidyl ester of p-iodobenzoate according to Orlova and co-workers (18) and designated as 125 I-PIB-Z HER2:342 .…”

Section: Methodsmentioning

confidence: 99%

“…Figure 4 presents the biodistribution of the labeled conjugates in normal mice 4 h pi. For comparison, we also included the previously described 99m Tc-maGGG-Z HER2:342 (22) in the study. The biodistribution studies showed rapid renal excretion with about 50% IA/g trapped in the kidneys for 99m Tc-CGG-and CGGG-Z HER2:342 (both directly and indirectly labeled) 4 h pi, while the 99m Tc-maGGG-Z HER2:342 displayed much lower uptake, less than 7% IA/g.…”

Section: Peptidementioning

confidence: 99%

“…For this reason, we started to investigate alternative labeling strategies. Earlier we have evaluated the incorporation of the mercaptoacetyltriglycylcontaining chelating sequence, maGGG (MAG3), for 99m Tclabeling of a synthetic variant of Z HER2:342 (22). This conjugate enables imaging of HER2-expression in LS174T and SKOV-3 xenografts, both at 6 and 24 h pi.…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Evaluation of Cysteine-Based Chelators for Attachment of ^99mTc to Tumor-Targeting Affibody Molecules

et al. 2007

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Affibody molecules present a new class of affinity proteins, which utilizes a scaffold based on a 58-amino acid domain derived from protein A. The small (7 kDa) Affibody molecule can be selected to bind to cell-surface targets with high affinity. An Affibody molecule (Z HER2:342 ) with a dissociation constant (K d ) of 22 pM for binding to the HER2 receptor has been reported earlier. Preclinical and pilot clinical studies have demonstrated the utility of radiolabeled Z HER2:342 in imaging of HER2-expressing tumors. The small size and cysteine-free structure of Affibody molecules enable complete peptide synthesis and direct incorporation of radionuclide chelators. The goal of this study was to evaluate if incorporation of the natural peptide sequences cysteine-diglycine (CGG) and cysteine-triglycine (CGGG) sequences would enable labeling of Affibody molecules with 99m Tc. In a model monomeric form, the chelating sequences were incorporated by peptide synthesis. The HER2-binding affinity was 280 and 250 pM for CGG-Z HER2:342 and CGGG-Z HER2:342, respectively. Conjugates were directly labeled with 99m Tc with 90% efficiency and preserved the capacity to bind specifically to HER2-expressing cells. The biodistribution in normal mice showed a rapid clearance from the blood and the majority of organs (except kidneys). In the mice bearing SKOV-3 xenografts, tumor uptake of 99m Tc-CGG-Z HER2:342 was HER2-specific and a tumorto-blood ratio of 9.2 was obtained at 6 h postinjection. Gamma-camera imaging with 99m Tc-CGG-Z HER2:342 clearly visualized tumors at 6 h postinjection. The results show that the use of a cysteine-based chelator enables 99m Tclabeling of Affibody molecules for imaging.

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Design and evaluation of radiolabeled tracers for tumor imaging

Wållberg

Ståhl

2013

Biotech and App Biochem

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The growing understanding of tumor biology and the identification of tumor-specific genetic and molecular alterations, such as the overexpression of membrane receptors and other proteins, allows for personalization of patient management using targeted therapies. However, this puts stringent demands on the diagnostic tools used to identify patients who are likely to respond to a particular treatment. Radionuclide molecular imaging is a promising noninvasive method to visualize and characterize the expression of such targets. A number of different proteins, from full-length antibodies and their derivatives to small scaffold proteins and peptide receptor-ligands, have been applied to molecular imaging, each demonstrating strengths and weaknesses. Here, we discuss the concept of molecular targeting and, in particular, molecular imaging of cancer-associated targets. Additionally, we describe important biotechnological considerations and desired features when designing and developing tracers for radionuclide molecular imaging.

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Imaging of HER2-expressing tumours using a synthetic Affibody molecule containing the 99mTc-chelating mercaptoacetyl-glycyl-glycyl-glycyl (MAG3) sequence

Abstract: Incorporation of a mercaptoacetyl-containing chelating sequence during chemical synthesis enabled site-specific (99m)Tc labelling of the Z(HER2:342) Affibody molecule with preserved targeting capacity.

Cited by 83 publications

References 46 publications

Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with ¹⁸F-4-Fluorobenzaldehyde

Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with ¹⁸F-4-Fluorobenzaldehyde

In Vivo Evaluation of Cysteine-Based Chelators for Attachment of ^99mTc to Tumor-Targeting Affibody Molecules

Design and evaluation of radiolabeled tracers for tumor imaging

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Imaging of HER2-expressing tumours using a synthetic Affibody molecule containing the 99mTc-chelating mercaptoacetyl-glycyl-glycyl-glycyl (MAG3) sequence

Abstract: Incorporation of a mercaptoacetyl-containing chelating sequence during chemical synthesis enabled site-specific (99m)Tc labelling of the Z(HER2:342) Affibody molecule with preserved targeting capacity.

Cited by 83 publications

References 46 publications

Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with 18F-4-Fluorobenzaldehyde

Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with 18F-4-Fluorobenzaldehyde

In Vivo Evaluation of Cysteine-Based Chelators for Attachment of 99mTc to Tumor-Targeting Affibody Molecules

Design and evaluation of radiolabeled tracers for tumor imaging

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Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with ¹⁸F-4-Fluorobenzaldehyde

Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with ¹⁸F-4-Fluorobenzaldehyde

In Vivo Evaluation of Cysteine-Based Chelators for Attachment of ^99mTc to Tumor-Targeting Affibody Molecules