186Re-maSGS-ZHER2:342, a potential Affibody conjugate for systemic therapy of HER2-expressing tumours

Abstract

Purpose: Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule Z_HER2:342 has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for ^99mTc-labelling, we have found that synthetic Z _HER2:342 conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. Methods: maGGG-Z_HER2:342 and maGSG-Z_HER2:342 were labelled with ¹⁸⁶Re and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by ¹⁸⁶Re-maGSG-Z_HER2:342 were studied. Results: Gluconate-mediated labelling of maGGG-Z_HER2:342 and maGSG-Z _HER2:342 with ¹⁸⁶Re provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both ¹⁸⁶Re-maGGG-Z _HER2:342 and ¹⁸⁶Re-maGSG-Z_HER2:342 demonstrated lower renal uptake than their ^99mTc-labelled counterparts. ¹⁸⁶Re-maGSG-Z_HER2:342 provided the lowest uptake in healthy tissues. Biodistribution of ¹⁸⁶Re-maGSG-Z_HER2:342 in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84±0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Conclusion: Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.

Original language	English
Pages (from-to)	260-269
Number of pages	10
Journal	European Journal of Nuclear Medicine and Molecular Imaging
Volume	37
Issue number	2
DOIs	https://doi.org/10.1007/s00259-009-1268-9
Publication status	Published - Feb 2010
Externally published	Yes

Keywords

Affibody molecules
Chelator
HER2
Mercaptoacetyl
Rhenium

ASJC Scopus subject areas

Radiology Nuclear Medicine and imaging

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10.1007/s00259-009-1268-9

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@article{61236f0421d54750ac0d078017852ef4,

title = "186Re-maSGS-ZHER2:342, a potential Affibody conjugate for systemic therapy of HER2-expressing tumours",

abstract = "Purpose: Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule ZHER2:342 has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for 99mTc-labelling, we have found that synthetic Z HER2:342 conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. Methods: maGGG-ZHER2:342 and maGSG-ZHER2:342 were labelled with 186Re and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by 186Re-maGSG-ZHER2:342 were studied. Results: Gluconate-mediated labelling of maGGG-ZHER2:342 and maGSG-Z HER2:342 with 186Re provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both 186Re-maGGG-Z HER2:342 and 186Re-maGSG-ZHER2:342 demonstrated lower renal uptake than their 99mTc-labelled counterparts. 186Re-maGSG-ZHER2:342 provided the lowest uptake in healthy tissues. Biodistribution of 186Re-maGSG-ZHER2:342 in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84±0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Conclusion: Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.",

keywords = "Affibody molecules, Chelator, HER2, Mercaptoacetyl, Rhenium",

author = "Anna Orlova and Tran, {Thuy A.} and Torun Ekblad and Karlstr{\"o}m, {Amelie Eriksson} and Vladimir Tolmachev",

note = "Funding Information: Acknowledgments This study was supported by grants from the Swedish Cancer Society (Cancerfonden) and the Swedish Research Council (Vetenskapsr{\aa}det). Copyright: Copyright 2010 Elsevier B.V., All rights reserved.",

year = "2010",

month = feb,

doi = "10.1007/s00259-009-1268-9",

language = "English",

volume = "37",

pages = "260--269",

journal = "European Journal of Nuclear Medicine and Molecular Imaging",

issn = "1619-7070",

publisher = "Springer Verlag",

number = "2",

}

TY - JOUR

T1 - 186Re-maSGS-ZHER2:342, a potential Affibody conjugate for systemic therapy of HER2-expressing tumours

AU - Orlova, Anna

AU - Tran, Thuy A.

AU - Ekblad, Torun

AU - Karlström, Amelie Eriksson

AU - Tolmachev, Vladimir

N1 - Funding Information: Acknowledgments This study was supported by grants from the Swedish Cancer Society (Cancerfonden) and the Swedish Research Council (Vetenskapsrådet). Copyright: Copyright 2010 Elsevier B.V., All rights reserved.

PY - 2010/2

Y1 - 2010/2

N2 - Purpose: Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule ZHER2:342 has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for 99mTc-labelling, we have found that synthetic Z HER2:342 conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. Methods: maGGG-ZHER2:342 and maGSG-ZHER2:342 were labelled with 186Re and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by 186Re-maGSG-ZHER2:342 were studied. Results: Gluconate-mediated labelling of maGGG-ZHER2:342 and maGSG-Z HER2:342 with 186Re provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both 186Re-maGGG-Z HER2:342 and 186Re-maGSG-ZHER2:342 demonstrated lower renal uptake than their 99mTc-labelled counterparts. 186Re-maGSG-ZHER2:342 provided the lowest uptake in healthy tissues. Biodistribution of 186Re-maGSG-ZHER2:342 in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84±0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Conclusion: Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.

AB - Purpose: Affibody molecules are a novel class of tumour-targeting proteins, which combine small size (7 kDa) and picomolar affinities. The Affibody molecule ZHER2:342 has been suggested for imaging of HER2 expression in order to select patients for trastuzumab therapy. When optimizing chelators for 99mTc-labelling, we have found that synthetic Z HER2:342 conjugated with mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) and mercaptoacetyl-glycyl-seryl-glycyl (maGSG) chelators provides relatively low renal uptake of radioactivity and could be suitable for therapy. Methods: maGGG-ZHER2:342 and maGSG-ZHER2:342 were labelled with 186Re and their biodistribution was studied in normal mice. Dosimetric evaluation and tumour targeting to HER2-overexpressed xenografts (SKOV-3) by 186Re-maGSG-ZHER2:342 were studied. Results: Gluconate-mediated labelling of maGGG-ZHER2:342 and maGSG-Z HER2:342 with 186Re provided a yield of more than 95% within 60 min. The conjugates were stable and demonstrated specific binding to HER2-expressing SKOV-3 cells. Biodistribution in normal mice demonstrated rapid blood clearance, low accumulation of radioactivity in the kidney and other organs, accumulating free perrhenate. Both 186Re-maGGG-Z HER2:342 and 186Re-maGSG-ZHER2:342 demonstrated lower renal uptake than their 99mTc-labelled counterparts. 186Re-maGSG-ZHER2:342 provided the lowest uptake in healthy tissues. Biodistribution of 186Re-maGSG-ZHER2:342 in nude mice bearing SKOV-3 xenografts showed specific targeting of tumours. Tumour uptake 24 h after injection (5.84±0.54%ID/g) exceeded the concentration in blood by more than 500-fold, and uptake in kidneys by about 8-fold. Preliminary dosimetric evaluation showed that dose-to-tumour should exceed dose-to-kidney by approximately 5-fold. Conclusion: Optimization of chelators improves biodistribution properties of rhenium-labelled small scaffold proteins and enables selection of promising radiotherapeutic agents based on the Affibody molecule.

KW - Affibody molecules

KW - Chelator

KW - HER2

KW - Mercaptoacetyl

KW - Rhenium

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UR - http://www.scopus.com/inward/citedby.url?scp=77949268342&partnerID=8YFLogxK

U2 - 10.1007/s00259-009-1268-9

DO - 10.1007/s00259-009-1268-9

M3 - Article

C2 - 19771426

AN - SCOPUS:77949268342

VL - 37

SP - 260

EP - 269

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

SN - 1619-7070

IS - 2

ER -

¹⁸⁶Re-maSGS-Z_HER2:342, a potential Affibody conjugate for systemic therapy of HER2-expressing tumours

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Fingerprint Dive into the research topics of '<sup>186</sup>Re-maSGS-Z<sub>HER2:342</sub>, a potential Affibody conjugate for systemic therapy of HER2-expressing tumours'. Together they form a unique fingerprint.

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