TY - JOUR
T1 - Optimized Molecular Design of ADAPT-Based HER2-Imaging Probes Labeled with 111 In and 68 Ga
AU - Lindbo, Sarah
AU - Garousi, Javad
AU - Mitran, Bogdan
AU - Vorobyeva, Anzhelika
AU - Oroujeni, Maryam
AU - Orlova, Anna
AU - Hober, Sophia
AU - Tolmachev, Vladimir
N1 - Funding Information:
The authors wish to thank Jessica Lövgren for help with cloning and production of proteins. This research was financially supported by grants from the Swedish Cancer Society [Grant Nos. CAN 2015/350 and 2017/425], Swedish Research Council [Grant Nos. 2015-02353 and 2015-02509], and the Swedish Agency for Innovation VINNOVA (Grant No. 2016-04060).
Publisher Copyright:
© 2018 American Chemical Society.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018/7/2
Y1 - 2018/7/2
N2 - Radionuclide molecular imaging is a promising tool for visualization of cancer associated molecular abnormalities in vivo and stratification of patients for specific therapies. ADAPT is a new type of small engineered proteins based on the scaffold of an albumin binding domain of protein G. ADAPTs have been utilized to select and develop high affinity binders to different proteinaceous targets. ADAPT6 binds to human epidermal growth factor 2 (HER2) with low nanomolar affinity and can be used for its in vivo visualization. Molecular design of 111 In-labeled anti-HER2 ADAPT has been optimized in several earlier studies. In this study, we made a direct comparison of two of the most promising variants, having either a DEAVDANS or a (HE) 3 DANS sequence at the N-terminus, conjugated with a maleimido derivative of DOTA to a GSSC amino acids sequence at the C-terminus. The variants (designated DOTA-C 59 -DEAVDANS-ADAPT6-GSSC and DOTA-C 61 -(HE) 3 DANS-ADAPT6-GSSC) were stably labeled with 111 In for SPECT and 68 Ga for PET. Biodistribution of labeled ADAPT variants was evaluated in nude mice bearing human tumor xenografts with different levels of HER2 expression. Both variants enabled clear discrimination between tumors with high and low levels of HER2 expression. 111 In-labeled ADAPT6 derivatives provided higher tumor-to-organ ratios compared to 68 Ga-labeled counterparts. The best performing variant was DOTA-C 61 -(HE) 3 DANS-ADAPT6-GSSC,which provided tumor-to-blood ratios of 208 ± 36 and 109 ± 17 at 3 h for 111 In and 68 Ga labels,respectively.
AB - Radionuclide molecular imaging is a promising tool for visualization of cancer associated molecular abnormalities in vivo and stratification of patients for specific therapies. ADAPT is a new type of small engineered proteins based on the scaffold of an albumin binding domain of protein G. ADAPTs have been utilized to select and develop high affinity binders to different proteinaceous targets. ADAPT6 binds to human epidermal growth factor 2 (HER2) with low nanomolar affinity and can be used for its in vivo visualization. Molecular design of 111 In-labeled anti-HER2 ADAPT has been optimized in several earlier studies. In this study, we made a direct comparison of two of the most promising variants, having either a DEAVDANS or a (HE) 3 DANS sequence at the N-terminus, conjugated with a maleimido derivative of DOTA to a GSSC amino acids sequence at the C-terminus. The variants (designated DOTA-C 59 -DEAVDANS-ADAPT6-GSSC and DOTA-C 61 -(HE) 3 DANS-ADAPT6-GSSC) were stably labeled with 111 In for SPECT and 68 Ga for PET. Biodistribution of labeled ADAPT variants was evaluated in nude mice bearing human tumor xenografts with different levels of HER2 expression. Both variants enabled clear discrimination between tumors with high and low levels of HER2 expression. 111 In-labeled ADAPT6 derivatives provided higher tumor-to-organ ratios compared to 68 Ga-labeled counterparts. The best performing variant was DOTA-C 61 -(HE) 3 DANS-ADAPT6-GSSC,which provided tumor-to-blood ratios of 208 ± 36 and 109 ± 17 at 3 h for 111 In and 68 Ga labels,respectively.
KW - ADAPT
KW - DOTA
KW - gallium-68
KW - HER2
KW - indium-111
KW - radionuclide imaging
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U2 - 10.1021/acs.molpharmaceut.8b00204
DO - 10.1021/acs.molpharmaceut.8b00204
M3 - Article
C2 - 29865791
AN - SCOPUS:85048138088
VL - 15
SP - 2674
EP - 2683
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 7
ER -