TY - JOUR
T1 - Radionuclide therapy using ABD-fused ADAPT scaffold protein
T2 - Proof of Principle
AU - Garousi, Javad
AU - von Witting, Emma
AU - Borin, Jesper
AU - Vorobyeva, Anzhelika
AU - Altai, Mohamed
AU - Vorontsova, Olga
AU - Konijnenberg, Mark W.
AU - Oroujeni, Maryam
AU - Orlova, Anna
AU - Tolmachev, Vladimir
AU - Hober, Sophia
N1 - Funding Information:
This research was funded by the Swedish Cancer Society (grants CAN 2017/425 , CAN 2018/436 ), the Swedish Research Council (grants 2015–02509, 2019–00994 ), the Swedish Agency for Innovation VINNOVA ( 2019/00104 ) and Ministry of Science and Higher Education of the Russian Federation ( 075-15-2019-1925 ). The funding sources had no influence in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Publisher Copyright:
© 2020 The Authors
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2021/1
Y1 - 2021/1
N2 - Molecular recognition in targeted therapeutics is typically based on immunoglobulins. Development of engineered scaffold proteins (ESPs) has provided additional opportunities for the development of targeted therapies. ESPs offer inexpensive production in prokaryotic hosts, high stability and convenient approaches to modify their biodistribution. In this study, we demonstrated successful modification of the biodistribution of an ESP known as ADAPT (Albumin-binding domain Derived Affinity ProTein). ADAPTs are selected from a library based on the scaffold of ABD (Albumin Binding Domain) of protein G. A particular ADAPT, the ADAPT6, binds to human epidermal growth factor receptor type 2 (HER2) with high affinity. Preclinical and early clinical studies have demonstrated that radiolabeled ADAPT6 can image HER2-expression in tumors with high contrast. However, its rapid glomerular filtration and high renal reabsorption have prevented its use in radionuclide therapy. To modify the biodistribution, ADAPT6 was genetically fused to an ABD. The non-covalent binding to the host's albumin resulted in a 14-fold reduction of renal uptake and appreciable increase of tumor uptake for the best variant, 177Lu-DOTA-ADAPT6-ABD035. Experimental therapy in mice bearing HER2-expressing xenografts demonstrated more than two-fold increase of median survival even after a single injection of 18 MBq 177Lu-DOTA-ADAPT6-ABD035. Thus, a fusion with ABD and optimization of the molecular design provides ADAPT derivatives with attractive targeting properties for radionuclide therapy.
AB - Molecular recognition in targeted therapeutics is typically based on immunoglobulins. Development of engineered scaffold proteins (ESPs) has provided additional opportunities for the development of targeted therapies. ESPs offer inexpensive production in prokaryotic hosts, high stability and convenient approaches to modify their biodistribution. In this study, we demonstrated successful modification of the biodistribution of an ESP known as ADAPT (Albumin-binding domain Derived Affinity ProTein). ADAPTs are selected from a library based on the scaffold of ABD (Albumin Binding Domain) of protein G. A particular ADAPT, the ADAPT6, binds to human epidermal growth factor receptor type 2 (HER2) with high affinity. Preclinical and early clinical studies have demonstrated that radiolabeled ADAPT6 can image HER2-expression in tumors with high contrast. However, its rapid glomerular filtration and high renal reabsorption have prevented its use in radionuclide therapy. To modify the biodistribution, ADAPT6 was genetically fused to an ABD. The non-covalent binding to the host's albumin resulted in a 14-fold reduction of renal uptake and appreciable increase of tumor uptake for the best variant, 177Lu-DOTA-ADAPT6-ABD035. Experimental therapy in mice bearing HER2-expressing xenografts demonstrated more than two-fold increase of median survival even after a single injection of 18 MBq 177Lu-DOTA-ADAPT6-ABD035. Thus, a fusion with ABD and optimization of the molecular design provides ADAPT derivatives with attractive targeting properties for radionuclide therapy.
KW - Lu
KW - ABD (Albumin binding domain)
KW - ADAPT (Albumin-binding domain derived affinity ProTein)
KW - Biodistribution modification
KW - HER2
KW - Radionuclide therapy
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U2 - 10.1016/j.biomaterials.2020.120381
DO - 10.1016/j.biomaterials.2020.120381
M3 - Article
AN - SCOPUS:85093694427
VL - 266
JO - Biomaterials
JF - Biomaterials
SN - 0142-9612
M1 - 120381
ER -