Preclinical Evaluation of HER2-Targeting DARPin G3: Impact of Albumin-Binding Domain (ABD) Fusion

Preclinical Evaluation of HER2-Targeting DARPin G3: Impact of Albumin-Binding Domain (ABD) Fusion

Bibliographic Details
Parent link:International Journal of Molecular Sciences.— .— Basel: MDPI AG
Vol. 25, iss. 8.— 2024.— Article number 4246, 17 p.
Other Authors: Deev S. M. Sergey Mikhaylovich, Oroujeni M. Maryam, Garousi J. Javad, Gräslund T. Torbjörn, Li R. Ruonan, Rosly A. H. B. Alia Hani Binti, Orlova A. M. Anna Markovna, Konovalova E. V. Elena Valerjevna, Shulga (Schulga) A. A. Aleksey Anatolievich, Vorobjeva (Vorobyeva) A. G. Anzhelika Grigorjevna, Tolmachev V. M. Vladimir Maksimilianovich
Summary:Title screen
Designed ankyrin repeat protein (DARPin) G3 is an engineered scaffold protein. This small (14.5 kDa) targeting protein binds with high affinity to human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in several cancers. The use of the DARPin G3 for radionuclide therapy is complicated by its high renal reabsorption after clearance via the glomeruli. We tested the hypothesis that a fusion of the DARPin G3 with an albumin-binding domain (ABD) would prevent rapid renal excretion and high renal reabsorption resulting in better tumour targeting. Two fusion proteins were produced, one with the ABD at the C-terminus (G3-ABD) and another at the N-terminus (ABD-G3). Both variants were labelled with 177Lu. The binding properties of the novel constructs were evaluated in vitro and their biodistribution was compared in mice with implanted human HER2-expressing tumours. Fusion with the ABD increased the retention time of both constructs in blood compared with the non-ABD-fused control. The effect of fusion with the ABD depended strongly on the order of the domains in the constructs, resulting in appreciably better targeting properties of [177Lu]Lu-G3-ABD. Our data suggest that the order of domains is critical for the design of targeting constructs based on scaffold proteins.
Текстовый файл
Language:English
Published: 2024
Subjects:
электронный ресурс
труды учёных ТПУ
DARPin G3
albumin-binding domain (ABD)
HER2
SKOV-3 xenograft
Lutetium-177 (177Lu)
SPECT imaging
Online Access:https://doi.org/10.3390/ijms25084246
Format: Electronic Book Chapter
KOHA link:https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=672867

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