Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein

Albumin binding domain derived affinity proteins (ADAPTs) are a class of small and folded engineered scaffold proteins that holds great promise for targeting cancer tumors. Here, we have extended the in vivo half-life of an ADAPT, targeting the human epidermal growth factor receptor 2 (HER2) by fusi...

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Autores principales:	Javad Garousi, Haozhong Ding, Emma von Witting, Tianqi Xu, Anzhelika Vorobyeva, Maryam Oroujeni, Anna Orlova, Sophia Hober, Torbjörn Gräslund, Vladimir Tolmachev
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ADAPT human epidermal growth factor receptor 2 HER2 DM1 albumin binding domain Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/63cc572ea3ff4bcab28ecc7f10b18676
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spelling	oai:doaj.org-article:63cc572ea3ff4bcab28ecc7f10b186762021-11-25T18:41:08ZTargeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein10.3390/pharmaceutics131118471999-4923https://doaj.org/article/63cc572ea3ff4bcab28ecc7f10b186762021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1847https://doaj.org/toc/1999-4923Albumin binding domain derived affinity proteins (ADAPTs) are a class of small and folded engineered scaffold proteins that holds great promise for targeting cancer tumors. Here, we have extended the in vivo half-life of an ADAPT, targeting the human epidermal growth factor receptor 2 (HER2) by fusion with an albumin binding domain (ABD), and armed it with the highly cytotoxic payload mertansine (DM1) for an investigation of its properties in vitro and in vivo. The resulting drug conjugate, ADAPT6-ABD-mcDM1, retained binding to its intended targets, namely HER2 and serum albumins. Further, it was able to specifically bind to cells with high HER2 expression, get internalized, and showed potent toxicity, with IC<sub>50</sub> values ranging from 5 to 80 nM. Conversely, no toxic effect was found for cells with low HER2 expression. In vivo, ADAPT6-ABD-mcDM1, radiolabeled with <sup>99m</sup>Tc, was characterized by low uptake in most normal organs, and the main excretion route was shown to be through the kidneys. The tumor uptake was 5.5% ID/g after 24 h, which was higher than the uptake in all normal organs at this time point except for the kidneys. The uptake in the tumors was blockable by pre-injection of an excess of the monoclonal antibody trastuzumab (having an overlapping epitope on the HER2 receptor). In conclusion, half-life extended drug conjugates based on the ADAPT platform of affinity proteins holds promise for further development towards targeted cancer therapy.Javad GarousiHaozhong DingEmma von WittingTianqi XuAnzhelika VorobyevaMaryam OroujeniAnna OrlovaSophia HoberTorbjörn GräslundVladimir TolmachevMDPI AGarticleADAPThuman epidermal growth factor receptor 2HER2DM1albumin binding domainPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1847, p 1847 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ADAPT human epidermal growth factor receptor 2 HER2 DM1 albumin binding domain Pharmacy and materia medica RS1-441
spellingShingle	ADAPT human epidermal growth factor receptor 2 HER2 DM1 albumin binding domain Pharmacy and materia medica RS1-441 Javad Garousi Haozhong Ding Emma von Witting Tianqi Xu Anzhelika Vorobyeva Maryam Oroujeni Anna Orlova Sophia Hober Torbjörn Gräslund Vladimir Tolmachev Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein
description	Albumin binding domain derived affinity proteins (ADAPTs) are a class of small and folded engineered scaffold proteins that holds great promise for targeting cancer tumors. Here, we have extended the in vivo half-life of an ADAPT, targeting the human epidermal growth factor receptor 2 (HER2) by fusion with an albumin binding domain (ABD), and armed it with the highly cytotoxic payload mertansine (DM1) for an investigation of its properties in vitro and in vivo. The resulting drug conjugate, ADAPT6-ABD-mcDM1, retained binding to its intended targets, namely HER2 and serum albumins. Further, it was able to specifically bind to cells with high HER2 expression, get internalized, and showed potent toxicity, with IC<sub>50</sub> values ranging from 5 to 80 nM. Conversely, no toxic effect was found for cells with low HER2 expression. In vivo, ADAPT6-ABD-mcDM1, radiolabeled with <sup>99m</sup>Tc, was characterized by low uptake in most normal organs, and the main excretion route was shown to be through the kidneys. The tumor uptake was 5.5% ID/g after 24 h, which was higher than the uptake in all normal organs at this time point except for the kidneys. The uptake in the tumors was blockable by pre-injection of an excess of the monoclonal antibody trastuzumab (having an overlapping epitope on the HER2 receptor). In conclusion, half-life extended drug conjugates based on the ADAPT platform of affinity proteins holds promise for further development towards targeted cancer therapy.
format	article
author	Javad Garousi Haozhong Ding Emma von Witting Tianqi Xu Anzhelika Vorobyeva Maryam Oroujeni Anna Orlova Sophia Hober Torbjörn Gräslund Vladimir Tolmachev
author_facet	Javad Garousi Haozhong Ding Emma von Witting Tianqi Xu Anzhelika Vorobyeva Maryam Oroujeni Anna Orlova Sophia Hober Torbjörn Gräslund Vladimir Tolmachev
author_sort	Javad Garousi
title	Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein
title_short	Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein
title_full	Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein
title_fullStr	Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein
title_full_unstemmed	Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein
title_sort	targeting her2 expressing tumors with a potent drug conjugate based on an albumin binding domain-derived affinity protein
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/63cc572ea3ff4bcab28ecc7f10b18676
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Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein

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