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Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model

SIMPLE SUMMARY: Drug conjugates, consisting of a tumor targeting part coupled to a highly toxic molecule, are promising for treatment of many different types of cancer. However, for many patients it is not curative, and investigation of alternative or complimentary types of drug conjugates is motiva...

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Autores principales: Xu, Tianqi, Ding, Haozhong, Vorobyeva, Anzhelika, Oroujeni, Maryam, Orlova, Anna, Tolmachev, Vladimir, Gräslund, Torbjörn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794879/
https://www.ncbi.nlm.nih.gov/pubmed/33396753
http://dx.doi.org/10.3390/cancers13010085
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author Xu, Tianqi
Ding, Haozhong
Vorobyeva, Anzhelika
Oroujeni, Maryam
Orlova, Anna
Tolmachev, Vladimir
Gräslund, Torbjörn
author_facet Xu, Tianqi
Ding, Haozhong
Vorobyeva, Anzhelika
Oroujeni, Maryam
Orlova, Anna
Tolmachev, Vladimir
Gräslund, Torbjörn
author_sort Xu, Tianqi
collection PubMed
description SIMPLE SUMMARY: Drug conjugates, consisting of a tumor targeting part coupled to a highly toxic molecule, are promising for treatment of many different types of cancer. However, for many patients it is not curative, and investigation of alternative or complimentary types of drug conjugates is motivated. Here, we have devised and studied a novel cancer cell-directed drug conjugate Z(HER2:2891)-ABD-E(3)-mcDM1. We found that it could induce efficient shrinkage and, in some cases, complete regression of human tumors implanted in mice, and thus holds promise to become a therapeutic agent for clinical use in the future. ABSTRACT: The human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in a variety of cancers and therapies targeting HER2 are routinely used in the clinic. Recently, small engineered scaffold proteins, such as affibody molecules, have shown promise as carriers of cytotoxic drugs, and these drug conjugates may become complements or alternatives to the current HER2-targeting therapies. Here, we investigated if a monovalent HER2-binding affibody molecule, Z(HER2:2891), fused with a plasma half-life extending albumin binding domain (ABD), may be used as carrier of the cytotoxic maytansine derivate mcDM1. We found that the resulting drug conjugate, Z(HER2:2891)-ABD-E(3)-mcDM1, had strong affinity for its cognate molecular targets: HER2 and serum albumin. Z(HER2:2891)-ABD-E(3)-mcDM1 displayed potent cytotoxic activity towards cells with high HER2 expression, with IC(50) values ranging from 0.6 to 33 nM. In vivo, an unspecific increase in uptake in the liver, imparted by the hydrophobic mcDM1, was counteracted by incorporation of hydrophilic and negatively charged glutamate residues near the site of mcDM1 conjugation. A dose-escalation experiment showed that increasing doses up to 15.1 mg/kg gave a proportional increase in uptake in xenografted HER2-overexpressing SKOV3 tumors, after which the tumors became saturated. Experimental therapy with four once-weekly injection of 10.3 or 15.1 mg/kg led to efficient regression of tumors in all animals and complete regression in some. Weight loss was detected for some animals in the group receiving the highest dose, suggesting that it was close to the maximum tolerated dose. In conclusion, the monovalent HER2-targeting affibody drug conjugate presented herein have potent anti-tumor activity in vivo.
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spelling pubmed-77948792021-01-10 Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model Xu, Tianqi Ding, Haozhong Vorobyeva, Anzhelika Oroujeni, Maryam Orlova, Anna Tolmachev, Vladimir Gräslund, Torbjörn Cancers (Basel) Article SIMPLE SUMMARY: Drug conjugates, consisting of a tumor targeting part coupled to a highly toxic molecule, are promising for treatment of many different types of cancer. However, for many patients it is not curative, and investigation of alternative or complimentary types of drug conjugates is motivated. Here, we have devised and studied a novel cancer cell-directed drug conjugate Z(HER2:2891)-ABD-E(3)-mcDM1. We found that it could induce efficient shrinkage and, in some cases, complete regression of human tumors implanted in mice, and thus holds promise to become a therapeutic agent for clinical use in the future. ABSTRACT: The human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in a variety of cancers and therapies targeting HER2 are routinely used in the clinic. Recently, small engineered scaffold proteins, such as affibody molecules, have shown promise as carriers of cytotoxic drugs, and these drug conjugates may become complements or alternatives to the current HER2-targeting therapies. Here, we investigated if a monovalent HER2-binding affibody molecule, Z(HER2:2891), fused with a plasma half-life extending albumin binding domain (ABD), may be used as carrier of the cytotoxic maytansine derivate mcDM1. We found that the resulting drug conjugate, Z(HER2:2891)-ABD-E(3)-mcDM1, had strong affinity for its cognate molecular targets: HER2 and serum albumin. Z(HER2:2891)-ABD-E(3)-mcDM1 displayed potent cytotoxic activity towards cells with high HER2 expression, with IC(50) values ranging from 0.6 to 33 nM. In vivo, an unspecific increase in uptake in the liver, imparted by the hydrophobic mcDM1, was counteracted by incorporation of hydrophilic and negatively charged glutamate residues near the site of mcDM1 conjugation. A dose-escalation experiment showed that increasing doses up to 15.1 mg/kg gave a proportional increase in uptake in xenografted HER2-overexpressing SKOV3 tumors, after which the tumors became saturated. Experimental therapy with four once-weekly injection of 10.3 or 15.1 mg/kg led to efficient regression of tumors in all animals and complete regression in some. Weight loss was detected for some animals in the group receiving the highest dose, suggesting that it was close to the maximum tolerated dose. In conclusion, the monovalent HER2-targeting affibody drug conjugate presented herein have potent anti-tumor activity in vivo. MDPI 2020-12-30 /pmc/articles/PMC7794879/ /pubmed/33396753 http://dx.doi.org/10.3390/cancers13010085 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Xu, Tianqi
Ding, Haozhong
Vorobyeva, Anzhelika
Oroujeni, Maryam
Orlova, Anna
Tolmachev, Vladimir
Gräslund, Torbjörn
Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model
title Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model
title_full Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model
title_fullStr Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model
title_full_unstemmed Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model
title_short Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model
title_sort drug conjugates based on a monovalent affibody targeting vector can efficiently eradicate her2 positive human tumors in an experimental mouse model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794879/
https://www.ncbi.nlm.nih.gov/pubmed/33396753
http://dx.doi.org/10.3390/cancers13010085
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