Experimental HER2-Targeted Therapy Using ADAPT6-ABD-mcDM1 in Mice Bearing SKOV3 Ovarian Cancer Xenografts: Efficacy and Selection of Companion Imaging Counterpart.

ADAPT DM1 HER2 albumin binding domain cancer therapy engineered scaffold protein human epidermal growth factor receptor 2

Journal

Pharmaceutics
ISSN: 1999-4923
Titre abrégé: Pharmaceutics
Pays: Switzerland
ID NLM: 101534003

Informations de publication

Date de publication:
02 Aug 2022
Historique:
received: 04 07 2022
revised: 28 07 2022
accepted: 29 07 2022
entrez: 26 8 2022
pubmed: 27 8 2022
medline: 27 8 2022
Statut: epublish

Résumé

Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast and gastric cancer is exploited for targeted therapy using monoclonal antibodies and antibody-drug conjugates. Small engineered scaffold proteins, such as the albumin binding domain (ABD) derived affinity proteins (ADAPTs), are a promising new format of targeting probes for development of drug conjugates with well-defined structure and tunable pharmacokinetics. Radiolabeled ADAPT6 has shown excellent tumor-targeting properties in clinical trials. Recently, we developed a drug conjugate based on the HER2-targeting ADAPT6 fused to an albumin binding domain (ABD) for increased bioavailability and conjugated to DM1 for cytotoxic action, designated as ADAPT6-ABD-mcDM1. In this study, we investigated the therapeutic efficacy of this conjugate in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. A secondary aim was to evaluate several formats of imaging probes for visualization of HER2 expression in tumors. Administration of ADAPT6-ABD-mcDM1 provided a significant delay of tumor growth and increased the median survival of the mice, in comparison with both a non-targeting homologous construct (ADAPT

Identifiants

pubmed: 36015242
pii: pharmaceutics14081612
doi: 10.3390/pharmaceutics14081612
pmc: PMC9415843
pii:
doi:

Types de publication

Journal Article

Langues

eng

Subventions

Organisme : VINNOVA
ID : 2019/00104
Organisme : Swedish Cancer Society
ID : CAN 21 1861 Pj
Organisme : Swedish Cancer Society
ID : 2020/181
Organisme : Swedish Cancer Society
ID : 20 0893 Pj

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Auteurs

Javad Garousi (J)

Department of Protein Science, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden.

Tianqi Xu (T)

Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.

Yongsheng Liu (Y)

Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.

Olga Vorontsova (O)

Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.

Sophia Hober (S)

Department of Protein Science, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden.

Anna Orlova (A)

Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.

Vladimir Tolmachev (V)

Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.

Torbjörn Gräslund (T)

Department of Protein Science, KTH Royal Institute of Technology, 106 91 Stockholm, Sweden.

Anzhelika Vorobyeva (A)

Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.

Classifications MeSH