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A human antibody against human endothelin receptor type A that exhibits antitumor potency.
- Source :
-
Experimental & molecular medicine [Exp Mol Med] 2021 Sep; Vol. 53 (9), pp. 1437-1448. Date of Electronic Publication: 2021 Sep 29. - Publication Year :
- 2021
-
Abstract
- Endothelin receptor A (ET <subscript>A</subscript> ), a class A G-protein-coupled receptor (GPCR), is involved in the progression and metastasis of colorectal, breast, lung, ovarian, and prostate cancer. We overexpressed and purified human endothelin receptor type A in Escherichia coli and reconstituted it with lipid and membrane scaffold proteins to prepare an ET <subscript>A</subscript> nanodisc as a functional antigen with a structure similar to that of native GPCR. By screening a human naive immune single-chain variable fragment phage library constructed in-house, we successfully isolated a human anti-ET <subscript>A</subscript> antibody (AG8) exhibiting high specificity for ET <subscript>A</subscript> in the β-arrestin Tango assay and effective inhibitory activity against the ET-1-induced signaling cascade via ET <subscript>A</subscript> using either a CHO-K1 cell line stably expressing human ET <subscript>A</subscript> or HT-29 colorectal cancer cells, in which AG8 exhibited IC <subscript>50</subscript> values of 56 and 51 nM, respectively. In addition, AG8 treatment repressed the transcription of inhibin βA and reduced the ET <subscript>A</subscript> -induced phosphorylation of protein kinase B and extracellular regulated kinase. Furthermore, tumor growth was effectively inhibited by AG8 in a colorectal cancer mouse xenograft model. The human anti-ET <subscript>A</subscript> antibody isolated in this study could be used as a potential therapeutic for cancers, including colorectal cancer.<br /> (© 2021. The Author(s).)
- Subjects :
- Animals
Antibodies, Monoclonal chemistry
Antibodies, Monoclonal immunology
Antineoplastic Agents, Immunological chemistry
CHO Cells
Cell Line, Tumor
Cricetulus
Disease Models, Animal
Dose-Response Relationship, Drug
Endothelin A Receptor Antagonists chemistry
Enzyme-Linked Immunosorbent Assay
Humans
Mice
Protein Engineering
Xenograft Model Antitumor Assays
Antibodies, Monoclonal pharmacology
Antineoplastic Agents, Immunological pharmacology
Endothelin A Receptor Antagonists pharmacology
Receptor, Endothelin A immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2092-6413
- Volume :
- 53
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Experimental & molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 34588605
- Full Text :
- https://doi.org/10.1038/s12276-021-00678-9