A human antibody against human endothelin receptor type A that exhibits antitumor potency

• Published in: Experimental & molecular medicine 2021, 53(0), , pp.1-12
• Main Authors: Ju, Man-Seok, Ahn, Hye-Mi, Han, Seong-Gu, Ko, Sanghwan, Na, Jung-Hyun, Jo, Migyeong, Lim, Chung Su, Ko, Byoung Joon, Yu, Yeon Gyu, Lee, Won-Kyu, Kim, Youn-Jae, Jung, Sang Taek
• Format: Article
• Language: English
• Subjects: 101/1; 38/39; 631/154/51/1568; 631/1647/2163; 631/61/51/1568; 64/60; 82/1; 82/16; 82/58; 82/80; 82/83; 96/95; AKT protein; Animals; Antibodies; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antigens; Antineoplastic Agents, Immunological - chemistry; Antineoplastic Agents, Immunological - pharmacology; Arrestin; Biomedical and Life Sciences; Biomedicine; Breast; Cell Line, Tumor; CHO Cells; Clinical trials; Colorectal cancer; Colorectal carcinoma; Cricetulus; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin 1; Endothelin A Receptor Antagonists - chemistry; Endothelin A Receptor Antagonists - pharmacology; Enzyme-Linked Immunosorbent Assay; G protein-coupled receptors; Humans; Immunosuppressive agents; Inhibin; Kinases; Lung cancer; Medical Biochemistry; Metastases; Metastasis; Mice; Molecular Medicine; Ovarian cancer; Phages; Phosphorylation; Prostate cancer; Protein Engineering; Receptor, Endothelin A - immunology; Stem Cells; Transcription; Xenograft Model Antitumor Assays; Xenografts; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00678-9

Endothelin receptor A (ET A ), 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 A 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 A antibody (AG8) exhibiting high specificity for ET A in the β-arrestin Tango assay and effective inhibitory activity against the ET-1-induced signaling cascade via ET A using either a CHO-K1 cell line stably expressing human ET A or HT-29 colorectal cancer cells, in which AG8 exhibited IC 50 values of 56 and 51 nM, respectively. In addition, AG8 treatment repressed the transcription of inhibin βA and reduced the ET A -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 A antibody isolated in this study could be used as a potential therapeutic for cancers, including colorectal cancer. Cancer: Human antibody shows therapeutic potential A therapeutic antibody that targets a receptor involved in cancer progression shows significant anti-cancer effects in trials in mice. Endothelin receptor A (ET A ) promotes the progression and metastasis of several cancers, and patients with high ET A expression often have poor survival rates. Several small molecule drugs that target ET A are currently undergoing trials. Now, Sang Taek Jung at the Korea University in Seoul, together with scientists across South Korea, have identified and isolated a human antibody that specifically binds to ET A . The team developed an antigen that mimics ET A , and identified and isolated the antibody it bound to. The antibody exhibited potent anti-tumor effects in cell cultures and trials in mice. Such therapeutic antibodies show higher affinity for their targets than other drugs, resulting in fewer side effects and higher efficacy.