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

Endothelin receptor A (ETA), 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 ETA 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-ETA antibody (AG8) exhibiting high specificity for ETA in the β-arrestin Tango assay and effective inhibitory activity against the ET-1-induced signaling cascade via ETA using either a CHO-K1 cell line stably expressing human ETA or HT-29 colorectal cancer cells, in which AG8 exhibited IC50 values of 56 and 51 nM, respectively. In addition, AG8 treatment repressed the transcription of inhibin βA and reduced the ETA-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-ETA antibody isolated in this study could be used as a potential therapeutic for cancers, including colorectal cancer. A therapeutic antibody that targets a receptor involved in cancer progression shows significant anti-cancer effects in trials in mice. Endothelin receptor A (ETA) promotes the progression and metastasis of several cancers, and patients with high ETA expression often have poor survival rates. Several small molecule drugs that target ETA 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 ETA. The team developed an antigen that mimics ETA, 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.