Endothelin receptor A (ETA), a class A G protein-coupled receptor (GPCR), is a promising tumor-associated antigen due to its close association with the progression and metastasis of many types of cancer, such as colorectal, breast, lung, ovarian, and prostate cancer. However, only small-molecule drugs have been developed as ETA antagonists with anticancer effects. In a previous study, we identified an antibody (AG8) with highly selective binding to human ETA through screening of a human naïve immune antibody library. Although both in vitro and in vivo experiments indicated that the identified AG8 had anticancer effects, there is a need for improvement in biochemical and physicochemical properties such as the ETA binding affinity, thermostability, and productivity. In this study, we engineered the framework regions of AG8 and isolated an anti-ETA antibody (MJF1) exhibiting significantly improved thermostability and ETA binding affinity. Subsequently, our previously isolated PFc29, an Fc variant with an enhanced pH-dependent human FcRn binding profile, was introduced to MJF1, and the resulting Fc-engineered anti-ETA antibody (MJF1-PFc29) inhibited the proliferation of tumor cells comparably to MJF1 and showed a 4.2-fold increased serum half-life in human FcRn transgenic mice. Moreover, MJF1-PFc29 elicited higher tumor growth inhibition in colorectal cancer xenograft mice compared to MJF1. Our results demonstrate that the engineered human anti-ETA antibody MJF1-PFc29 has great therapeutic potential and high antitumor potency against various types of cancers including colorectal cancer.
Bibliographical noteFunding Information:
This work was supported by grants from the Bio & Medical Technology Development Programs (2020M3E5E2037775) and the Basic Science Research Programs (2022R1F1A1073014 and 2019R1A4A1029000) through the National Research Foundation of Korea funded by the Ministry of Science and ICT and by grants from the National Cancer Center, Republic of Korea (NCC-2210750 and NCC-2212500).
The National Research Foundation of Korea (2020M3E5E2037775, 2022R1F1A1073014, and 2019R1A4A1029000) and the National Cancer Center, Republic of Korea (NCC-2210750 and NCC-2212500).
© 2022 American Chemical Society.
- antibody engineering
- antibody therapeutics
- anticancer potency
- endothelin receptor
- G protein-coupled receptor
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery