1. Engineered Human Antibody with Improved Endothelin Receptor Type A Binding Affinity, Developability, and Serum Persistence Exhibits Excellent Antitumor Potency
- Author
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Ko, Sanghwan, Ju, Man-Seok, Ahn, Hye-Mi, Na, Jung-Hyun, Ko, Woo Hyung, Jo, Migyeong, Kyung, Munsu, Lim, Chung Su, Ko, Byoung Joon, Lee, Won-Kyu, Kim, Youn-Jae, and Jung, Sang Taek
- Abstract
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 ETAantagonists with anticancer effects. In a previous study, we identified an antibody (AG8) with highly selective binding to human ETAthrough 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 ETAbinding affinity, thermostability, and productivity. In this study, we engineered the framework regions of AG8 and isolated an anti-ETAantibody (MJF1) exhibiting significantly improved thermostability and ETAbinding 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-ETAantibody (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-ETAantibody MJF1-PFc29 has great therapeutic potential and high antitumor potency against various types of cancers including colorectal cancer.
- Published
- 2023
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