An Fc variant with two mutations confers prolonged serum half-life and enhanced effector functions on IgG antibodiesopen access
- Authors
- Ko, Sanghwan; Park, Sora; Sohn, Myung Ho; Jo, Migyeong; Ko, Byoung Joon; Na, Jung-Hyun; Yoo, Hojin; Jeong, Ae Lee; Ha, Kyungsoo; Woo, Ju Rang; Lim, Chungsu; Shin, Jung Hyu; Lee, Dohyun; Choi, So-Young; Jung, Sang Taek
- Issue Date
- Nov-2022
- Publisher
- 생화학분자생물학회
- Citation
- Experimental and Molecular Medicine, v.54, no.11, pp 1850 - 1861
- Pages
- 12
- Indexed
- SCIE
SCOPUS
KCI
- Journal Title
- Experimental and Molecular Medicine
- Volume
- 54
- Number
- 11
- Start Page
- 1850
- End Page
- 1861
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/61791
- DOI
- 10.1038/s12276-022-00870-5
- ISSN
- 1226-3613
2092-6413
- Abstract
- The pH-selective interaction between the immunoglobulin G (IgG) fragment crystallizable region (Fc region) and the neonatal Fc receptor (FcRn) is critical for prolonging the circulating half-lives of IgG molecules through intracellular trafficking and recycling. By using directed evolution, we successfully identified Fc mutations that improve the pH-dependent binding of human FcRn and prolong the serum persistence of a model IgG antibody and an Fc-fusion protein. Strikingly, trastuzumab-PFc29 and aflibercept-PFc29, a model therapeutic IgG antibody and an Fc-fusion protein, respectively, when combined with our engineered Fc (Q311R/M428L), both exhibited significantly higher serum half-lives in human FcRn transgenic mice than their counterparts with wild-type Fc. Moreover, in a cynomolgus monkey model, trastuzumab-PFc29 displayed a superior pharmacokinetic profile to that of both trastuzumab-YTE and trastuzumab-LS, which contain the well-validated serum half-life extension Fcs YTE (M252Y/S254T/T256E) and LS (M428L/N434S), respectively. Furthermore, the introduction of two identified mutations of PFc29 (Q311R/M428L) into the model antibodies enhanced both complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity activity, which are triggered by the association between IgG Fc and Fc binding ligands and are critical for clearing cancer cells. In addition, the effector functions could be turned off by combining the two mutations of PFc29 with effector function-silencing mutations, but the antibodies maintained their excellent pH-dependent human FcRn binding profile. We expect our Fc variants to be an excellent tool for enhancing the pharmacokinetic profiles and potencies of various therapeutic antibodies and Fc-fusion proteins.
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Collections - 3. Graduate School > Biomedical Research Center > 1. Journal Articles
- 3. Graduate School > Graduate School > 1. Journal Articles
- 4. Research institute > Institute of Human Genetics > 1. Journal Articles
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