한빛사논문
- 조회776
Sanghwan Ko 1 2, Sora Park 3, Myung Ho Sohn 3, Migyeong Jo 1 4, Byoung Joon Ko 3 5, Jung-Hyun Na 6, Hojin Yoo 3, Ae Lee Jeong 3, Kyungsoo Ha 3, Ju Rang Woo 3, Chungsu Lim 3, Jung Hyu Shin 3, Dohyun Lee 3, So-Young Choi 7, Sang Taek Jung 8 9 10 11
1Department of Biomedical Sciences, Graduate School, Korea University, Seongbuk-gu, Seoul, 02707, Republic of Korea.
2Institute of Human Genetics, Korea University College of Medicine, Seoul, Republic of Korea.
3New Drug Development Center, Osong Medical Innovation Foundation, 123, Cheongju, Chungcheongbuk-do, 28160, Republic of Korea.
4BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea.
5School of Biopharmaceutical and Medical Sciences, Sungshin Women's University, Seoul, 02844, Republic of Korea.
6Department of Pharmaceutical Engineering, Sangji University, Wonju, Gangwon-do, 26339, Republic of Korea.
7New Drug Development Center, Osong Medical Innovation Foundation, 123, Cheongju, Chungcheongbuk-do, 28160, Republic of Korea.
8Department of Biomedical Sciences, Graduate School, Korea University, Seongbuk-gu, Seoul, 02707, Republic of Korea.
9Institute of Human Genetics, Korea University College of Medicine, Seoul, Republic of Korea.
10BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea.
11Biomedical Research Center, Korea University Anam Hospital, Seoul, Republic of Korea.
Corresponding authors : Correspondence to So-Young Choi or Sang Taek Jung
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.
논문정보
- Research article
- 2022년 11월 (BRIC 등록일 2023-01-10)
- 국내 연구진
- 의약학 > 면역의학
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