Engineered human Fc gamma RIIa fusion: A novel strategy to extend serum half-life of therapeutic proteins
- Authors
- Jo, Migyeong; Ko, Sanghwan; Hwang, Bora; Min, Sung-Won; Ha, Ji Yeon; Lee, Ji Chul; Jang, Se-Eun; Jung, Sang Taek
- Issue Date
- 8월-2020
- Publisher
- WILEY
- Keywords
- directed evolution; human FcRn; human Fc gamma RIIa; serum half-life; therapeutic protein
- Citation
- BIOTECHNOLOGY AND BIOENGINEERING, v.117, no.8, pp.2351 - 2361
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOTECHNOLOGY AND BIOENGINEERING
- Volume
- 117
- Number
- 8
- Start Page
- 2351
- End Page
- 2361
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/53887
- DOI
- 10.1002/bit.27374
- ISSN
- 0006-3592
- Abstract
- The immunoglobulin G (IgG) molecule has a long circulating serum half-life (similar to 3 weeks) through pH- dependent FcRn binding-mediated recycling. To hijack the intracellular trafficking and recycling mechanism of IgG as a way to extend serum persistence of non-antibody therapeutic proteins, we have evolved the ectodomain of a low-affinity human Fc gamma RIIa for enhanced binding to the lower hinge and upper CH2 region of IgG, which is very far from the FcRn binding site (CH2-CH3 interface). High-throughput library screening enabled isolation of an Fc gamma RIIa variant (2A45.1) with 32-fold increased binding affinity to human IgG1 Fc (equilibrium dissociation constant: 9.04 x 10(-7) M for wild type Fc gamma RIIa and 2.82 x 10(-8) M for 2A45.1) and significantly improved affinity to mouse serum IgG compared to wild type human Fc gamma RIIa. The in vivo pharmacokinetic profile of PD-L1 fused with engineered Fc gamma RIIa (PD-L1-2A45.1) was compared with that of PD-L1 fused with wild type Fc gamma RIIa (PD-L1-wild type Fc gamma RIIa) and human PD-L1 in mice. PD-L1-2A45.1 showed 11.7- and 9.7-fold prolonged circulating half-life (t(1/2)) compared to PD-L1 when administered intravenously and intraperitoneally, respectively. In addition, the AUC(inf) of PD-L1-2A45.1 was two-fold higher compared to that of PD-L1-wild type Fc gamma RIIa. These results demonstrate that engineered Fc gamma RIIa fusion offers a novel and successful strategy for prolonging serum half-life of therapeutic proteins.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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