Engineered human Fc gamma RIIa fusion: A novel strategy to extend serum half-life of therapeutic proteins
DC Field | Value | Language |
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dc.contributor.author | Jo, Migyeong | - |
dc.contributor.author | Ko, Sanghwan | - |
dc.contributor.author | Hwang, Bora | - |
dc.contributor.author | Min, Sung-Won | - |
dc.contributor.author | Ha, Ji Yeon | - |
dc.contributor.author | Lee, Ji Chul | - |
dc.contributor.author | Jang, Se-Eun | - |
dc.contributor.author | Jung, Sang Taek | - |
dc.date.accessioned | 2021-08-30T18:06:13Z | - |
dc.date.available | 2021-08-30T18:06:13Z | - |
dc.date.created | 2021-06-19 | - |
dc.date.issued | 2020-08 | - |
dc.identifier.issn | 0006-3592 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/53887 | - |
dc.description.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. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | WILEY | - |
dc.subject | HUMAN-IGG | - |
dc.subject | PHARMACOKINETIC PROPERTIES | - |
dc.subject | RECEPTOR-I | - |
dc.subject | ALBUMIN | - |
dc.subject | AFFINITY | - |
dc.subject | PEG | - |
dc.subject | HETEROGENEITY | - |
dc.subject | RECOGNITION | - |
dc.subject | PEGYLATION | - |
dc.subject | PEPTIDE | - |
dc.title | Engineered human Fc gamma RIIa fusion: A novel strategy to extend serum half-life of therapeutic proteins | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Jung, Sang Taek | - |
dc.identifier.doi | 10.1002/bit.27374 | - |
dc.identifier.scopusid | 2-s2.0-85084632384 | - |
dc.identifier.wosid | 000532923900001 | - |
dc.identifier.bibliographicCitation | BIOTECHNOLOGY AND BIOENGINEERING, v.117, no.8, pp.2351 - 2361 | - |
dc.relation.isPartOf | BIOTECHNOLOGY AND BIOENGINEERING | - |
dc.citation.title | BIOTECHNOLOGY AND BIOENGINEERING | - |
dc.citation.volume | 117 | - |
dc.citation.number | 8 | - |
dc.citation.startPage | 2351 | - |
dc.citation.endPage | 2361 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Biotechnology & Applied Microbiology | - |
dc.relation.journalWebOfScienceCategory | Biotechnology & Applied Microbiology | - |
dc.subject.keywordPlus | HUMAN-IGG | - |
dc.subject.keywordPlus | PHARMACOKINETIC PROPERTIES | - |
dc.subject.keywordPlus | RECEPTOR-I | - |
dc.subject.keywordPlus | ALBUMIN | - |
dc.subject.keywordPlus | AFFINITY | - |
dc.subject.keywordPlus | PEG | - |
dc.subject.keywordPlus | HETEROGENEITY | - |
dc.subject.keywordPlus | RECOGNITION | - |
dc.subject.keywordPlus | PEGYLATION | - |
dc.subject.keywordPlus | PEPTIDE | - |
dc.subject.keywordAuthor | directed evolution | - |
dc.subject.keywordAuthor | human FcRn | - |
dc.subject.keywordAuthor | human Fc gamma RIIa | - |
dc.subject.keywordAuthor | serum half-life | - |
dc.subject.keywordAuthor | therapeutic protein | - |
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