論文 - 詳細
| RRC ID | 61535 |
|---|---|
| 著者 | Mimoto F, Katada H, Kadono S, Igawa T, Kuramochi T, Muraoka M, Wada Y, Haraya K, Miyazaki T, Hattori K. |
| タイトル | Engineered antibody Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIa(R131) and FcγRIIa(H131). |
| ジャーナル | Protein Eng Des Sel |
| Abstract |
Engaging inhibitory FcγRIIb by Fc region has been recently reported to be an attractive approach for improving the efficacy of antibody therapeutics. However, the previously reported S267E/L328F variant with enhanced binding affinity to FcγRIIb, also enhances binding affinity to FcγRIIa(R131) allotype to a similar degree because FcγRIIb and FcγRIIa(R131) are structurally similar. In this study, we applied comprehensive mutagenesis and structure-guided design based on the crystal structure of the Fc/FcγRIIb complex to identify a novel Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIa(R131) and FcγRIIa(H131). This novel variant has more than 200-fold stronger binding affinity to FcγRIIb than wild-type IgG1, while binding affinity to FcγRIIa(R131) and FcγRIIa(H131) is comparable with or lower than wild-type IgG1. This selectivity was achieved by conformational change of the C(H)2 domain by mutating Pro to Asp at position 238. Fc variant with increased binding to both FcγRIIb and FcγRIIa induced platelet aggregation and activation in an immune complex form in vitro while our novel variant did not. When applied to agonistic anti-CD137 IgG1 antibody, our variant greatly enhanced the agonistic activity. Thus, the selective enhancement of FcγRIIb binding achieved by our Fc variant provides a novel tool for improving the efficacy of antibody therapeutics. |
| 巻・号 | 26(10) |
| ページ | 589-98 |
| 公開日 | 2013-10-1 |
| DOI | 10.1093/protein/gzt022 |
| PII | gzt022 |
| PMID | 23744091 |
| PMC | PMC3785249 |
| MeSH | Animals Crystallography, X-Ray Humans Immunoglobulin Fc Fragments / chemistry Immunoglobulin Fc Fragments / genetics* Immunoglobulin Fc Fragments / metabolism* Immunoglobulin Fc Fragments / pharmacology Immunoglobulin G / chemistry Mice Models, Molecular Mutagenesis Platelet Activation / drug effects Platelet Aggregation / drug effects Protein Binding Protein Conformation Protein Engineering* Receptors, IgG / metabolism* Recombinant Proteins / chemistry Recombinant Proteins / genetics* Recombinant Proteins / metabolism* Recombinant Proteins / pharmacology Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology |
| IF | 1.774 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 266 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 12.0 |
| リソース情報 | |
| ヒト・動物細胞 | CTLL-2(RCB0637) |