Engineered antibody Fc variant with selectively enhanced FcgammaRIIb binding over both FcgammaRIIa(R131) and FcgammaRIIa(H131).
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Mimoto F, Katada H, Kadono S, Igawa T, Kuramochi T, Muraoka M, Wada Y, Haraya K, Miyazaki T, Hattori K
Engineered antibody Fc variant with selectively enhanced FcgammaRIIb binding over both FcgammaRIIa(R131) and FcgammaRIIa(H131).
Protein Eng Des Sel. 2013 Oct;26(10):589-98. doi: 10.1093/protein/gzt022. Epub 2013 Jun 5.
- PubMed ID
- 23744091 [ View in PubMed]
- Abstract
Engaging inhibitory FcgammaRIIb 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 FcgammaRIIb, also enhances binding affinity to FcgammaRIIa(R131) allotype to a similar degree because FcgammaRIIb and FcgammaRIIa(R131) are structurally similar. In this study, we applied comprehensive mutagenesis and structure-guided design based on the crystal structure of the Fc/FcgammaRIIb complex to identify a novel Fc variant with selectively enhanced FcgammaRIIb binding over both FcgammaRIIa(R131) and FcgammaRIIa(H131). This novel variant has more than 200-fold stronger binding affinity to FcgammaRIIb than wild-type IgG1, while binding affinity to FcgammaRIIa(R131) and FcgammaRIIa(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 FcgammaRIIb and FcgammaRIIa 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 FcgammaRIIb binding achieved by our Fc variant provides a novel tool for improving the efficacy of antibody therapeutics.