Title : Engineered antibody
Fc variant with selectively enhanced
FcγRIIb binding over both
FcγRIIa(R131 ) and
FcγRIIa(H131 )
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
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