Abstract
Antibody fragments are emerging as promising biopharmaceuticals because of their relatively small size and other unique properties. However, compared with full-size antibodies, these antibody fragments lack the ability to bind the neonatal Fc receptor (FcRn) and have reduced half-lives. Fc engineered to bind antigens but preserve interactions with FcRn and Fc fused with monomeric proteins currently are being developed as candidate therapeutics with prolonged half-lives; in these and other cases, Fc is a dimer of two CH2-CH3 chains. To further reduce the size of Fc but preserve FcRn binding, we generated three human soluble monomeric IgG1 Fcs (mFcs) by using a combination of structure-based rational protein design combined with multiple screening strategies. These mFcs were highly soluble and retained binding to human FcRn comparable with that of Fc. These results provide direct experimental evidence that efficient binding to human FcRn does not require human Fc dimerization. The newly identified mFcs are promising for the development of mFc fusion proteins and for novel types of mFc-based therapeutic antibodies of small size and long half-lives.
Highlights
The Fc region of an antibody is a homodimer of two CH2-CH3 chains
The newly identified Monomeric IgG1 Fcs (mFcs) are promising for the development of mFc fusion proteins and for novel types of mFcbased therapeutic antibodies of small size and long half-lives
Identification of mFc from Library of Fc Mutants—To identify mFcs, we utilized a combination of structure-based rational protein design combined with multiple screening strategies of Fc mutant libraries
Summary
The Fc region of an antibody is a homodimer of two CH2-CH3 chains. Results: Monomeric IgG1 Fcs (mFcs) were generated by using a novel panning/screening procedure. To further reduce the size of Fc but preserve FcRn binding, we generated three human soluble monomeric IgG1 Fcs (mFcs) by using a combination of structure-based rational protein design combined with multiple screening strategies. -called “monomeric Fc fusion proteins” were generated by fusing a single active protein to dimeric wildtype Fc [23,24,25] Such smaller molecules have been shown to possess extended half-lives compared with the dimeric version and are promising for therapeutic applications. Despite this advancement, the Fc domain in a fusion protein is still dimeric and of relatively large size (ϳ50 kDa).
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