title: Soluble monomeric IgG1 Fc.
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.
authors.affiliation: Protein Interactions Group, Centre for Cancer Research Nanobiology Program, Centre for Cancer Research, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Maryland 21702, USA. yingt@mail.nih.gov
authors.forename: Tianlei
authors.initials: T
authors.lastname: Ying
authors.forename: Weizao
authors.initials: W
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Gong
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
mesh_terms: D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D011961:Receptors, Fc / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D012995:Solubility
chemical_list: D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C100688:Fc receptor, neonatal