title: Engineered antibody domains with significantly increased transcytosis and half-life in macaques mediated by FcRn.
abstract: Engineered antibody domains (eAds) are promising candidate therapeutics but their half-life is relatively short partly due to weak or absent binding to the neonatal Fc receptor (FcRn). We developed a novel approach to increase the eAd binding to FcRn based on a combination of structure-based design, computational modeling and phage display methodologies. By using this approach, we identified 2 IgG1 CH2-derived eAds fused to a short FcRn-binding motif derived from IgG1 CH3 that exhibited greatly enhanced FcRn binding with strict pH dependency. Importantly, the increased affinity resulted in significantly enhanced FcRn-mediated epithelial transcytosis and prolonged elimination half-life (mean 44.1 hours) in cynomolgus macaques. These results demonstrate for the first time that the half-life of isolated eAds can be prolonged (optimized) by increasing their binding to FcRn while maintaining their small size, which has important implications for development of therapeutics, including eAd-drug conjugates with enhanced penetration in solid tissues.
authors.affiliation: a Key Laboratory of Medical Molecular Virology of Ministries of Education and Health; Shanghai Medical College; Fudan University ; Shanghai , China.
authors.forename: Tianlei
authors.initials: T
authors.lastname: Ying
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Ponraj
authors.initials: P
authors.lastname: Prabakaran
authors.forename: Rui
authors.initials: R
authors.lastname: Gong
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Karalyne
authors.initials: K
authors.lastname: Crowder
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
mesh_terms: D000818:Animals; D002942:Circular Dichroism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000378:metabolism*; D007074:Immunoglobulin G / Q000737:chemistry; D008252:Macaca fascicularis; D015202:Protein Engineering / Q000379:methods*; D011961:Receptors, Fc / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D057900:Transcytosis / Q000502:physiology; D014162:Transfection
chemical_list: D015395:Histocompatibility Antigens Class I; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal
keywords: CH2; CH3; FcRn; antibody domains; half-life; macaques; transcytosis