title: Single chain antibody fragments with pH dependent binding to FcRn enabled prolonged circulation of therapeutic peptide in vivo.
abstract: The neonatal Fc receptor for IgG (FcRn) is considered critical for the regulation of endogenous IgG and serum albumin (SA) and their circulation half-life in vivo. Both IgG and SA can bind to FcRn tightly at acidic pH but not so much at neutral pH. Here we reported a few novel single chain antibody fragments (scFv) obtained based on screening of a phage library. FnAb-8 and FnAb-12 can bind to human FcRn with higher affinities than IgG at acidic pH but similar or lower affinities than IgG at pH7.4. Fusion proteins consisted of the therapeutic peptide, GLP-1 (Glucagon-like peptide-1) connected to the N-terminus of FnAb-8 and FnAb-12, named as G8 and G12, were shown to retain the pH-dependent binding capabilities to FcRn while also bound to the GLP-1 receptor. In vivo efficacy studies in diet induced diabetes mice confirmed the GLP-1 receptor (GLP-1R) agonist activities and sustained blood sugar lowering effect. In vivo pharmacokinetics (PK) studies were performed in nonhuman primates and FnAb-8 was found to have circulation half-life several folds longer than what have been reported for scFvs. G8 may be developed into long acting GLP-1R agonists with great potentials in clinical applications.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd, Shanghai 200240, PR China.
authors.forename: Yangsheng
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd, Shanghai 200240, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lv
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd, Shanghai 200240, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd, Shanghai 200240, PR China. Electronic address: yhxu@sjtu.edu.cn.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D057809:HEK293 Cells; D015395:Histocompatibility Antigens Class I / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008252:Macaca fascicularis; D008297:Male; D008810:Mice, Inbred C57BL; D011961:Receptors, Fc / Q000008:administration & dosage*; D057127:Single-Chain Antibodies / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067757:Glucagon-Like Peptide-1 Receptor
chemical_list: D052216:Glucagon-Like Peptide 1; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D057127:Single-Chain Antibodies; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; C100688:Fc receptor, neonatal
keywords: FcRn; Half-life extension; Phage display; pH-dependent; scFv