title: Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery.
abstract: Fc fusion protein technology has been successfully used to generate long-acting forms of several protein therapeutics. In this study, a novel Fc-based drug carrier, single chain Fc-dimer (sc(Fc)2), was designed to contain two Fc domains recombinantly linked via a flexible linker. Since the Fc dimeric structure is maintained through the flexible linker, the hinge region was omitted to further stabilize it against proteolysis and reduce FcγR-related effector functions. The resultant sc(Fc)2candidate preserved the neonatal Fc receptor (FcRn) binding. sc(Fc)2-mediated delivery was then evaluated using a therapeutic protein with a short plasma half-life, human growth hormone (hGH), as the protein drug cargo. This novel carrier protein showed a prolonged in vivo half-life and increased hGH-mediated bioactivity compared to the traditional Fc-based drug carrier. sc(Fc)2technology has the potential to greatly advance and expand the use of Fc-technology for improving the pharmacokinetics and bioactivity of protein therapeutics.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, 1985 Zonal Ave, Los Angeles, CA 90089-9121, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, 1985 Zonal Ave, Los Angeles, CA 90089-9121, United States.
authors.forename: Hsuan-Yao
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, 1985 Zonal Ave, Los Angeles, CA 90089-9121, United States; Department of Pharmaceutics, Jiangsu University School of Pharmacy, Zhenjiang, Jiangsu, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Tong
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, 1985 Zonal Ave, Los Angeles, CA 90089-9121, United States.
authors.forename: Curtis T
authors.initials: CT
authors.lastname: Okamoto
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, 1985 Zonal Ave, Los Angeles, CA 90089-9121, United States. Electronic address: weishen@usc.edu.
authors.forename: Wei-Chiang
authors.initials: WC
authors.lastname: Shen
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, 1985 Zonal Ave, Los Angeles, CA 90089-9121, United States; Department of Pharmaceutical Sciences, West Coast University School of Pharmacy, 590 N. Vermont Ave, Los Angeles, CA 90004, United States. Electronic address: jZaro@westcoastuniversity.edu.
authors.forename: Jennica L
authors.initials: JL
authors.lastname: Zaro
mesh_terms: D000818:Animals; D004355:Drug Stability; D004357:Drug Synergism; D057809:HEK293 Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D019382:Human Growth Hormone / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D011961:Receptors, Fc / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D019382:Human Growth Hormone; C100688:Fc receptor, neonatal
keywords: Fc fusion; Human growth hormone; Pharmacodynamics; Pharmacokinetics; Protein delivery; Single chain Fc